Five Decades of Hormone Therapy Research: The Long, the Short, and the Inconclusive

Abstract

The symptom burden of midlife ovarian senescence and its impact on physical, emotional, and sexual well-being has long been perceived as disruptive to the personal, social, and professional aspirations of postmenopausal women. Low serum estrogen levels prevailing after menopause have also been associated with accelerated aging of tissues and organs, particularly the skeletal and cardiovascular systems [1, 2]. With the triumphant development of the oral contraceptive pill in 1960 [3], hope grew that biological challenges unique to the female post-reproductive years can too be conquered with the use of synthetic sex steroids. This hope was stoked as well by Wilson’s negative portrayal of the menopause as an “estrogen deficiency state” which “must be replaced” to avoid the “tragedy” and “decay” of menopause [4, 5]. Within a decade of Wilson’s influential assertions, the number of menopausal women who had taken up long-term estrogen therapy had soared [6]. Few years later, a significant body of observational data would demonstrate that such menopausal hormone therapy (MHT) is not only effective for control of troublesome symptoms but may also have benefits for the prevention of chronic diseases commonly associated with female aging [7–9]. The promise that a pill may improve life’s quality, and possibly its quantity, by increasing the odds of avoiding a heart attack or a hip fracture captured the attention of tens of millions of menopausal women whose ranks in the USA were growing rapidly as the baby boom generation matured. The promise of MHT also captured the attention of employers and the insurance industry who have a perennial interest in workforce wellness and of the pharmaceutical industry who saw a tremendous opportunity for growth. In 1991, the 102nd US Congress got involved as well, passing the Women’s Health Equity Act of 1991 [10]. While this act failed to become law, significant portions of it were ultimately included in the NIH Revitalization Act of 1993 which did become law, appropriating significant resources for women’s health research [11]. This confluence of public and private interests set the stage for accelerated investigation in menopausal medicine, including federally funded research developed and coordinated by the newly minted Office of Women’s Health at the National Institutes of Health (NIH). With cancer, heart disease, and osteoporosis as the leading causes of death, disability, and impaired quality of life in older women, the NIH launched in 1993 a landmark 15-year effort, the Women’s Health Initiative (WHI), to study these matters with scientific rigor. The role of MHT figured prominently in this effort with the inclusion of two long-term prospective randomized controlled trials (RCTs) – the WHI estrogen and progesterone (WHI-EP) and the WHI estrogen (WHI-E)-alone hormone trials. The publication of results in 2002 and 2004 of these WHI hormone trials formed a watershed event with worldwide changes in clinical practice and social attitudes toward acceptance of MHT. The WHI results inspired not only new and innovative MHT research but also a second look at existing MHT data that had predated WHI. This chapter summarizes five decades of MHT research in chronological order and highlights trends in clinical practice which swayed the research agenda and in turn were influenced by the results.