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J Clin Endocrinol Metab. 2014 Mar;99(3):733-47. doi: 10.1210/jc.2013-3680. Epub 2014 Jan 1.

Current and evolving approaches to individualizing estrogen receptor-based therapy for menopausal women.

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  • 1Division of Endocrinology and Metabolism (R.J.S.), Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908; Department of Obstetrics, Gynecology, and Reproductive Sciences (R.K.), University of California-San Francisco, San Francisco, California 94143; E Bay Physicians Medical Group (R.K.), Sutter E Bay Medical Foundation, Berkeley, California 94705; Medical Affairs (C.J.A.), Women's Health, Pfizer Inc, New York, New York 10017; Medical Affairs (B.K., S.M.), Women's Health, Pfizer Inc, Collegeville, Pennsylvania 19426; and Department of Obstetrics, Gynecology, and Reproductive Sciences (H.S.T.), Yale School of Medicine, New Haven, Connecticut 06510.



Adding progestogens to estrogens changes the risk profile of hormonal therapy for menopausal women, and recent data support the need for progestogen-free options. Several current and evolving approaches to managing estrogen deficiency allow for progestogen omission. We review the mechanisms of estrogen activity and provide an overview of emerging and available estrogen receptor (ER)-based therapies.


PubMed was searched for relevant English-language articles using keywords pertaining to estrogen deficiency, menopause, hormone therapy, and estrogen-only therapy. Pivotal or recent randomized controlled trials, large observational studies, comprehensive meta-analyses, and established therapeutic guidelines were compiled.


Advances in our understanding of ER pharmacology have led to therapies designed to optimize ER activity, including selective ER modulators (SERMs) and tissue-selective estrogen complexes (TSECs). Each estrogen, SERM, and TSEC exhibits a unique profile of tissue-specific activity, spanning the spectrum from ER agonism to antagonism. Systemic estrogens unopposed by progestogens effectively manage menopausal symptoms in hysterectomized postmenopausal women but require progestogen use in postmenopausal women with a uterus. SERMs are effective for managing certain aspects of estrogen deficiency in postmenopausal women, but data suggest that pairing a SERM with estrogens to form a TSEC provides a more optimal therapeutic profile for women with a uterus.


Treating signs and symptoms of estrogen deficiency requires an individualized approach based on a woman's goals and the purported risks of different therapies. New and emerging agents have demonstrated efficacy in postmenopausal women with a uterus, while allowing these women to avoid progestogens and their possible adverse effects.

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