David Barad, MDCHR Grand RoundsApril 14, 2009

1940: DES used for “healthy pregnancy”

1966: Feminine Forever published by Dr. Wilson

1976: Unopposed estrogen linked to endometrial cancer

1980s: Estrogen and Progestin given

1993 to Present: WHI

Occur in 60 - 80% Severe in 15% Worse in iatrogenic

menopause Primary reason for

starting or restarting HRT

Primary SE of stopping HRT

Multifactorial: Stress, empty nesters, fatigue

The gamut of tears, laughter, depression

Estrogen/ Serotonin receptor association

Often reported by significant others

Vaginal dryness and burning

Thinned mucosa May complain of

pain with intercourse

Increased microhematuria

After menopause, cardiac risk approaches that of men

Cardiac disease is #1 killer of women

CHD Mortality in Men and Women by AgeMyth and paradox of coronary risk and menopause

Case-Control Studies

Psaty, 1994

Mann, 1994

Rosenberg, 1993

Thompson, 1989

Cohort Studies

Falkeborn, 1992

Clinical Trial

0.01 0.1 1

Estrogen+ Progestin

0.01 0.1 1 10

Cohort Studies

Falkeborn, 1992Wolf, 1991

Henderson, 1991Sullivan, 1990

Avila, 1990Criqui, 1988Petitti, 1987

LRC Prevalence Study: Bush, 1987Framingham: Wilson, 1985

Nurses Health Sutdy: Stampfer, 1985Angiographic Studies

McFarland, 1989Sullivan, 1988

Gruchow, 1988Case-Control Studies

Mann, 1994Rosenberg, 1993

Croft, 1989Beard, 1989Szklo, 1984Ross, 1981Bain, 1981

Adam, 1981Rosenberg, 1980

Pfeffer, 1978Talbott, 1977

Rosenberg, 1976Summary Relative Risk

Estrogen Only

Barrett-Connor. Annu Rev Public Health. 1998;19:55-72

Addressed etiology and prevention of major causes of morbidity and mortality in

Postmenopausal Women aged 50-59 enrolled 1993-1996 aged 60-79 enrolled 1993-1998

Three clinical trials (N=68,133) Hormone Therapy (HT) to prevent CHD Diet Modification (DM) to prevent cancer Calcium/Vitamin D (CaD) to prevent hip

fractures Large observational study (N=93, 676) Planned duration 8.4 years (average)

www.whi.org

www.whiscience.org

Event

Primary

Secondary

Tertiary

Health Promoti

on

RehabilitationAcute care

Disease Event

Primary

Secondary

Tertiary

Health Promoti

on

RehabilitationAcute care

CHD Mortality in Men and Women by AgeMyth and paradox of coronary risk and menopause

CHD Mortality in Men and Women by AgeMyth and paradox of coronary risk and menopause

Heart Disease - Not for Secondary Prevention AHA Position (HERS) Primary Prevention - believed favorableStroke - NOT for 2ndary Prevention; primary, unknownVTE (blood clots: lungs, PE; legs, DVT)- unfavorable Breast Cancer - believed unfavorableHip Fractures - believed favorable Vertebral Fractures - favorable?Memory, AD - believed favorableGallbladder Disease - unfavorable?Urinary Incontinence - favorable?

Postmenopausal Hormone Therapy for Aging

NOT KNOWN:

Hysterectomy

CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d

E Alone N = 10,739

YES

NO

Placebo

Conjugated equine estrogens (CEE) 0.625 mg/d

Placebo

E + PN=16,608

Stroke?

Threshold LevelEarly STOPPING for HARM

Threshold Level Early STOPPING for BENEFIT

Coronary Artery Disease(Heart Attacks)

Breast Cancer

Anticipated Risk Expected Benefit

Plan to follow to 2005 (average 8.5 years)

Additional Benefits:• Hip (Bone) Fractures• Overall Mortality

Additional Risks:• Blood Clots, VTELungs=PE; Legs=DVT

• Colon Cancer• Global Index: overall balance of benefits and risks

Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture, Colorectal Cancer, Death from other causes, Endometrial Cancer

26% Increase Breast Cancer

Also: DVTs

STOPPED Early, Clear Harm

Threshold Level

Risks

Benefits

*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

Stopped 3.3 yrs early* had 0.4 more yrs of data Other Fractures

26% Increase Breast Cancer

Also: DVTs

33% Decrease Hip Fracture

STOPPED Early, Clear Harm

Threshold Level

29% Increase CHD (Coronary Heart Disease)

