HORMONE REPLACEMENT THERAPY

'Hormone replacement therapy (HRT)' is a system of medical treatment for surgically menopausal, perimenopausal and postmenopausal women, based on the assumption that it may prevent discomfort and health problems caused by diminished circulating estrogen and progesterone 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 reinforce 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 delivered to the body via patches, tablets, creams, troches, IUDs, vaginal rings, 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 treat reduced sexual desire/(libido). It may also treat reduced energy and help reduce osteoporosis 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.

Contents

Types of Hormone Replacement Therapy

Bioidentical hormone replacement therapy

Results of the WHI hormone replacement therapy studies

Transgender transitioning

Recent Findings

Contraindications of HRT

References

See also

External links

Types of Hormone Replacement Therapy

Historically the most commonly prescribed forms of HRT has been proprietary mixtures of conjugated equine estrogens (CEE) as well as progestins that, while not progesterone, approximate its effects. 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. Because these have been used most commonly and for the longest time, there are many more studies of these forms of hormones than of some of the newer forms with newer delivery systems, and therefore the most is known about these kinds. Whether or not such risks exist with other forms of estrogens and progestins, and other delivery systems, remain to be seen.
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 studies of Premarin and PremPro do not necessarily generalize to supplementation with human forms of estrogen and progesterone. For example, a pilot study reported in ''JAMA'' by Smith, Heckbert, et al.^[1] found clinical evidence that oral conjugated equine estrogens caused clotting, but the other estrogen compound tested in the same study, bioidentical esterified estrogens, does not. Conjugatged equine estrogens were found to be associated with increased venous thrombotic risk. In sharp contrast, the study found that users of esterified estrogen had no increase in venous thrombotic risk.
Additionally, the route of administration may be as important as the type of estrogen administered. For example, in a large study published in the ''Lancet'' Scarabin et al.^[2] 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. This difference was likely due to the fact that transdermal estrogens are absorbed directly into the bloodstream, while oral estrogens are processed and changed by the liver before release into the blood stream.
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 inaccurate generalization in mind in reviewing press reports. 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, and there are fewer large scale studies of these items.
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 cardiovascular 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 Harvard 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 therapy. 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.

Bioidentical hormone replacement therapy

Main articles: Bioidentical hormone replacement therapy

Recently, interest in "bioidentical" hormone replacement therapy (BHRT) has risen. This term is used to refer to HRT formulated to contain the three main naturally occurring human estrogens estradiol, estrone, and estriol, as well as to refer to bioidentical human progesterone and sometimes testosterone. As recently as 2004, before the release of the Women's Health Initiative studies referenced below, the relative benefits of bioidentical hormones over xenoestrogens and progestins were regarded as not yet established.^[3] 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. Larger-scale studies are still needed to confirm the relative benefits and safety noted in pilot trials of Bioidentical hormone replacement compared with equine estrogen and oral progestins. While chemically, these hormones are identical to those found in the human body, they cannot replicate the delivery system of those produced by the human body, nor the amounts. The human body contains over 25 different types of estrogen, and estradiol, estrone, and estriol are merely the three most common types. However, the body is able to convert estrogens into different hormones to a certain extent.

Results of the WHI hormone replacement therapy studies

Clinical medical practice changed rapidly and dramatically with the results of the two parallel WHI studies of postmenopausal HRT. Prior studies were much smaller, and many were studies of women who were electively taking hormones. This self-selected group tended to be comprised of women who were more health-conscious, which was a possible factor to explain why these women tended to be healthier than the average. The WHI studies 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 preliminary study results indicated that the health risks of the conjugated equine estrogen and progestin exceeded benefits.
The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.^[4] It followed over 16 000 women for an average of 5.2 years, half of which taking a placebo, the other half taking a combination of the progestin medroxyprogesterone acetate and conjugated equine estrogens. The study found statistically signficant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. 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.
The risks of coronary heart disease varied according to age and years since the onset of menopause. Women aged 50 to 59 using HRT showed a small trend towards lower risk of coronary heart disease,^[5] as did women who were within five five years of the onset of menopause.^[6]
The adverse cardiovascular outcomes may only apply to oral dosing with progestin and equine estrogens, while other types of HRT such as topical estradiol and estriol may not produce the same risks. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased.^[2]
The WHI preliminary results in 2004 found a non-significant trend in the estrogen-alone clinical trial towards a reduced risk of breast cancer^[5] and a 2006 update of 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.^[9] 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.^[10] Estrogen-alone HRT ("unopposed estrogen") poses unacceptable cancer risks to women who have not previously had a hysterectomy.
After the increased clotting found in the first WHI results was reported in 2002, a large number of women who had been taking the proprietary mixtures of equine estrogens and progestins studied (PremPro) ceased filling their prescriptions. Some simply stopped all hormones, and others switched to bioidentical hormones. The number of PremPro prescriptions filled was abruptly cut almost in half.

