Homeostatic glucocorticoid signaling is required for normal pregnancy

Elizabeth Whitney Cashell

Glucocorticoids are steroid hormones that have biological roles in anti-inflammation, immune suppression, and gluconeogenesis. These stress hormones signal through the glucocorticoid receptor (NR3C1) and have tissue specific control through the 11[Beta]-hydroxysteroid dehydrogenase (HSD11B) enzymes. HSD11B1 is a bidirectional enzyme capable primarily of converting inactive cortisone to active cortisol. HSD11B2 is a unidirectional enzyme that converts active cortisol to inactive cortisone. Through early pregnancy in the mouse, NR3C1 is highly expressed in the decidua, around the developing conceptus and expands outward from the early embryo. Hsd11b1 is expressed within implantation sites and presumably allows for local production of glucocorticoids to signal through NR3C1. Activation of NR3C1 with dexamethasone (DEX), a strong NR3C1 agonist, during pseudopregnancy attenuates decidualization, observed through a distinct reduction in markers of decidualization, with a concomitant elevation in stromal cell proliferation. Conditional deletion of Nr3c1 (Nr3c1d/d) via the progesterone receptor (PGR) promoter driving cre-recombinase expression caused a 30% decline in pups per litter during a six month breeding trial. This subfertility phenotype is likely due in part to premature ovarian failure in Nr3c1d/d female mutant mice. A significant decrease in the number of oocytes ovulated was observed following superovulation in six-month-old nulliparous female mice (32.0 ± 2.3 Nr3c1f/f versus 14.8 ± 2.9 Nr3c1d/d, P=0.007). This faulty ovulation phenotype was even more dramatic at nine months of age (29.5 ± 4.8Nr3c1f/f versus 2.3 ± 1.43 Nr3c1d/d, P=0.002). In addition to an ovulatory phenotype, we observed problems in placentation within the uterus. On day of pregnancy (DOP) 14.5, Nr3c1f/f had 9.3 ± 0.3 implantation sites, while Nr3c1d/d littermates had 7.0 ± 1.0 (P=0.03). Further examination of DOP7.5 showed an 87.9% decline in the recruitment of uterine natural killer (uNK) cells, yet no alteration in the expression of CD45 positive immune cells was observed. The localization of NR3C1 within the murine uterus during early pregnancy suggests a potential role for this steroid activated transcription factor during early pregnancy. The present studies discovered that NR3C1 has biological roles in ovulation and pregnancy using a laboratory mouse model.

Homeostatic glucocorticoid signaling is required for normal pregnancy

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