41% Increase Stroke

Risks

Benefits

*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

Stopped 3.3 yrs early* had 0.4 more yrs of data

113% Increase Pulmonary Emboli

Other Fractures

Decreased Colorectal Cancer

Effects of Estrogen-Plus-Progestin and Placebo on Disease Rates

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CEE+MPA

Placebo

Risks Benefits

Total: 52.9/10,000 E+P vs 52.3/10,000 Breast Cancer: Increase in E+P arm

reason for stopping trial Not statistically significant, but exceeded

preset threshold by DSMB Colon Cancer: Decrease in E+P arm Endometrial Cancer: No difference

No increased risk for breast cancer during the first 2 years of combined estrogen and progesterone (E+P) potentially identifying a "safe" period.

Marked drop in the risk for breast cancer 2 years after postmenopausal women stopped taking the hormones. Cancer. Published online before print January 20, 2009. Abstract

N Engl J Med. 2009 :360:573-587.

CAD: Overall 29% higher rate in E+P Equal number of revascularization

procedures and cardiac deaths Excess events in non-fatal MI group

Stroke: Equal number of fatal strokes

DVT/PE: 10 x number reported by USPSTF

T score > 2.5 SD below young adults

10 million Americans

1.5 million fractures annually

Hip fractures 1 out of 6 women 1/2 can not walk

without assist 1/4 die within one

year of fracture

Hip fractures reduced by 34% Vertebral fractures reduced

Only 40% symptomatic No routine radiographs to screen for

vertebral fractues Patients with osteoporosis excluded

from enrollment

Enrolled 4500 women 65 – 79 Participants memory and cognitive functions

were tested yearly Tested rate of memory decline and for

presence of dementia Outcomes:

E+P does not protect from normal decline E+P showed increase in dementia

HR, 2.0595% CI, 1.21__3.48

WHIMS E+P: Probable Dementia Hazard Ratio

4532 women, aged 65-79; followed for 4.1 years

E+PPlacebo

No. at Risk

E+P

Placebo

2229 2112 2026 1915 1325 401 2303 2200 2125 1984 1392 477

0 1 2 3 4 5

Years Since Randomization

Cum

ulat

ive

Haz

ard

Enrolled 10,739 women, aged 50 -79, and treated with estrogen or placebo

Average follow-up of 6.8 years Tested primary prevention/safety

estrogen Outcomes:

Increased risk in stroke, decreased hip fx No change in breast CA, CAD, colon CA

STOPPED - Increased StrokeNo CHD Benefit

Threshold Level

37% Increase Stroke(55% Increase Ischemic Stroke)

Risks Benefits

*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

Stopped 1.5 yrs early* had 0.3 more yrs of data

N.S. 37% Increase Pulmonary Emboli47% increase DVTs

Other Fractures

33% Decrease Hip Fracture

No Effect on CHD No Increase Breast CancerNo Effect on Colorectal Cancer

Summary: WHI E+P* vs. E-Alone** Trial published: *July 2002 **April 2004

Concordant results Heart Disease – no benefit (for E+P, early harm) Strokes, Blood Clots – harmful Fractures – beneficial Dementia (if ≥ 65 yrs of age) – harmful

Disparate Results Breast Cancer

Increased in E+P Trial (women with a uterus) Not increased in E-Alone Trial (women with prior

hysterectomy) Increased breast cancer risk in women with highest baseline risk

Global Index Increased in E+P (CEE + MPA) Trial Neutral in E-Alone (CEE) Trial

JAMA 2003; 289:2651-2662 JAMA 2004; 291:2947-2958

N=4,532; 4.1 yrs follow-up N=2,947; 5.2 yrs follow-up

49% (NS)

34% (NS)105%

Effects of Estrogen-Alone and Placebo on Disease Rates

0

10

20

30

40

50

60

70

80

90

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CEEPlacebo

Effects of Estrogen-Plus-Progestin and Placebo on Disease Rates

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CEE+MPA

Placebo

Risks Benefits

Risk Benefit

Risk? Benefit?

