The MenopauseThe Menopause

Anne Z. Steiner, MD, MPHAnne Z. Steiner, MD, MPH

Assistant ProfessorAssistant Professor

Reproductive Endocrinology and InfertilityReproductive Endocrinology and Infertility

University of North Carolina at Chapel HillUniversity of North Carolina at Chapel Hill

ObjectivesObjectives Understand reproductive agingUnderstand reproductive aging

PhysiologyPhysiology StagesStages

Understand the physiologic changes and Understand the physiologic changes and symptoms associated with menopausesymptoms associated with menopause

Discuss treatment options for conditions Discuss treatment options for conditions associated with menopauseassociated with menopause

Define Premature Ovarian FailureDefine Premature Ovarian FailureHRT= Hormone Replacement Therapy (EPT, ET)

ET= Estrogen alone

EPT= Estrogen plus Progestin

Reproductive AgingReproductive Aging

Decline in reproductive potentialDecline in reproductive potential Puberty → Peak reproduction → Decline Puberty → Peak reproduction → Decline

in fertility → Anovulation (menstrual in fertility → Anovulation (menstrual irregularity) → Menopauseirregularity) → Menopause

Due to ovarian aging (physiology)Due to ovarian aging (physiology) Progresses with the decline in Progresses with the decline in

oocyte/follicular pooloocyte/follicular pool

Reproductive AgingReproductive Aging

Process begins in embryonic life.Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles.20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million folliclesAt birth - 1.5-2 million follicles At menarche - 300,000- 400,000 folliclesAt menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life.Follicular atresia continues throughout life. Follicular loss accelerates when the total Follicular loss accelerates when the total

number of follicles is ~25,000 number of follicles is ~25,000 When follicles are sufficiently depleted When follicles are sufficiently depleted

(<1000), menopause occurs.(<1000), menopause occurs.

Oocytes and Follicles

FSH

Ovary

Hypothalmus

Inhibin B+

GnRH

Normal Ovary

Reproductive AgingReproductive AgingHormonal Changes

FSH

Ovary

Hypothalmus

Estradiol / Inhibin B+

GnRH

Aging Ovary

Reproductive AgingReproductive AgingHormonal Changes

Reproductive AgingReproductive AgingHormonal Changes

FSH

Ovary

Hypothalmus

Estradiol / Inhibin B+

GnRH

Menopausal Ovary

Reproductive AgingReproductive AgingHormonal Changes

Stages of Reproductive Stages of Reproductive AgingAging

Reproductive StageReproductive Stage

Age in years

25%

12%

20 30 37 40 45

Miscarriage Rate / month

Pregnancy Rate / month

Stages of Reproductive Stages of Reproductive AgingAging

PerimenopausePerimenopause

Follows period of declining fertilityFollows period of declining fertility Precedes menopausePrecedes menopause Characterized byCharacterized by

cycle irregularity (shortening then cycle irregularity (shortening then lengthening)lengthening)

increasing symptomsincreasing symptoms Duration 2 to 8 years (average 5 years)Duration 2 to 8 years (average 5 years)

Diagnosing PerimenopauseDiagnosing Perimenopause

Clinical diagnosis based on Clinical diagnosis based on menstrual cycle pattern.menstrual cycle pattern.

Early follicular phase FSH and Early follicular phase FSH and symptoms may help solidify symptoms may help solidify diagnosis. diagnosis.

Rule out hypothyroidism, depression Rule out hypothyroidism, depression etc.etc.

Perimenopause -- Symptoms:Perimenopause -- Symptoms:

Vasomotor instability (85%)Vasomotor instability (85%) Sleep disturbancesSleep disturbances Mood disturbances.Mood disturbances. Somatic symptoms: Somatic symptoms:

Fatigue, palpitations, headache, increased Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. migraine, breast pain and enlargement.

Oligo- Oligo- Anovulation Anovulation heavier or irregular cycles.heavier or irregular cycles.

