Introduction
With the current controversy surrounding hormone replacement therapy (HRT), there is an increased demand by the general population for alternative therapies, particularly for the cancer survivor. The volume of information on HRT to which physicians and patients are exposed is growing exponentially. Nevertheless, there still remain as many questions as answers regarding the risks and benefits of this therapy.
Until the 1970s, women expected to have to suffer through menopausal symptoms as part of their reproductive life. It has since been clearly established that hormones, estrogen in particular, play a significant role in the physical and psychological well-being of women.
The symptoms of estrogen deficiency are often debilitating. The most commonly described are vasomotor symptoms (hot flashes), urinary frequency, mood swings, memory loss, difficulty in concentrating, insomnia, decreased libido, dyspareunia, and vaginal dryness and pruritus. The “silent killers” include heart disease, osteoporosis, and Alzheimer’s disease.
Hormone replacement was initially intended for the short-term treatment of vasomotor symptoms, but data showing a cardioprotective effect and a benefit on bone mineral density support a longer duration of use. The main questions that have arisen include the following:
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Is HRT safe to use?
- For how long a period can it be safely used?
- When should therapy begin?
- Who should receive HRT?
Because of the possible role that estrogen plays in the pathogenesis of breast and other cancers, its use for postmenopausal therapy has been challenged. As this article will show, HRT is still a safe option for many women, and our goal as clinicians should be to help identify those women who will benefit most from it. This article also will review alternative therapies that have emerged in response to the controversy surrounding hormone replacement. The needs and treatment options for the breast cancer survivor in particular will be addressed.
HRT and Cardiovascular Disease
Cardiovascular disease is the leading cause of noncancer death in postmenopausal women (Figure 1).[1] In Caucasian women 50 to 94 years old, the cumulative risk of death from coronary artery disease is 31%, as compared with a 2.8% risk of death from breast cancer or osteoporosis. These data underscore the need to address cardiovascular and fracture risk in postmenopausal women. Ideally, those at risk should be identified during their reproductive years.
A number of studies have evaluated the role of HRT in the prevention of cardiovascular disease. The cardioprotective mechanism of this therapy is not well elucidated but is postulated to relate to its effects on lipid accumulation in arterial walls, promotion of blood flow, and modulation of vascular responsiveness.
The Nurses’ Health Study,[2] conducted by Grodstein et al from 1976 to 1992, examined the association between hormone replacement and the risk of cardiovascular disease, breast cancer, colorectal cancer, and overall mortality.[2-5] The study followed 59,337 women (age, 30 to 55 years at study entry) for 16 years.
This study showed a significant decrease in cardiovascular disease risk among current users of HRT (Figure 2), with a relative risk (RR) of 0.60 (95% confidence interval [CI], 0.43 to 0.78); the greatest benefit was seen among users of estrogen alone (RR, 0.39; 95% CI, 0.19 to 0.78).[2] The apparent benefit disappeared within 5 years after discontinuation of therapy (Table 1).
In a subsequent publication, Grodstein et al[3] evaluated the relationship between HRT and mortality. Current hormone use was associated with the lowest risk of death (RR, 0.63; 95% CI, 0.56 to 0.70), and this benefit appeared to diminish after 10 or more years of use. This was attributable primarily to a 43% increase in death due to breast cancer (RR, 1.43; 95% CI, 0.82 to 2.48). Those women with cardiac risk factors had the largest reduction in mortality (RR, 0.51; 95% CI, 0.45 to 0.57).
The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial[6] was designed to compare the effects of placebo, unopposed estrogen, and three combination hormonal regimens on selected cardiac risk factors. All of the active regimens had a positive effect on lipid profiles. Unopposed estrogen was the most effective regimen but carried an unacceptably high risk of endometrial hyperplasia (34%, vs 1% with combination therapy), limiting its use to women without a uterus. Micronized progesterone(Drug information on progesterone) had the greatest effect on lipids. The overall findings estimated a 40% to 50% reduction in cardiac deaths.
Most recently, the results of a study evaluating the role of estrogens(Drug information on estrogens) in the secondary prevention of cardiac disease were published.[7] The investigators concluded that, in individuals with already established coronary artery disease, HRT posed an increased risk of thromboembolic disease (RR, 2.89; 95% CI, 1.50 to 5.58) and gallbladder disease (RR, 1.38; 95% CI, 1.00 to 1.92). The hormone-treated group experienced an 11% decrease in low-density lipoprotein cholesterol and a 10% increase in high-density lipoprotein cholesterol. Despite this effect, the hormone-treated patients exhibited a 50% increase in the rate of myocardial infarction during the first year of the trial. This group had a 40% decreased rate of myocardial infarction during the last 2 years of the trial, suggesting that the positive effect of estrogen on cardiovascular disease is delayed even when lipid profiles are improved.
This study had many limitations. The investigators did not follow patients enrolled in the latter part of the study period long enough to show an effect. (Mean follow-up was 4.1 years.) Moreover, no patients were taking unopposed estrogen, and medroxyprogesterone(Drug information on medroxyprogesterone) acetate was the only progestational agent studied. These data underscore the need for other treatments and lifestyle alterations, with or without HRT.
