MENOPAUSE MATTERS from The Truth About Bioidentical www.menopause.org Hormone Therapy

JoAnn V. Pinkerton, MD, NCMP

Confusion and unsubstantiated claims surround the custom- compounded bioidentical hormone therapy products used to treat menopausal symptoms, such as hot fl ashes. This review attempts to dispel some of the confusion.

What Is Bioidentical implants, suppositories). Some of the Hormone Therapy? hormones used are not government ap- Bioidentical hormone therapy (BHT) proved (estriol) or monitored, and some- refers to exogenous hormones that are times the compounded therapies con- biochemically similar to those pro- tain nonhormonal ingredients (eg, dyes, duced endogenously by the ovaries or preservatives) that some women cannot elsewhere in the body.1 They are gener- tolerate.4 In addition, compounders do ally derived from soy and yams, but the not have to: plant product needs to be chemically al- ◾ Test for effi cacy or safety. tered to become a therapeutic agent for ◾ Provide product information about humans (eg, estrone, estradiol, estriol, proven benefi ts and risks. progesterone, and testosterone).2 Claims ◾ Give proof of batch and dose standard- by compounding pharmacies that BHT ization or purity. is “natural” and “identical” to the hor- By way of comparison, there are mones made in the body are not true.3 17β-estradiol and progesterone products Custom-made HT formulations that are that have been well tested and are regu- compounded for an individual woman larly inspected. Estradiol is available in according to a health care provider’s oral, patch, gel, ring, lotion, and mist prescription are not subject to govern- formulations. Micronized progesterone ment regulations or tested for safety. is available as oral or vaginal products. There are, however, HT products regu- These products have been rigorously lated and approved by the Food and studied in clinical trials and are regulat- Drug Administration (FDA) that contain ed by the government. They are sold with hormones chemically identical to those package inserts and product information. produced by women. (See Table for a list of FDA-approved bioi- dentical HT products.) Another hormone, What Is the Difference testosterone (shown to improve sexual Between Compounded desire), is not currently available as an and FDA-approved BHT? FDA-approved bioidentical product. Custom compounding of HT may com- bine several hormones (eg, estradiol, es- Dr Pinkerton is Director of the Midlife Health Center and trone, and estriol) and use nonstandard Professor of Obstetrics and Gynecology, University of routes of administration (eg, subdermal Virginia, Charlottesville, VA.

16 The Female Patient | VOL 37 SEPTEMBER 2012 All articles are available online at www.femalepatient.com Pinkerton

Many misconceptions surround the Table. FDA-approved Bioidentical BHT products custom compounded for Hormone Therapy Products menopausal symptom relief. Unsub- stantiated claims include that BHT pro- Composition Product Name motes weight loss, prevents Alzheimer’s Oral 17β-estradiol Estrace disease and breast cancer, and provides control of the aging process. Various generics Oral estradiol acetate Femtrace Here are some unconfi rmed statements that need to be dispelled about BHT. 17β-estradiol matrix patch Alora Climara Compounded BHT—Busted Esclim Claim: There is good scientifi c data to support the safety and effi cacy Fempatch of compounded BHT. Menostar Truth: No large, long-term studies have Vivelle been conducted to determine the effec- Vivelle-Dot tiveness, safety, or adverse effects of com- pounded BHT. No data have been submit- Various generics ted to the FDA to demonstrate that estriol 17β-estradiol reservoir patch Estraderm is safe and effective. The FDA stated in 2008 that pharmacies should not com- 17β-estradiol transdermal gel EstroGel pound products containing estriol un- Elestrin less the prescriber has submitted a valid Divigel investigational new drug application.5,6 Additionally, custom-compounded 17β-estradiol topical emulsion Estrasorb BHT does not inform patients of the 17β-estradiol transdermal spray Evamist “black box” warning carried on all FDA-approved HT products about in- 17β-estradiol vaginal cream Estrace vaginal cream creased risks of myocardial infarction, β stroke, invasive breast cancer, pulmo- 17 -estradiol vaginal ring Estring nary embolism, and deep vein thrombo- Estradiol acetate vaginal ring Femring sis in postmenopausal women. Effi cacy claims by self-proclaimed experts, mar- Estradiol hemihydrates vaginal tablet Vagifem keters, and popular literature are often Vagifem LD false and misleading, creating a popula- tion of misinformed women.7 Estradiol valerate injection Delestrogen Estradiol cypionate injection Depot-estradiol Claim: Custom-compounded BHT adheres to quality control regulations. Oral micronized progesterone Prometrium Truth: Because compounding pharma- Vaginal progesterone cream Crinone* cies are not regulated by the FDA nor are their products tested for quality, Vaginal progesterone ovules Endometrin* purity, and potency, BHT preparations *FDA approved for infertility, not menopausal hormone therapy. can vary substantially from batch to Complete information available on the NAMS website at www.menopause.org/bioidenticalcharts.pdf.15 batch.2,8 Women might overdose or un- derdose on compounded BHT, and they might be exposed to unidentifi ed risks. Claim: Salivary testing accurately Compounding pharmacies buy the hor- refl ects a midlife woman’s hormone levels. mones from distributors. It is not known Truth: Many proponents of compound- how many of the hormones are imported ed BHT promote the testing of estrogen from other countries. levels in a woman’s saliva for prescrib-

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ing “individualized” HT. There is no provide a valuable medical service scientifi c basis for using saliva testing to patients who have not been able to to adjust hormone levels.9 Free serum fi nd a commercial product that meets hormone concentrations in a midlife their individual needs. But the major- woman’s body change from day to day ity of symptomatic menopausal women depending on diet, time of day, the spe- should be able to fi nd an FDA-approved cific hormone being tested, and other product from the large variety in type of variables.10 The dosing of compounded delivery and doses available.

