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Page: Types of Hormone Replacement Therapy
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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, remains to be seen.
Thus, 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 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. 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. The overwhelming majority of studies that have found adverse health effects were studies of equine estrogens and progestins that 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, 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.
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