Ovarian steroid regulation of the midbrain corticotropin releasing factor and urocortin systems in macaques

A significant number of postmenopausal women report increased anxiety and vulnerability to stress, which has been linked to decreased secretion of ovarian steroids. Communication between the serotonin system and the corticotropin releasing factor (CRF) system determines stress sensitivity or resilience. This study examines the effects of the ovarian steroids, estradiol (E) and progesterone (P) on the CRF system components that impact serotonin neurons in the midbrain of nonhuman primates. Ovariectomized rhesus macaques were treated with placebo, E alone for 1 month, or E supplemented with P for the last 2 weeks. Quantitative (q)RT-PCR and immunocytochemistry were employed. E±P treatment decreased CRF-R1 and increased CRF-R2 gene expression in hemi-midbrain blocks and in laser captured serotonin neurons. Also in hemi-midbrains, E treatment increased urocortin 1 (UCN1) and CRFBP gene expression, but supplemental P treatment reversed these effects. E±P decreased CRF fiber density in the dorsal, interfascicular and median raphe nuclei and decreased CRF-R1 immunostaining in the dorsal raphe. E increased CRF-R2 immunostaining in the dorsal and median raphe. E±P increased UCN1 immunostaining in the cell bodies and increased UCN1 fiber density in the caudal linear nucleus. Estrogen receptor beta (ERβ), but not ERα was detected in the nucleus of UCN1-positive neurons. While the mechanism of ovarian hormone regulation of the midbrain CRF system requires further investigation, these studies clearly demonstrate another pathway by which ovarian hormones may have positive effects on anxiety and mood regulation.