Download hormone replacement therapy (hrt): the good, the

HORMONE REPLACEMENT THERAPY (HRT): THE GOOD, THE BAD, AND
THE UGLY
WOMEN AND HEART DISEASE
MI, stroke, and other coronary heart disease have killed more women than men each year since 1984
In 1995, 455,000 men and 505,000 women died from Coronary Heart Disease
Diseases of the heart and blood vessels kill more American women than the next 16 causes of death combined,
including all cancers
CHD occurs in 1 out of 8 women ages 45 to 64, and in 1 out of 3 over age 65
In women 55 to 64 years old with CHD, 36% are disabled and in women over age 75, more than 55% are disabled
For postmenopausal women, lifetime risk of death from CHD is 31%, compared to hip fracture (2.8/%), breast cancer
(2.8%)
Hospital mortality from MI is higher in women (16%) than men (11%)
Women have poorer outcomes after MI than men, whether or not they receive thrombolytic therapy.
with thrombolytic therapy: in hospital mortality was 9.3% in women and 4.5% in men
without thrombolytic therapy: mortality in women was 16% and 10.9% in men
HEART DISEASE RISK FACTORS IN WOMEN In 1991, in women ages 20-­74 years:
more than 33% have hypertension
more than 25% have total cholesterol greater than 240 mg/dl
53% of non-­hispanic white women older than 20 have borderline-­high or high cholesterol
more than 25% smoke cigarettes (smoking triples the risk of MI and lowers the age of initial MI;; women who smoke
fewer than 5 cigarettes/day have twice the risk of CHD over non-­smokers)
more than 25% of women are obese (greater than 20% over ideal body weight)
ATHEROSCLEROSIS IS AN EQUAL OPPORTUNITY KILLER Five placebo-­controlled clinical trials reveal that the best way to reduce and prevent coronary heart disease and stroke in
women is statin drugs, not estrogen replacement therapy. The major, placebo-­controlled, statin drug trials are as follows:
1. Care: Pravachol vs placebo (people with previous MI)
Major coronary events fell 46% in women and 20% in men.
2. 4S: Simvastatin vs placebo (people with previous CHD)
Major CHD events fell 35% in women.
3. POSCH: Partial ileal bypass in women
31% reduction in CHD morbidity/mortality
30% reduction in Coronary Artery Bypass CABG
58% reduction in angioplasty.
4. LCAS: Fluvastatin (people with previous CHD)
benefit in women as well as in men
5. AFCAPS/TexCAPS: 997 women (without clinically evident CHD, with average serum cholesterol levels)
Lovastatin 20-­40 mg/day reduced cardiovascular events in men and women, women better than men (after 5.2 years
followup)
American Heart Association Science Advisory: HRT and CHD Recommendation 1: Before ever giving estrogen-­containing oral contraceptives, estrogen replacement therapy, Evista, or
Tamoxifen, or in women already on such therapy, screen using the serologic resistance to activated protein C assay, and
genotype for the prothrombin gene, or genotype for both the prothrombin and V Leiden mutations by cDNA-­PCR assay (MDL
lab [513-­475-­6631]). In women already on ERT, or pregnant, the assay of choice is the cDNA-­PCR test, since it is not effected
by exogenous estrogen, unlike the serologic test.
Recommendation 2: In women, heterozygous for the Factor V Leiden mutation, and/or heterozygous for the prothrombin
gene mutation, HRT is contraindicated.
After years of taking the opposite tack, the American Heart Association (AHA) is recommending that HRT should not be
initiated for secondary prevention of cardiovascular disease (CVD) in postmenopausal women.
The recommendation follows clinical trials suggesting there is no cardiovascular benefit. In fact, when women with
documented atherosclerosis began to take HRT, there was an increased risk of cardiovascular disease events.
The AHA recommendations are needed because physicians have asked for clarification of the data surrounding HRT, said
Lori Mosca, MD, PhD, lead author of the AHA science advisory and director of preventive cardiology at New York Presbyterian
Hospital in New York City. "For many years, cardiologists and other health care providers who take care of women have
assumed that HRT protects the heart," Mosca said. "At this time there is not sufficient evidence to make that claim. Our
purpose is to clarify the role of hormones in heart disease prevention." The two key trials cited in the recommendation are the
Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) Trial.
In HERS, researchers found that after an average of 4.1 years of follow-­up, there was no difference in the primary outcome of
nonfatal myocardial infarction and coronary death between the women taking hormone and those on a placebo. In fact, they
found a 52% increase in cardiovascular events in the first year in the HRT group compared with the placebo group.
The ERA trial, to test the effect of estrogen replacement therapy (ERT) and HRT on the progression of atherosclerosis in
postmenopausal women with documented coronary stenosis, showed no benefit from either one (N Engl J Med.
