During the menopausal transition, there is a natural diminution of the sex hormones estrogen and progesterone. Hormone replacement therapy (HRT), or hormone therapy (HT), is a medical treatment for symptoms related to the menopause and the menopausal transition. Clinically, HT has also been administered to protect against disorders such as osteoporosis and atherosclerotic cardiovascular disease (CVD). However, recent studies have cast doubt on the protective effect of HT and have identified risks involved with its use.
Menopause is the permanent cessation of menstruation due to the loss of ovarian follicular function. The perimenopause refers to the time period immediately preceding menopause when fertility wanes and menstrual cycle irregularity increases. This period continues until 12 months after cessation of menses, at which time the woman is considered menopausal. The mean duration of the perimenopause is 4 years, while signs consistent with the perimenopause may precede the final menses by 2 to 8 years.
There is strong evidence that the transition to menopause is associated with vasomotor symptoms (hot flashes and night sweats). For instance, in one U.S. study, nearly 60% of women reported hot flashes in the 2 years before their final menses. There is also reasonable evidence that this period can cause sleep disturbances in some women. However, there is inconclusive or insufficient evidence that a decrease in ovarian mass is the major cause of mood swings, depression, impaired memory and the ability to concentrate, somatic symptoms, urinary incontinence, or sexual dysfunction. Notably, symptom intensity, duration, frequency, and effects on quality of life are highly variable.
The decision to use postmenopausal HT for the treatment of the symptoms and conditions listed above is complicated. Although many women rely on their health care providers for a definitive answer to the question of whether to use postmenopausal hormones, balancing the benefits and risks for an individual patient is challenging, especially when the individual risk for HT-associated morbidity cannot be precisely quantitated. Despite this context and until the earlier years after the turn of the 20th century, many were prescribed HT as a means of alleviating vasomotor symptoms, for which its effectiveness has been well demonstrated. However, HT was increasingly promoted as a potential preventive strategy against disorders that accelerate after menopause, such as osteoporosis and atherosclerotic CVD.
These positions were based on results primarily from observational cohort studies. Although previous observational studies suggest that HT prevents cardiovascular and other chronic diseases, some of the apparent benefits may have resulted from differences between women who opt to take postmenopausal hormones and women who do not. Specifically, in these observational studies, those using HT tended to be healthier, have greater access to medical care, were more compliant with prescribed treatments, and maintained a more health-promoting lifestyle. On the other hand, randomized trials, which eliminate these confounding factors, have not consistently confirmed the benefits found in observational studies. For example, by enrolling more than 27,000 women from 50 to 70 years of age (mean age: 63 years), the Women’s Health Initiative (WHI) was the largest randomized clinical trial of both estrogen-progestin and estrogenalone postmenopausal hormone therapies. After a follow-up period of 5 to 7 years, both WHI hormone trials were stopped early because of an overall unfavorable risk-benefit ratio in the estrogen-progestin arm and an excess risk of stroke that was not offset by a reduced risk of coronary heart disease in the estrogen-only arm. Thus, recent clinical trials have raised doubts about the use of HT for prevention of chronic diseases, especially when initiated more than a decade past menopause.
Against this background and based on a synthesis of currently available evidence, the following summary of the risks and benefits of postmenopausal hormone therapy is provided.
A summary of benefits and risks of postmenopausal HT in primary prevention studies in provided in Table 1.
There is compelling clinical trial and observational study evidence that estrogen therapy is highly effective for controlling vasomotor and genitourinary symptoms. Although they are less effective than HT, alternative therapies such as antidepressants, gabapentin, clonidine, or vitamin E or the consumption of soy-based products/phytoestrogens may also alleviate vasomotor symptoms. For genitourinary symptoms, the efficacy of vaginal estrogen is similar to that of oral or transdermal estrogen.
Estrogen slows the aging-related bone loss experienced by most postmenopausal women by reducing bone turnover and resorption rates. More than 50 randomized trials have demonstrated that postmenopausal estrogen therapy, with or without a progestogen, rapidly increases bone mineral density at the spine by 4% to 6% and at the hip by 2% to 3%. These increases are maintained during treatment.
