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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 the actions of prolactin (PRL) within the brain have been investigated extensively, its specific effects at the level of pituitary gonadotroph target cells remain unclear. Here, we provide evidence that the actions of PRL within the gonadotroph are more complex than originally envisaged. Using a gonadotroph cell monoculture, the first series of experiments showed that PRL is, paradoxically, a potent stimulator of LH release, with a three- to fourfold 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 studies revealed that the stimulatory effects of PRL on LH release are not mediated by the conventional cytokine receptor pathways but, rather, by a novel JAK2-PIK3-PKC-dependent signaling cascade. Moreover, the experiments showed that these actions of PRL within gonadotroph cells are controlled by dopamine, the main hypothalamic inhibitory regulator of PRL release in vivo. Our findings have unraveled specific actions of PRL within the gonadotroph and the cell-signaling interactions that ultimately underlie hyperprolactinemia-induced infertility.

Original publication

DOI

10.1095/biolreprod.110.084947

Type

Journal article

Journal

Biol Reprod

Publication Date

2010

Volume

83

Pages

1046 - 1055

Keywords

Animals Cell Line Dopamine/metabolism Dopamine Agonists/pharmacology Gene Expression Regulation/drug effects Gonadotrophs/drug effects/*metabolism Gonadotropin-Releasing Hormone/metabolism Hyperprolactinemia/physiopathology Infertility/etiology/metabolism Janus Kinase 2/metabolism Kinetics Luteinizing Hormone/metabolism Luteinizing Hormone, beta Subunit/genetics/metabolism Mice Phosphatidylinositol 3-Kinase/metabolism Prolactin/*metabolism Protein Kinase C/metabolism RNA, Messenger/metabolism Receptors, Dopamine D2/agonists Signal Transduction/drug effects