Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR36-Ovarian & Uterine Function
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 104 (Moscone Center)
Shannon Deanne Whirledge*1, Francesco J DeMayo2, John P Lydon2 and John A Cidlowski3
1NIEHS, Durham, NC, 2Baylor College of Medicine, Houston, TX, 3NIEHS/NIH, Research Triangle Pk, NC
Amenorrhea and infertility in Cushing’s patients, which suffer from prolonged exposure to elevated cortisol, suggests precise regulation of glucocorticoid signaling is required to achieve pregnancy. Well studied glucocorticoid signaling at sites central to reproductive biology include the hypothalamus and the pituitary where this stress steroid influences the production and release of LH and FSH. Surprisingly, other components of the reproductive system have largely been ignored as targets for stress-induced infertility. The uterus expresses the glucocorticoid receptor (GR) at very high levels, suggesting the uterus may also be a direct target of glucocorticoid signaling, potentially involved in reproductive functions such as implantation, fertilization, and immunity. To clearly define those physiological events specifically attributable to uterine expressed GR in vivo, we have generated a mouse model that enables conditional ablation of GR function specifically in the uterus. Exons 3 and 4 of the murine GR gene were floxed to generate a conditional GRfl allele. The GRfl mice were crossed with progesterone receptor (PR)-Cre expressing mice, resulting in GR excision restricted to cells that express PR, such as the uterus. The uterine GR-knockout mice display a profound sub-fertile defect, producing a significant delay to litter and smaller average litter size. In embryo transfer assays, priming by exogenous gonadotrophins in the uterine GR-knockout mice results in a protracted uterotrophic response, as one would expect from unopposed estrogen action. Indeed, GR is required for glucocorticoid antagonism of the biological response to estradiol in the uterus. In wild-type littermates, estradiol induces a significant increase in uterine weight, attributable to both water uptake and increased cellularity. Co-administration of dexamethasone with estradiol blocks the uteruotrophic effects of estradiol. However, dexamethasone is not able to block the effects of estradiol in the uterine GR-knockout mice. Furthermore, transcriptional analysis from the uterus of GR-knockout mice reveals altered expression of genes important for fertility in both cycling females (PR and 11bHSD1) and in response to exogenous gonadotrophins (PR, LIF, and HOXA11). These results suggest that the glucocorticoid receptor regulates uterine biology and fertility through uterine-specific actions.

Nothing to Disclose: SDW, FJD, JPL, JAC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This research was supported by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences.