A New Bihormonal Model for the Brain Regulation of Gonadotropins in Teleosts

The brain-pituitary-gonadal tissues play a key role in the neuroendocrine regulation of reproduction in vertebrates. Brain hormones, especially gonadotropin-releasing hormone (GnRH) is considered an important stimulant of gonadotropins (luteinizing hormone and follicle-stimulating hormone) released from the anterior pituitary. The current concept proposes a single brain hormone (GnRH) stimulating the release of both gonadotropins in fish and mammals. However, two articles published in 2024 proposed a dual-hormone concept in the brain regulation of gonadotropins in female medaka and zebrafish.

The emerging concept proposes GnRH as the LH releasing hormone (LH-RH), and a second hormone, cholecystokinin (Cck), as the FSH-releasing hormone (FSH-RH) in these species. The two studies discussed here found that Cck is a potent FSH-RH. The line of evidence from the first study to support this notion includes the abundance of Cck receptors in the anterior pituitary Fsh-producing gonadotrophs, and severe reproductive defects in female medaka that genetically lacks Cck receptor 2. The second study used zebrafish, and found hypothalamic expression of Cck, anterior pituitary abundance of Cck receptors, and an all-male phenotype when Cck receptor 2 was knocked out. In both studies, Cck was found to be a more potent stimulant of intracellular Ca2+, when compared to GnRH effects.

These evidence from two independent studies indicate that Cck is a potent FSH-RH, and GnRH is the LH-RH, and supports a bihormonal model for the regulation of gonadotropin secretion from teleost pituitary. However, whether Cck elicits FSH-RH effects in other fish species remains unknown. In addition, the role of other hormones in the diverse endocrine milieu that regulate reproduction in modulating the phenotype seen in Cck receptor deficient fish warrants further consideration.