Sexually dimorphic regulation of gonadotrope cell hyperplasia in medaka pituitary via mitosis and transdifferentiation

The two pituitary gonadotropins, Fsh and Lh, regulate the reproductive function in vertebrates. While many studies have investigated the regulation of gonadotropin production and release by the sex steroid feedback, its role on the regulation of gonadotrope cell number remains unclear. Using medaka as a model and an optimized protocol to restore physiological sex steroids levels following gonadectomy, we show that gonadal sex steroids not only decrease fshb transcript levels, but also Fsh cell number in both sexes. We then investigated the origin of the Fsh cell hyperplasia induced by gonadectomy. In both sexes, BrdU incubation shows that this is achieved via Fsh cell mitosis. In situ hybridization reveals that new Fsh cells also originate from transdifferentiating Tsh cells in females, but not in males. Both phenomena are inhibited by sex steroid supplementation via feeding. In males (but not females), gonadectomy (without recovery with sex steroid supplementation) also reduces sox2 transcript levels and Sox2-immunopositive population volume, suggesting that sox2-progenitors may be recruited to produce new Fsh cells. Opposite to Fsh cells, gonadectomy decreases lhb levels in both sexes, and levels are not restored by sex steroid supplementation. In addition, the regulation of Lh cell number also seems to be sex dependent. Removal of gonadal sex steroids stimulates Lh cell mitosis in male (like Fsh cells), but not in females. To conclude, our study provides the first evidence on sexually dimorphic mechanisms used in the fish pituitary to remodel gonadotrope populations in response to sex steroids. HIGHLIGHTS - Supplementing gonadectomized fish with sex steroids via feeding allows for the recovery of physiological circulating levels of sex steroids. - Gonadal sex steroids not only regulate gonadotrope cell activity, but also gonadotrope cell number. - Removal of gonadal sex steroids induces Fsh cell hyperplasia via mitosis of Fsh cells in both sexes, and transdifferentiation of Tsh cells into bi-hormonal Tsh/Fsh cells in females only. - Gonadectomy also reduces the number of Sox2 progenitor cells in males (but not in females), suggesting that they may be recruited to contribute to Fsh cell hyperplasia. - Removal of gonadal sex steroids stimulates Lh cell mitosis in males, but not in females.