| | “Bioidentical” estrogens: Hope or hype?The vilification of conventional hormone therapy has made women desperate for something safer. Unfortunately, they are highly susceptible to exaggerated claims made on behalf of “natural hormones” that are heavily promoted as kinder, gentler, risk-free options for women seeking relief from menopausal symptoms.
▪Advocates of “bioidentical” estrogen capitalize on the fears of women, claiming that it prevents, rather than causes cancer; has a better risk/benefit profile than conventional pharmaceutical preparations; is “natural” rather than synthetic; and can be compounded to suit an individual's needs.
▪Compounding pharmacy websites and many alternative and advocacy menopause websites state definitively that estriol prevents cancer of the breast and endometrium, though interventional studies are completely lacking.
▪Soy and other phytoestrogens and isoflavone supplements derived from clover or soy have shown less than stellar ability to treat vasomotor symptoms, limit bone mineral loss, or ease vaginal atrophy.
▪So-called bioidentical compounded estrogens cannot be assumed to be safer than conventional pharmaceutical estrogens. Current evidence does not support the safety claims made in much of the promotion and advertising for these products.
▪With all estrogen therapies, treatment should be limited to the lowest dose for the shortest duration. The current standard of care dictates reevaluation of the need for therapy at 6–12 month intervals.
After the Women's Health Initiative (WHI) failed to confirm many of the long-term health outcomes suggested by earlier observational studies, symptomatic menopausal women continue to hold hope that something out there will provide relief without risks associated with conventional hormone therapy. Women, reacting to the media coverage of the WHI, have come to believe that conventional pharmaceutical estrogens hold a clear and present danger. Conjugated estrogens (CE) used in the WHI have been particularly tarnished. In January–June 2003, prescriptions declined 66% for Prempro (conjugated estrogens/medroxyprogesterone acetate) and 33% for Premarin (conjugated estrogens), relative to 2002 figures.1
“Bioidentical”: What's in a name?  While CE-containing prescriptions have declined, the use of so-called “bioidentical” estrogens has increased since the WHI. The lay press and self-help hormone books have been replete with information suggesting that bioidentical estrogens offer the relief women need with fewer attendant risks, despite this FDA pronouncement: “Other doses of conjugated estrogens and medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar.” While pharmaceutical companies are bound by these limits, the alternative medicine and compounding pharmacy segments of the medical marketplace have sidestepped the warnings and have been promoting “natural” hormones as a risk-free option for women suffering from symptoms of the climacteric. Claims about “bioidentical” estrogen include:
•Prevention, rather than cause of, cancer
•No risk of endometrial cancer
•Better side-effect profile
•Provide “physiologic” estrogens
•Are “natural,” not synthetic
•Custom-blending, compounding to individual needs.
The term “bioidentical” is used loosely, and means different things to different people. Most often it is applied to 17 beta-estradiol, but it is often used interchangeably with the term plant-based estrogens, and in some quarters refers to compounded estrogen products containing a blend of estradiol with estriol and sometimes with estrone. Defining terms The term natural estrogens, those occurring in “nature,” should be reserved for steroids produced by the ovaries in mammals (see Table 1). Prior to the ability to build hormones in the laboratory, equine, bovine, ovine, and porcine ovaries were the sourcing for estrogens for hormone therapy. CE from pregnant mares' urine (Premarin) is the only estrogen product that is truly natural: that is, the steroids are packaged in the unmodified, unaltered form produced by the animal. After extraction from urine by a proprietary process, the only “modification” made to conjugated equine estrogens is standardization of the ratio of the principal components, to keep the ratio of the various estrogens consistent from batch to batch—not unlike the blending of a finely balanced Meritage wine.
 | Natural (mammalian) | |
| Natural unmodified | |
| | Conjugated equine estrogens | |
| Native synthetics synthesized from diosgenin | |
| | 17 betastradiol | |
| | Estrone | |
| | Estrone sulfate | |
| | Synthetic conjugated estrogens | |
| | Esterified estrogens | |
| | Estriol | |
| Synthetic (synthesized) | |
| Ethinyl estradiol | |
| Dienestrol | |
| Diethylstilbestrol | | | | |
Native estrogens or human bioidentical hormones are exact mimics of the endogenous estrogens produced by the human ovary, and are synthesized in the laboratory. They include estrone, estradiol, and estriol. The native estrogens used in the United States are made from a weakly estrogenic plant precursor molecule, diosgenin, which is first converted to progesterone and then used as the skeleton for building other sex steroids. Most diosgenin is processed from high-yield yam sources, usually dioscorea mexicana or dioscorea barbasco, or from soy. Three products in the US market also contain equine estrogens synthesized from the same plant sources used to produce estradiol, principally soy and yam. Equine steroids were incorporated in the formulations in an effort to copy the clinical profile of Premarin. The term synthetic is often wrongly applied to equine estrogens by lay menopause “experts.” Synthetic has two meanings within the lexicon and classification of menopausal estrogens. Synthetic applies to the biosynthetic processing that is used to manufacture all the natural estrogens that are currently sold. Synthetic also applies to estrogens that are “artificial”—unknown in nature—compounds that interact with the receptor in a manner similar to that of true estrogens, but do not have the configuration of mammalian sex hormones. The two most well-known examples of these synthetics are diethylstilbestrol (DES) and ethinyl estradiol (EE). The advocates for “natural” hormones also invoke the term “plant estrogen,” which is a malapropism. If we agree to define estrogens as mammalian steroid products, then plants cannot make them. Plants do produce phytosterols that interact with the estrogen receptor, but the binding and receptor interactions are generally weak and vary from tissue to tissue. The phytosterols of plants more correctly should be termed phyto-SERMs, phyto-selective estrogen receptor modulators, since they are agonists in some tissues and antagonists in others. The phytosterols, in particular genistein