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Slide 1 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill
Slide 2 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin
Slide 3 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool
Slide 4 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles
Slide 5 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes
Slide 6 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes
Slide 7 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes
Slide 8 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes
Slide 9 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging
Slide 10 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month
Slide 11 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging
Slide 12 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years)
Slide 13 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc.
Slide 14 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable
Slide 15 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances
Slide 16 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause
Slide 17 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause
Slide 18 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery
Slide 19 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height
Slide 20 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause
Slide 21 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone
Slide 22 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years
Slide 23 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-)
Slide 24 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA
Slide 25 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract
Slide 26 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression
Slide 27 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65
Slide 28 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause
Slide 29 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism
Slide 30 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1
Slide 31 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease
Slide 32 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S.
Slide 33 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause
Slide 34 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin
Slide 35 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis
Slide 36 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium
Slide 37 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5.
Slide 38 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss
Slide 39 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors
Slide 40 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates
Slide 41 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies
Slide 42 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System
Slide 43 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder
Slide 44 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy
Slide 45 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT *
Slide 46 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits
Slide 47 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks
Slide 48 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern
Slide 49 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern
Slide 50 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives
Slide 51 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency.
Slide 52 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates
Slide 53 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency.
Slide 54 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group
Slide 55 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group Premature Ovarian Failure Sex chromosome abnormalities (usually involving the X Chromosome) Fragile X premutation Autoimmune Chemotherapy/Irradiation
Slide 56 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group Premature Ovarian Failure Sex chromosome abnormalities (usually involving the X Chromosome) Fragile X premutation Autoimmune Chemotherapy/Irradiation Evaluation of Premature Ovarian Failure Karyotype (<30 years of age) Assessment for Fragile X premutation (number of CGG repeats) Survey for other autoimmune diseases (such as hypothyroidism, adrenal insufficiency)
Slide 57 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group Premature Ovarian Failure Sex chromosome abnormalities (usually involving the X Chromosome) Fragile X premutation Autoimmune Chemotherapy/Irradiation Evaluation of Premature Ovarian Failure Karyotype (<30 years of age) Assessment for Fragile X premutation (number of CGG repeats) Survey for other autoimmune diseases (such as hypothyroidism, adrenal insufficiency) Premature Ovarian Failure is Different from Menopause !!!! 10-20% of women with POF with normal karyotypes will ovulate again 5% spontaneous pregnancy rate Not normal reproductive aging
Slide 58 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group Premature Ovarian Failure Sex chromosome abnormalities (usually involving the X Chromosome) Fragile X premutation Autoimmune Chemotherapy/Irradiation Evaluation of Premature Ovarian Failure Karyotype (<30 years of age) Assessment for Fragile X premutation (number of CGG repeats) Survey for other autoimmune diseases (such as hypothyroidism, adrenal insufficiency) Premature Ovarian Failure is Different from Menopause !!!! 10-20% of women with POF with normal karyotypes will ovulate again 5% spontaneous pregnancy rate Not normal reproductive aging Treatment of Premature Menopause Hormone replacement therapy!!! Counseling Oocyte donation