HERSWHIE+P WHI

E only

Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53

% o

f En

rolled

Pop

ula

tion

552233.3%

751045.2%

357621.5%

12,30474.1%

326219.6%

1035 6.2%

505830.6%

582635.3%

563634.1%

Mean =63.3 yrs Mean =28.5 kg/m2

JAMA. 2002;288: 321-333

N

Age (yrs) Prior HT UseBody Mass Index

% o

f En

rolled

Pop

ula

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JAMA. 2004;291: 1701-1712

331030.8%

485245.2%

257724.0%

220620.7%

370734.7%

475944.6%

Mean =63.6 yrs Mean =30.1 kg/m2

553951.6%3819

35.6%137712.8%

N

Age (yrs) Prior HT UseBody Mass Index

E-alone (32.7%)

E+P (21.5%)

50-59 60-69 70-79

0

5

10

15

20

25

Black Hispanic Black Hispanic Black Hispanic

Hysterectomy (75.3% White) Uterus (84.0 % White )

E-alone (22.0%)

E+P (12.5%)

E-alone (13.9%)

E+P ( 8.6%)

Percent Minority

Perc

en

t

Ann Epidemiol 2003; 13: S78-S86

Arch Intern Med. 2006;166:357-365

Age 50-59 y Age 60-69 y Age 70-79 y

P for interaction=0.07

Manson et al, NEJM 2007; 356: 2591-2602

Women aged 50-59 at time of randomization into E-Alone trial (with prior hysterectomy) at 28 (of 40) WHI sites

After mean 7.4 years of treatment; 1.3 yrs after trial was completed

- Did not study older women in E-only trial or women in E+P trial

Baseline Characteristics (N=1064: 537 CEE, 527 Placebo) Age: Mean 55 years (50-54, 39.5%; 55-59, 60.5%)

Age at Menopause: Mean 43.5 years

Age at Hysterectomy: < 35 (28%); 35-39 (25%); 40-44 (22.5%); ≥ 45 (23%)

Ethnicity: White, ~ 75% Black, 16.5% Hispanic, 6% Asian/PI, 0.3% American Indian, <1%

Body Mass Index: 30.5 kg/m2; Hypertension: 35.5%; Diabetes: 6.3%

CAC Categories

Intent-to-Treat Analyses Adherent AnalysesMultivariate P=0.03 Multivariate P=0.004

Manson et al, NEJM 2007; 356: 2591-2602

Among women aged 50-59 in E-alone Trial calcified plaque burden in coronary arteries was lower in CEE group than placebo 1.3 yrs after 7.4 yrs of treatment. Did not study older women or E+P trial

WHI data do not suggest CHD harm for short-term therapy to relieve menopausal symptoms.

HRT and the Young at Heart: Mendelssohn ME, Karas RH. NEJM 2007; 356: 2639-2641

Timing Hypothesis: The beneficial effects of HRT in preventing atherosclerosis occur only when the therapy is initiated before advanced atherosclerosis develops.

Predicts that HRT is NOT beneficial when given to older women, because the underlying biologic characteristics of the vessel wall and vascular response to HRT are altered in older, more atherosclerotic vessels.

Age is a powerful risk factor for atherosclerosis; risk is low for majority of women aged 50-59.

Women starting hormones close to the menopause may have fewer heart attacks and deaths due to HT compared to increases in women distant from the menopause

Provides some reassurance that younger women using hormones for the short term for relief of hot flashes and night sweats are not at increased risk of heart disease

Stroke increased irrespective of age or years since menopause (Breast cancer also increased in E+P only)

Rossouw et al JAMA 2007;297:1465-1477

Older women with moderate/severe hot flashes or night sweats appear to be at high risk if they start hormone therapy

In part explained by higher prevalence of risk factors (obesity, high blood pressure, high blood cholesterol, diabetes) in women with vasomotor symptoms

Rossouw et al JAMA 2007;297:1465-1477

“one estrogen and one estrogen/progestin” Most commonly prescribed HT

“Women with moderate to severe menopausal symptoms discouraged” Not a study of symptoms… symptomatic

women were considered to have greater noncompliance

QOL measurement tools Standardized and highly reliable, no QOL tool

for menopause existed at the initiation of the WHI

Estrogens and progestins should not be used for the prevention of cardiovascular disease.

Other doses of CEE and MPA and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar

Estrogens and progestins should not be used for the prevention of cardiovascular disease.

Other doses of CEE and MPA and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar

HRT is not recommended for prevention of CAD

HRT is approved for treatment of moderate to severe menopausal sx

HRT is approved for osteoporosis prevention in certain patients

For approved conditions HRT should be used in the low dose for short duration

Treatment of moderate to severe symptoms associated with menopause

Treatment of moderate to severe symptoms associated with vaginal and vulvar atrophy assoc. with menopause

Prevention of postmenopausal osteoporosis in women at significant risk, after considering non-hormonal rx

www.menopause.org: NAMS http://www.cme.wisc.edu/online/

menopause/sld001.htm: UW menopause review

www.4women.gov/owh: DHHS Office of Women’s Health

www.nhlbi.nih.gov/health/women/index.htm: WHI website