Gestational hypoxia modulates expression of corticotropin-releasing hormone and arginine vasopressin in the paraventricular nucleus in the ovine fetus.

Maturation of the fetal hypothalamo-pituitary-adrenocortical (HPA) axis is critical for organ maturation necessary for the fetus to transition to the ex-utero environment. Intrauterine stressors can hasten maturation of the HPA axis leading to fetal growth restriction and in sheep, premature birth. We have previously reported that high-altitude mediated, long-term-moderate gestational hypoxia (LTH) during gestation has a significant impact on the fetal HPA axis. Significant effects were observed at the level of both the anterior pituitary and adrenal cortex resulting in elevated plasma ACTH during late gestation with decreased adrenocortical expression of enzymes rate limiting for cortisol synthesis. As such, these fetuses exhibited the normal ontogenic rise in fetal plasma cortisol but an exaggerated cortisol response to acute stress. This study extended these findings to ACTH secretagogue expression in the PVN using in situ hybridization. We report that the expression of AVP but not CRH was increased in the medial parvocellular PVN (mpPVN) in the LTH fetus. This represented an increase in both AVP mRNA per neuron as well as an increase in AVP hybridizing neurons with no increase in mpPVN CRH neurons. LTH had no effect on PVN volume, area of CRH or AVP hybridization, thus LTH did not have a trophic effect on the size of the nucleus. In conclusion, there appears to be a switch from CRH to AVP as a primary ACTH secretagogue in response to LTH, supporting our previous findings of increased anterior pituitary sensitivity to AVP over CRH in the LTH fetus.

Interleukin 1ß regulates progesterone metabolism in human cervical fibroblasts.

Progesterone plays a critical role in regulating cervical structure necessary for pregnancy maintenance. Preterm labor and early cervical ripening are often associated with localized infection. We hypothesized that proinflammatory cytokines enhance progesterone metabolism in human cervical fibroblasts (HCFs) in vitro, through the regulation of the expression of 20α-hydroxysteroid dehydrogenases (aldo-keto reductase [AKR]1C1, AKR1C2, or AKR1C3), 5α-reductase type 1 (5α-RDT1), and/or 17ß-hydroxysteroid dehyrogenases (17ß-HSD) type 1 and 2. The expression of both progesterone receptor (PR) and estrogen receptor α (ERα) was also studied. Human cervical fibroblasts were found to express AKR1C1, C2, and C3, with AKR1C1 exhibiting the greatest expression. These cells also expressed 5α-RDT1 and 17ß-HSD1 and 2, albeit to a lesser level compared to the aldo-keto reductases. The fibroblasts also expressed both PR and ERα. Interleukin 1ß (IL-1ß) significantly increased the expression of AKR1C1 and C2 but not C3 but did not alter 5α-RDT1 nor 17ß-HSD1 or 2 expression. Interleukin 1ß treatment significantly increased progesterone metabolism by these cells. Use of specific inhibitors for aldo-keto reductases or 5α reductases confirmed that the increased progesterone metabolism was a consequence of the increased expression and/or activity of AKR1C1/2. Our results indicate that a major proinflammatory cytokine, IL-1ß, can facilitate local progesterone metabolism in a cell type critical for maintaining cervical structure via regulating expression of AKR1C1 and 2.