It is highly likely that women aged 60 to 90 have vivid memories of the astonishing healthcare news from 2002 when the Women's Health Initiative (WHI), a comprehensive long-term national health study, was abruptly terminated earlier than expected. The initial trial results sent shockwaves through the medical community and had a profound impact on the lives of numerous women. Furthermore, this news fundamentally transformed the perception of routine menopausal hormone replacement prescriptions for years to follow.
The WHI was launched in 1991 as a 15-year trial, one of the largest women’s health studies in the United States, enrolling more than 161,000 women at 40 clinical centers. The WHI included trials designed to examine the effects of the current postmenopausal hormone replacement therapy (HRT), physical activity, diet modification, and calcium with vitamin D supplements on heart disease, bone fractures, breast, and colorectal cancer. These were all major causes of disability, frailty and in some cases death, for women of all races and socioeconomic backgrounds. The WHI hormone clinical trial consisted of two studies, one which looked at the effect of hormone therapy (HT) on the prevention of heart disease and osteoporosis and a separate study that looked at HT and its associated risk of breast cancer. The HT used in the two studies are described below (1):
- Estrogen-plus-progestin study of women with a uterus – Premarin® (oral 0.625 mg) plus Provera® (oral 2.5 mg) or placebo (inactive pill)
- Estrogen-alone study of women without a uterus - (Premarin (oral 0.625 mg) or placebo (inactive pill)
However, the estrogen plus progestin study was abruptly halted in July 2002 due to perceived evidence of an increased risk of breast cancer, coronary heart disease, stroke and pulmonary embolism. The unopposed estrogen-only trial was halted in February 2004 on the basis that unopposed estrogen did not appear to affect the risk of heart disease, the primary outcome. However, the estrogen-only trial did show a decrease in breast cancer risk (2).
The difference between the two studies is interesting in that the estrogen-plus-progestin study used Provera, (medroxyprogesterone acetate or MPA), a synthetic progestin, instead of bioidentical progesterone. While Provera has an antiproliferative effect on the endometrium as does progesterone, a 2008 review article reported MPA is different from progesterone in its effects on the cardiovascular system. MPA increases vasoconstriction of arteries and results in impaired endothelial function, both of which contribute to cardiovascular disease (3). Progesterone, meanwhile, has been found to have vasodilating effects and has been used for myocardial infarction and post-stroke care (4, 5).
The average age of menopause usually begins around age 51 but may occur earlier or later. Each year thousands of women enter the phase of aging called menopause, including surgical menopause, resulting in the natural decline or abrupt interruption of estrogen being produced by the ovaries. With the subsequent lack of estrogen women commonly experience a myriad of symptoms including hot flashes, night sweats, brain fog, mood swings, sleep disruption, vaginal dryness, and low libido. These symptoms often profoundly alter the quality of a woman’s life, disrupting a previously normal existence and/or work routine. The menopausal transition can last for months to several years. However, hope for relief from women’s symptoms was in sight with the FDA patent approval in 1943 of a Wyeth-Ayerst pharmaceutical product, Premarin.
Premarin was the first conjugated estrogen, formulated from pregnant mares’ urine as a menopausal “estrogen replacement therapy (ERT)” (6). Although a couple of early articles published indicated an increased risk of endometrial cancer with prolonged use of ERT, in 1986 the FDA announced that Premarin was effective for preventing bone loss and granted an osteoporosis indication. Suddenly, the view of estrogen as a “short-term treatment for menopause, was the treatment of choice for bone loss, a long-term, chronic problem” (7). In the 1990s Premarin became the most frequently prescribed drug in the US with more than 30 million prescriptions written (8).
However, due to the conclusions drawn from the WHI study, women, as well as medical professionals, became fearful of using and prescribing estrogen. As a result, Premarin prescriptions dropped dramatically as medical professional declined to refill prescriptions for Premarin or estrogen in general. Many women just ceased taking their Premarin, for fear of breast cancer, with the subsequent return of menopausal symptoms disrupting their lives. Hormone prescriptions for women approaching menopause were also questioned.
With the ensuing reviews of the WHI data, researchers found there were some misleading claims. The age of a woman when starting hormone replacement was found to be more significant than use of the hormone themselves. “A Bayesian meta-analysis of women receiving HT who were under 60 years old, showed a statistically significant reduction in coronary disease” (9). There was also a statistical decrease in mortality, of all causes, in women beginning hormones 10 years or less before menopause. More recent analyses of WHI data regarding HT and breast cancer risk “…is greater in older rather than younger women…” The timing hypothesis that was constructed from the WHI HT trial and other data “suggested that the younger the women were in the trial, the more they showed benefit” (9).
In the years following the WHI report, medical professionals and women began reconsidering hormone replacement, but with a difference. More attention has been given as to the timing hormones are initiated, the length of time HT is used, as well as the type of hormone delivery, oral or transdermal, delivered in a patch or topical cream. Most of the estrogen now on the manufactured, pharmaceutical market are all bioidentical. Bioidentical progesterone manufactured product Prometrium® also became available as a generic and compounding pharmacies flourished as doctors and pharmacists sought to individualize treatments for women’s menopausal symptoms.
The previously prescribed, pharmaceutically derived Premarin and Provera used in the WHI study have largely been replaced with bioidentical hormones, both in pharmaceutical estrogen preparations and those made up specifically for an individual by a specialized, compounding pharmacy. Bioidentical hormones are defined as hormones with the same molecular structure as the body’s own biologic hormones. Many medical professionals view compounded bioidentical hormones as a safer option for their patients, compared to the pharmaceutical counterparts. While there needs to be more research for the safety of bioidentical hormone use, they continue to be prescribed for menopausal symptom relief with good results.
- National Heart, Lung and Blood Institute. National Institutes of Health. U.S. Department of Health and Human Services. Women’s Health Initiative. 1991.
- Wikipedia contributors. Women’s Health Initiative. Wikipedia, The Free Encyclopedia. April 26, 2023, 16:40 UTC. Accessed May 19, 2023.
- Hermsmeyer RK, Thompson TL, Pohost GM, et al. Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity? Nat Clin Pract Cardiovasc Med. 2008;5(7):387-395.
- Kaemmle LM, Stadler A, Janka H, et al. The impact of micronized progesterone on cardiovascular events - a systematic review. Climateric. 2022;25(4):327-336.
- Gouennoun R. Progesterone in the brain: hormone, neurosteroid and neuroprotectant. Int J Mol Sci. 2020;21(15):5271.
- Allin J. Trace the history of Premarin with this revealing timeline. Tuesday's Horse. Fund for Horses. March 5, 2012.
- MacLennan WJ. Osteoporosis. Br Med Bull. 1990;46(1):94-112.
- Kling J. The Strange Case of Premarin. Mod Drug Discov. 2000;3(8):46-52,
- Lobo RA. Where are we 10 years after the Women's Health Initiative? J Clin Endocrinol Metab. 2013;98(5):17711780.