Bioidentical Hormones: Advances in Research and What to Ask Your Provider

Advances in HRT Research-Safety

One of the earliest uses of HRT was documented in an 1897 publication highlighting the use of desiccated ovarian extracts to alleviate vasomotor symptoms.⁴ As science evolved, publications emerged describing the extraction of hormones from pregnant female urine (Emmenin®) in 1934 and eventually pregnant mare urine (Premarin®) in 1937 for the therapeutic relief of menopausal symptoms.^11,12 Premarin®, or conjugated estrogens (CE), rapidly became the dominant form of HRT. Although progesterone was first isolated shortly after the production of Emmenin®, synthetic progestins were not used for uterine protection until the 1970s.^13-17 However, extensive safety research was not performed on CE or progestins until the 1990s and early 21st century.

The HERS was the first of the CHT safety publications.¹⁸ The authors of the study concluded that conventional HRT should not be used for cardiovascular protection. Women were found to have an increased risk for developing cardiovascular disease and the risk persisted with continued use as shown in their follow-up trial. The WHI, the largest CHT study to date, similarly demonstrated that CE did not provide cardiovascular protection and increased the risk for venous thromboembolism. Additionally, the WHI identified the use of combination CE and progestins as a significant risk factor for breast cancer and cardiovascular disease. ^19,20

Although not as large in size or scope as CHT studies, several BHRT studies have been conducted to assess the safety of bioidentical hormones. Concerning cardiovascular disease, studies by the Postmenopausal Estrogen/Progestin Interventions Group (PEPI) and Gerhard et al demonstrated that natural progesterone does not negatively impact cardiovascular disease progression, unlike synthetic progestins.^21,22 Additionally, vascular reactivity was improved with percutaneous estradiol in Gerhard’s trial. In further support of these findings, Hodis et al demonstrated that estradiol reduces subclinical vascular diseases and may serve as a possible alternative to lipid lowering therapy.²³ Canonico and colleagues found that percutaneous estradiol and progesterone does not increase the risk of venous thromboembolism, unlike oral estrogen and/or progestin therapy.²⁴ With regard to breast cancer, Chang and Foidart conducted identical trials which demonstrated that progesterone counteracts breast epithelial proliferation and prevents breast epithelial hyperplasia.^25,26 Fournier and colleagues have shown that estriol and combination estradiol and progesterone does not increase the risk of breast cancer in their observational cohort study of 80,000 women. ²⁷ From the available data, BHRT may prove to be cardioprotective and not increase the risk for breast cancer. Practioner’s must rely on the available medical literature to make clinical decisions for their patients.

Advances in BHRT Research-Routes of Administration

The most common routes of BHRT administration include oral, transdermal, vaginal, and sublingual. The use of oral estrogen replacement has fallen out of favor due to the risk of VTE highlighted in trials such as Canonico’s ESTHER trial.²⁴ Additionally, oral progesterone has sedative effects due to metabolites produced from hepatic metabolism.²⁸ Thus, routes of administration with fewer side effects, such as topical administration, have been utilized. However, trials have demonstrated inconsistent therapeutic outcomes despite various anecdotal claims of effectiveness. These inconsistent outcomes are generally attributed to the pharmacokinetic profiles of topical BHRT. Moreover, the pharmacokinetics of topical progesterone is not well defined. Studies have demonstrated that topical progesterone administration does not result in significant elevations in serum hormone levels, yet can achieve measureable levels in the uterine lining.^29-31 Additionally, studies which have sought to determine the effectiveness of topical progesterone for the relief of vasomotor and mood symptoms have shown mixed results, some favoring effectiveness and other not.^{30, 32-34} Vaginal delivery methods have not gained attraction aside from administration of bioidentical estrogens to aid with vaginal dryness. Thus, alternative routes are continuously examined for improved outcomes while maintaining a favorable safety profile.

The sublingual route of administration is being used at increasing rates in the United States. Sublingual administration is non-invasive and provides several clinical benefits. First, hormones are rapidly absorbed into the bloodstream, owing to the high vascularization sublingually. This allows for significant increases in blood hormone levels within hours, providing for more rapid relief of menopausal symptoms compared to topical dosage forms. Secondly, the sublingual route allows for the bypass of first pass metabolism. First pass metabolism is responsible for the significant reduction in hormone bioavailability following oral administration. By bypassing this effect, the sublingual route provides for hormone levels significantly higher than those provided by oral administration. For example, progesterone serum levels have been measured to be 10-fold higher with sublingual administration compared to oral administration. ^35-37

Questions to Ask

The decision to begin BHRT is complex and involves evaluation of several patient-specific factors. A physician will evaluate the patient’s age, laboratory values, medical history, surgical history (e.g., hysterectomy), and symptoms (including severity). Patients who exhibit low hormone levels in conjunction with hormone imbalance/deficiency symptoms will likely be candidates for BHRT, with consideration taken for other medical conditions, such as prior history of breast cancer or cardiovascular disease.

