Transcript HRT Story What Went Wrong? - Faculty of Medicine, McGill

Story of HRT
Irina Proskorovsky
Timeline
1821- French physician de Gardanne
invented the term menopause to describe
the phenomenon of transition phase in a
woman’s life and the problems thereof
 1890 - doctors start to experimented with
testicular extracts for men and ovarian
extracts for women
 1923-1938 Research leads to identifying
estrogen and other hormones
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Timeline
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1941 – FDA approves estrogen for treatment
of menopausal symptoms
1942 - First estrogen pill (Premarin) was
introduced in US
In the 1950s, Ayerst Laboratories funded a
massive campaign to educate doctors on
menopause, menopausal symptoms, and the
consequences of estrogen loss—and on the use
of its product Premarin to treat menopausal
symptoms
1966 - Robert Wilson (Brooklyn gynecologist)
published his best seller “Feminine Forever”
Timeline (Con’t)
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1975 - New England Journal of Medicine published two
articles that found an increase risk of endometrial cancer
1980 - Few studies show HRT prevents Osteoporosis
1985 - Nurses’ Health Study showed a protective effect of
HRT on CVD
1991 – Meta-Analysis of the effect of estrogen
replacement therapy showed increase risk of breast cancer
1998 – Results of Heart and Estrogen/Progestin
Replacement Study (HERS) published
2001 – Risk and Benefits of Estrogen Plus Progestin in
Healthy Postmenopausal Women-Women’s Health
Initiative
Menopause
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Menopause is the permanent cessation of
menstruation due to loss of ovarian activity and the
depletion of follicles
During menopause women produces less hormones
(estrogen and progesterone)
Symptoms include changes in the menstrual cycle,
hot fleshes, night sweats, dryness, itching, burning, or
thinning of the vagina
Quote from Egyptian medical text, 2000 B.C.: “If a
menopausal woman has pain or makes trouble, pound
her hard on the jaw”.
Development of HRT
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Before 1880 treatments for menopausal symptoms had
primarily consisted of herbals: a selection of belladonna,
cannabis, or opium
In 1889, Dr. Brown-Sequard's made the following
announcement: "I sent to the Society of Biology a
communication, which was followed by several others,
showing the remarkable effects produced on myself by
subcutaneous injection of a liquid obtained by the maceration
on a mortar of the testicle of a dog or of a guinea pig to which
one has added a little water" (Medvei 1982:289)
In the 1890's Merck offered flavored powder made by drying
and pulverizing cow ovaries called Ovariin, that may have
been the first substance commercially available for treatment
of menopausal symptoms that was derived from animal
sources
Research by Dr. Allen and Dr. Doisy between 1923-1938 led
to discovery of estrogen and all other hormones
Development of HRT
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Emminen, the first replacement therapy to contain
conjugated estrogens, was extracted in Ayerst
Laboratories from the urine of pregnant women and
became commercially available in 1933
1942 Premarine (PREgnant MARes’s urINe) available in
US
1938 English chemists, including Charles Dodds,
developed powerful synthetic, nonsteroidal estrogen
diethylstilbestrol (“DES”), that had the same effects as
estrogens but 3 time more powerful (pulled from the
market in 1971 when babies born to DES users were
found to have increased incidence of cancer of the
reproductive organs)
1980 Progestin developed to balance estrogen
Marketing HRT
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In the 1950s, Ayerst Laboratories funded a
massive campaign to educate doctors on
menopause, menopausal symptoms, and the
consequences of estrogen loss—and on the use
of its product Premarin to treat menopausal
symptoms
1966 Robert Wilson argued in his book
“Feminine Forever” that menopause was not
natural age-related condition and estrogen
become long-term treatment for chronic ills of
aging
Scientific Evidence
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1976 -The Nurses' Health Study was
established by Dr. Frank Speizer with funding
from the National Institutes of Health. The
primary motivation in starting the NHS was to
investigate the potential long term
consequences of the use of oral contraceptives,
a potent drug that was being prescribed to
hundreds of millions of normal women.
Nurses' Health Study
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Design: Prospective, observational Cohort
Setting: Nurses health study with follow up
from 1976 to 1996
Participants: postmenopausal women with no
hx of CVD in whom major coronary events
and strokes were identified
Comparisons: Current HRT Users, Past Users,
Never
Main Outcomes: CVD
Results of NHS (JAMA 1985)
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During 105,786 person-years of observation among 32,317
postmenopausal women who were initially free of coronary
disease, 90 women had either nonfatal myocardial infarctions
(65 cases) or fatal coronary heart disease (25 cases).
Ever vs. never RR= 0.5 (95% CI; 0.3 -0.8; P = 0.007)
Current vs. never RR= 0.3 (95% CI, 0.2 - 0.6; P = 0.001)
The relative risks were similar for fatal and nonfatal disease
and were unaltered after adjustment for cigarette smoking,
hypertension, diabetes, high cholesterol levels, a parental
history of myocardial infarction, past use of oral
contraceptives, and obesity.
These data support the hypothesis that the postmenopausal use
of estrogen reduces the risk of severe coronary heart disease.