HRT and Cardiovascular Disease
Hormone replacement therapy also has been shown to be effective in the prevention and treatment of osteoporosis—a condition that is still largely underdiagnosed. The data point to the need to address fracture risk and its attendant morbidity in the postmenopausal patient and, ideally, to identify those who are at risk even during their reproductive years.
The PEPI trial also assessed the effect of hormone replacement on bone mineral density, and concluded that women assigned to placebo had a significantly lower spine and hip bone mineral density than those in the active treatment groups.[8] Medroxyprogesterone acetate was more effective than micronized progesterone in increasing bone mineral density. (Bone mineral density was up to 5% higher in the spine with medroxyprogesterone vs 3.8% with other regimens.)
The Rancho Bernardo Study[9] addressed the optimal timing of hormone replacement for maximizing bone mineral density. This study concluded that estrogen therapy instituted at any time is beneficial, but that the greatest benefit occurs when therapy is started at the onset of menopause and continued indefinitely. Women who used estrogen, even for more than 10 years, and discontinued therapy did not maintain their protection. Among current hormone users, there was no significant difference in bone mineral density between women who started taking estrogen at menopause and those who started it after 60 years of age.
HRT and Alzheimer’s Disease
Alzheimer’s disease is among the most common reasons for nursing home admissions. The disorder affects twice as many women as men, in part because of the longer life expectancy of women.
Kawas et al[10] performed the Baltimore Longitudinal Study of Aging, a prospective, multidisciplinary study of normal aging. The sample consisted of 472 postmenopausal or perimenopausal women followed for up to 16 years. Current or ever-users of estrogen were considered “users.” The findings showed that 45% of the women in the cohort had used estrogen replacement therapy. There were 34 incident cases of Alzheimer’s disease, 9 of which occurred in estrogen users. The calculated RR for Alzheimer’s disease in estrogen users as compared to nonusers was 0.46 (95% CI, 0.209 to 0.997), supporting a protective effect of estrogen.
HRT and Colon Cancer
At least 18 published epidemiologic studies have examined the relationship between HRT and colon cancer.[11] Of these studies, 12 suggested an inverse association between colon cancer risk and hormone use, with an RR usually in the 0.4 to 0.8 range. In a study by Calle et al,[12] the greatest reduction in risk was seen in current estrogen users (RR, 0.55; 95% CI, 0.40 to 0.76) and with longer duration of use (P = .0001). The mechanism by which estrogen protects against colon cancer is thought to be mediated through a decrease in bile acid concentration and effects at the molecular level.
HRT and Vasomotor Symptoms
Hot flashes are experienced by 85% of postmenopausal women in western countries and may begin in the perimenopausal period when gonadotropin levels are fluctuating. The mechanism by which vasomotor flashes occur has not been well elucidated, but they are associated with changes in core temperature and coincide with luteinizing hormone surges.
Vasomotor symptoms are usually self-limited, dying out by 2 to 3 years after menopause. In the interim, however, these symptoms can be debilitating. Hormones can relieve vasomotor symptoms in up to 90% of women.
HRT and Breast Cancer
Although hormone replacement appears to have many benefits, there is growing concern that long-term use may be associated with breast cancer development. Current attention by the media has served only to increase this fear.
The following findings support an association between estrogens and breast cancer:[13,14]
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Oophorectomy has been shown to protect against the occurrence of breast cancer and to favorably alter its prognosis.
- The presence of estrogen receptors affects prognosis.
- Antiestrogens are used in the treatment of breast cancer
- In vitro and in vivo studies have shown that estrogens have a mitogenic effect on breast epithelial cells.
Estrogens have been postulated to act as growth factors, through initiation of mutations, and as promoters and cocarcinogens.[15]
The Nurses’ Health Study concluded that the RR of breast cancer was 1.32 (95% CI, 1.14 to 1.54) in the estrogen-only group and 1.41 (95% CI, 1.15 to 1.74) in the combination therapy group.[4] With more than 5 years of use, the RR increased to 1.46 (95% CI, 1.20-1.74; Table 2). Past users or those with less than 5 years of use showed risks similar to never-users, with the exception of women over the age of 55 years (Figure 3).
Stanford et al[16] evaluated breast cancer risk in a population-based case-control study that involved 537 breast cancer patients and 492 controls. Hormone replacement therapy had been used by 57.6% of the breast cancer patients and 61% of controls—a negative finding.
The Collaborative Group on Hormonal Factors in Breast Cancer[17] provided perhaps the most informative data but was limited by the problems inherent in a meta-analysis. The collaborative group reviewed approximately 90% of the worldwide epidemiologic evidence on the relationship between breast cancer risk and HRT. As shown in
Figure 4, this meta-analysis showed that breast cancer risk appears to increase after 15 or more years of use (RR, 1.58). Current users were at greatest risk, and the risk was reversed 5 or more years after discontinuation of therapy. The increase of 2.3% per year of use is comparable to the 2.8% per year increase in risk for each year that menopause is delayed (assumed average onset of menopause is 51 years).
The epidemiologists from the Nurses’ Health Study[18] also performed a meta-analysis of 25 case-control and six cohort studies. They concluded that ever-use of estrogen carried no increased risk, and current use was associated with an increased risk, which was reversed 2 years after discontinuation of therapy.
