Objective: Currently available treatments for menopausal symptoms are associated with differing endometrial safety and endometrium-related tolerability profiles. This article reviews the differential endometrial effects associated with estrogen therapy, estrogen-progestin therapy (EPT), selective estrogen receptor modulators (SERMs), and tissue-selective estrogen complex (TSEC).
Methods: Searches of electronic databases and of recent presentations at congresses were performed. Articles and abstracts relevant to the endometrial effects of estrogen therapy, EPT, SERMs, and TSECs were summarized in this interpretive literature review.
Results: Owing to their effects on the endometrium, cyclic and continuous-combined EPT can induce irregular uterine bleeding. Cyclic EPT may induce endometrial proliferation. Continuous-combined EPT reduces the incidence of endometrial cancer. In the endometrium, SERM activity ranges from essentially neutral to agonist, depending on the individual SERM. Raloxifene, tamoxifen, lasofoxifene, ospemifene, and bazedoxifene (BZA) demonstrated different degrees of endometrial tissue effects in preclinical and clinical studies. BZA inhibits the effects of conjugated estrogens on the endometrium. These effects are attributable to tissue-specific estrogen receptor degradation, which effectively diminishes the molecular target of estrogen activity in the endometrium. Conjugated estrogens/BZA, a TSEC, has a favorable endometrial profile, with incidences of hyperplasia and bleeding/spotting similar to those of placebo.
Conclusions: Endometrial safety is a significant hurdle in the development of new hormone therapies for postmenopausal women. Preclinical and clinical findings suggest that BZA has an endometrial profile distinct from those of other SERMs. TSECs are a novel approach to providing relief of menopausal symptoms with adequate endometrial safety profile.
From the 1Pfizer Inc, Collegeville, PA; 2Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA; 3Division of Reproductive Endocrinology and Infertility, Yale University School of Medicine, New Haven, CT; and 4Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
Received September 12, 2013; revised and accepted November 7, 2013.
Funding/support: Medical writing support was provided by Katie Gersh, PhD (MedErgy) and Diane M. Sloan, PharmD (Peloton Advantage) and was funded by Pfizer.
Financial disclosure/conflicts of interest: S.M. and B.S.K. are employees of Pfizer Inc. D.F.A. is a consultant to and has received funding support for clinical research from Pfizer. H.S.T. has served as a consultant to Pfizer and has received grants (to Yale University) for research support.J.H.P. was formerly an employee of Wyeth Research and has consulted for Wyeth/Pfizer, Depomed, BHR Pharma, ASCEND Therapeutics, TherapeuticsMD, Ausio Pharmaceuticals, and Shionogi.
Address correspondence to: Sebastian Mirkin, MD, Room B-4250, 500 Arcola Road, Collegeville, PA 19426. E-mail: Sebastian.Mirkin@pfizer.com