Slide 59 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group Premature Ovarian Failure Sex chromosome abnormalities (usually involving the X Chromosome) Fragile X premutation Autoimmune Chemotherapy/Irradiation Evaluation of Premature Ovarian Failure Karyotype (<30 years of age) Assessment for Fragile X premutation (number of CGG repeats) Survey for other autoimmune diseases (such as hypothyroidism, adrenal insufficiency) Premature Ovarian Failure is Different from Menopause !!!! 10-20% of women with POF with normal karyotypes will ovulate again 5% spontaneous pregnancy rate Not normal reproductive aging Treatment of Premature Menopause Hormone replacement therapy!!! Counseling Oocyte donation
Slide 60 - The Menopause Anne Z. Steiner, MD, MPH Assistant Professor Reproductive Endocrinology and Infertility University of North Carolina at Chapel Hill Objectives Understand reproductive aging Physiology Stages Understand the physiologic changes and symptoms associated with menopause Discuss treatment options for conditions associated with menopause Define Premature Ovarian Failure HRT= Hormone Replacement Therapy (EPT, ET) ET= Estrogen alone EPT= Estrogen plus Progestin Reproductive Aging Decline in reproductive potential Puberty → Peak reproduction → Decline in fertility → Anovulation (menstrual irregularity) → Menopause Due to ovarian aging (physiology) Progresses with the decline in oocyte/follicular pool Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes Reproductive Aging Hormonal Changes FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes Stages of Reproductive Aging Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month Stages of Reproductive Aging Perimenopause Follows period of declining fertility Precedes menopause Characterized by cycle irregularity (shortening then lengthening) increasing symptoms Duration 2 to 8 years (average 5 years) Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances Managing Perimenopause “The ovaries, after long years of service, have not the ability of retiring in graceful old age, but become irritated, transmit their irritation to the abdominal ganglia, which in turn transmit the irritation to the brain, producing disturbances in the cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.” AM Farnham, Uterine Disease as a factor in the production of insanity. Alienist Neurologica 1887. Menopause Menopause Marks the end of reproductive life Cessation of menses for 12 months Clinical diagnosis (not labs) Result of egg depletion and estrogen production by the ovary due to…. Natural aging or surgery Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height Age (years) Date Age at menopause *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington, DC: January 1850 1940 2000 Menopause Summary of Key Physical Changes Vasomotor instability Metabolic Changes Coronary Artery Disease Accelerated bone loss Skin changes Urogenital atrophy Cognition (?) Libido (?) Brain Eyes Teeth Vasomotor Heart Breast Colon Urogenital tract Skin Bone Hot Flushes (aka Hot Flashes) “Sudden onset of reddening of the skin over the head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by profuse perspiration” Number 1 complaint to physicians Few seconds to several minutes Rare to recurrent every few minutes Most severe at night and during times of stress More common among overweight women Usually last for 1-2 years 25% will last for more than 5 years Managing Hot Flushes/Flashes Set realistic goals! Lower the ambient temperature Estrogen (80-95% reduction) Alternative therapies High dose progestins Tibolone SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-)) Gabapentin Clonidine (+/-) Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/day or at least 50 flushes per week at baseline. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range, 11.3–13.8). Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065-79. 0.625 CEE Placebo 0.625 CEE/2.5 MPA Complementary Approaches May be effective Black Cohosh Soy/Phytoestrogens Vitamin E (1 hot flash per day less) No evidence Dong quai Acupuncture Yoga Chinese herbs Evening primrose Ginseng Kava Red Clover Abstract Sleep and Mood Disturbances Vasomotor episodes have an adverse impact on quality of sleep Sleep disturbances lead to a reduced ability to hand problems and stresses Women with a history of depression are at risk of reoccurrence during menopause HRT may provide additional benefit to anti-depressants in the management of postmenopausal depression Cognition Lack of agreement on impact of menopause on cognition No clear evidence that HRT prevents cognitive aging or enhances cognitive function Vascular infarcts associated with estrogen may worsen dementia in women over 65 Metabolic Changes with Menopause Mechanisms of Menopause-Related Increases in Adiposity Hormonal changes of the menopause transition Preferential abdominal fat accumulation Increased fat accumulation Increased abdominal and intra-abdominal adiposity Altered energy metabolism “The Menopausal Metabolic Syndrome” Lipid Triad Hypertriglyceridemia  LDL Cholesterol Abnormalities in Insulin Insulin resistance  insulin elimination HT reduces onset of DM and improves insulin resistance Other Factors Endothelial dysfunction  visceral fat  uric acid  HDL Cholesterol  insulin secretion Hyperinsulinemia  SHBG  blood pressure  PAI-1 Cardiovascular Disease Annual Incidence of Myocardial Infarction in Women and Men in the U.S. Hormone Replacement Therapy and CAHD Secondary