2000;;343:522-­529).
The Heart Association recommends that physicians treating women with CVD on HRT should decide to continue or stop long-­
term therapy based on established noncoronary benefits and risks and patient
preference. It also recommended that if a woman with CVD who is undergoing HRT develops an acute event, such as
myocardial infarction, or is immobilized, it is prudent to consider discontinuing HRT or to consider
anticoagulants while she is hospitalized to minimize the risk of developing a blood clot. Whether or not to restart HRT should
then be based on established noncoronary benefits and risks, as well as patient preference.
USE FOR PRIMARY PREVENTION The AHA cited an analysis showing an approximate 35% reduction in CHD events among uses of ERT and of HRT. But the
AHA said there is insufficient data to suggest that HRT should be initiated only for primary prevention of CVD, and that it would
withhold firm clinical recommendations for use of HRT for primary prevention until results are published from ongoing clinical
trials.
WOMEN'S HEALTH INITIATIVE DATA Last year, investigators informed participants in an ongoing trial, the Women's Health Initiative, that during the study's first 24
months there was a small increase in the number of myocardial infarctions, strokes, and blood clots in women taking HRT or
ERT compared with those taking placebo. This June, the investigators informed participants that the data through February
28, 2001, still showed that a small number, less than one half of 1% per year, continue to have acute cardiovascular events.
For primary prevention of CVD, the AHA recommends the tried-­and-­true approach: women should attempt to reduce their risk
factors through lifestyle modifications as smoking cessation, increased exercise, and weight loss, and, if needed, medications
to improve cholesterol levels and lower elevated blood pressure.
COAGULATION PROBLEMS AND ERT: Osteonecrosis of the hip (adults and children) and jaw (adults). Factor V Leiden and prothrombin gene mutations have
been shown to interact with ERT to promote osteonecrosis.
A major risk factor for retinal vein thrombosis (adults) and for non arteritic ischemic optic neuropathy (NAION). Factor V
Leiden mutation and the prothrombin gene mutation have been shown to interact with ERT to promote retinal vein
thrombosis and retinal artery thrombosis.
A major risk factor for first trimester miscarriage and for major complications of pregnancy. Physiologic
hyperestrogenemia of pregnancy interacts with Factor V Leiden and prothrombin gene mutations.
A major risk factor when interacting with estrogen for venous and arterial thrombosis.
ESTROGEN-­INDUCED HYPERTRIGLYCERIDEMIA AND PANCREATITIS Q: Are estrogens or SERMS (Evista, Tamoxifen) contraindicated in some women?
A: Yes! Most women with triglycerides greater than 300 mg/dl should never take estrogens or SERMS.
when fasting triglycerides are greater than 500 mg/dl estrogen is absolutely contraindicated
when fasting triglycerides are greater than 300 mg/dl relatively contraindicated
Q: Why?
A: Women with inherited high triglycerides who take either estrogen or SERMS increased risk for pancreatitis, heart attack,
and stroke. Triglycerides in these women can rise above 1000 mg/dl and the estrogen prevents the triglyceride-­lowering
medications from working.
Q: If the triglycerides are normal, are there any other reasons to avoid taking estrogen?
A: Yes! All women heterozgyous for the mutant Factor V Leiden gene or for the prothrombin gene should avoid taking
estrogen or SERMS.
Q: Why?
A: When estrogen and probably SERMS are given to V Leiden or Prothromin gene heterozygotes, the risk of blood clots rises
to 40 times that of the general population.
HRT, BREAST CANCER, ENDOMETRIAL CANCER With every medication there are benefits and risks. The benefits of HRT include prevention of osteoporosis and easing of
menopausal symptoms (night sweats, hot flashes, vaginal dryness, etc). In the past, it was felt that HRT reduced risk of heart
attack and stroke. As summarized above, new evidence shows that HRT may increase coronary heart disease event rates,
particularly in women heterozygous for the V Leiden or Prothrombin gene mutations (11% of the Caucasian population). The
risks of HRT, beyond elevation of triglycerides, and increased risk of venous thrombosis involve cancer of the breast,
endometrium, and ovaries.
The relative risk of breast cancer is moderately elevated in current and recent HRT users, and increases by about 2.3% per
year with longer duration of use. The effect drops after cessation, and largely but not totally disappears after about 5 years.
Unopposed estrogen use is strongly related to increased enometrial cancer, but cyclic estrogen-­progestin use appears to
reduce this side effect if progestins are used for at least 14 days per cycle. Unfortunately, however, combined HRT is
associated with increased risk of breast cancer as opposed to estrogen alone.
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