Critical Issue of Disentangling Critical Issue of Disentangling Menopause from Aging Menopause from Aging S. Mitchell Harman, MD, PhDS. Mitchell Harman, MD, PhD

Director and PresidentDirector and PresidentKronos Longevity Research InstituteKronos Longevity Research Institute

Phoenix, ArizonaPhoenix, Arizona

Nanette F. Santoro, MDNanette F. Santoro, MDProfessor and DirectorProfessor and Director

Department of Ob/Gyn and Women’s HealthDepartment of Ob/Gyn and Women’s HealthAlbert Einstein College of MedicineAlbert Einstein College of Medicine

Bronx, New YorkBronx, New York

Defining the Stages of Defining the Stages of Reproductive AgingReproductive Aging

Premenopause Regular cycling without Regular cycling without interruptioninterruption

Early transition <60 days amenorrhea or <60 days amenorrhea or irregularity; >7days between irregularity; >7days between cyclescycles

Late transition >60–90 days amenorrhea but >60–90 days amenorrhea but <12 months amenorrhea<12 months amenorrhea

Postmenopause 12 months amenorrhea12 months amenorrhea

Hormonal Significance of Hormonal Significance of Transition StagesTransition Stages

Estrogen StatusEstrogen Status Signs and SymptomsSigns and Symptoms

PremenopausePremenopause • Estrogen replete, Estrogen replete, elevated in some elevated in some circumstancescircumstances

• No prolonged No prolonged hypoestrogenemiahypoestrogenemia

• Bone density preservedBone density preserved• Mild increase in symptomsMild increase in symptoms

Early Early transitiontransition

Hormonal Significance of Hormonal Significance of Transition StagesTransition Stages

Estrogen StatusEstrogen Status Signs and SymptomsSigns and Symptoms

PremenopausePremenopause • Estrogen replete, Estrogen replete, elevated in some elevated in some circumstancescircumstances

• No prolonged No prolonged hypoestrogenemiahypoestrogenemia

• Bone density preservedBone density preserved• Mild increase in symptomsMild increase in symptoms

Early Early transitiontransition

Late transitionLate transition Estrogen decliningEstrogen declining Estrogen-dependent Estrogen-dependent processes impactedprocesses impacted• Biggest increase Biggest increase

in hot flashesin hot flashes• Biggest increase in Biggest increase in

vaginal symptomsvaginal symptoms• Bone demineralization Bone demineralization

beginsbegins• Sleep problems worsenSleep problems worsen

Annual Rate of Change in Bone Mineral Annual Rate of Change in Bone Mineral Density over the Menopause TransitionDensity over the Menopause Transition

-0.03-0.03

-0.02-0.02

-0.01-0.01

00

0.010.01

BM

D C

han

ge

(g/d

mB

MD

Ch

ang

e (g

/dm

22 /y)/y

)

Lumbar spineLumbar spine Total hipTotal hip

PostmenopausePostmenopause

Late transitionLate transition

Early transitionEarly transition

PremenopausePremenopause

RegionRegion

BMD = bone mineral density.BMD = bone mineral density.Reprinted from Finkelstein JS, et al. J Clin Endocrinol Metab. 2008;93:861, with permission from The Endocrine Society.

Vasomotor Symptoms Increase Vasomotor Symptoms Increase Across the TransitionAcross the Transition

Transition StageTransition Stage OROR 95% CI95% CI

PremenopausePremenopause –– ––

Early transitionEarly transition 1.861.86 1.47–2.341.47–2.34

Late transitionLate transition 6.646.64 4.80–9.204.80–9.20

PostmenopausePostmenopause 4.964.96 3.51–7.013.51–7.01

Gold EB, et al. Am J Public Health. 2006;96:1226.OR = odds ratio; CI = confidence interval.

