Differential effects of menopausal therapies on the endometrium

Menopause. 2014 Aug;21(8):899-908. doi: 10.1097/GME.0000000000000186.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Endometrium / drug effects*
  • Estrogen Replacement Therapy*
  • Estrogens, Conjugated (USP) / administration & dosage
  • Female
  • Hot Flashes / drug therapy*
  • Humans
  • Menopause*
  • Selective Estrogen Receptor Modulators / administration & dosage


  • Estrogens, Conjugated (USP)
  • Selective Estrogen Receptor Modulators