Mechanisms regulating norgestomet inhibition of endometrial gland morphogenesis in the neonatal ovine uterus

In many species, endometrial gland adenogenesis occurs neonatally in an ova ry-and steroid-independent manner. Chronic exposure of the developing neona tal ovine uterus to norgestomet (NOR) from birth permanently ablates endome trial gland morphogenesis or adenogenesis, creating an adult ovine uterine gland knockout (UGKO) phenotype. This study was conducted to determine the mechanism(s) whereby NOR inhibits adenogenesis in the neonatal ewe. Ewe lam bs received no implant or a NOR implant at birth and on postnatal day (PND) 14, and they were necropsied on PND28. Histological analyses of the tracts indicated NOR exposure specifically inhibited endometrial adenogenesis, bu t no histoarchitectural differences were observed in the oviduct, cervix, o r vagina. No effect of NOR treatment was detected on proliferating cell nuc lear antigen (PCNA) expression in the endometrial luminal epithelium (LE), stroma, or myometrium. In control (CX) ewes, estrogen receptor alpha (ER-al pha) and progesterone receptor (PR) mRNA and protein were expressed strongl y in nascent and proliferating glandular epithelium (GE) but were undetecte d in epithelium of NOR uteri. Expression of c-met and fibroblast growth fac tor receptor 2IIIb (FGFR2IIIb) mRNA was detected in the LE and GE of CX ute ri. In NOR uteri, c-met was expressed in the LE similar to CX uteri, but FG FR2IIIb mRNA levels were lower than in the LE of CX uteri. Uterine hepatocy te growth factor (HGF), the ligand for c-met, and FGFR2IIIb mRNA expression was substantially lower in NOR ewes, but expression of FGF-7 and FGF-10 mR NAs, ligands for FGFR2IIIb, was unaffected. These results indicate that NOR disrupts endometrial adenogenesis by ablating epithelial ER-alpha expressi on and altering expression of paracrine growth factors and/or receptors inv olved in epjthelio-mesenchymal interactions. Likewise, these mechanisms are proposed to be important regulators of normal uterine gland morphogenesis in the neonate. (C) 2000 Wiley-Liss, Inc.