Follow the EstrogenFollow the Estrogen

The previously presentedThe previously presented types of processes follow types of processes follow

along and correlate with estradiol and follicle-along and correlate with estradiol and follicle-

stimulating hormone patternsstimulating hormone patterns

Vasomotor symptomsVasomotor symptoms

Sleep disturbancesSleep disturbances

Bone densityBone density

FSH, Estradiol, and Inhibin Changes FSH, Estradiol, and Inhibin Changes in Relation to Final Menstrual Periodin Relation to Final Menstrual Period

Reprinted from Burger HG, et al. J Clin Endocrinol Metab. 1999;84:4025, with permission from The Endocrine Society.

FSH = follicle-stimulating hormone.

Age-Related ProcessesAge-Related Processes

Decreased distensibility of blood vessels Decreased distensibility of blood vessels

– Increased blood pressureIncreased blood pressure

Increased insulin resistanceIncreased insulin resistance

Increased atherogenesisIncreased atherogenesis

Increased body mass indexIncreased body mass index

Complex InteractionsComplex Interactions

Menopause interacts with atherogenesisMenopause interacts with atherogenesis

Estrogen retards accumulation ofEstrogen retards accumulation ofcomplex plaquecomplex plaque

BUTBUT

Once complex plaque is present, estrogen may Once complex plaque is present, estrogen may

– Destabilize plaque, increasingDestabilize plaque, increasingcardiovascular riskcardiovascular risk

– Increase thrombotic tendency (oral route)Increase thrombotic tendency (oral route)

Mendelsohn ME, et al. Science. 2005;308:1587.

Age-Related Diseases Potentially Age-Related Diseases Potentially Linked to Estrogen TreatmentLinked to Estrogen Treatment

Vascular diseasesVascular diseases– Coronary heart diseaseCoronary heart disease– StrokeStroke– Thrombophlebitis/pulmonary embolusThrombophlebitis/pulmonary embolus

MalignanciesMalignancies– Breast cancerBreast cancer– Endometrial cancerEndometrial cancer– Ovarian cancerOvarian cancer– Lung cancerLung cancer– Colon cancerColon cancer

OsteoporosisOsteoporosis Alzheimer’s disease–dementiasAlzheimer’s disease–dementias Macular degenerationMacular degeneration

Observational Studies of ERT/HRT and CHDObservational Studies of ERT/HRT and CHD

0 0.5 1.0 2.0 5.0

Stampfer MJ, et al (1985)

Wilson PW, et al (1985)

Bush TL, et al (1987)

Petitti DB, et al (1987)

Boysen G, et al (1988)

Criqui MH, et al (1988)

Henderson BE, et al (1988)

van der Giezen AM, et al (1990)

Wolf PH, et al (1991)

Falkeborn MI, et al (1992)

Psaty BM, et al (1994)

Folsom AR, et al (1995)

Relative Risk

Grodstein F, et al (1996a)

ERT = estrogen-replacement therapy; HRT = hormone-replacement therapy; CHD = coronary heart disease.

Adapted from Burkman RT, et al. Am J Obstet Gynecol. 2001;185:S13, with permission from Elsevier. aGrodstein F, et al. N Engl J Med. 1996;335:453.

Breast Cancer

Cardiovascular Events

Strokes

Thromboembolic Disease

Colon Cancer

All Fractures

Deaths

0 50 100 150 200

Estrogen + progestin

Placebo

Ou

tco

me

sIncidences of Clinical Events in the Women’s Incidences of Clinical Events in the Women’s Health Initiative Estrogen + Progestin Trial Health Initiative Estrogen + Progestin Trial

Number per 10,000 Women per Year

JAMA. 2002;288:321. Graphic courtesy of S. Mitchell Harman, MD.

Estrogen plus Progestin and the Risk of CHD Estrogen plus Progestin and the Risk of CHD in Various Subgroups of WHI Womenin Various Subgroups of WHI Women

0.0

0.2

0.4

0.60.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

Ris

k R

ati

o F

or

CV

D

0 5 10 15 20 25 30Years Postmenopause at Randomization

<10

10–19

≥20

?HR = 0.62

r = .994P = .071

Assume mean postmenopausal durations of 5, 15, and 25 years for the <10, 10-20, and ≥20 year groups, respectively (actual means not provided).

