Experts in the Art & Science of Pharmaceutical Compounding

v o l u m e V II, chapter 12 The Role of Compounding and Customizing Estrogen in Hormone Replacement Therapy

Points/Quotes from Articles 1. Menopause management requires effective collaboration between the patient and provider. Careful consideration, in-depth education and discussion are essential when initiating or continuing any form of hormone therapy.3 A compounding pharmacist can customize hormone replacement therapy to meet a patient’s specific need. Customizing options include making the hormone replacement in a variety of dosage forms, such as transdermal creams or sustained release capsules.1 2. Individualizing hormone replacement addresses the No. 1 problem with HRT: compliance. Many women tire of taking numerous medications a day. Compounding has the ability to combine the medications into one capsule, encouraging compliance through ease of dosing.1 3. Bio-identical hormone replacement therapy (BHRT) uses hormones containing the exact molecular structure as hormones made in the body. These hormones are chemically indistinguishable from endogenous hormones and exert the same physiologic response as endogenously produced hormones in the body.1 4. Estrogen is not a single hormone. Rather, it is a group of different but related hormones that perform functions normally attributed to estrogens. The three estrogens that predominate in an adult woman are: estrone (E1), which constitutes approximately 10-20% of circulating estrogens; estradiol (E2), which constitutes approximately 10-20% of circulating estrogens, and estriol (E3), which constitutes approximately 60-80% of circulating estrogens.2 5. The goal of BHRT is to mimic normal physiology as much as possible, putting the hormones back to levels where they are beneficial for relief of symptoms.3 6. Estrogen effects are mediated through 2 different estrogen receptors: estrogen receptor-alpha (ER-a) and estrogen receptor-beta (ER-). ER-a promotes breast cell proliferation, while ER- inhibits proliferation and prevents breast cancer development via G2 cell cycle arrest.4 7. Estradiol equally activates ER-a and ER-, while estrone selectively activates ER-a at a ratio of 5:1. In contrast, estriol selectively binds to ER- at a ratio of 3:1. This unique property of estriol, in contrast to the selective ER-a binding by other estrogens, imparts to estriol a potential for breast cancer prevention, while other estrogens would be expected to promote breast cancer.4 8. Melamed et al. demonstrated that, when administered with estradiol, estriol may have a unique ability to protect breast tissue from excessive estrogen-mediated stimulation. Acting alone, estriol is a weak estrogen, but when give with estradiol, it functions as an antiestrogen. Interestingly, estriol competitively inhibits estradiol binding and also inhibits activated receptor binding to estrogen response elements, which limits transcription.4,10 9. Estriol is very effective in alleviating vaginal and urinary symptoms in postmenopausal women.1 10. Estriol showed significant reduction in hot flashes,5,6,7 night sweats,5 vaginal dystrophy and insomnia.5,7 11. While conventional hormone replacement therapy provides certain benefits, it is not without significant risks. Estriol has been found to provide some of the protection without the risk associated with stronger estrogens.7 12. Oestriol protects against breast carcinoma as induced by two carcinogens, DMBA and procarbazine.8 13. Estriol did not induce any breast density increases. Estriol may be a preferable HRT for women in whom breast cancer is a concern.9 14. Estriol is a safe and effective alternative for relieving climacteric symptoms in postmenopausal women. In a 12-month study, no stimulatory effects of the breast and endometrial tissue were observed. Histologic evaluation of the endometrium and ultrasound assessment of the breast following 12 months of estriol treatment found normal results in all women.5 15. Estriol can be a very good alternative to standard estradiol or other conjugated estrogens in hormone replacement therapy for all climacteric women, especially with advantages for those who have suspected risks of thromboembolism or endometrial cancer or those who do not wish regular uterine bleeding.6 16. No manufactured product mimics the body’s production of the hormones mentioned above. Some commercially available products contain one of the three estrogens the body produces, but not a combination of the three. Some products that contain 17-estradiol, such as Estrace and certain transdermal patches, such as Climara.1 17. Bi-estrogen (often called Biest in compounding) contains a combination of two of the three bio-identical estrogens in combination. The most commonly prescribed combination is 80% and 20% (80/20) or 70% and 30% (70/30).1 This combination is only available through a compounding pharmacy.

References 1. Romero, M. Bioidentical hormone replacement therapy – customizing care for perimenopausal and menopausal women. Advance for Nurse Practitioners. 2002; 10(11): 47-52. 2. Wright J, Schliesman B, Robinson L. Comparative measurements of serum estriol, estradiol, and estrone in non-pregnant, premenopausal women: a preliminary investigation. Alternative Medicine Review. 1999; 4(4): 266-270. 3. Campbell S. Bioidentical hormones-Achieving the perfect fit. Advance for Nurse Practitioners. 2006; 14(2):25-29. 4. Holtorf, K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgraduate Medicine. 2009; 121(1): 1-13 5. Takahashi K et al. Efficacy and safety of oral estriol for managing postmenopausal symptoms. Maturitas – The European Menopause Journal. 2000; 34: 169-177. 6. Yang T, Tsan S, Chang S, Ng H. Efficacy and safety of estriol replacement therapy for climacteric women. Chinese Medical Journal (Taipei). 1995; 55: 386-391. 7. Head KA. Estriol: Safety and Efficacy. Alternative Medicine Review. 1998; 3(2): 101-113. 8. Lemon HM. Pathophysiologic consideration in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma. Acta endocrinologica. 1980; S233: 17-27. 9. Valdivia I, Ortega D. Mammographic density in postmenopausal women treated with tibolone, estriol, or conventional hormone replacement therapy. Clinical Drug Investigation. 2000; 20 (2): 101-107. 10. Melamed M, et al. Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol. Molecular Endocrinology. 1997; 11(12): 1868-1878

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03.23.09