The uterine gland knock-out ewe: a model to study the role of endometrial glands in uterine function

Abstract

Endometrial glands are hypothesized to be required for normal mammalian uterine function. Therefore, the following studies were conducted with ewes to determine: 1) the mechanism by which neonatal progestin treatment altered endometrial development; 2) the role of endometrial glands in the uterine-dependent estrous cycle; and 3) the role of endometrial glands in the ability of the uterus to support establishment and maintenance of pregnancy. The first study determined the mechanism by which neonatal progestin exposure ablated endometrial gland morphogenesis and effects, if any, on development of extrauterine reproductive tract structures. Progestin exposure only affected uterine development in the neonatal ewe, resulting in a uterine gland knockout (UGKO) phenotype. Results suggested that progestins inhibit estrogen receptor-[] expression and epithelial-mesenchymal interactions by altering expression of growth factors and their receptors. The consequences of progestin disruption of these events was ablation of endometrial gland development. The second study identified length of neonatal progestin exposure necessary to ablate endometrial gland development in the adult and effects of this phenotype on ability of adult ewes to reach puberty and exhibit normal estrous cycles. Results indicated that only eight weeks of progestin exposure from birth was sufficient to block adenogenesis. Absence of endometrial glands induced a defect in the uterine-dependent luteolytic mechanism which was manifest in varied interestrous intervals in UGKO ewes. The third study examined effects of neonatal progestin treatment on reproductive tract development in the adult ewe and the ability of UGKO ewes to establish and maintain pregnancy. Consistent with the first study, uterine glands were not formed in adult ewes neonatally exposed to progestin, and no other reproductive tract structures were affected. Bred UGKO ewes were unable to establish and/or maintain pregnancy to Day 35. The uteri of some UGKO ewes demonstrated a partial penetrant phenotype and number of uterine glands present was directly correlated to conceptus survival and developmental state on Day 14 post-mating. Collectively, results of these studies suggest that endometrial glands are unequivocally required for normal ovine uterine function. Absence of endometrial glands results in defects in development of the luteolytic mechanism and inability to support a successful pregnancy. Endometrial glands and their secretions are necessary for conceptus survival and elongation during the peri-implantation stage. The UGKO ewe model will be useful to identify genes involved in uterine gland development and function. The UGKO partial penetrant phenotype may be useful to investigate the role of endometrial glands during later pregnancy.