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.
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.
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. 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. 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
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.[2] 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. Large scale studies are needed to see how these hormone regimens compare with equine estrogen and oral progestins and if they have any of the same risks in common. 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 Women's Health Initiative (WHI) studies of postmenopausal hormone replacement therapy (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 the health risks of the conjugated equine estrogen and progestin 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
|
Change in number of events |
|---|---|---|
|
1.26 (1.00-1.59) |
8 more |
|
|
1.29 (1.02-1.63) |
7 more |
|
|
1.41 (1.07-1.85) |
8 more |
|
|
2.13 (1.39-3.25) |
8 more |
|
|
0.63 (0.43-0.92) |
6 fewer |
|
|
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") 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) quit refilling 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.
A study [3] by M.D. Anderson reported in a medical conference [4] in San Antonio Texas in December 2006 looked at new cancer diagnoses in the U.S. in 2003, the year following the initial reports of clotting in connection with use of PremPro. A staggering 7% drop in new diagnoses of breast cancer in the U.S. was noted in 2003, compared with 2002 levels. One third of the decrease could have been related to a reduced number of mammographies. But the balance appeared to be related to widespread cessation of PremPro use. Reductions were by far the sharpest in women over 50, the age group among whom prior PremPro use (and thus discontinuation) was most likely. This and other studies suggest that the shift away from the proprietary PremPro combination was a key factor. These studies are consistent with the possibility that replacing PremPro with bioidentical hormones could reduce cancer risks. Long-term use of hormone combinations other than PremPro has already been found to be associated with lowered incidence of cancer. For example a large 2004 population study of women who used birth control pills found a reduced risk of heart disease and stroke and an overall decreased risk of cancer. In this study, women who had used birth control pills at some point in their lives were noted to have an 8% lower risk of heart disease, no increased risk of breast cancer, and a 7% lower overall cancer risk including significant reductions in ovarian and colon cancer. This 2004 study of the contraceptive pill's protective effects followed smaller studies that had found a slight breast cancer promotion associated with use of certain oral contraceptives. The favorable picture of contraceptive benefits emerged from the 2004 study's analysis of the very large body data collected from the over 160,000 women who had participated in the Women's Health Initiative study.
see: U.S. Hormone Replacement Therapiesfor a chart of hormone replacement therapies available in the United States, and UK Hormone Replacement Therapiesfor a chart of hormone replacements available in the United Kingdom. These charts do not yet include Elestrin, a fast-drying gel formulation of bio-identical estradiol approved by the U.S. Food and Drug Administration in December 2006, at dosages of either 0.87-gram or 1.7-gram. Although the 0.87 gram dose is 50% less than the next lowest dose of estradiol currently on the market, in studies it has provided significant relief of menopause symptoms to 80% of its users.[7]
Recent Findings
According to a recent report on CNN's website at (http://www.cnn.com/2007/HEALTH/conditions/05/02/hormones.dementia.ap/index.html) 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
- ^ http://jama.ama-assn.org/cgi/content/abstract/292/13/1581 |Esterified Estrogens and Conjugated Equine Estrogens and the Risk of Venous Thrombosis |Smith, Heckbert, et al. |JAMA. 2004; 292:1581-1587, Vol. 292 No. 13, October 6, 2004 |Vol. 292 No. 13, October 6, 2004 Original Contribution .
- ^ [1]
- ^ http://www.medpagetoday.com/MeetingCoverage/SABCSMeeting/tb/4697J
- ^ http://www.ctrc.net/wps/portal/sabcs
See also
- Andropause
- Estrogen
- Hormone replacement therapy (trans)
- Hormones
- Life extension
- List of transgender-related topics
- Male lactation
- Osteoporosis
- Progesterone
- Prolactin
- Wiley protocol