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Elizabeth Micks, Greta B Raglan and Jay Schulkin

Steroid hormones have been in use for more than a half a century as contraceptive agents, and only now are researchers elucidating the biochemical mechanisms of action and non-target effects. Progesterone and synthetic progestins, critical for women's health in the US and internationally, appear to have important effects on immune functioning and other diverse systems. Apart from the contraceptive world is a separate field that is devoted to understanding progesterone in other contexts. Based on research following a development timeline parallel to hormonal contraception, progesterone and 17-hydroxyprogesterone caproate are now administered to prevent preterm birth in high-risk pregnant women. Preterm birth researchers are similarly working to determine the precise biochemical actions and immunological effects of progesterone. Progesterone research in both areas could benefit from increased collaboration and bringing these two bodies of literature together. Progesterone, through actions on various hormone receptors, has lifelong importance in different organ systems and researchers have much to learn about this molecule from the combination of existing literatures, and from future studies that build on this combined knowledge base.

Open access

Greta B Raglan, Louis A Schmidt and Jay Schulkin

The stress response has been linked to the expression of anxiety and depression, but the mechanisms for these connections are under continued consideration. The activation and expression of glucocorticoids and CRH are variable and may hold important clues to individual experiences of mood disorders. This paper explores the interactions of glucocorticoids and CRH in the presentation of anxiety and depressive disorders in an effort to better describe their differing roles in each of these clinical presentations. In addition, it focuses on ways in which extra-hypothalamic glucocorticoids and CRH, often overlooked, may play important roles in the presentation of clinical disorders.

Open access

Bingbing Wang, Mayra Cruz Ithier, Nataliya Parobchak, Stacy M Yadava, Jay Schulkin and Todd Rosen

Maternal vitamin D deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study, we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3′-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p- or miR-26b-5p-mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms by which vitamin D downregulates pro-labor genes and could lower the risk of preterm delivery.