and diadzein, have failed to demonstrate significant biological impact in treating estrogen deficiency conditions. Soy and other phytoestrogens and isoflavone supplements derived from clover or soy have shown less than stellar ability to treat vasomotor symptoms, limit bone mineral loss, or ease vaginal atrophy. Compounded estrogens While some women will ask their physician for a bioidentical estrogen, and be contented with a pharmaceutical estradiol, others, prodded and provoked by the popular press, will insist on a compounded product. Most often they ask for a product that contains estriol, occasionally as a monotherapy, but more often in combination with estradiol (“biest”) or in combination with estradiol and estrone (“triest”). These products are promoted as kinder, gentler forms of hormone therapy. They are often touted as plant-derived or plant-based, but as we have cited earlier, most components of current hormone therapy are plant-derived. Women have also been led to believe that these estrogens are made by green plants when, in fact, all compounded products are native synthetic estrogens, “built” through biosynthetic manufacturing processes. Proponents of “bioidentical” estrogens capitalize on the fears of women, promising that estriol-containing compounded products provide a risk/benefit profile that differs significantly from that of conventional pharmaceutical preparations. In the past, pharmaceutical estrogen therapy products in Europe did indeed contain estriol in combination with estradiol or estradiol and estrone. Studies of these more complex blends, when compared to single-agent estrogen therapy, found no objective or subjective differences in clinical performance. To simplify production and to lower manufacturing costs, companies stopped including estriol in their estrogen products. Estriol continues to be used alone in vaginal preparations and retains some popularity as an oral estrogen in Japan. Estriol and symptoms Commercial estriol is marketed in the European Union for systemic estrogen therapy. The product has approval for “atrophy of the lower urogenital tract related to estrogen deficiency and for climacteric complaints such as hot flushes and night sweating.” While the initial dose of estriol is set at 4–8 mg per day during the first weeks, the prescribing information states that maintenance therapy should use the lowest effective dosage, generally 2 mg. In the US, compounding pharmacies formulate biest products with 80% estriol and 20% estradiol by milligram doses. Triest products typically contain estriol 80%, estradiol 10%, and estrone 10%. Figure 1 shows the composition of several representative products. Most triest and biest preparations, when taken according to the directions, offer a cumulative dose of estradiol of at least 0.5 mg per day, the same amount of estradiol as in Estrace 0.5 mg. Thus, triest and biest preparations typically rely on estradiol to provide the functional benefits of hormone therapy. The estriol provides additional estrogen activity, but the amount is difficult to estimate. Estimates of the potency of estriol vary greatly, ranging from 1/10 to 1/100 that of estradiol.2 Taking 4 mg of estriol equates to approximately an additional 400 micrograms to 0.4 mg of estradiol, a small but perhaps significant additional estrogen exposure. Estriol and breast cancer Compounding pharmacy websites and many alternative and advocacy menopause websites state definitively that estriol prevents cancer of the breast and endometrium, though interventional studies are completely lacking. These conclusions are rooted in research done in the 1970's by Lemon. Estriol administered prior to exposure to carcinogens limited the growth of breast tumors in female Sprague Dawley rats.3 Estriol also was found to induce regression and remission of breast tumors in rats and humans.4 Similar statements can be made about DES, estrone, and estradiol, all of which, at one time or another, have been used successfully to induce short-term remissions in breast cancer subjects. Endometrial effects of estriol When estriol is given in doses comparable to estradiol, and administered more frequently to compensate for rapid metabolic clearance, estriol does induce endometrial hyperplasia.5 Biopsies of the endometrium in women treated with estriol alone, estradiol alone, or estriol plus estradiol produced similar dose-dependent histologic proliferative and hyperplastic changes.6, 7 Weiderpass, in reporting data from the Swedish cancer registries, noted that oral estriol in doses of 1–2 mg daily was associated with a 3-fold increase in endometrial cancer and an 8.3-fold increase in atypical hyperplasia after 5 years of use. The cancers were generally well differentiated with limited invasion, and the excess risk appeared to dissipate rapidly after treatment with estriol ceased.8 Bone effects of estriol Estriol has generally been believed to be a poor bone agonist. Yang stated that estriol does not prevent bone loss.9 The literature suggests that its bone tropic effects are very mild. Itoi reported on a group of recently menopausal women and found the bone-preserving effect of 2.0 mg of oral estriol was comparable to that of 0.625 mg of conjugated estrogen.10 Summary Oral estriol is quite capable of producing endometrial hyperplasia and endometrial cancer. It offers no evidence of a higher degree of endometrial safety than other estrogens. Added to other estrogens, it does not limit endometrial risks. There are no long-term studies on the impact of estriol on breast cancer rates. With all estrogen therapies, treatment should be limited to the lowest dose for the shortest duration. Current standard of care dictates reevaluation of the need for therapy at 6–12 month intervals. So-called bioidentical compounded estrogens cannot be assumed to be safer than conventional pharmaceutical estrogens. The current evidence does not support the safety claims made in much of the promotion and advertising for these products. The vilification of conventional hormone therapy has made women desperate for something safer, and made them highly susceptible to the exaggerated claims made about compounded products. There is no doubt about the efficacy of biest and triest or estriol alone, but claims promoting greater safety cannot be corroborated. References 1.
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a Women's Health, Clinical Research & Medical Affairs—Endocrinology, Novo Nordisk Inc.  Women's Health, Clinical Research & Medical Affairs—Endocrinology, Novo Nordisk Inc., 100 College Road West, Princeton, NJ 08540
PII: S1546-2501(05)00038-1 doi:10.1016/j.sram.2005.09.003 © 2005 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. | |
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