Data from observational studies indicate a 50% to 80% lower risk of incident vertebral fracture and a 25% to 30% lower risk of hip, wrist, and other peripheral fractures among current estrogen users. In the WHI, 5 to 7 years of either combined estrogenprogestin or estrogen-only therapy was associated with a 30% to 40% reduction in hip fracture and 20% to 30% fewer total fractures among a population unselected for osteoporosis. Like estrogen therapy, bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM), have each been shown in randomized trials to increase bone mass density and decrease fracture rates. Similarly, a recently available option for treatment of osteoporosis is parathyroid hormone. Unlike estrogen therapy that is not combined with a progestin, the bisphosphonates, SERMs, and parathyroid hormone analogs do not appear to have adverse effects on the endometrium and may therefore be considered in women with a uterus. Increased physical activity and adequate calcium (1,000 to 1,500 mg/day through diet or supplements in two to three divided doses) and vitamin D (400 to 800 IU/day) intakes may also reduce the risk of osteoporosis-related fractures and should serve as first-line options for the prevention of declines in bone mineral density and associated fractures.
Results from a combined analysis of 30 observational studies indicate a tripling of risk for endometrial cancer among short-term (1 to 5 years) users of unopposed estrogen, while those who with use for ≥10 years had a nearly 10-fold higher risk. These findings are supported by results from the randomized Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. In PEPI, 24% of women assigned to unopposed estrogen for 3 years developed premalignant endometrial hyperplasia, whereas only 1% of women assigned to placebo were found to have this condition. Notably, the concomitant use of a progestogen eliminates these risks.
A meta-analysis of 12 studies of differing design found that current estrogen use was associated with a doubling of risk for venous thromboembolism in postmenopausal women. The relative risks were even greater (2.7 to 5.1) in the three clinical trials included in this analysis. Similarly, in the WHI clinical trials of postmenopausal women, there was a doubling of risk for the combined endpoint of venous and pulmonary thromboembolism among those in the estrogenprogestin arm, while those in the estrogen-only arm had a one-third higher risk for thromboembolism.
In contrast to findings for endometrial cancer, combined estrogen-progestin regimens appear to increase breast cancer risk more than estrogen alone. Furthermore, the increased risk of breast cancer among current or recent estrogen users is likely related directly to duration of use. For example, a meta-analysis of 51 case-control and cohort studies revealed that shortterm use (< 5 years) of postmenopausal HT did not appreciably elevate breast cancer incidence, whereas long-term use (≥ 5 years) was associated with a 35% increase in risk.
Data from randomized trials also indicate that estrogen-progestin raises breast cancer risk. Results from the WHI indicate that over 5.6 years of followup, women assigned to the estrogen-progestin arm were 24% more likely to develop breast cancer than women assigned to placebo. Similarly, in the Heart and Estrogen/Progestin Replacement Study (HERS), 4 years of combination therapy was associated with a 27% increase in breast cancer risk. Although the latter finding was not statistically significant, the totality of evidence strongly implicates estrogen-progestin therapy in breast carcinogenesis. Conversely, over an average of 7.1 years of follow-up, those in the estrogen-only arm of the WHI did not experience an increased risk for breast cancer.
Large observational studies report a two- to threefold increased risk of gallstones or cholecystectomy among postmenopausal women taking oral estrogen. In the WHI, women randomized to estrogen-progestin or estrogen alone had a 67% and 93% greater risk, respectively, of undergoing cholecystectomy than those assigned to placebo. Increased risks were also observed in HERS.
On the basis of multiple observational studies demonstrating a benefit of hormone therapy, HT had, until recently, been enthusiastically recommended in the prevention of CVD. The biologic plausibility of such an association is supported by data demonstrating that exogenous estrogen has beneficial effects on both lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels. Administration of estrogen also favorably affects lipoprotein(a) levels, LDL oxidation, endothelial vascular function, and fibrinogen and plasminogen activator inhibitor-1. However, estrogen therapy raises both triglyceride and C-reactive protein levels and adversely affects several markers of thrombosis. In addition, estrogen may increase levels of matrix metalloproteinases, which have been implicated in the rupture of atherosclerotic plaques. Hence, the data on risk factors for CVD are inconclusive.
