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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
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