Hormone replacement therapy (HRT) is a system of medical treatment for perimenopausal and postmenopausal women, based on the assumption that it may prevent discomfort and health problems caused by diminished circulating estrogen hormones. The treatment involves a series of drugs designed to artificially boost hormone levels. The main types of hormones involved are estrogens, progesterone or progestins, and sometimes testosterone.
Historically the most commonly prescribed forms of HRT has been proprietary mixtures. These combinations have been composed of equine estrogens rather than bio-identical human estrogens, and have favored the use of progestins, rather than the human form of progesterone. With the passage of time, an increasing number of studies have shown that certain risks are associated with these combinations of progestins and equine estrogens.
Apart from a few studies funded by the U.S. National Institutes of Health, the overwhelming majority of research on hormone supplementation has been financed by manufacturers and has used their products combining progestins and equine estrogens. Bioidentical forms of human estrogen and progesterone have been very little studied. This distinction is important, because the adverse biological effects of xenoestrogens and progestins revealed by the studies do not necessarily generalize to supplementation with human forms of estrogen and progesterone. For example, a pilot study reported in JAMA. 2004;292:1581-1587, Vol. 292 No. 13, October 6, 2004 by Smith, Heckbert, et al. found clinical evidence that the adverse effects from oral conjugated equine estrogens were in fact not generalizable to the other estrogen compound tested in the same study. Conjugated equine estrogen, but not esterified estrogen, was associated with increased venous thrombotic risk. The study found that users of esterified estrogen had no increase in venous thrombotic risk, in sharp contrast to the users of equine estrogens.
Studies finding adverse health effects of equine estrogens and progestins have often been reported, inaccurately, as revealing effects of "estrogen" and "progesterone." It is important to keep this habitual inaccuracy in mind in reviewing press reports. The overwhelming majority of studies which have found adverse health effects were studies of equine estrogens and progestins which have nonetheless been uncritically reported in the media as studies of estrogen or progesterone in general.
It has become increasingly clear that oral progestin and equine estrogen pills can increase a number of risks, including the risks of exacerbation of existing liver or gallbladder problems and of dangerous blood clots. Long term use of equine estrogens probably also increases the risk of breast cancer. In women with a uterus, therapy with equine estrogen, unopposed by progesterone, is generally acknowledged to increase the risk of uterine cancers in women with intact uterine linings. This proprietary combination can also affect blood triglyceride levels and increase the risk of adverse cardiovascular events. Although HRT with progestins and equine estrogens was once widely thought to promote cadiovascular health in women, on February 4, 2004, the American Heart Association released guidelines stating that it should no longer be considered as an agent to increase heart health or to decrease the chances of cardiovascular disease.
In 2006, results from the large ongoing observational Nurses' study showed that those taking a pill containing a combination of estrogen with methyltestosterone (a synthetic testosterone analogue) had higher risk of breast cancer than those not taking the methyltestosterone. Unfortunately, few or no studies have tested the safety or benefits of human bioidentical testosterone, or of low-dose non-pill administration of testosterone that avoids the first pass through the liver.
Due to the risks and potential problems of progestins and equine estrogens, a number of alternative therapies have been developed, including lifestyle changes, non-hormone drug therapy, and bioidentical hormone replacement. To reduce the risk of osteoporosis without hormones, dietary changes that increase calcium uptake, exercise, and drugs such as biphosphates, selective estrogen receptor modulators or calcitonin have been tried. As the risks of equine estrogens and progestins have become more evident, interest has intensified in the use of HRT formulated to contain the three main naturally occurring human estrogens estradiol, estrone and estriol, as well as bioidentical human progesterone and sometimes testosterone. This method of HRT is often called bioidentical hormone replacement therapy(BHRT). BHRT is often delivered via topical administration of a cream or gel solution of the hormones to the skin, reducing concerns about adverse liver effects of oral medications.