Use of HRT in Canada
Ilona Csizmadi, Andrea Benedetti, Jean-François Boivin, James A. Hanley, and Jean-Paul Collet
Use of postmenopausal estrogen replacement therapy from 1981 to 1997 CMAJ. 2002 January 22; 166(2): 187–188
Walnut Creek Study (1987)
Walnut Creek Study (N=16,500)
 Diana Petitti also found a reduced risk of
CHD among women taking HRT
 But!!! She also found an even more
dramatic reduction in death from
homocide, suicide and accidents
 Her conclusion: something else appear to
be confounding the observed association
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HERS Trial (JAMA 1998)
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Design: Randomized, blinded, placebo-controlled secondary
prevention trial
Setting: Outpatient and community settings at 20 US clinical
centers
Participants: 2,763 Women with CHD, < 80 years,
postmenopausal with an intact uterus
Intervention: Either 0.625 mg of conjugated equine estrogens
plus 2.5 mg medroxyprogesterone daily or placebo
Compliance: 82% of those assign to HRT at 1 year, 75% at
end of year 3
Main Outcomes:
 Primary: Non-fatal MI or CHD
 Secondary: Coronary revascularization, unstable angina,
congestive heart failure, stroke, TIA, PAD, cardiac arrest
HERS Trial Results
Figure 3.—Kaplan-Meier estimates of the cumulative incidence of primary coronary
heart disease (CHD) events (left) and to its constituents: nonfatal myocardial infarction
(MI) (center) and CHD death (right). The number of women observed at each year of
follow-up and still free of an event are provided in parentheses, and the curves become
fainter when this number drops below half of the cohort. Log rank P values are .91 for
primary CHD events, .46 for nonfatal MI, and .23 for CHD death.
HERS Conclusions
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In postmenopausal women with established coronary
disease and an average age of 66.7 years, daily use of
conjugated equine estrogens and
medroxyprogesterone acetate did not reduce the
overall risk for MI and CHD death or any other
cardiovascular outcome during an average of 4.1
years of follow-up
This therapy did increase the risk of venous
thromboembolic events and gallbladder disease
Extended follow-up of the HERS cohort and
additional randomized trials are needed to clarify the
cardiovascular effects of postmenopausal hormone
therapy
Woman’s Health Initiative RCT (JAMA-2002)
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Design: Randomized Controlled double blind primary
prevention Trial
Settings: most women recruited by population-based direct
mailing campaign in conjunction with media awareness
campaign
Participants: postmenopausal women age 50-79 with intact
uterus at baseline
Intervention: Either 0.625 mg of conjugated equine estrogens
plus 2.5 mg medroxyprogesterone daily or placebo
Compliance: 90% and 95% at year 1, 80% and 85% at year 3,
69% and 74% at year 5 for women on HRT and placebo
respectively
Main Outcomes:
 Primary: Non-fatal MI, CHD and CHD Death and Cancer
(AE)
 Global Index: 2 primary outcomes plus stroke, pulmonary
embolism, endometrial cancer, colorectal cancer, hip
fracture and death due to other causes
WHI Results
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After 5.2 years of follow up trial of estrogen plus
progestin vs. placebo was stopped because the test
statistic for invasive breast cancer exceeded the
stopping boundary and an overall balance of harm
was found to be greater than benefit with respect to 8
prespecified outcomes
WHI-ET, the estrogen-only trial stopped 2 years
prematurely in 2004, after an average of 6.6 years.
The main reason for stopping this trial early was a
39% increased incidence of stroke among ET users
and a very low likelihood for future cardiac benefit.
Results of HERS and WHI
Hazard Ratio (95% CI)
Clinical event
HERS (estrogen +
progestin)
WHI (estrogen +
progestin)
WHI (estrogen)
CHD events
0.99 (0.80–1.22)
1.29 (1.02–1.63)
0.91 (0.75–1.12)
Stroke
1.23 (0.89–1.70)
1.41 (1.07–1.85)
1.39 (1.10–1.77)
Pulmonary
embolism
2.79 (0.89–8.75)
2.13 (1.39–3.25)
1.34 (0.87–2.06)
Breast cancer
1.30 (0.77–2.19)
1.26 (1.00–1.59)
0.77 (0.59–1.01)
Colon cancer
0.69 (0.32–1.49)
0.63 (0.43–0.92)
1.08 (0.75–1.55)
Hip fracture
1.10 (0.49–2.50)
0.66 (0.45–0.98)
0.61 (0.41–0.91)
Death
1.08 (0.84–1.38)
0.98 (0.82–1.18)
1.04 (0.88–1.22)
NA
1.15 (1.03–1.28)
1.01 (0.91–1.12)
Global index
USE of HRT in US
Figure 3. Annual Number of US Prescriptions for Hormone
Therapy by Formulation, 1995-July 2003
Hersch AL, Stefanick ML, Stafford RS. 2004. National
use of postmenopausal hormone therapy. JAMA 291:47–53 (43, figure 3, p. 50)
Why Results of NHS and 3 Trials are So
Different
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Bias of Healthy Users: people who are taking
drugs as prescribed, or eating healthy diet are
fundamentally different from those who don’t
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Women who take HRT are more thinner, have
fewer risk factors for heart disease, more educated
and wealthier, generally more health conscious
Prescriber Effect: The reasons a physician will
prescribe one medication to one patient and
none to other are often complex and subtle
Why Results of NHS and 3 Trials are So
Different
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Measurement Error: In NHS study women
were asked if they were taking HRT every two
years
Timing
Clinical Trials: What happens if older women gets
HRT years after menopause
 Observational Studies: What happens to women
taking HRT near onset of menopause
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