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Menopause Matters

Bioidentical Hormones: Separating Science From Marketing

Wulf H. Utian, MD, PhD

Many manufacturers are promoting bioidentical hormones as Ànatural” and thus safer alternatives to hormone therapy. Physicians need to take a more proactive role in informing patients about the risks posed by these Ànatural” products.

In the quest for safer, more Ànatural” treatments, many women are looking to bioidentical hormones for treatment of menopause-related symptoms. But exactly what are bioidentical hormones, and do they have a different risk-benefit profile than other hormones?

DEFINITION

In a scientific context, bioidentical hormones refers to exogenous hormones that are exact chemical replicas of endogenous hormones. These include the estrogens estrone, estradiol, and estriol, as well as progesterone. The US Food and Drug Administration (FDA) has approved many prescription products that contain bioidentical hormones. However, this term can also refer to hormones that are custom compounded from a prescription into formulations such as topical creams, gels, and lotions or sublingual tablets, subdermal implants, and suppositories.

A major difference between the commercial prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety. Products from compounding pharmacies are not regulated in this fashion. As a result, dosing and purity can vary, and safety and efficacy are unknown.

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ESTROGEN FORMULATIONS

Some compounded estrogen formulations contain sufficient doses to produce the same biologic effects as associated with commercial estrogen preparations. However, clinical studies have not documented that any of these custom-compounded products confers equal (or better) efficacy and safety.

One commonly compounded estrogen formulation contains estriol, which is not available in commercial preparations. Often, claims are made that estriol is safer than commercial estrogen products. Case-controlled data have shown that oral (but not vaginal) estriol used without a progestational agent increases the risk of endometrial cancer,1 indicating that its biological behavior is similar to that of other estrogens.

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TOPICAL PROGESTERONE

Many brands of topical progesterone are available in over-the-counter (OTC) lotions, gels, and creams. However, nonprescription progesterone preparations vary widely in dosages, formulations, and additional ingredients. For example, random tests have found that the progesterone concentration of the various OTC brands varies widely, from no active ingredient to 450 mg/oz. By comparison, prescription custom- compounded progesterone cream usually contains 400 to 450 mg/oz of progesterone.

Health claims from OTC manufacturers of topical progesterone products range from relief of hot flashes and other menopause-related symptoms (purportedly by balancing the hyperestrogenic surges of perimenopause) to protection against osteoporosis and breast cancer. Despite extensive clinical experience, scientific evidence of efficacy for menopause-related symptoms is limited. In randomized clinical trials evaluating the use of topical progesterone cream for hot flashes, results were insufficient to support a claim of efficacy.2,3

Anecdotal and limited clinical trial evidence suggests that absorption of topical progesterone cream is minimal, varies from woman to woman, and produces low serum levels of progesterone.4 No improvement has been documented for endpoints including bone mineral density, cardiovascular markers, or endometrial protection.5 Also, no data have documented a reduced risk of breast cancer with topical progesterone.

It is especially important for clinicians to emphasize to women that topical progesterone formulations do not produce the significant changes in systemic progesterone levels needed to prevent the endometrial hyperplasia associated with unopposed estrogen therapy.6 That is, topical progesterone formulations cannot protect the uterus from the effects of unopposed estrogen.

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SALIVARY ASSAYS

The use of bioidentical hormones is frequently based on salivary hormone assays. In theory, these assays can be used to individualize hormone administration by identifying a particular woman¡s hormone deficiencies. However, such testing does not constitute valid clinical practice.

Salivary hormone levels vary widely between individuals, and also from measurement to measurement within the same individual. Thus, no Àcorrect” level has been established for postmenopausal women. Furthermore, the clinical studies needed to document a correlation between salivary hormone levels and clinical state or responses to therapy are lacking, and probably would not yield useful information because of the variability in salivary hormone values.

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CLINICAL IMPLICATIONS

Clinicians are advised to discuss the following points with their patients regarding bioidentical hormones:

• Prescription bioidentical products are federally regulated and tested for purity, potency, efficacy, and safety; products from compounding pharmacies are not. Concentrations of active ingredients vary widely, as does the choice of inactive ingredients.
• There is no evidence to suggest that prescription bioidentical estrogen products are safer or more effective than conventional prescription estrogen products.
• Topical progesterone cream is not recommended to lower the risk of osteoporosis or breast cancer or to prevent estrogen-induced endometrial hyperplasia. Furthermore, there is little evidence to support the contention that progesterone has a more favorable impact on the cardiovascular system than synthetic progestins.

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CONCLUSION

Both patients and physicians need to maintain a healthy skepticism when evaluating the marketing claims of custom-compounded bioidentical hormones and topical progesterone creams. At best, many such products may be similar to standard prescription products but more expensive; at worst, some may be harmful.

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Wulf H. Utian, MD, PhD, is Arthur H. Bill professor emeritus of reproductive biology, Case Western Reserve University School of Medicine, and consultant in women¡s health, The Cleveland Clinic Foundation, both in Cleveland, Ohio. Dr Utian is also executive director, The North American Menopause Society.

References

1. Weiderpass E, Baron JA, Adami HO, et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. 1999;353(9167):1824-1828.
2. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999;94(2):225-228.
3. Wren BG, Champion SM, Willetts K, Manga RZ, Eden JA. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause. 2003;10(1):13-18.
4. Cooper A, Spencer C, Whitehead MI, Ross D, Barnard GJ, Collins WP. Systemic absorption of progesterone cream from Progest cream in postmenopausal women. Lancet. 1998;351(9111):1255-1256.
5. The North American Menopause Society. Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society. Menopause. 2003;10(2):113-132.
6. Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol. 1999;180(6 pt 1):1504-1511.

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