Patient should be highly involved in the decision to begin a BHRT regimen. Some important questions to ask your provider before beginning BHRT include the following:

What are the risks involved with using BHRT?
How long should BHRT be continued?
How soon will I recognize a change in symptoms?
What benefits, other than symptom relief, evolve from using BHRT?

It is also important for the patient to provide the practitioner with an accurate medical history and medication list. These factors are important for the practitioner because some symptoms commonly seen in menopause are also associated with other medical conditions or medications. Also, some medications may have additional effects in the body when used in combination with BHRT.

References:

References

1. Reed-Kane D. Natural hormone replacement therapy: What it is and What consumers really want. Int J Pharmaceut Compounding 200; 5: 332.
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;121:73-85.
3. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8 Suppl 1:3-63.
4. Fosbery WHS. Severe climacteric flushings successfully treated by ovarian extract. Br Med J.1897;1:1039.
5. Lee J. What your doctors may not tell you about menopause. New York: Time Warner; 1996.
6. Wright JV, Morgenthaler J. Natural hormone replacement: for women over 45. Ptaluma: Smart Publications; 1997.
7. Greene R, Dalton K. The premenstrual syndrome. Br Med J 1953;1:1007-14.
8. Dalton K. Progesterone or progestogens? Br Med J 1976;2:1257.
9. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician- Gynecologists. Use of botanicals for management of menopausal symptoms. Obstet Gynecol 2001;97:suppl 1-11.
10. Kaufert P, Boggs PP, Ettinger B, Woods NF, Utian WH. Women and menopause: beliefs, attitudes, and behaviors. The North American Menopause Society 1997 Menopause Survey. Menopause 1998;5:197-202.
11. Moskowitz D. A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Altern Med Rev 2006;11:208-23.
12. Collip JB. The ovary stimulating hormone of the placenta. Can Med Assoc J 1930;22:215 9.
13. Makepeace AW, Weinstein GL, Friedman MH. The effect of progestin and progesterone on ovulation in the rabbit Am J Physiol 1937;119:512-6.
14. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975;293:1164-7.
15. Gambrell RD, Jr., Bagnell CA, Greenblatt RB. Role of estrogens and progesterone in the etiology and prevention of endometrial cancer: review. Am J Obstet Gynecol 1983;146:696-707.
16. Thom MH, White PJ, Williams RM, et al. Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. Lancet 1979;2:455-7.
17. Whitehead MI, Townsend PT, Pryse-Davies J, Ryder TA, King RJ. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. N Engl J Med 1981;305:1599-605.
18. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
19. Rossouw JE, Anderson GL, Prentice RL, 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;288:321-33.
20. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.
21. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995;273:199-208.
22. Gerhard M, Walsh BW, Tawakol A, et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation 1998;98:1158-63.
23. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-53.
24. 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.
25. Chang KJ, Lee TT, Linares-Cruz G, Fournier S, de Lignieres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995;63:785-91.
26. Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998;69:963-9.
27. 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.
28. de Lignieres B, Dennerstein L, Backstrom T. Influence of route of administration on progesterone metabolism. Maturitas. 1995 Apr;21(3):251-7.
29. Cooper A, Spencer C, Whitehead MI. Systemic absorption of progesterone from Progest cream in postmenopausal women. Lancet. 1998 Apr 25;351 (9111):1255-6.
30. Vashisht A, Wadsworth F, Carey A, Carey B, Studd J. A study to look at hormonal absorption of progesterone cream used in conjunction with transdermal estrogen. Gynecol Endocrinol 2005;21:101-5.
31. Bulletti C, de Ziegler D, Flamigni C. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod. 1997 May;12(5):1073-9.
32. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225-8.
33. 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;10:13-8.
34. Benster B, Carey A, Wadsworth F, Vashisht A, Domoney C, Studd J. A doubleblind placebo-controlled study to evaluate the effect of progestelle progesterone cream on postmenopausal women. Menopause Int 2009;15:63-9.
35. Wren BG, Day RO, McLachlan AJ. Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Climacteric. 2003 Jun; 6(2):104-11.
36. Price TM, Blauer KL, Hansen M. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol. Obstet Gynecol. 1997 Mar;89(3):340-5.
37. Gass MS, Rebar RW, Cuffie-Jackson C. A short study in the treatment of hot flashes with buccal administration of 17-beta estradiol. Maturitas. 2004 Oct 15;49(2):140-7.