Questions and Answers About Menopause Therapy with Nese Yuksel

By Nese Yuksel, BScPharm, PharmD, FCSHP, NCMP

Division Chair, Pharmacy Practice
Faculty of Pharmacy and Pharmaceutical Sciences
University of Alberta


How does physiologic estrogen differ from synthetic estrogen?

There are three physiologic estrogens present in the human body: estrone, estradiol (or 17ß-estradiol), and estriol. Estradiol, produced in the ovaries, is the most biologically active of the estrogens, followed by estrone (approximately one third the activity). Estrone is reversibly converted from estradiol, as well as derived from androstenedione in adipose tissue. Estriol is the least active estrogen (< 10% of the activity) and is a by-product of estradiol and estrone metabolism, with the highest amounts seen during pregnancy. In a premenopausal woman, estradiol is the predominant estrogen, however after menopause this shifts to estrone (2:1 ratio).

The term “bio-identical hormone therapy” (BHT) often is used to refer to hormone therapy (HT) regimens that include physiologic hormones. Though there is no medical definition, BHT refers to hormones that are identical in molecular structure to human hormones.1 In Canada, several commercially available, Health Canada-approved products contain bio-identical estrogens including 17ß-estradiol (oral, transdermal patches, gels and vaginal products) and estrone (vaginal cream).2 Estriol has not been approved for use in Canada, though it is included as part of compounded BHT. Bio-identical estrogens are extracted from plant sources and chemically synthesized to the active ingredient.

Ethinyl estradiol (EE), a synthetic estrogen that has been formulated to increase potency and extend half-life compared to physiologic estrogens, is found in combined hormonal contraceptives (1 mg oral 17ß-estradiol is equivalent to approximately 5 µg EE).2 Conjugated estrogens contain a mixture of estrogens and are derived from plants or animals. Conjugated equine estrogen (CEE), a mixture of 10 estrogens extracted from pregnant-mare urine, is not bio-identical, nor would it be considered synthetic.3 Other synthetic estrogens include the esterified estrogens.

Unfortunately, there are very few comparative trials evaluating the different estrogens. Most of our information on HT efficacy and safety is with CEE, as this is the most commonly studied estrogen.4 There is little evidence available to support greater efficacy of physiologic estrogens vs. other estrogens. However, route of administration may affect risk, as there are differences in terms of hepatic effects depending on the formulation.

Oral estrogens in HT products have a high first-pass effect in the liver and result in stimulation of hepatic proteins leading to increases in not only HDL-cholesterol, but also triglycerides, sex hormone-binding globulin (SHBG), and coagulation factors.3 All transdermal HT products contain 17ß-estradiol and have the advantage of bypassing the first-pass effect in the liver. At low to standard doses, transdermal estrogens may have a reduced risk of venous thromboembolism compared to oral estrogen.5,6 EE may have a more pronounced hepatic effect compared to estradiol, because of the higher potency, and this effect is maintained with the different EE formulations.6

The difference between various estrogens in terms of breast-cancer risk is not clear. Estriol often is promoted as being associated with lower risk of breast cancer, however there is no clear evidence the risk is lower compared to other estrogens.7 The current recommendation is that, until further evidence is available, the efficacy and safety profiles should be considered similar for all estrogens.2,4

What do you tell a patient who asks about bio-identical hormones?

There is no scientific definition for “bio-identical hormones,” but this commonly refers to any hormones that are identical to human hormones in terms of molecular structure.1 Bio-identical hormones include estrogens (estradiol, estrone and estriol), micronized progesterone, testosterone and dehydroepiandrosterone (DHEA). Bio-identical hormone therapy (BHT) often is mistaken for compounded formulations, however there are many commercially available, Health Canada-approved products that contain bio-identical hormones including estradiol, estrone and micronized progesterone.2 Compounded BHT includes the use of estriol in combination with estradiol and/or estrone, as well as the use of progesterone creams in some settings. No commercial estriol product has been approved in Canada.

Women may have misconceptions about BHT because of the ways in which these products are promoted.8 As healthcare professionals, we can help clarify many of these misconceptions. One common misnomer is that BHT is “natural.” In reality, these products are derived from plant-based sources, and then chemically converted to have the same molecular structure as human hormones. Another issue is that BHT often is promoted as being safer and more efficacious than other HT; however not enough evidence exists to make these claims. There are preliminary data that there may be benefits with certain bio-identical hormones. For example, micronized progesterone may have favorable outcomes in terms of sleep, moods and breast-cancer risk compared to synthetic estrogens.9,10 Additionally, transdermal estradiol formulations bypass the first-pass effect in the liver and may have less risk of venous thromboembolism vs. oral HT.6

Estriol often is used in compounded BHT formulations, as it is purported to be protective against breast cancer; however there are no studies to substantiate this claim.7 Estriol at adequate doses may stimulate breast-tissue cells similar to other estrogens.11 Women also should be cautioned about the use of compounded progesterone creams for endometrial protection with estrogens, as cases of endometrial cancer have been reported.12 Salivary levels sometimes are used to individualize therapy and adjust doses to “balance” hormones. Unfortunately, there is a great deal of inter-patient variability in terms of hormone levels, and no clear guidelines exist on using salivary or blood levels to tailor the dose.13 Patient symptoms are the best way to monitor and adjust doses.

Professional organizations, including the North American Menopause Society (NAMS) and the Society of Obstetricians and Gynaecologists of Canada (SOGC), indicate that, until further data are available, the benefits and risks should apply equally with the different HT products.2,4 Meanwhile, however, as healthcare providers, we can help women make informed decisions based on the available evidence, and guide choice of therapy to address patient-specific needs.


1. Whelan A, Jurgens T, Trinacty M. Defining bioidentical hormones for menopause-related symptoms. Pharmacy Practice 2011; 9:16-22.

2. Reid R, Abramson BL, Blake J, et al. Managing menopause. J Obstet Gynaecol Can 2014; 36(9):830-8.

3. Khul H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005; 8(Suppl 1):3-63.

4. Gass ML, Heights M, Manson JE, et al. The 2012 hormone therapy position statement of the North American Menopause Society. Menopause 2012; 19:257-71.

5. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women. Impact of the route of estrogen administration and progestogens: the ESTHER Study. Circulation 2007; 115:840-5.

6. Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010; 30:340-5.

7. McBane SE, Borgelt LM, Barnes KN, et al. Use of compounded bioidentical hormone therapy in menopausal women: an opinion statement of the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 2014; 34(4):410-23.

8. Yuksel N, Brochu L, Malik B, et al. Promotion and marketing of bioidentical hormone therapy on the internet: a content analysis of websites. Menopause 2014; 21:1329.

9. Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril 1999; 72:389-97.

10. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008; 107:103-11.

11. Lippman M, Monaco ME, Bolan G. Effects of estrone, estradiol, and estriol on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 1977; 37:1901-7.

12. Davis R, Batur P, Thacker HL. Risks and effectiveness of compounded bioidentical hormone therapy: a case series. J Womens Health 2014; 23(8):642-8.

13. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: A review. Menopause 2004; 11:356-67.

Development of this article was sponsored by Merck Canada Inc. The author had complete editorial independence in the development of this article and is responsible for its accuracy. The sponsor exerted no influence in the selection of content or material published.