Randomized trials of estrogen or combined estrogen-progestin in women with preexisting CVD have not confirmed the benefits reported in observational studies. In HERS, a secondary prevention trial designed to test the efficacy and safety of estrogenprogestin therapy on clinical cardiovascular outcomes in high-risk women, the 4-year incidence of coronary mortality and nonfatal myocardial infarction was similar in the active treatment and placebo groups, and a 50% increase in risk of coronary events was noted during the first year of the study among participants assigned to the active treatment group. Moreover, in the Papworth Hormone Replacement Therapy Atherosclerosis Study, the Women’s Estrogen for Stroke Trial (WEST), and the Estrogen in the Prevention of Reinfarction Trial (ESPRIT), there were no cardiovascular benefits of the regimens studied. Thus, in clinical trials, HT has not proved effective for the secondary prevention of CVD in postmenopausal women.
Postmenopausal HT trials in women without preexisting CVD (primary prevention) also suggest an early increase in cardiovascular risk and absence of cardioprotection overall. In the WHI, women assigned to 5.6 years of estrogen-progestin therapy were 24% more likely to develop coronary heart disease and 31% more likely to suffer a stroke than those assigned to placebo. In the estrogen-only arm of the WHI, a similar increase in stroke and no effect on CHD were observed.
A closer look at available data suggests that timing of initiation of HT may influence the association between estrogen therapy and CHD. It is hypothesized that estrogen may have differential effects on clinical coronary events depending on stage of the atherosclerotic lesion. That is, estrogen may slow or even reverse progression in early stages of atherosclerosis but have adverse effects on advanced atherosclerotic lesions and vulnerable plaques. Specifically, the prothrombotic and proinflammatory effects of estrogen may manifest among women with subclinical lesions who initiate HT well after the menopausal transition, whereas women with minimal atherosclerotic disease who start HT early in menopause may derive cardiovascular benefit. Nonhuman primate data support this concept. Conjugated estrogens had no effect on the extent of coronary artery plaque in cynomolgus monkeys assigned to estrogen alone or combined with progestin starting 2 years (approximately 6 human years) after oophorectomy and well after the establishment of atherosclerosis. However, administration of exogenous hormones immediately after oophorectomy, during the early stages of atherosclerosis, reduced the extent of plaque by 70%.
Lending further credence to this hypothesis are results of subgroup analyses of observational and clinical trial data. For example, although there was no association between estrogen-only therapy and CHD in the overall WHI cohort, this therapy was associated with a CHD risk reduction of 37% among participants aged 50 to 59 years. In contrast, a risk reduction of only 8% was observed among those aged 60 to 69, and a risk increase of 11% was found among those aged 70 to 79. Due to the relatively small number of cases of myocardial infarction or coronary death, especially in the younger women, these intra- and inter-age-group differences were not statistically significant. However, when the definition of CHD was widened to include coronary bypass surgery or percutaneous coronary interventions, estrogen-only therapy was associated with a significant 45% reduction in CHD among women in the youngest age group. Furthermore, a meta-analysis of 30 trials with more than 26,000 subjects by Salpeter and colleagues found that HT was significantly associated with a 39% reduction in total mortality in those below 60 years of age. There was no association between HT and total mortality in those above the age of 60 years. Similarly, the risk for CVD mortality was 32% lower in those less than 60 years, but 11% higher in those above 60.
Clearly, further research is needed on age, time since menopause, and other clinical characteristics as well as on biomarkers that predict increases or decreases in cardiovascular risk associated with exogenous HT. Also, whether different doses, formulations, or routes of administration of HT will produce different cardiovascular effects remains uncertain.
Observational studies have suggested that HT reduces risks of colon and rectal cancer, although the estimated magnitudes of the relative benefits ranged from 8% to 34% in various meta-analyses. In the WHI, the sole trial to examine the issue, estrogenprogestin was associated with a significant 44% reduction in colorectal cancer over a 5.6-year period, although no benefit was seen with 7 years of estrogenonly therapy.
A meta-analysis of 10 case-control and 2 cohort studies suggested that postmenopausal HT is associated with a 34% decreased risk of dementia. Subsequent randomized trials, however, have failed to demonstrate any benefit of estrogen or estrogen-progestin therapy on the progression of mild to moderate Alzheimer’s disease. The WHI, which assessed cognitive function and incidence of dementia among women randomized to HT at age 65 or older, found no evidence of benefit and a suggestion of increased risk. Whether the discrepancies between observational studies and clinical trials are due to differences in age and time since menopause at HT initiation (as for CHD) remains uncertain.
Cancer; Cardiovascular Disease; Clinical Trials; Osteoporosis; Women’s Health Issues
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