Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform.

Withdrawal of progestational support for pregnancy is part of the final common pathways for parturition, but the role of nuclear progesterone receptor (PGR) isoforms in this process is not known. To determine if the PGR-B isoform participates in cervical remodeling at term, cervices were obtained from mice lacking PGR-B (PGR-BKO) and from wild-type (WT) controls before or after birth. PGR-BKO mice gave birth to viable pups at the same time as WT controls during the early morning of Day 19 postbreeding. Morphological analyses indicated that by the day before birth, cervices from PGR-BKO and WT mice had increased in size, with fewer cell nuclei/area as well as diminished collagen content and structure, as evidenced by optical density of picrosirius red-stained sections, compared to cervices from nonpregnant mice. Moreover, increased numbers of resident macrophages, but not neutrophils, were found in the prepartum cervix of PGR-BKO compared to nonpregnant mice, parallel to findings in WT mice. These results suggest that PGR-B does not contribute to the growth or degradation of the extracellular matrix or proinflammatory processes associated with recruitment of macrophages in the cervix leading up to birth. Rather, other receptors may contribute to the progesterone-dependent mechanism that promotes remodeling of the cervix during pregnancy and in the proinflammatory process associated with ripening before parturition.

Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids.

Adaptation to stress in vertebrates occurs via activation of hormonal and neuronal signaling cascades in which corticotropin-releasing hormone (CRH) plays a central role. Expression of brain CRH is subject to strong, brain-region specific regulation by glucocorticoid hormones and neurogenic intracellular signals. We hypothesized that Steroid Receptor Coactivator 1 (SRC-1), a transcriptional coregulator of the glucocorticoid receptor, is involved in the sensitivity of CRH regulation by stress-related factors. In the brains of SRC-1 knockout mice we found basal CRH mRNA levels to be lower in the central nucleus of the amygdala. Hypothalamic CRH up-regulation after chronic (but not acute) stress, as well as region-dependent up- and down-regulation induced by synthetic glucocorticoids, were significantly attenuated compared with wild type. The impaired induction of the crh gene by neurogenic signals was corroborated in AtT-20 cells, where siRNA and overexpression experiments showed that SRC-1 is necessary for full induction of a CRH promoter reporter gene by forskolin, suggestive of involvement of transcription factor CREB. In conclusion, SRC-1 is involved in positive and negative regulation of the crh gene, and an important factor for the adaptive capacity of stress.