Characterization of the effects of prolactin in gonadotroph target cells

Hyperprolactinemia is a major cause of infertility, brought about by inhibition of gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus and impairment of luteinizing hormone (LH) output from the pituitary gland. However, whereas prolactin (PRL) actions within the brain have been investigated extensively, its specific effects at the level of pituitary gonadotrope target cells remain unclear. Here, we provide evidence that the actions of PRL within the gonadotrope are more complex than originally envisaged. Using a gonadotrope cell monoculture, the first series of studies showed that PRL is paradoxically a potent stimulator of LH release, with a three- to four-fold increase in LH values at hyperprolactinemic concentrations of PRL. Conversely, PRL dose-dependently modulated the LH secretory response to GnRH in a biphasic manner, with classical suppression of LH output only detected under a narrow dose range. In contrast, at all doses tested, PRL blocked the LHB mRNA response to the secretagogue. Subsequent work revealed that the stimulatory effects of PRL on LH release are not mediated by the conventional cytokine receptor pathways, but by a novel JAK2-PIK3-PKC-dependent signaling cascade. Moreover, the studies showed that these actions of PRL within gonadotrope cells are controlled by dopamine, the main hypothalamic inhibitory regulator of prolactin release in vivo. Our findings have unraveled specific actions of PRL within the gonadotrope and the cell-signaling interactions that ultimately underlie hyperprolactinemia-induced infertility.