Extrapolate the best fit regression line to a value of 0 postmenopausal years.

Draw best fit regression line.

Hazard Ratio for CHDNo. of cases of CHD(annualized percentage)

Subgroup P value for Interaction

Age (y) E + P Placebo 0.36

50-–59 37 (0.22) 27 (0.17)

60–69 75 (0.35) 68 (0.34)

70–79 76 (0.78) 52 (0.55)

Years since menopause 0.33

<10 31 (0.19) 34 (0.22)

10–19 63 (0.38) 51 (0.32)

≥20 74 (0.75) 44 (0.46)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

1.27

1.05

1.44

0.89

1.22

1.71

CHD = coronary heart disease; WHI = Women’s Health Initiative; E+P = estrogen + progestin; CVD = cardiovascular disease.

Top graphic from Manson JE, et al. N Engl J Med. 2003;349:530. Copyright © 2003. Massachusetts Medical Society. All rights reserved. Bottom graphic courtesy of S. Mitchell Harman, MD.

Event Hazard Ratios by Age Subgroups Event Hazard Ratios by Age Subgroups in WHI Estrogen-Only Armin WHI Estrogen-Only Arm

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Hazard Ratio (95% CI)

50–5960–6970–79

50–59Stroke 60–69

70–79

50–59Thromboembolism 60–69

70–79

50–59Breast Cancer 60–69

70–79

HR = 0.56CoronaryHeart Disease

HR = 1.08

HR = 1.22

HR = 0.72

WHI = Women’s Health Initiative; HR = hazard ratio; CI = confidence interval.Adapted from Anderson GL, et al. JAMA. 2004;291:1701, with permission from the American Medical Association.

In 50–59 y Group

Vascular biologist’s definition ofVascular biologist’s definition ofprimary preventionprimary prevention

Clinician’s definition ofClinician’s definition ofprimary preventionprimary prevention

AdventitiaMedia

lamina

Fatty streak/plaque

Internalelastic

Clarkson TB. Int J Fertil. 2002;47:61. Courtesy of TB Clarkson, MD.

Necrotic core

Plaque

Fibrouscap

MMP-9

Fibrous

Plaque

cap

Gradual, progressive(years)

Event

Thrombus

Sudden, rapid, (hours)

Primary Prevention of AtherosclerosisPrimary Prevention of Atherosclerosis

Estrogen effects

?Estrogen effects

Differential Effects of Oral vs Differential Effects of Oral vs Transdermal Estrogen Therapy on Transdermal Estrogen Therapy on

Thromboembolic DiseaseThromboembolic Disease

StudyStudy Oral Oral EstrogenEstrogen

OR (95% CI)OR (95% CI)

Transdermal Transdermal EstrogenEstrogen

OR (95% CI)OR (95% CI)

Scarabin TY, et al Scarabin TY, et al (2003)(2003)11

3.5 3.5 (1.8–6.8)(1.8–6.8)

0.90.9(0.5–1.6)(0.5–1.6)

Canonico M, et al Canonico M, et al (2007)(2007)22

4.24.2(1.5–11.6)(1.5–11.6)

0.90.9(0.4–2.1)(0.4–2.1)

1. Scarabin TY, et al. Lancet. 2003;362:428. 2. Canonico M, et al. Circulation. 2007;115:840.

CEE UseCEE Use Women-Women-YearsYears CasesCases Multivariate Multivariate

Risk RatioRisk RatioAdjusted Adjusted (95% CI)(95% CI)

NeverNever 313,661313,661 160160 1.01.0 ----

0.3 mg/d0.3 mg/d 19,96419,964 44 0.430.43 (0.16–1.16)(0.16–1.16)

0.625 mg/d0.625 mg/d 116,150116,150 7373 1.441.44 (1.07–1.93)(1.07–1.93)

1.25+ mg/d1.25+ mg/d 39,02639,026 2929 2.002.00 (1.32–3.05)(1.32–3.05)

Effects of Estrogen by Dose on Ischemic Effects of Estrogen by Dose on Ischemic Stroke Risk in the Nurses Health StudyStroke Risk in the Nurses Health Study

CEE = conjugated equine estrogen.CEE = conjugated equine estrogen.Adapted from Grodstein F, et al. Ann Internal Med. 2000;133:933, with permission from the American College of Physicians.

