Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: implications for gender differences in migraine.

Neurogenic inflammation including calcitonin gene-related peptide (CGRP) and substance-P (SP) release plays a pivotal role in migraine pathogenesis. Prevalence of migraine is ~ 3 folds higher in women than in men, but its underlying mechanisms remained unclear. We investigated the effects of female sex hormones estrogen and progesterone on CGRP and SP in in-vivo and ex-vivo in rats of both sexes. For in-vivo experiments, male, female and ovariectomized rats were separated into four groups (n = 7) as control, estrogen, progesterone and estrogen + progesterone, respectively. Groups received daily intraperitoneal vehicle, 17β-estradiol, progesterone and 17β-estradiol + progesterone for 5 days, respectively. For ex-vivo experiments in both sexes, isolated trigeminal ganglia and hemiskull preparations were divided into four groups (n = 6 or 8), respectively, as in-vivo groups, and administered the same test substances. CGRP and SP contents in plasma and superfusates were determined using ELISA. In in-vivo experiments, 17β-estradiol decreased CGRP levels in males and SP levels in ovariectomized rats. Progesterone increased both CGRP and SP levels in females. Their combination decreased both CGRP and SP levels in males, and only SP levels in ovariectomized rats. In ex-vivo experiments, 17β-estradiol reduced CGRP release in males and SP release in females in trigeminal ganglia. While progesterone increased CGRP release in trigeminal ganglia, it reduced SP release from hemiskulls in both sexes. Their combination restored progesterone-mediated changes in neuropeptides releases in both trigeminal ganglia and hemiskulls in both sexes. Estrogen alleviates neurogenic inflammation through modulation of CGRP and SP release. Progesterone has dual effects on these neuropeptides in different sites associated with migraine pain.