Conclusion FOCUSPOINT For most women suffering from meno- pause-related symptoms, commercially For most women suffering from available and approved HT will provide appropriate therapy without the risks of menopause-related symptoms, commercially unpredictable custom preparations. Ac- available and approved hormone therapy will cording to the FDA and NAMS, use of BHT is justifi ed when a woman cannot provide appropriate therapy without the risks tolerate some of the ingredients in an ap- proved product, when she needs a lower of unpredictable custom preparations. dose than is available, or she has spe- cifi c medical needs. There are currently no peer-reviewed scientific data from randomized controlled trials to suggest progesterone is particularly diffi cult to that compounded HT is safer or more assess because the levels in serum, sa- effective than conventional drugs.4,14 liva, and tissue are markedly different.2 Neither estriol nor topical progesterone It is not necessary to test hormone levels cream has been shown to reduce the to treat symptoms. risk of osteoporosis or breast cancer or to prevent estrogen-induced endometri- Claim: Compounded progesterone al hyperplasia—claims made by certain is adequate to protect the uterus compounding pharmacies and self-pro- from estrogen. claimed experts. Truth: The absorption of transdermal The FDA and NAMS advocate that compounded progesterone cream is BHT products should include a patient variable and unpredictable. Serum lev- package insert identical to that required els of transdermal progesterone were for government-approved products. This shown in three studies to be insuffi cient package information delineates the con- to protect against estrogenic stimulation traindications and warnings required of the endometrium for women with a by the FDA in class labeling for HT. In uterus.10-12 There were also mixed re- the absence of effi cacy and safety data sults in randomized controlled trials of for BHT, the generalized benefi t-risk ra- treatment of hot fl ashes. tio data of commercially available HT products should apply equally to BHT, Claim: Compounding pharmacies along with additional risks intrinsic to that make BHT should be closed down. unregulated compounding. Truth: This statement is not true. The It is the responsibility of a practitioner FDA has no interest in eliminating ap- to provide adequate education to each propriate pharmacy compounding and woman about the risks and benefi ts of focuses instead on the subset of inap- any type of HT including the lack of propriate compounders who mislead quality control and scientific data for the public.13 The FDA believes that tra- custom-compounded products and the ditional compounding pharmacists unique risks these products pose. There

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is no scientifi c evidence to support the mone therapy. Int J Impot Res. 2008;20(1):45-52. claims of increased safety or effi cacy for 8. Report: Limited FDA survey of compounded drug prod- ucts. US Food and Drug Administraion. http://www.fda. compounded BHT. gov/Drugs/GuidanceComplianceRegulatoryInformation/ PharmacyCompounding/ucm155725.htm. Accessed In the past 12 months, Dr Pinkerton has served as July 10, 2012. consultant for Endoceutics, Noven, Novogyn, and 9. Boothby LA, Doering PL, Kipersztok S. Bioidentical hor- Pfizer and received research support for multi- mone therapy: a review. Menopause. 2004;11(3):356-367. center clinical trials from Bionovo, Depomed, and 10. Lewis JG, McGill H, Patton VM, Elder PA. Caution on the Endoceutics. Previous clinical trial support was use of saliva measurements to monitor absorption of pro- received from Pfi zer. gesterone from transdermal creams in postmenopausal women. Maturitas. 2002;41(1):1-6. 11. Cooper A, Spencer C, Whitehead MI, Ross D, Barnard References GJ, Collins WP. Systemic absorption of progesterone 1. Sites CK. Bioidentical hormones for menopausal therapy. from Progest cream in postmenopausal women. Lancet. Womens Health (Lond Engl). 2008;4(2):163-171. 1998;351(9111):1255-1256. 2. Bhavnani BR, Stanczyk FZ. Misconception and concerns 12. Wren BG, McFarland K, Edwards L. Micronised trans- about bioidentical hormones used for custom-com- dermal progesterone and endometrial response. Lancet. pounded hormone therapy. J Clin Endocrinol Metab. 1999;354(9188):1447-1448. 2012;97(3):756-759. 13. FDA takes action against compounded menopause 3. Moskowitz D. A comprehensive review of the safety and hormone therapy drugs. US Food and Drug Administra- effi cacy of bioidentical hormones for the management tion Web site http://www.fda.gov/newsevents/newsroom/ of menopause and related health risks. Altern Med Rev. pressannouncements/2008/ucm116832.htm. Accessed 2006;11(3):208-223. July 10, 2012. 4. North American Menopause Society. The 2012 hormone 14. Fugh-Berman A, Bythrow J. Bioidentical hormones for therapy position statement of: The North American Meno- menopausal hormone therapy: variation on a theme. J pause Society. Menopause. 2012;19(3):257-271. Gen Intern Med. 2007;22(7):1030-1034. 5. Patsner B. Compounded bioidentical hormones: what’s 15. FDA-approved bioidentical hormones for postmenopausal the harm? The North American Menopause Society Web use in the United States and Canada. The North American site. http://www.menopause.org/Patsnertranscript.pdf. Menopause Society Web site. http://www.menopause. Accessed July 10, 2012. org/bioidenticalcharts.pdf. Accessed July 10, 2012. 6. Compounded menopausal hormone therapy questions and answers. US Food and Drug Administration Web site. http://www.fda.gov/Drugs/GuidanceComplianceRegulato- For a PATIENT HANDOUT on ryInformation/PharmacyCompounding/ucm183088.htm. Accessed July 10, 2012. bioidentical hormone therapy, see page 49. 7. Rosenthal MS. Ethical problems with bioidentical hor-

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