Abstract
Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By 20 weeks of age, uterine gland development was comparable to controls, but pathologies, including squamous neoplasia, tubal neoplasia, and cribriform glandular structures, were observed. Induction of ovulations by periodic human chorionic gonadotropin treatment did not rescue post-pubertal uterine gland development. Interestingly, progesterone receptor knockout mice, which lack progesterone signaling, also have defects in post-pubertal uterine gland development. However, progesterone treatment did not rescue post-pubertal uterine gland development. These studies indicate that chronically elevated levels of estradiol with low progesterone and therefore an absence of cyclic ovarian hormone secretion disrupts post-pubertal uterine gland development and homeostasis.
Footnotes
Summary sentence: Gnrhr E90K homozygous mutant female mice exhibit chronic estrus that disrupts post-pubertal endometrial gland development and homeostasis.
Grant support: Supported by grant HD030284 from the U.S. National Institutes of Health and the Ben F. Love Endowment (to R.R.B.), 12BGIA11860006 from the American Heart Association and the University of Houston Division of Research Small Grants Program 1HOU08 (to M.D.S). Veterinary resources were supported by NIH grant CA16672.