Female Reproductive Tract

Estrogen and Anti-estrogen Effects on Neonatal Ovine Uterine Development

Abstract

Postnatal development of the ovine uterus between birth and postnatal day (PND) 56 involves differentiation of the endometrial glandular epithelium from the luminal epithelium followed by tubulogenesis and branching morphogenesis. These critical events coincide with expression of estrogen receptor alpha (ER) by nascent endometrial glands and stroma. In order to test the working hypothesis that estrogen and uterine ER regulates uterine growth and endometrial gland morphogenesis in the neonatal ewe, ewes were treated daily from birth (PND 0) to PND 55 with: (1) saline and corn oil as a vehicle control (CX); (2) estradiol-17 valerate (EV), an ER agonist; (3) EM-800, an ERantagonist; or (4) CGS 20267, a nonsteroidal aromatase inhibitor. On PND 14, ewes were hemi-hysterectomized, and the ipsilateral oviduct and ovary were removed. The remaining uterine horn, oviduct and ovary were removed on PND 56. Treatment with CGS 20267 decreased plasma E2-17 levels, whereas EM-800 had no effect compared to CX ewes. Uterine horn weight and length were not affected by EM-800 and CGS 20267, but were decreased in EV ewes on PND 56. On PND 14 and PND 56, treatment with EV decreased endometrial thickness, but increased myometrial thickness. The number of ductal gland invaginations and endometrial glands was not affected by CGS, but was lower in EM-800 ewes on PND 56. Exposure to EV completely inhibited endometrial gland development and induced luminal epithelial hypertrophy, but did not alter uterine cell proliferation. Exposure to EV substantially decreased expression of ER, IGF-I and IGF-II in the endometrium. Results indicate that circulating E2-17 does not regulate endometrial gland differentiation or development. Although ER does not regulate initial differentiation of the endometrial glandular epithelium, results indicate that ER does regulate, in part, coiling and branching morphogenesis of endometrial glands in the neonatal ewe. Ablation of endometrial gland genesis by EV indicates that postnatal uterine development is a critical period and exquisitely sensitive to the detrimental effects of inappropriate steroid exposure.