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Initiative for Women’s Health: A Look Back
Women between the ages of 60 and 90 are likely to recall the 2002 healthcare news that shocked the nation: the abrupt end to the Women’s Health Initiative (WHI). Initial trial results shocked the medical community and altered the course of many women’s lives forever. Furthermore, the revelation permanently impacted how people viewed the common prescription for hormone replacement therapy for women experiencing menopause.
The Women’s Health Initiative (WHI) is a 15-year experiment that began in 1991 and is one of the largest studies of women’s health in the United States, having enrolled over 161,000 women at 40 clinical locations. Heart disease, bone fractures, breast cancer, and colorectal cancer were all studied in WHI-conducted trials of current HRT, exercise, dietary change, and supplemental calcium and vitamin D. For women of all racial and economic origins, they were the leading causes of incapacity, weakness, and even death. Two investigations were conducted as part of the WHI hormone clinical trial; one examined the role of HT in reducing the risk of cardiovascular disease and osteoporosis, while the other examined the role of HT in increasing the risk of breast cancer. Below is a description of the HT employed in the two studies:
Women with uteruses were given either Premarin® (0.625 mg orally) and Provera® (2.5 mg orally) or a placebo (inactive tablet) in an estrogen-and-progesterone research study.
Women lacking uteruses were given either an estrogen pill (Premarin, oral 0.625 mg) or a sugar pill (placebo).
Breast cancer, heart disease, stroke, and pulmonary embolism were all thought to be elevated in the estrogen plus progestin study; hence, it was stopped unexpectedly in July 2002. Since unopposed estrogen did not appear to influence the risk of heart disease, the primary outcome, the experiment was stopped in February 2004. There was a reduction in breast cancer risk, but only in the estrogen-only trial (2).
The synthetic progestin Provera (medroxyprogesterone acetate, or MPA) was employed in the estrogen-plus-progestin trial, which is an interesting contrast to the use of bioidentical progesterone in the other study. While both Provera and progesterone have an antiproliferative impact on the endometrium, a research article published in 2008 found that MPA had different effects on the cardiovascular system than progesterone. Arterial vasoconstriction and decreased endothelial function are both factors in the development of cardiovascular disease (3) that are exacerbated by exposure to MPA. Meanwhile, progesterone has been employed for myocardial infarction and post-stroke therapy due to its vasodilatory actions (4, 5).
Menopause typically begins between the ages of 51 and 55, though it can start earlier or later. Thousands of women go through menopause every year, and this includes those who undergo surgical menopause. This causes the ovaries to gradually decrease or cease producing estrogen. As a result of estrogen decline, many women suffer from menopausal symptoms such as hot flashes, night sweats, cognitive dysfunction, emotional swings, disturbed sleep, vaginal dryness, and diminished libido. Because of the severity of these symptoms, a woman’s daily life and/or career may be severely disrupted. Menopause can last anywhere from a few months to a few years. In 1943, the FDA granted a patent on Premarin, a drug developed by Wyeth-Ayerst and aimed at relieving women’s symptoms.
Premarin, the first conjugated estrogen, was created from the urine of pregnant mares and used to treat women going through menopause. The FDA approved Premarin for the treatment of osteoporosis in 1986, despite the fact that a few early publications suggested a higher risk of endometrial cancer with continued use of ERT. Estrogen, formerly viewed as a “short-term treatment for menopause, was the treatment of choice for bone loss, a long-term, chronic problem” (7). More than 30 million Premarin prescriptions were written in the United States in the 1990s, making it the most widely prescribed medicine at the time.
Women and doctors alike were alarmed by the WHI study’s findings and grew wary of hormone therapy as a result. As a result, there was a precipitous reduction in the number of prescriptions for Premarin as doctors stopped issuing refills for the drug and other estrogen replacement therapies. The reappearance of menopausal symptoms has disrupted the lives of many women who abruptly stopped taking Premarin out of concern for breast cancer. Prescriptions of hormones to women who are entering menopause have also been called into doubt.
Reviewing the WHI data that followed, scientists discovered certain exaggerations. Hormone replacement therapy was found to be less important than a woman’s age at initiation. Women under 60 who received HT exhibited a substantial decrease in coronary disease in a Bayesian meta-analysis (9). Women who started hormone therapy 10 years or less before menopause also had a lower risk of dying from any cause. The risk of breast cancer from HT “is greater in older rather than younger women,” according to recent studies of WHI data. “suggested that the younger the women were in the trial, the more they showed benefit” (9), according to the timing hypothesis derived from the WHI HT trial and other data. To learn more about the timing theory, check out Getting to the Heart of Estrogen | Skylab Laboratory on the Skylab Clinical Laboratory website.
After the release of the WHI report, doctors and women started thinking differently about hormone replacement. The timing of hormone initiation, the duration of hormone therapy (HT), and the method of hormone distribution (orally or transdermally, via a patch or topical cream) have all received increased focus. Bioidentical estrogens make up the vast majority of the synthetic and pharmaceutical estrogens available today. Generic versions of the bioidentical progesterone-produced product Prometrium® appeared, and compounding pharmacies grew in popularity as doctors and pharmacists searched out more personalized approaches to treating women’s menopausal symptoms.
Bioidentical hormones, both in pharmaceutical estrogen preparations and those manufactured individually for a person by a specialist compounding pharmacy, have essentially supplanted the previously prescribed, pharmaceutically derived Premarin and Provera utilized in the WHI research. Hormones that are bioidentical to the body’s own biologic hormones are those that share the same molecular structure. When compared to their pharmaceutical counterparts, many doctors believe that bioidentical hormones that have been compounded are safer for their patients. Despite the lack of conclusive evidence on the safety of bioidentical hormone use, these medications are routinely given for the treatment of menopausal symptoms.