Health & Medical Menopause health

Hormone Therapy and Risk of Cardiovascular Events in Women

Hormone Therapy and Risk of Cardiovascular Events in Women

Abstract and Introduction


Objective. Research comparing hormone therapy (HT) doses, regimens, and routes of delivery in relation to cardiovascular disease (CVD) outcomes has been limited. This study directly compared different estrogen doses, routes of delivery, and HT formulations in postmenopausal women in relation to the risk of coronary heart disease (CHD), stroke, CVD mortality, total CVD, and all-cause mortality.

Methods. The Women’s Health Initiative Observational Study is a multicenter prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50 to 79 years at study entry who were recruited from September 1994 to December 1998, with annual follow-up through August 14, 2009.

Results. The mean follow-up was 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR, 0.64; 95% CI, 0.40-1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but nonsignificantly lower risk of CHD compared with oral CEE (HR, 0.63; 95% CI, 0.37-1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women.

Conclusions. In direct comparisons, various HT doses and regimens are associated with similar rates of cardiovascular events and all-cause mortality. However, oral estradiol may be associated with a lower risk of stroke, and transdermal estradiol may be associated with a lower risk of CHD, compared with conventional-dose oral CEE. Additional research is needed to confirm these hypotheses.


The Women’s Health Initiative clinical trial (WHI-CT) of oral estrogen plus progestin was stopped in 2002 (3 y earlier than planned) owing to an unfavorable balance of health benefits and risks when hormone therapy (HT) was used to prevent chronic disease. The Women’s Health Initiative (WHI) estrogen-alone trial also failed to demonstrate that treatment benefits exceeded risks under these conditions. The HT prescribing guidelines of several professional organizations were revised to recommend the lowest effective HT dose for the shortest duration of time primarily for vasomotor symptom management rather than for chronic disease prevention. As women continue to use HT for symptom management, the comparative safety of lower estrogen dosing, different formulations, and alternative routes of delivery with regard to cardiovascular disease (CVD) outcomes deserves further study. New lower-dose estrogens that can be administered orally or transdermally are now available and being increasingly used, but research on these regimens has been limited. Randomized clinical trial comparisons of differing HT regimens and clinical CVD outcomes are not available. In addition, previous observational studies have not been large enough or have not collected sufficiently detailed histories of HT use to provide head-to-head comparisons of different estrogen doses, formulations, and routes of delivery with respect to CVD events.

Hypothetically, lower-dose estrogen HT could be safer owing to lower dose-related adverse CVD effects. Furthermore, transdermal HT delivery avoids "first-pass" liver metabolism, which increases serum coagulation factors, triglycerides, C-reactive protein, and a host of other factors; it also provides a more physiologic ratio of estradiol to estrone. The health effects of the addition of progestogens, used in combination HT for women with intact uterus, have only recently been compared with estrogen alone with respect to coronary heart disease (CHD), stroke, and other health outcomes. For example, CVD outcomes from the WHI estrogen-alone trial showed no increased risk of myocardial infarction, whereas the WHI-CT of estrogen plus progestin demonstrated an overall increase in CVD risk. This has led to speculation that the addition of a progestational agent to HT is a contributing factor for CVD risk.

Although both synthetic and bioidentical estrogens are effective for treating vasomotor symptoms, there are no data comparing these formulations in relation to CVD outcomes. Conjugated equine estrogens (CEE) have a complex composition with multiple biologically active estrogens and related steroids: estrone sulfate is believed to be the major active component. Whether there are differences in CVD outcomes related to CEE versus estradiol—possibly related to differences in pharmacodynamic estrogen receptor affinity, metabolism, or other variables—has been suggested but has not been well explored.

Several studies have demonstrated an elevated risk of CVD within the first 1 to 2 years of HT initiation. Although we updated HT use during follow-up, the observational nature of the present study did not allow for a detailed examination of this relationship because many women had long-term use before enrollment. We did not include nonusers of HT in our analyses because of known confounding factors that influence the decision to use HT and because our analyses were intended to offer insight into how alternative HT formulations compare with conventional-dose oral CEE on CVD outcomes. Using data from the large-scale Women’s Health Initiative Observational Study (WHI-OS) of 93,676 postmenopausal women, we performed direct comparisons between different estrogen doses, formulations, and routes of delivery, as well as the risks of major CHD, stroke, CVD mortality, total CVD (major CHD, stroke, and CVD mortality), and all-cause mortality. Furthermore, we analyzed the results by time since menopause (<10 vs ≥10 y since menopause onset) and duration of HT use (<5 vs ≥5 y) to determine whether the results varied by these factors.

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