Highly Variable

Managing PerimenopauseManaging Perimenopause

Goals: Goals: Patient educationPatient education Prevention of endometrial cancerPrevention of endometrial cancer Individualized symptomatic reliefIndividualized symptomatic relief

Menstrual controlMenstrual control Minimizing hot flashesMinimizing hot flashes Mood disturbancesMood disturbances

Managing PerimenopauseManaging PerimenopauseSymptomSymptom

ReliefRelief

Menstrual Menstrual Cycle Cycle ControlControl

Birth Birth ControlControl

Endometrial Endometrial Cancer Cancer PreventionPrevention

Hormonal Hormonal contraceptives contraceptives (oral or ring)(oral or ring)

++++++ ++++++ ++++++ ++++++

Cyclic progestin Cyclic progestin therapytherapy

+/-+/- +/-+/- -- ++++

Progesterone Progesterone IUDIUD

-- +/-+/- ++++++ ++++++

EPTEPT ++++ -- -- ++++++

“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

MenopauseMenopause

Marks the end of reproductive lifeMarks the end of reproductive life Cessation of menses for 12 monthsCessation of menses for 12 months Clinical diagnosis (not labs)Clinical diagnosis (not labs) Result of egg depletion and estrogen Result of egg depletion and estrogen

production by the ovary due to….production by the ovary due to…. Natural aging or surgeryNatural aging or surgery

Menopause FactsMenopause Facts Average age at menopause: 51 years Average age at menopause: 51 years

(1% at age 40, 5% after age 55)(1% at age 40, 5% after age 55) Factors impacting age at menopauseFactors impacting age at menopause

Maternal age at menopauseMaternal age at menopause Tobacco useTobacco use SES/ EducationSES/ Education Alcohol useAlcohol use Body Mass IndexBody Mass Index

Factors that probably don’t impact on age at Factors that probably don’t impact on age at menopausemenopause OCP useOCP use ParityParity RaceRace HeightHeight

0

10

20

30

40

50

60

70

80

90

100

Ag

e (

yea

rs)

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

MenopauseMenopause

Summary of Key Physical ChangesSummary of Key Physical Changes

Vasomotor instabilityVasomotor instability Metabolic ChangesMetabolic Changes Coronary Artery DiseaseCoronary Artery Disease Accelerated bone lossAccelerated bone loss Skin changesSkin changes Urogenital atrophyUrogenital atrophy Cognition (?)Cognition (?) Libido (?)Libido (?)

Brain

Eyes

Teeth

VasomotorHeart

Breast

Colon

Urogenitaltract

Skin

Bone

Hot Flushes (aka Hot Flashes)Hot Flushes (aka Hot Flashes) ““Sudden onset of reddening of the skin over the Sudden onset of reddening of the skin over the

head, neck, and chest accompanied by a feeling of head, neck, and chest accompanied by a feeling of intense body heat and sometimes concluded by intense body heat and sometimes concluded by profuse perspiration”profuse perspiration”

Number 1 complaint to physiciansNumber 1 complaint to physicians

Few seconds to several minutesFew seconds to several minutes

Rare to recurrent every few minutesRare to recurrent every few minutes

Most severe at night and during times of stressMost severe at night and during times of stress

More common among overweight womenMore common among overweight women

Usually last for 1-2 yearsUsually last for 1-2 years

25% will last for more than 5 years25% will last for more than 5 years

Managing Hot Managing Hot Flushes/FlashesFlushes/Flashes

Set realistic goals!Set realistic goals! Lower the ambient temperatureLower the ambient temperature Estrogen (80-95% reduction)Estrogen (80-95% reduction) Alternative therapiesAlternative therapies

High dose progestinsHigh dose progestins TiboloneTibolone SSRI’s (Paroxetine, Fluoxetine(+/-))SSRI’s (Paroxetine, Fluoxetine(+/-)) SNRI (Velafaxine (+/-))SNRI (Velafaxine (+/-)) GabapentinGabapentin Clonidine (+/-)Clonidine (+/-)

Effect of ERT and HRT on Number Effect of ERT and HRT on Number of Hot Flushes Over 12 Weeksof 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

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12

Week

Ad

just

ed D

aily

Mea

n

Nu

mb

er*

0.625 CEEPlacebo

0.625 CEE/2.5 MPA

Complementary ApproachesComplementary Approaches May be effectiveMay be effective

Black CohoshBlack Cohosh Soy/PhytoestrogensSoy/Phytoestrogens

Vitamin E (1 hot flash per day less)Vitamin E (1 hot flash per day less) No evidenceNo evidence

Dong quaiDong quai AcupunctureAcupuncture YogaYoga Chinese herbsChinese herbs Evening primroseEvening primrose GinsengGinseng KavaKava Red Clover AbstractRed Clover Abstract

Sleep and Mood DisturbancesSleep and Mood Disturbances

Vasomotor episodes have an adverse impact Vasomotor episodes have an adverse impact on quality of sleepon quality of sleep

Sleep disturbances lead to a reduced ability to Sleep disturbances lead to a reduced ability to hand problems and stresseshand problems and stresses

Women with a history of depression are at risk Women with a history of depression are at risk of reoccurrence during menopauseof reoccurrence during menopause

HRT may provide additional benefit to anti-HRT may provide additional benefit to anti-depressants in the management of depressants in the management of postmenopausal depressionpostmenopausal depression

CognitionCognition

Lack of agreement on impact of Lack of agreement on impact of menopause on cognition menopause on cognition

No clear evidence that HRT prevents No clear evidence that HRT prevents cognitive aging or enhances cognitive cognitive aging or enhances cognitive functionfunction

Vascular infarcts associated with Vascular infarcts associated with estrogen may worsen dementia in estrogen may worsen dementia in women over 65women over 65

Metabolic Changes with Metabolic Changes with MenopauseMenopause

Mechanisms of Menopause-Mechanisms of Menopause-Related Increases in AdiposityRelated Increases in Adiposity

Hormonal changes of the

menopause transition

Preferentialabdominal fataccumulation

Increased fataccumulation

Increased abdominal and intra-abdominal

adiposity

Alteredenergy

metabolism

““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 CholesterolHDL Cholesterol

insulin secretioninsulin secretion HyperinsulinemiaHyperinsulinemia

SHBGSHBG blood pressureblood pressure PAI-1PAI-1

Cardiovascular DiseaseCardiovascular Disease

Annual Incidence of Myocardial Infarction Annual Incidence of Myocardial Infarction in Women and Men in the U.S.in Women and Men in the U.S.

0

100

200

300

400

500

29-44 45-64 >65

Age, years

Men

WomenNo.

X 103

Hormone Replacement Therapy Hormone Replacement Therapy and CAHDand CAHD

Secondary Prevention of CAHDSecondary Prevention of CAHD HERS (Heart and Estrogen/progestin HERS (Heart and Estrogen/progestin

Replacement Study)Replacement Study) No BenefitNo Benefit

Primary Prevention of CAHDPrimary Prevention of CAHD WHI (Women’s Health Initiative)WHI (Women’s Health Initiative) No Benefit*********No Benefit*********

*******Potential benefit to women 50-59 and/or within *******Potential benefit to women 50-59 and/or within 2-3 years of the onset of menopause2-3 years of the onset of menopause

OsteoporosisOsteoporosis

Pathogenesis of Estrogen Pathogenesis of Estrogen Deficiency and Bone LossDeficiency and Bone Loss

Estrogen loss triggers increases Estrogen loss triggers increases in IL-1, IL-6, and TNF.in IL-1, IL-6, and TNF.

Increased cytokines lead to increased Increased cytokines lead to increased osteoclast development and lifespan.osteoclast development and lifespan.

Increased turnover of osteoblasts.Increased turnover of osteoblasts. Impacts vitamin D metabolismImpacts vitamin D metabolism Impacts on renal and intestinal handling Impacts on renal and intestinal handling

of calciumof calcium

Consequences of OsteoporosisConsequences 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 When to Measure BMD in Postmenopausal WomenPostmenopausal Women

Age Age >> 65 65 Caucasian raceCaucasian race Family historyFamily history History of fractureHistory of fracture History of fallsHistory of falls Bad eyesightBad eyesight DementiaDementia Early menopause Early menopause

(<45)(<45)

