Vol. 17 • Issue 9
• Page 37
Widespread Internet use and the aging of baby boomers have transformed medicine. The debate over hormone replacement therapy is a prime example. Formerly, such debates took place in restricted scientific circles. Now, medical questions are discussed by all types of people. The current debate around hormone therapy (HT) safety is highly publicized, is highly political and has enormous financial implications. To make wise decisions, we need to look carefully at the evidence.
Amid the ongoing debate over HT, bioidentical hormone therapy (BHT) has emerged as a popular choice. The safety of bioidentical hormones as compared with synthetic and animal-derived HT preparations is a primary point of interest. Extensive literature about BHT is available, dating back more than 30 years. These studies reflect basic research on hormone physiology as well as physiologic effects of bioidentical, synthetic and animal-derived hormone preparations. Bioidentical hormones are available as pharmaceutical preparations and as individually formulated prescriptions made by compounding pharmacists.
The imprecise, often inaccurate terminology used in some discussions of hormone therapy has resulted in confusion. The term "bioidentical hormone" refers to hormone preparations that have a chemical structure identical to endogenous hormones, the hormones produced in the human body. Although they are identical to human hormones, bioidentical hormone preparations are chemically synthesized from precursor steroidal molecules derived from wild yam or soy. Therefore, the term "natural hormone" is misleading, because bioidentical hormones are in fact chemically synthesized in the lab.
On the other hand, preparations such as conjugated equine estrogen or CEE (Premarin, from the urine of pregnant mares) are prepared from a "natural" source, but the chemical structure in these preparations is foreign to the human body. CEE contains 10 active estrogens, only one of which is identical to human estrogen.
The terms "estrogen" and "estrogen replacement therapy" are also sources of confusion. Humans make three types of estrogen: 17-beta-estradiol, estrone and estriol. Each has a distinctive though similar chemical structure, and each has distinguishable effects on cellular estrogen receptors. Media reports about HT often fail to specify which type of estrogen was used in a particular study. This makes it impossible to truly understand the research results.
The term "progesterone" has been used interchangeably with progestin or progestogen, again contributing to confusion. Progesterone (bioidentical) has a different chemical structure from the various "progestogens" or "progestins" on the market, including synthetically derived medroxyprogesterone acetate, or MPA (Provera).
Generalizations in terminology have resulted in generalizations about findings and conclusions. This type of error occurred in reporting results from the Women's Health Initiative. This study used only oral CEE (Premarin) in conjunction with MPA (Provera), yet the conclusions were generalized to include all HT, and women have been frightened away from all hormone preparations as a result.1Studies show that although both the synthetic and bioidentical versions of hormones interact with the same estrogen and progesterone receptors on target cells, the physiologic effects of each are profoundly different.
A review of the literature shows a need for further research, especially larger placebo-controlled clinical studies of women who use bioidentical hormones. Nevertheless, numerous smaller studies on humans, extensive animal research and cell studies have been published. An article published early this year provides an extensive review of the scientific literature on this subject.2This meta-analysis contains almost 200 citations and concluded that bioidentical hormones have a superior safety profile.2
Breast Cancer Risk
Numerous studies have investigated physiologic differences between synthetic progestins and bioidentical progesterone.2This research shows that progestins may significantly increase estrogen-stimulated breast cell proliferation and mitotic activity, while progesterone does not.3Progesterone down-regulates estrogen receptors in the breast and reduces mitotic breast cell activity. Exposure to progesterone reduced the estradiol-induced proliferation of normal breast epithelial cells in postmenopausal women.4Synthetic progestins, however, show estrogenic or stimulatory effects in breast tissue.
