Hormone replacement therapy

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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 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 patches, tablets, creams, gels or, more rarely, by injection. Dosage is often varied cyclically, with estrogens taken daily and progesterone or progestins taken for about two weeks every month or two; 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, and is a more recent innovation. 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. Younger women with Premature ovarian failure or surgical menopause may use hormone replacement therapy for many years, until the age that natural menopause would be expected to occur.

1 HRT with bioidentical human hormones distinguished from animal and chemical analogues
2 Results of the WHI hormone replacement therapy studies
3 See also
4 External links

[edit] HRT with bioidentical human hormones distinguished from animal and chemical analogues

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. Nonetheless, it seems likely that the route of administration may be more important than the type of estrogen administered. For example, in a large study published in the Lancet Scarabin et al. compared effects of oral vs. transdermal (skin patch) estrogen (mainly estradiol-17 beta, the "bioidentical" human estrogen) and found that the oral route was associated with a 3-fold increase in risk of venous clotting disease (thrombophlebitis, pulmonary embolus), whereas the skin patch produced no excess risk.

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. On the other hand, creams, gels, etc. containing "biodentical" hormones custom-prepared by compounding pharmacies are not subject to FDA monitoring or regulation, so that doses delivered and hormone blood levels produced are unpredictable and may be highly variable.

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)[1]. 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.

[edit] Results of the WHI hormone replacement therapy studies

Clinical medical practice changed rapidly and dramatically with the results of the two parallel Women's Health Initiative (WHI) studies of postmenopausal hormone replacement therapy (HRT). These were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women. The WHI estrogen-plus-progestin trial and estrogen-alone trial were both halted early (in July 2002 and February 2004 respectively) because the health risks of the hormone replacement studied exceeded benefits.

The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.[2]. It followed a total of 16,608 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 the progestin medroxyprogesterone acetate and conjugated 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). The results were almost universally reported as risks and problems associated with HRT in general, rather than with the specific proprietary combination of conjugated equine estrogen and progestin studied.

Adverse event	Relative risk (95% CI)	Change in number of events per 10,000 women in one year
Breast cancer	1.26 (1.00-1.59)	8 more
Heart disease	1.29 (1.02-1.63)	7 more
Stroke	1.41 (1.07-1.85)	8 more
Pulmonary embolism	2.13 (1.39-3.25)	8 more
Colorectal cancer	0.63 (0.43-0.92)	6 fewer
Hip fracture	0.66 (0.45-0.98)	5 fewer

The cardiac results of the above WHI study of estrogen plus progestin were age specific. The participants average age was 63, and the overall results were as shown above. The blending of younger and older women in the study obscures possible cardiac benefits of HRT in women who begin HRT at the younger end of the range of 59 - 79 of the study participants. In the estrogen + progestin study, women who were less than 5 years postmenopausal showed a trend toward reduced heart disease risk (relative risk = 0.89, 95% CI 0.5-1.7). For the subset of women who were age 50-59 in the WHI estrogen-alone study, an even stronger trend was observed towards a reduced risk of cardiovascular disease (relative risk = 0.56, 95% CI 0.30-1.03) but neither trend was statistically significant. No increase in stroke risk was observed in the younger women in the latter study (relative risk for stroke = 1.08, 95% CI 0.57-2.04).

The adverse cardiovascular outcomes observed in the WHI study may not apply to other forms of estrogen replacement therapy such as topically administered estradiol and estriol. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased [3].

In the preliminary 2004 results of the WHI estrogen-alone clinical trial there was an observed trend, that was not statistically significant, towards a reduced risk of breast cancer (relative risk = 0.77, 95% CI 0.59-1.01).[4] In a recently published 2006 update of the WHI estrogen-alone study, researchers concluded that use of estrogen-only HRT for 7 years does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy.[5] The results of the WHI estrogen-alone trial suggest that the progestin used in the WHI estrogen-plus-progestin trial increased the risk for breast cancer above that associated with estrogen alone.[6] Hormone replacement therapy with estrogen alone ("unopposed estrogen") is recommended only to women who had previous hysterectomy.

see: U.S. Hormone Replacement Therapies for a chart of hormone replacement therapies available in the United States, and UK Hormone Replacement Therapies for a chart of hormone replacements available in the United Kingdom.