Role of Luteal Glucocorticoid Metabolism during Maternal Recognition of Pregnancy in Women

Abstract

The human corpus luteum (hCL) is an active, transient, and dynamic endocrine gland. It will experience extensive tissue and vascular remodeling followed by 1) demise of the whole gland without any apparent scarring or 2) maintenance of structural and functional integrity dependent on conceptus-derived human chorionic gonadotropin (hCG). Because cortisol has well-characterized roles in tissue remodeling and repair, we hypothesized that it may have a role in controlling luteal dissolution during luteolysis and would be locally produced toward the end of the luteal cycle. Glucocorticoid-metabolizing enzymes [11beta-hydroxysteroid dehydrogenase (11betaHSD) types 1 and 2] and the glucocorticoid receptor (GR) were assessed in hCL and cultures of luteinized granulosa cells (LGC) using immunofluorescence and quantitative RT-PCR. Furthermore, the effect of cortisol on steroidogenic cell survival and fibroblast-like cell activity was explored in vitro. The hCL expressed 11betaHSD isoenzymes in LGC and nuclear GR in several cell types. hCG up-regulated the expression and activity of 11betaHSD type 1 (P < 0.05) and down-regulated type 2 enzyme (P < 0.05) in vitro and tended to do the same in vivo. Cortisol increased the survival of LGC treated with RU486 (P < 0.05) and suppressed the activity of a proteolytic enzyme associated with luteolysis in fibroblast-like cells (P < 0.05). Our results suggest that, rather than during luteolysis, it is luteal rescue with hCG that is associated with increased local cortisol generation by 11betaHSD type 1. Locally generated cortisol may therefore act on the hCL through GR to have a luteotropic role in the regulation of luteal tissue remodeling during maternal recognition of pregnancy.

Activin A reduces luteinisation of human luteinised granulosa cells and has opposing effects to human chorionic gonadotropin in vitro

“…As expected (Myers et al 2007b), hCG markedly upregulated the expression, of HSD11B1 (P!0 . 001), in cultures of luteinised granulosa cells by over 30-fold (Fig.…”

“…HSD11B1 protein is not found in antral follicular granulosa cells whilst HSD11B2 is abundant. Similar to the mRNA transcripts patterns observed in the human corpus luteum (Myers et al 2007b), both 11bHSD isoforms are present in granulosalutein cells; however, there has been a marked switch in the predominant isoform to type 1 with only low levels of type 2 still detectable. We have now shown that activin A suppresses hCG actions on HSD11B1 expression, while hCG attenuates activin actions on HSD11B2.…”

“…However, we were able to confirm parallel protein changes at a tissue and functional level. In addition, previous studies have shown a strong correlation between mRNA concentrations in these cells and functional protein expression (Myers et al 2007b).…”

Expression and regulation of oestrogen receptors in the human corpus luteum

“…We also investigated the effect of oestradiol on two other molecules that seem to be important in human luteal function, namely activin (Myers et al 2007a) and locally produced glucocorticoids (Myers et al 2007b). Oestradiol regulated mRNA expression of INHBA and HSD11B1.…”

Role of Glucocorticoids in Cystic Ovarian Disease: Expression of Glucocorticoid Receptor in the Bovine Ovary

“…Ovulation has been described as an inflammatory process where a series of events leads to proteolytic degradation of a specific point in the follicular wall to permit the release of the oocyte [Espey et al, 2004;Richards et al, 2008]. Glucocorticoids (GCs), which are stress-induced hormones, are synthesized under the control of the hypothalamic-pituitary-adrenal axis and have been described as anti-inflammatory agents that act to modulate the production of cytokines and prostaglandins in the different reproductive processes: ovulation, luteolysis, embryo implantation, fetal growth and placental development [Hillier and Tetsuka, 1998;Andersen, 2002;Myers et al, 2007;Tetsuka, 2007;Duong et al, 2012;Kuse et al, 2013]. Therefore, cortisol, an active GC released in response to stress, could inhibit ovulation due to its local action as an anti-inflammatory agent at the ovulatory site [Vanholder et al, 2006].…”