Progesterone has anticarcinogenic effects in breast cancer cells.5A study of more than 54,000 postmenopausal women in France found that when combined with synthetic progestins, oral and transdermal bioidentical estrogen were associated with a significantly increased risk of breast cancer.6Researchers found no evidence of increased risk when estrogens were combined with bioidentical progesterone.6
A meta-analysis of 61 studies documented a consistent increase in breast cancer risk with synthetic HT. The average increase was 7.6% per years of use, with higher doses conferring a significantly higher risk.7A cohort study of 80,000 women ages 40 to 67 followed them for 13 years. Among women older than 50, current use of synthetic HT increased breast cancer risk by 61%.8In terms of estradiol versus CEE, the Women's Health Initiative found that CEE alone did not result in a statistically significant increase in breast cancer risk over 7 years.9This arm of the WHI trial was stopped early due to a slight increase in stroke risk.
Research about breast cancer risk and estrogen use point to causes for concern. One study reanalyzed worldwide data that examined the relationship between levels of endogenous sex hormones and breast cancer risk in postmenopausal women. The results showed that breast cancer risk rose significantly with increasing concentrations of all sex hormones examined in the study. These included estradiol and estrone, which were associated with a strong increase in breast cancer risk at increased levels.10A study that examined breast cancer risk and endogenous hormone levels in premenopausal women produced similar results.11
Another study of interest examined the use of bioidentical oral estradiol in different dosages. The researchers measured urine metabolite levels and found that the often recommended dosage of 1 mg to 2 mg per day resulted in urinary excretion of estrone at values five to 10 times the upper limit of the reference range for premenopausal women. This may contribute to increased breast cancer risk.12CEE contains at least 10 types of estrogen, only one of which is identical to the human form (17-beta estradiol). All 10 estrogen types are biologically active, and some have potent estrogenic effects. These estrogen subtypes are all processed by the liver into specific metabolites that may promote the formation of cancer.13Another study found that CEE metabolites could result in DNA damage, which may play a role in the carcinogenic effects of this type of estrogen.14
Studies that investigated the metabolism of endogenous estrogens by the liver documented differences in estrogen metabolism among women who are not on HT, and this may account for differences in breast cancer risk.
One study found that 16-alpha hydroxyestrone, one of the liver metabolites of estradiol, is associated with DNA damage, abberant gene expression and hyperproliferation of breast cells.15Estradiol can also be metabolized to a more benign form, 2-alpha hydroxyestrone.15Individual differences in metabolism may be due to genetic predispositions and dietary habits. Dietary factors, such as the use of cruciferous vegetables and flax seed lignans as well as supplements such as I3C, diindolylmethane and cruciferous sprout extracts, can favorably influence the metabolism of estrogen toward benign forms. Estrogen metabolism can be measured in urine.
The tendency for cardiovascular risk to increase among women as they age is a complex, multidimensional subject. Age-related change in hormone levels is one of a number of players in the orchestra. Research is ongoing with regard to how hormones interact with parameters including blood pressure, insulin resistance, weight gain, hematocrit increases, changes in muscle mass and bone density, and increases in blood viscosity and clotting factors.
Certain hormone preparations may favorably influence some of these parameters, but others negatively affect them. In addition, the method of hormone delivery can influence risk. A recent study found that the use of oral estrogens by women with borderline platelet levels increased clotting risk, while transdermal preparations did not.16Testing for blood viscosity parameters prior to initiation of hormone therapy represents another avenue for refining our prescribing practices to individualize care and reduce risk.
