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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

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the menopause

The Menopause

Anne Z. Steiner, MD, MPH

Assistant Professor

Reproductive Endocrinology and Infertility

University of North Carolina at Chapel Hill

  • 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
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 aging4
Reproductive Aging

Oocytes and Follicles

  • 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.

Reproductive Aging

Hormonal Changes




Inhibin B


Normal Ovary



Reproductive Aging

Hormonal Changes




Estradiol / Inhibin B


Aging Ovary


reproductive aging7
Reproductive Aging

Hormonal Changes


Reproductive Aging

Hormonal Changes




Estradiol / Inhibin B


Menopausal Ovary


reproductive stage
Reproductive Stage

Miscarriage Rate / month



Pregnancy Rate / month

20 30 37 40 45

Age in years

  • 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
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
Perimenopause -- Symptoms:

Highly Variable

  • Vasomotor instability (85%)
  • Sleep disturbances
  • Mood disturbances.
  • Somatic symptoms:
    • Fatigue, palpitations, headache, increased migraine, breast pain and enlargement.
  • Oligo-  Anovulation
    • heavier or irregular cycles.
managing perimenopause
Managing Perimenopause


  • Patient education
  • Prevention of endometrial cancer
  • Individualized symptomatic relief
    • Menstrual control
    • Minimizing hot flashes
    • Mood disturbances


“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.

  • 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
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)

Age at menopause





*Projected estimate.

Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: Accessed 1/3/02.US Department of Health and Human Services. Healthy People 2010. Washington, DC: January

summary of key physical changes









Summary of Key Physical Changes
  • Vasomotor instability
  • Metabolic Changes
  • Coronary Artery Disease
  • Accelerated bone loss
  • Skin changes
  • Urogenital atrophy
  • Cognition (?)
  • Libido (?)



hot flushes aka hot flashes
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
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
Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeks


0.625 CEE

0.625 CEE/2.5 MPA

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.

complementary approaches
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
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
  • 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
mechanisms of menopause related increases in adiposity
Mechanisms of Menopause-Related Increases in Adiposity


abdominal fat


Increased abdominal and intra-abdominal adiposity

Hormonal changes of the menopause transition

Increased fat




the menopausal metabolic syndrome
“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
annual incidence of myocardial infarction in women and men in the u s






X 103








Age, years

Annual Incidence of Myocardial Infarction in Women and Men in the U.S.
hormone replacement therapy and cahd
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

pathogenesis of estrogen deficiency and bone loss
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
consequences of osteoporosis
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


Early menopause (<45)

Smoking cigarettes

Low body weight



Poor nutrition


Certain medical conditions

When to Measure BMD in Postmenopausal Women

One or more risk factors

prevention of osteoporosis
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
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
physiologic 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
urogenital symptoms
Urogenital symptoms
  • Dysuria
  • Urgency
  • Frequency
  • Recurrent UTIs
  • Dysparunia
  • Pruritus
  • Stenosis
  • Treatment
  • Vaginal estrogen (progestogen not necessary)
  • HRT *
hormone replacement therapy
Hormone Replacement Therapy


  • Decrease hot flashes
  • Prevents/treats osteoporosis and hip and vertebral fractures
  • Prevents/treats urogenital atrophy
hormone replacement therapy45
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

hormone replacement therapy46
Hormone Replacement Therapy

Areas of Concern

  • Possible increase in cardiac events in older women started on EPT (not ET)
  • Probably increase in (ischemic) strokes in older women started on HRT
hormone replacement therapy47
Hormone Replacement Therapy

Areas of Concern

  • 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
hormone therapy guidelines
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
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
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 points51
Key Points
  • Currently, the primary reason to prescribe HRT in postmenopausal women is for the relief of symptoms associated with estrogen deficiency.
premature menopause
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
Premature Ovarian Failure
  • Sex chromosome abnormalities (usually involving the X Chromosome)
  • Fragile X premutation
  • Autoimmune
  • Chemotherapy/Irradiation
evaluation of premature ovarian failure
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
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
Treatment of Premature Menopause
  • Hormone replacement therapy!!!
  • Counseling
  • Oocyte donation
hiv and menopause
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