Fertility: Role of Repressor of Estrogen Receptor Activity

Uterine adenogenesis, a unique postnatal event in mammals, refers to morphological differentiation and development of the uterus that is vulnerable to adverse effects of endocrine disrupters (1). Key morphogenetic events in uterine adenogenesis include 1) organization and stratification of stromal cells, 2) differentiation and growth of the myometrium, and 3) differentiation and morphogenesis of the uterine glands (1, 2). Progressive development of uterine luminal epithelium (LE) gives rise to buds that transition to glandular epithelium (GE) followed by tubulogenesis and coiling and branching morphogenesis to form mature uterine glands (see Fig. 1). Uterine adenogenesis is disrupted by inappropriate exposure of the neonatal lamb to either estradiol-17 or progesterone between postnatal day (PND) 0 and PND 56 (2) resulting in an aglandular uterus. Exposure of the neonatal mouse to progesterone between PND 3 and PND 9 also abrogates uterine adenogenesis (3). Disruption of uterine adenogenesis in both ewes and mice results in infertility. The effectiveness of nuclear hormone-receptor complexes depends on coregulator partner proteins, some of which affect uterine development and fertility. The importance of the coregulator designated repressor of estrogen receptor activity (REA) in uterine adenogenesis has been clarified through research of collaborating scientists at the University of Illinois and Baylor College of Medicine (4).Globaldeletionof theREAgenewas embryonic lethal; therefore, REA was conditionally deleted only in cells that express progesterone receptors to determine effects on postembryonic stages of development in mice. Mice conditionally homozygous for deletion of REA (REAd/d) developed to adulthood and had normal ovarian function but were infertile due to disruption of uterine adenogenesis resulting in the absence of uterine glands and failure of implantation and endometrial decidualization. However, mice heterozygous for REA (REAf/d) were hyperresponsive to estradiol-17 as evidenced by increased proliferation of uterine LE and enhanced fluid imbibition associated with altered expression of aquaporin genes. Park et al. (4) concluded that uterine development and regulation of estrogen receptor activities have a bimodal dependence on gene dosage of REA. There was normal uterine development and function in wild-type mice, whereas partial deletion of REA (REAf/d) resulted in uterine hyperresponsiveness and subfertility, and complete deletion of REA (REAd/d) abrogated uterine adenogenesis and fertility. Uterine adenogenesis also fails in mice lacking functional genes required for interactions between epithelium and stroma including Wnt7a (5), Wnt5a (6), Foxa2 (7), a member of the forkhead transcription factor family, and E-cadherin (Cdh1) (8). Hormonal regulation of Cdh1 in uteri of mice is not known, but expression of Wnt7a, Wnt5a, and Foxa2 genes is affected by sex steroids (7, 9). At birth, uteri of mice and rats consist of uterine LE supported by undifferentiated mesenchyme (10). On PND 5, epithelial invaginations form buds for development of uterine GE and developed GE are present on PND 7 and 9 in mice and rats, respectively (11). In rats, uterine adenogenesis proceeds from PND 9 through PND 15, resulting in development of simple, tubular, and slightly coiled uterine glands (11). Interestingly, Park et al. (4) found the altered uterine phenotype in REAd/d mice between PND 10 and 14, the period of development of uterine glands.