Hormone replacement therapy


 * This article is about the treatment with sex steroids. For hormone replacement therapy in general, and for other instances in which hormones might be prescribed, see hormone therapy.

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.

HRT is also used by transgendered or transsexual people to aid them in attaining the secondary sex characteristics of their desired sex. See Hormone replacement therapy (trans). It is also given to some intersex people (depending on the precise intersex condition), either starting in childhood to confirm the gender they were assigned, or later, if this gender assignment has proven to be incorrect.

HRT is available in various forms. It generally provides a low dosages of one or more estrogens, and often also provides either progesterone or a chemical analogue, called a progestin. Testosterone may also be included. In women who have had a hysterectomy an estrogen compound is usually given without any progesterone, a therapy referred to as unopposed estrogen therapy. HRT may be by tablets, creams, or ointment. Dosage is often varied cyclically, with estrogens taken daily and progesterone or progestins taken for about two weeks every month; a method called sequentially combined HRT or scHRT. An alternate method, a constant dosage with both types of hormones taken daily, is called continuous combined HRT or ccHRT. Sometimes an androgen, generally testosterone, is added to help reduce osteoporosis and to treat reduced energy and sexual desire (libido) after menopause.

HRT is seen as either a short-term relief (often one or two years, usually less than five) from menopausal symptoms (hot flashes, irregular menstruation, fat redistribution etc.) or as a longer term treatment to reduce the risk of osteopenia leading to osteoporosis.

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.

It has become increasingly clear that oral progestin and equine estrogen pills can increases 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, may also increase the risk of uterine cancers. This combination can also effect blood triglyceride levels and so may increase the risk of cardiovascular problems. 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.

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 naturally occurring human estrogens estradiol 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 liver effects. Favorable attention to BHRT has included reports of positive personal experiences by celebrities such as Suzanne Somers, Robin Strasser, Patti LaBelle, and Valerie Harper.

Results of the WHI hormone replacement therapy studies
Much of the controversy regarding hormone replacement therapy (HRT) result from a study by the Women's Health Initiative, which came out in 2002. It followed a total of 166,08 women, aged 50 to 79 (average age = 63 at study intake). One arm followed patients for 5.2 years who were either on a combination of progestins and equine estrogens (8506 women) or a placebo (8102 women). The WHI study found that the measured risks of this combination outweighed its measured benefits (see the table, below). Regrettably, the results were almost universally mis-reported as risks and problems associated with HRT in general, rather than with the specific proprietary combination of progestins and equine estrogens that was actually studied.

It is not clear to what extent the results of the "Progestin plus Estrogen" study (above) should be applied to women who begin HRT at a young age. For the women age 50-59 in this study, there was an observed trend towards a reduced risk of cardiovascular disease (relative risk = 0.56, 95% CI 0.30-1.03) and a statistically significant increase in blood clotting was not observed (relative risk for stroke = 1.08, 95% CI 0.57-2.04). Absent research with bioidentical estrogen and progesterone, there is no sure basis assessing whether the results of this study are relevant to other forms of estrogen replacement therapy such as topically administered estradiol and estriol. Results from other studies suggest that when equine estrogens are administered orally, liver function is altered and the risk of blood clots is increased. The results of the WHI “Estrogen Alone” clinical trial suggest that the synthetic progestin used in the "Estrogen-plus-Progestin" study was the cause of the increased risk of breast cancer, rather than the equine estrogens. In the "Estrogen Alone" clinical trial there was an observed trend towards a reduced risk of breast cancer (relative risk = 0.77, 95% CI 0.59-1.01). In a recently published update of the WHI study, researchers have concluded that use of estrogen alone hormone replacement therapy does not increase the risk of breast cancer. Estrogen alone hormone replacement therapy is recommended only to women who had previous hysterectomy.