What the Women's Health Initiative has taught us about menopausal hormone therapy

Abstract

Our understanding of the complex relationship between menopausal hormone therapy (MHT) and cardiovascular disease (CVD) risk has been informed by detailed analyses in the Women's Health Initiative (WHI), the largest randomized, placebo-controlled trial evaluating MHT in postmenopausal women. Although the WHI demonstrated increased risk of CVD events with MHT in the overall cohort, subsequent secondary analyses demonstrated that these risks were influenced by the woman's age and time since menopause, with lower absolute risks and hazard ratios for younger than older women. As MHT is the most effective treatment for the vasomotor symptoms of menopause, it is important to understand its risks and how to conduct risk stratification for symptomatic women. In addition to reviewing the WHI findings, studies pre- and post-WHI are reviewed to describe the relationship between MHT and CVD risk in menopausal women. The absolute risks of adverse cardiovascular events for MHT initiated in women close to menopause are low, and all-cause mortality effects are neutral or even favorable for younger menopausal women. The WHI has advanced and refined our understanding of the relationship between MHT and CVD risk. Although MHT should not be used for CVD prevention, absolute risks of CVD are low when MHT is started close to menopause in healthy women and hazard ratios tend to be lower for younger than older women. For women in early menopause and without contraindications to treatment, the benefits of MHT are likely to outweigh the risks when used for menopausal symptom management.

The role of bioidentical hormone replacement therapy in anti‐aging medicine: a review of the literature

“…Several studies have criticized the WHI for prematurely drawing conclusions on the safety profile of estrogen and progesterone replacement therapy among postmenopausal women . For example, the WHI published that HRT in postmenopausal women exhibited a significant increase in risk for cardiovascular disease (CVD); however, the study failed to recognize and highlight the influence of age and onset of menopause in this population of women.…”

“…For example, the WHI published that HRT in postmenopausal women exhibited a significant increase in risk for cardiovascular disease (CVD); however, the study failed to recognize and highlight the influence of age and onset of menopause in this population of women. A second analysis was conducted on the dataset and showed that CVD events with postmenopausal women on HRT were at significantly less risk than initially described, even suggesting that the risk of perimenopausal women on HRT had low risk of CVD events and all‐cause mortality was not increased . Furthermore, in response to the results shown by the WHI, two studies, KEEPS and ELITE, were published with the purpose of evaluating the HRT safety in early postmenopausal women.…”

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs

“…The usage of MHT was significantly affected, with reduced use of oral formulations [40] and an increase in transdermal MHT [41]. Nevertheless, it should be acknowledged that the previous observational studies were in younger participants, who largely had menopausal symptoms, which the majority in the WHI study did not, and the age of the WHI participants was older than the mean age of menopause in Europe or North America, 51 years [37].…”

“…The first phase (pre-2002) was characterised by the supposition that the benefits of MHT outweighed the risks, and it was widely used for prevention and treatment of menopausal symptoms. It was therefore one of the most prescribed medications at the time, peaking in 2001, with 40% of postmenopausal women using MHT [36,37]. Observational studies of the time suggested a potential benefit to cardiac health (with up to a 50% reduction in coronary heart disease).…”

Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis?

“…MHT was widely used in the 1980s and 1990s for the prevention of symptoms associated with the menopause, such as hot flushes, night sweats and sleep disturbance, with the widely prevailing view that prevention of cardiovascular disease and osteoporosis were additional benefits [7,8]. The rationale for such an approach was an evidence-base consisting principally of observational studies, in which the use of hormone replacement therapy (as it was known at that time) was associated with generally improved health outcomes, particularly in relation to cardiovascular disease.…”