Causes of Death Among US WomenCauses of Death Among US Women

Heart Disease (45%)Heart Disease (45%)Other (25%)Other (25%)

COPD (4%)COPD (4%)

Pneumonia (4%)Pneumonia (4%)

Ovarian Cancer (<2%)Ovarian Cancer (<2%)

Breast Cancer (4%)Breast Cancer (4%)

Lung Cancer (5%)Lung Cancer (5%)

Other Cancer (11%)Other Cancer (11%)

Graphic courtesy of S. Mitchell Harman, MD.COPD = chronic obstructive pulmonary disease.COPD = chronic obstructive pulmonary disease.

Grodstein F, et al. N Engl J Med. 1997;336:1769. Copyright © 1997. Massachusetts Medical Society. All rights reserved.

NeverNeverCause of DeathCause of Death

All causesAll causes

Relative risk (95% CI)Relative risk (95% CI)

1.01.0 0.630.63 (0.56–0.70)(0.56–0.70) 1.031.03 (0.94–1.12)(0.94–1.12)

Coronary heart diseaseCoronary heart disease 1.01.0 0.470.47 (0.32–0.69)(0.32–0.69) 0.990.99 (0.75–1.30)(0.75–1.30)

StrokeStroke 1.01.0 0.680.68 (0.39–1.16)(0.39–1.16) 1.071.07 (0.68–1.69)(0.68–1.69)

All cancerAll cancer 1.01.0 0.710.71 (0.62–0.81)(0.62–0.81) 1.041.04 (0.92–1.17)(0.92–1.17)

Breast cancerBreast cancer 1.01.0 0.760.76 (0.56–1.02)(0.56–1.02) 0.830.83 (0.63–1.09)(0.63–1.09)

aaValues are adjusted for age, age at menopause, type of menopause, body mass index, Values are adjusted for age, age at menopause, type of menopause, body mass index, diabetes, high blood pressure, high cholesterol, smoking, oral contraceptive use, family history diabetes, high blood pressure, high cholesterol, smoking, oral contraceptive use, family history of myocardial infarction or breast cancer, parity.of myocardial infarction or breast cancer, parity.

CurrentCurrent PastPast

Hormone Use –Hormone Use –

AdjustedAdjustedaa Relative Risk of Death in the Relative Risk of Death in the Nurses Health StudyNurses Health Study

ConclusionsConclusions Physiologic changes associated with aging process Physiologic changes associated with aging process

may be inappropriately attributed to menopausemay be inappropriately attributed to menopause

It is not always possible to isolate menopause or It is not always possible to isolate menopause or estrogen per se as theestrogen per se as thesole variablesole variable

Many relationships are time dependent, complex, and Many relationships are time dependent, complex, and require further elucidation require further elucidation

Hormone therapy in menopausal women has Hormone therapy in menopausal women has complex and variable (beneficial and adverse) complex and variable (beneficial and adverse) effects on risks for several major age-related effects on risks for several major age-related diseasesdiseases

Outcomes depend in part uponOutcomes depend in part upon– Agent(s)Agent(s)– Dose Dose – Route of administrationRoute of administration– Timing of initiationTiming of initiation– Duration of treatmentDuration of treatment

– Patient characteristics (age, habits, genetic)Patient characteristics (age, habits, genetic) Net effects (risk/benefit ratio) and all-cause Net effects (risk/benefit ratio) and all-cause

mortality appear beneficial for recently menopausal mortality appear beneficial for recently menopausal womenwomen

ConclusionsConclusions