Smoking cigarettesSmoking cigarettes Low body weightLow body weight ETOHETOH Immobility*Immobility* Poor nutritionPoor nutrition MedicationsMedications Certain medical Certain medical

conditionsconditions

One or more risk factors

Prevention of Osteoporosis Prevention of Osteoporosis CalciumCalcium

1500mg elemental Calcium daily1500mg elemental Calcium daily One serving of dairy=300mgOne serving of dairy=300mg Supplements (citrate, carbonate)Supplements (citrate, carbonate)

Divided dosesDivided doses With mealsWith meals

Vitamin D supplementationVitamin D supplementation SunshineSunshine 400 IU/daily400 IU/daily

Weight bearing exerciseWeight bearing exercise Smoking cessationSmoking cessation Moderation of alcohol intakeModeration of alcohol intake

Pharmacologic(generally not recommended)

•HRT

•Raloxifene

•Bisphosphonates

Treatment of Osteoporosis Treatment of Osteoporosis (for prevention of fractures)(for prevention of fractures)

First Line AgentsFirst Line Agents BisphosphonatesBisphosphonates RaloxifeneRaloxifene

Second Line AgentsSecond Line Agents Human recombinant PTHHuman recombinant PTH Nasal salmon calcitoninNasal salmon calcitonin HRTHRT

Fall prevention strategiesFall prevention strategies

Changes in the Changes in the UrogenitalUrogenital

SystemSystem

Physiologic Changes in Physiologic Changes in the Urogenital Systemthe Urogenital System

Decrease in production of vaginal Decrease in production of vaginal lubricating fluidlubricating fluid

Loss of vaginal elasticity and thickness of Loss of vaginal elasticity and thickness of epithelium (vaginal atrophy)epithelium (vaginal atrophy)

Development of uretheral carunclesDevelopment of uretheral caruncles Mucosal thinning of urethra and bladderMucosal thinning of urethra and bladder

Vaginal AtrophyVaginal Atrophy

Urogenital symptomsUrogenital symptoms

DysuriaDysuria UrgencyUrgency FrequencyFrequency Recurrent UTIsRecurrent UTIs DysparuniaDysparunia PruritusPruritus StenosisStenosis

Treatment

1) Vaginal estrogen (progestogen not necessary)

2) HRT *

Hormone Replacement TherapyHormone Replacement Therapy

Decrease hot flashesDecrease hot flashes Prevents/treats osteoporosis and hip and Prevents/treats osteoporosis and hip and

vertebral fracturesvertebral fractures Prevents/treats urogenital atrophyPrevents/treats urogenital atrophy

Benefits

Hormone Replacement TherapyHormone Replacement Therapy

Increased risk for venous thrombosis Increased risk for venous thrombosis and embolism**and embolism**

Increased risk for breast cancer with Increased risk for breast cancer with prolonged (>3-5yrs) use (EPT, not ET) prolonged (>3-5yrs) use (EPT, not ET)

Increased risk for endometrial cancer Increased risk for endometrial cancer with ET (not EPT) (if uterus present)with ET (not EPT) (if uterus present)

****may be dependent on route of administrationmay be dependent on route of administration

Risks

Hormone Replacement TherapyHormone Replacement Therapy

Possible increase in cardiac events in Possible increase in cardiac events in older women started on EPT (not ET)older women started on EPT (not ET)

Probably increase in (ischemic) strokes Probably increase in (ischemic) strokes in older women started on HRTin older women started on HRT

Areas of Concern

Hormone Replacement TherapyHormone Replacement Therapy

Risks are dependent onRisks are dependent on Age (total mortality reduced by 30% if started at age Age (total mortality reduced by 30% if started at age

<60)<60) Time since menopauseTime since menopause Age at menopauseAge at menopause Duration of therapyDuration of therapy Type of HTType of HT Route of administrationRoute of administration Dose of HTDose of HT

Benefits are dependent onBenefits are dependent on Number of menopause related symptomsNumber of menopause related symptoms

Areas of Concern

Hormone Therapy Hormone Therapy GuidelinesGuidelines Indication: estrogen deficiency symptomsIndication: estrogen deficiency symptoms

Vasomotor symptomsVasomotor symptoms Hot flushes, night sweatsHot flushes, night sweats

Disturbed sleep patternsDisturbed sleep patterns Fatigue, concentration, memoryFatigue, concentration, memory

GU atrophyGU atrophy Bladder irritability, vaginal dryness, dyspareuniaBladder irritability, vaginal dryness, dyspareunia

Guiding principleGuiding principle Minimum dose for shortest time requiredMinimum dose for shortest time required

Consider non-hormonal alternativesConsider non-hormonal alternatives

Summary of Key PointsSummary of Key Points

Reproductive aging is due to a decline Reproductive aging is due to a decline in the number of ovarian follicles.in the number of ovarian follicles.