Prevention of CAHD HERS (Heart and Estrogen/progestin Replacement Study) No Benefit Primary Prevention of CAHD WHI (Women’s Health Initiative) No Benefit********* *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause Prevention of CAHD In general HRT should not be continued or started to prevent heart disease Discuss other methods of CVD prevention: Exercise Diet Smoking cessation Cholesterol lowering medicines – Statins Aspirin Osteoporosis Pathogenesis of Estrogen Deficiency and Bone Loss Estrogen loss triggers increases in IL-1, IL-6, and TNF. Increased cytokines lead to increased osteoclast development and lifespan. Increased turnover of osteoblasts. Impacts vitamin D metabolism Impacts on renal and intestinal handling of calcium Spinal BMD by Age and Menopausal Status BMD (g/cm2) Perimenopausal Menopausal for 4 Years Menopausal for 5-14 Years Menopausal for 15 Years Mean Age (years) n = 1426. Pouillès JM, et al. J Bone Miner Res. 1994;9:311-5. Consequences of Osteoporosis Spinal (vertebral) compression fractures Back pain Loss of height and mobility Postural deformities Colles’ (forearm) fractures Hip Fractures Tooth loss When to Measure BMD in Postmenopausal Women Age > 65 Caucasian race Family history History of fracture History of falls Bad eyesight Dementia Early menopause (<45) Smoking cigarettes Low body weight ETOH Immobility* Poor nutrition Medications Certain medical conditions One or more risk factors Prevention of Osteoporosis Calcium 1500mg elemental Calcium daily One serving of dairy=300mg Supplements (citrate, carbonate) Divided doses With meals Vitamin D supplementation Sunshine 400 IU/daily Weight bearing exercise Smoking cessation Moderation of alcohol intake Pharmacologic (generally not recommended) HRT Raloxifene Bisphosphonates Treatment of Osteoporosis (for prevention of fractures) First Line Agents Bisphosphonates Raloxifene Second Line Agents Human recombinant PTH Nasal salmon calcitonin HRT Fall prevention strategies Changes in the Urogenital System Physiologic Changes in the Urogenital System Decrease in production of vaginal lubricating fluid Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy) Development of uretheral caruncles Mucosal thinning of urethra and bladder Vaginal Atrophy Urogenital symptoms Dysuria Urgency Frequency Recurrent UTIs Dysparunia Pruritus Stenosis Treatment Vaginal estrogen (progestogen not necessary) HRT * Hormone Replacement Therapy Decrease hot flashes Prevents/treats osteoporosis and hip and vertebral fractures Prevents/treats urogenital atrophy Benefits Hormone Replacement Therapy Increased risk for venous thrombosis and embolism** Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) Increased risk for endometrial cancer with ET (not EPT) (if uterus present) **may be dependent on route of administration Risks Hormone Replacement Therapy Possible increase in cardiac events in older women started on EPT (not ET) Probably increase in (ischemic) strokes in older women started on HRT Areas of Concern Hormone Replacement Therapy Risks are dependent on Age (total mortality reduced by 30% if started at age <60) Time since menopause Age at menopause Duration of therapy Type of HT Route of administration Dose of HT Benefits are dependent on Number of menopause related symptoms Areas of Concern Hormone Therapy Guidelines Indication: estrogen deficiency symptoms Vasomotor symptoms Hot flushes, night sweats Disturbed sleep patterns Fatigue, concentration, memory GU atrophy Bladder irritability, vaginal dryness, dyspareunia Guiding principle Minimum dose for shortest time required Consider non-hormonal alternatives Summary of Key Points Reproductive aging is due to a decline in the number of ovarian follicles. Menopause Signals the end of the reproductive years Diagnosed clinically Not a disease Symptoms are due to estrogen deficiency. Key Points CAD Rise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this time Osteoporosis Evaluate all postmenopausal women over 65 (earlier screening recommended if they have one or more risk factors) Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessation Primary treatment: Raloxifene, Bisphosphonates Key Points Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency. Premature Menopause Definitions: Early: age 40-44 Premature: <40 Causes Surgical removal of uterus** Surgical removal of ovaries Premature ovarian failure **Further discussions exclude this group Premature Ovarian Failure Sex chromosome abnormalities (usually involving the X Chromosome) Fragile X premutation Autoimmune Chemotherapy/Irradiation Evaluation of Premature Ovarian Failure Karyotype (<30 years of age) Assessment for Fragile X premutation (number of CGG repeats) Survey for other autoimmune diseases (such as hypothyroidism, adrenal insufficiency) Premature Ovarian Failure is Different from Menopause !!!! 10-20% of women with POF with normal karyotypes will ovulate again 5% spontaneous pregnancy rate Not normal reproductive aging Treatment of Premature Menopause Hormone replacement therapy!!! Counseling Oocyte donation HIV and Menopause Mean age of menopause in HIV-infected women is 47-48 (not adjusted for risk factors). May be difficult to differentiate HIV symptoms from symptoms of menopause. Further research needed on the additive effects of menopause, HIV, and anti-retroviral therapies. Further research need on depression during the menopause transition in HIV affected women. Safety of HRT in HIV+ postmenopausal women has not been studied. Conde et al. Menopause 2009;16:199-213