Postmenopausal Hormone Therapy and Quality of Life: Title and subTitle BreakNo Cause for Celebration

Despite the common perception that postmenopausal hormone therapy improves quality of life in women, few randomized clinical trials have addressed this issue. Moreover, the high rates of discontinuation of hormone therapy in the first few years of use in both observational studies^{1 - 2} and randomized trials³ cast doubt on this assumption. The study by Hlatky et al⁴ in this issue of THE JOURNAL presents important and intriguing data regarding hormone therapy and quality of life that were previously lacking. This report is particularly informative because the investigators stratify their results according to the presence or absence of vasomotor flushing symptoms at baseline.

Hlatky et al compared the effect of hormone therapy vs placebo on quality-of-life parameters among women in the Heart Estrogen/Progestin Replacement Study (HERS) trial, a randomized clinical trial of combined conjugated equine estrogens and medroxyprogesterone acetate among women with pre-existing coronary heart disease. Women who received hormone therapy rather than placebo had larger declines in physical function and a trend toward increased symptoms of fatigue, but they experienced an improvement in depressive symptoms. Most women (84.3%) did not have vasomotor flushing symptoms at baseline; among these women there were greater declines in physical function and energy with hormone therapy than placebo while no changes were noted for mental health or depressive symptoms. Although baseline quality-of-life parameters were worse among 15.7% of women who reported vasomotor flushing, hormone therapy in these women was associated with improvement in mental health and reduction in depressive symptoms without significant effects on physical function or energy level.

The fact that hormone therapy improves menopausal symptoms, such as hot flashes, quality of life among symptomatic women is not a new or unexpected finding; prior studies have consistently reported benefit for women who experience symptoms.⁵ Thus, this report's primary contribution is that the majority of women without vasomotor symptoms at baseline experienced a decrease in physical function and no improvement in mental health with hormone therapy. Although not specifically addressed by the investigators, the greater decline in physical function among women treated with hormone therapy compared with placebo may well have been due to the increased rates of cardiovascular events associated with hormone therapy, especially during the first year of the HERS trial.³ Improvement in mental health and depressive symptoms in women who received hormone therapy was confined to those with menopausal symptoms at baseline.

The study by Hlatky et al provides additional evidence that hormone therapy may have an unfavorable benefit/risk ratio among older women who have cardiovascular disease. Among women with established cardiovascular disease, randomized trials do not suggest overall benefit and raise the possibility of harm. The HERS trial^{3 ,6} found no reduction in the risk of coronary events and decreased event-free survival with 4 years of therapy among women randomly assigned to receive combined estrogen and progesterone. Similarly, in the Estrogen Replacement and Atherosclerosis Trial,⁷ angiographic progression of atherosclerosis was not reduced by treatment with either estrogen alone or combined estrogen and progesterone. The Women's Estrogen for Stroke Trial⁸ found no benefit on total stroke incidence and an increased risk of fatal stroke among women with prior ischemic stroke who were assigned to estradiol therapy. An increase in cardiovascular events with estradiol was also suggested by the Papworth Trial.⁹ Additionally, among women with established cardiovascular disease in HERS, the risk of venous thromboembolism was increased nearly 3-fold¹⁰ and the risk of gallbladder disease was increased by 40%¹¹ among women randomly assigned to receive active hormone therapy. Thus, for women with cardiovascular disease, the lack of benefit on quality-of-life outcomes in addition to the increased risks of cardiovascular disease, venous thromboembolism, and gallbladder disease would suggest that the risks outweigh the benefits, especially since there are several other options for preventing osteoporosis.¹²

The implications of the study by Hlatky et al for primary prevention are less clear. Whether these quality-of-life results will be replicated in primary prevention trials, such as the Women's Health Initiative (WHI), is of immense interest. The WHI has collected detailed information on mental health, fatigue, and physical function and will examine the effects of estrogen alone as well as combined estrogen and progestin on these parameters over a longer period (8-9 years) in a more representative and diverse study population with a broader range of age groups than those in other published randomized trials. With regard to other health outcomes, although observational studies have found a consistent 35% to 50% reduction in the risk of coronary heart disease among women who use hormone therapy,^{13 - 14} randomized trial evidence from a meta-analysis of small clinical trials¹⁵ and from the WHI¹⁶ suggests a small increase in the risk of cardiovascular events, especially in the first 2 years of therapy. In light of the secondary prevention trials, the potential benefits of hormone therapy for cardiovascular disease prevention seem at best unproven. In addition to increased risk of venothromboembolism and gallbladder disease, an increased risk of breast cancer, especially with duration of hormone therapy use for 5 years or more has been reported.¹⁷ Although hormone therapy has proven benefits on bone density,¹⁸ other therapies are available for prevention and treatment of osteoporosis. Prior analyses suggesting that hormone therapy was likely to prolong life for women¹⁹ relied heavily on the expected cardiovascular benefits, which now seem much less certain.

How then, should clinicians help patients place these data in perspective? Physicians need to counsel patients to have realistic expectations about the benefits and risks associated with hormone therapy, as well as an appreciation of the uncertainties. For short-term treatment of menopausal symptoms, hormone therapy has been proven effective and improves quality of life⁴ although there may be increased risk of venous thromboembolism, gallbladder disease, and an early increased risk of cardiovascular events. Hormone therapy should not be prescribed for the express purpose of preventing cardiovascular disease, and decision making should be based on noncoronary benefits and risks. Focusing on other proven cardiovascular disease prevention strategies, such as control of lipid levels and blood pressure and promotion of a healthful lifestyle, is more likely to confer benefit and avoid harm in most patients. For women at increased risk of osteoporosis, hormone therapy must be weighed against other potential treatments. Thus, the study by Hlatky et al, which shows no benefit of hormone therapy on quality-of-life parameters, only strengthens the clinical recommendations^{12 ,20} that hormone therapy should be avoided or considered only as a secondary option among women with coronary heart disease.

Several areas remain unresolved and could not be addressed in the study by Hlatky et al. First, as the authors point out, the HERS study was a secondary prevention trial among women who were generally older (mean age 67 years), an age at which hot flashes are relatively uncommon. The effects of hormone therapy on quality of life, risk of cardiovascular events, and other outcomes among younger women and those without prior cardiovascular disease are less clear. Second, the HERS trial tested only a combined regimen of conjugated equine estrogens and medroxyprogesterone acetate. Although this is the most commonly used hormone therapy regimen among US women who have an intact uterus, it remains unknown whether estrogen alone, other formulations, or routes of administration of estrogen and progestin will have the same effects on quality-of-life measures and disease outcomes. In the meantime, the study by Hlatky et al⁴ should challenge the widely held belief that hormone therapy helps women remain more youthful, active, or vibrant. Future randomized studies of hormone therapy should include quality-of-life assessment and provide additional data on this important outcome.