Estrogen used alone (CEE or bioidentical) has cardioprotective effects via its beneficial impact on lipids. The Women's Health Initiative demonstrated that the addition of the progestin MPA to CEE resulted in a substantial increase in heart attack and stroke.1MPA negates the cardioprotective effects of estrogen. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was the first study to examine progesterone, progestins and CEE.12The progestin (MPA) negatively affected high-density lipoprotein levels (HDL), but bioidentical progesterone added to CEE was associated with a significantly higher HDL level, thus sparing the beneficial lipid effects provided by CEE.17Other studies have supported these findings.18-20
In a blinded, randomized, crossover study, postmenopausal women with coronary arter disease were treated with estradiol for 4 weeks and then received progesterone or MPA. Exercise time to myocardial ischemia was significantly increased in the progesterone group compared with the medroxyprogesterone acetate group.18
Another parameter of cardiovascular risk is coronary spasm, which increases heart attack or stroke risk. The addition of MPA to estrogen increases vasoconstriction; the addition of bioidentical progesterone protects against artery spasm.19
Atherosclerotic Plaque Formation
In yet another risk parameter, atherosclerotic plaque formation, progesterone is protective compared with MPA. Progesterone inhibits molecular initiators of atherosclerotic plaque formation, whereas this positive effect is not observed using MPA.20
Hyperviscosity is another important risk factor for cardiovascular disease. Studies comparing oral and transdermal delivery routes of hormones found that transdermal estradiol had no detrimental effects on coagulation and no observed risk for venous thromboembolism. In contrast, studies have documented increased risk for venous thromboembolic events (VTE) with oral CEE.21Another study found that synthetic progestin given orally or transdermally increased VTE incidence.2
The use of synthetic progestins can significantly increase insulin resistance compared with the use of estrogen with progesterone.2
Numerous studies on symptom control and quality-of-life issues have documented superior efficacy for bioidentical progesterone. Four studies compared the effects of switching from synthetic progestins to progesterone. Women in all four studies reported greater satisfaction, fewer side effects and improved quality of life with progesterone as compared with MPA.22
Conclusions About BHT
Bioidentical hormones have physiologic effects that are distinctly different from those of their synthetic counterparts. In the areas of breast cancer, heart disease, heart attack and stroke risk, substantial evidence shows that bioidentical hormones are safer and more efficacious forms of hormone therapy than synthetic versions.2More randomized control trials are needed to further delineate these differences.2
FDA-approved pharmaceutical bioidentical hormone preparations are on the market. These include the following:
• oral estradiol (Estrace, Femtrace)
• estradiol transdermal patches (Alora, Climara, Estraderm, Menostar, Vivelle, Vivelle-Dot)
• estradiol transdermal gel (Divigel, Elestrin, EstroGel)
• estradiol spray (Evamist)
• estradiol topical emulsion (Estrasorb)
• vaginal estradiol cream (Estrace) and ring (Estring, Femring)
• progesterone as oral micronized progesterone (Prometrium) and vaginal gel (Crinone).
Estradiol patches are available in combination with a synthetically produced progestin. No combination bioidentical preparations are on the market.
In addition to these preparations, individually prescribed bioidentical hormone preparations can be made by compounding pharmacists. Compounding pharmacies are regulated by each state's pharmacy board and by the Pharmaceutical Compounding Accreditation Board.23The hormones they use are regulated by the U.S. Pharmacopoeia and the Code of Federal Regulations, which requires purity testing. The preparations made at compounding pharmacies are not FDA regulated or FDA approved.23
NPs who prescribe compounded formulations like the freedom to combine bioidentical hormones in individualized dosages and combinations with delivery systems that are not commercially available. Compounded prescriptions can also specify the creation of hypoallergenic creams and gels without the use of excipients and chemical preservatives.
In a consumer health bulletin published in 2008, the FDA presented its views on compounded versus prepared medications.24The bulletin states that the agency is not aware of any credible evidence to support claims about safety and effectiveness of compounded bioidentical hormone therapy drugs.
Unresolved questions about compounded BHT attracted public attention when the FDA disallowed the use of estriol in compounded medications, unless the prescriber has a valid investigational new drug application.23Estriol is often combined with estradiol in compounded medications because of its weaker estrogenic effects compared with estradiol.
In 2005, Wyeth filed a citizens petition with the FDA charging that drugs compounded with the human estrogen estriol pose a "serious threat to public health."23In 2008, the FDA restricted the use of compounded BHT containing estriol.
The Estriol Debate
Estriol is the weakest of the three estrogens. Estriol's safety is safe and effective for the treatment of menopausal symptoms.25The International Academy of Compounding Pharmacists has conducted a comprehensive literature review of estriol.26,27
In the United States, estriol is available only as part of a compounded prescription. In Europe, estriol is part of formulations made by major drug companies.
In 2008, resolutions were introduced in the U.S. Congress to urge the FDA to reverse its policy on estriol. The 2008 Congress did not take action on them. The IACP has been working with members of the 2009 Congress to reintroduce these resolutions.
Putting It Into Practice
The decision to use hormone therapy should be left to each woman and her healthcare provider, as should the choice of formulation, dosage, delivery method and length of use. This is an exciting arena for NPs who want to individualize their care of women who are interested in hormone therapy.
Elaine Weil is a women's health nurse practitioner who specializes in integrative approaches at Amitabha Medical Clinic and Healing Center in Sebastopol, Calif. She has been using bioidentical hormones in her practice for the past 10 years as one tool in a comprehensive approach to healthy aging. Weil's YouTube video on bioidentical hormone therapy has been viewed by more than 6,000 people and is available on the ADVANCE for Nurse Practitioners Web site.
1. Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
2. Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009;121(1):73-85.
3. Wood CE, et al. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007;101(2):125-134.
4. Foidart JM, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998;69(5):963-969.
5. Formby B, Wiley TS. Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis. Mol Cell Biochem. 1999;202(1-2):53-61.
6. Fournier A, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448-454.
7. Lee SA, et al. An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br J Cancer. 2005;92(11):2049-2058.
8. Ewertz M, et al. Hommone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br J Cancer. 2005;92(7):1293-1297.
9. The Women's Health Initiative Participant Web site, Frequently Asked Questions About the Estrogen-Alone Findings. Available at: http://www.whi.org/faq/faq-ealonephp. Accessed June 9, 2009.
10. Key T, et al and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94(8)606-616.
11. Eliassen AH, et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst. 2006;98(19):1406-1415.
12. Friel PN, et al. Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone. Altern Med Review. 2005;10(1):36-41.
13. Bhavanani BR. Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism. Pro Soc Exp Biol Med. 1998;217(1):6-16.
14. Shen L, et al. Alkylation of 2'-deoxynucleosides and DNA by the Premarin metabolite 4-hydroxyequilenin semiquinone radical. Chem Res Toxicol. 1998;11(2)94-101.
15. Fishman J, et al. The role of estrogen in mammary carcinogenesis. Ann NY Acad Sci. 1995;768:91-100.
16. Flaumenhaft R, et al. Association of oral but not transdermal estrogen therapy with enhanced platelet reactivity in a subset of postmenopausal women. Menopause. 2009;16(2):407-412.
17. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273(3):199-208.
18. Rosano GM, et al. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000;36(7):2154-2159.
19. Miyagawa K, et al. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med. 1997;3(3):324-327.
20. Adams MR, et al. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Throb Vasc Biol. 1997;17(1):217-221.
21. Scarabin PY, et al. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized, controlled trial. Arterioscler Thromb Vasc Biol. 1997;17(11):3071-3078.
22. Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause. 2002;9(4):253-263.
23. Wyeth Campaign Fact Sheet. Available at: http://www.iacprx.org/site/PageServer?pagename=CCH_info. Accessed June 9, 2009.
24. Bioidenticals. Sorting Myths From Facts. Food and Drug Administration Web Site. Available at: www.fda.gov/consumer/updates/bioidenticals040808.html. Accessed June 9, 2009.
25. Takahashi K, et al. Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Hum Reprod. 2000;15(5):1028-1036.
26. Biundo B, et al. Estriol literature summation, February 2008. Available at: www.iacprx.org/site/DocServer/Estriol_Lit_Review.pdf?docID=3481. Accessed June 9, 2009.
27. Estriol white paper. Available at: http://www.iacprx.org/site/PageServer?pagename=CCH_info. Accessed June 9, 2009.