Transgender transitioning

Main articles: Hormone replacement therapy (trans)

For transsexual men and women, hormone replacement therapy causes the development of many of the secondary sexual characteristics of their desired sex. However, many of the existing primary and secondary sexual characteristics cannot be reversed by HRT. For example, HRT can induce breast growth for transsexual women but cannot reduce breasts for transsexual men. HRT can prompt facial hair growth for transsexual men, but cannot regress facial hair for transsexual women. HRT may, however, change some characteristics, such as distribution and percentage of body fat and muscle, as well as menses in transsexual men. Generally, those traits that are easily reversible will revert upon cessation of hormonal treatment, unless chemical or surgical castration has occurred, though for many transsexual people, surgery is required to obtain satisfactory physical characteristics.
As with all medical activities, health risks are associated with hormone replacement therapy, especially when high hormone doses are taken as is common for pre-operative transsexual patients. It is always advised that all changes in therapeutic hormonal treatment should be supervised by a physician because starting, stopping or changing dosages can have physical and psychological health risks.
Although some transsexual women use herbal phytoestrogens as alternatives to pharmaceutical estrogens, little research has been performed with regard to the safety or effectiveness of such products. Anecdotal evidence suggests that the results of herbal treatments are minimal and very subtle, if at all noticeable, when compared to conventional hormone therapy.

Recent Findings

According to a recent report^[11] citing early findings reported at a recent American Academy of Neurology meeting, hormone therapy taken soon after menopause may help protect against dementia, even though it raises the risk of mental decline in women who do not take the drugs until they are older. Dementia risk was 1.7 % in women who started HRT early, and 1% in women who didn't,
(e.g. women who didn't take it seem to have had—on average—a 70% higher relative risk of dementia).
also :
HRT doesn't seem to increase risk of MI in women between 50 and 59, and is associated with decreased mortality / increased survival, though the exact mechanisms of decreased mortality and increased survival are not yet fully understood.

Contraindications of HRT

absolute contraindications:

★ undiagnosed vaginal bleeding

★ severe liver disease

★ pregnancy

★ Coronary artery disease (CAD)

★ venous thrombosis

★ Well-differentiated and early endometrial cancer (once treatment for the malignancy is complete, is no longer an absolute contraindication.) Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens.
Relative contraindications:

★ Migraine headaches

★ personal history of breast cancer

★ History of fibroids

★ Atypical ductal hyperplasia of the breast

★ Active gall bladder disease (Cholangitis, Cholecystitis )

References

1. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis, Smith NL, Heckbert SR, Lemaitre RN, ''et al'', , , JAMA, 2004
2. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk, Scarabin PY, Oger E, Plu-Bureau G, , , Lancet, 2003
3. Bioidentical hormone therapy: a review, Boothby LA, Doering PL, Kipersztok S, , , Menopause (New York, N.Y.), 2004
4. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial, Rossouw JE, Anderson GL, Prentice RL, ''et al'', , , JAMA, 2002
5. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial, Anderson GL, Limacher M, Assaf AR, ''et al'', , , JAMA, 2004
6. Estrogen plus Progestin and the Risk of Coronary Heart Disease, , J.E., Manson, The New England Journal of Medicine, 2003
7. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk, Scarabin PY, Oger E, Plu-Bureau G, , , Lancet, 2003
8. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial, Anderson GL, Limacher M, Assaf AR, ''et al'', , , JAMA, 2004
9. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy, Stefanick ML, Anderson GL, Margolis KL, ''et al'', , , JAMA, 2006
10. The WHI estrogen-alone trial--do things look any better?, Hulley SB, Grady D, , , JAMA, 2004
11. summarized at http://www.uspharmd.com/2007/2007_05_03.html

See also

★ Andropause

★ Estrogen

★ Hormone replacement therapy (trans)

★ Hormones

★ Life extension

★ List of transgender-related topics

★ Male lactation

★ Osteoporosis

★ Progesterone

★ Prolactin

★ Wiley Protocol

External links

★ Council on Hormone Education

★ North American Menopause Society

★ FDA article on Menopause and Hormones

★ Hormone Therapy: The Risks and Benefits, article by the National Research Center for Women & Families