Menopause Menopause Signals the end of the reproductive yearsSignals the end of the reproductive years Diagnosed clinicallyDiagnosed clinically Not a diseaseNot a disease Symptoms are due to estrogen deficiency.Symptoms are due to estrogen deficiency.

Key PointsKey Points CADCAD

Rise in risk probably due to metabolic changesRise in risk probably due to metabolic changes HRT not indicated for prevention or treatment at this HRT not indicated for prevention or treatment at this

timetime

OsteoporosisOsteoporosis Evaluate all postmenopausal women over 65 Evaluate all postmenopausal women over 65

(earlier screening recommended if they have one or (earlier screening recommended if they have one or more risk factors)more risk factors)

Prevention: Calcium, Vitamin D, weight-bearing Prevention: Calcium, Vitamin D, weight-bearing exercise, smoking cessationexercise, smoking cessation

Primary treatment: Raloxifene, BisphosphonatesPrimary treatment: Raloxifene, Bisphosphonates

Key PointsKey Points

Currently, the primary reason to Currently, the primary reason to prescribe HRT in postmenopausal prescribe HRT in postmenopausal women is for the women is for the relief of symptomsrelief of symptoms associated with estrogen deficiency.associated with estrogen deficiency.

Premature MenopausePremature Menopause

Definitions:Definitions: Early: age 40-44Early: age 40-44 Premature: <40Premature: <40

CausesCauses Surgical removal of uterus**Surgical removal of uterus** Surgical removal of ovariesSurgical removal of ovaries Premature ovarian failurePremature ovarian failure

**Further discussions exclude this group

Premature Ovarian Premature Ovarian FailureFailure

Sex chromosome abnormalities (usually Sex chromosome abnormalities (usually involving the X Chromosome)involving the X Chromosome)

Fragile X premutationFragile X premutation AutoimmuneAutoimmune Chemotherapy/IrradiationChemotherapy/Irradiation

Evaluation of Premature Evaluation of Premature Ovarian FailureOvarian Failure

Karyotype (<30 years of age)Karyotype (<30 years of age) Assessment for Fragile X premutation Assessment for Fragile X premutation

(number of CGG repeats)(number of CGG repeats) Survey for other autoimmune diseases Survey for other autoimmune diseases

(such as hypothyroidism, adrenal (such as hypothyroidism, adrenal insufficiency)insufficiency)

Premature Ovarian Premature Ovarian Failure is Different from Failure is Different from Menopause !!!!Menopause !!!!

10-20% of women with POF with normal 10-20% of women with POF with normal karyotypes will ovulate againkaryotypes will ovulate again

5% spontaneous pregnancy rate5% spontaneous pregnancy rate Not normal reproductive agingNot normal reproductive aging

Treatment of Premature Treatment of Premature MenopauseMenopause

Hormone replacement therapy!!!Hormone replacement therapy!!! CounselingCounseling Oocyte donationOocyte donation

HIV and MenopauseHIV and Menopause

Mean age of menopause in HIV-infected women is 47-Mean age of menopause in HIV-infected women is 47-48 (not adjusted for risk factors).48 (not adjusted for risk factors).

May be difficult to differentiate HIV symptoms from May be difficult to differentiate HIV symptoms from symptoms of menopause.symptoms of menopause.

Further research needed on the additive effects of Further research needed on the additive effects of menopause, HIV, and anti-retroviral therapies.menopause, HIV, and anti-retroviral therapies.

Further research need on depression during the Further research need on depression during the menopause transition in HIV affected women.menopause transition in HIV affected women.

Safety of HRT in HIV+ postmenopausal women has not Safety of HRT in HIV+ postmenopausal women has not been studied.been studied.

Conde et al. Menopause 2009;16:199-213