Characterization of the Effects of Prolactin in Gonadotroph Target Cells1

Abstract

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.

Plasticity of the Prolactin (PRL) Axis: Mechanisms Underlying Regulation of Output in Female Mice

“…Hyperprolactinaemia leads to a loss of fertility in female rodents (reviewed in [19]), suppressing pulsatile luteinizing hormone (LH) at both the level of the hypothalamus and pituitary [20,21]. This suggests an important role for PRL in timing of fertility to prevent a conflict between the metabolic requirements of pregnancy and lactation.…”

“…Whilst rodents have suppressed fertility during lactation, they have evolved a window of opportunity for mating with a postpartum ovulation immediately after birth, although there are mechanisms which delay implantation so that the subsequent litter is not born until the current pups are weaned [22]. Recent studies in rats have suggested that the pathway leading to this suppression of fertility is via kisspeptin neuron inhibition by the high PRL levels during lactation [23], together with direct effects upon LH release from pituitary gonadotrophs [20,24].…”

Grass carp prolactin: Molecular cloning, tissue expression, intrapituitary autoregulation by prolactin and paracrine regulation by growth hormone and luteinizing hormone

“…In gonadotroph cell lines, e.g., αT3 (Henderson et al, 2008) and LβT2 cells (Hodson et al, 2010a), PRL treatment can elevate both basal and GnRH-induced LH release with a parallel drop in LHβ mRNA levels. However, similar studies in primary culture of pituitary cells, e.g, in sheep (Gregory et al, 2004) and horse (Hodson et al, 2010b), or whole pituitary culture, e.g. in rat (Cheung, 1983), were found to have opposite effects.…”

“…In ovine (Gregory et al, 2004) or equine pituitary cells (Hodson et al, 2010a), PRL treatment could reduce basal and block GnRHinduced LH secretion. However, similar treatment in mouse gonadotrophs was found to up-regulate LH release with no effects on LHβ mRNA levels (Hodson et al, 2010b). Of note, LH receptor (LHR) expression in lactotrophs has not been reported and it is still unclear if LH released locally can play a role in paracrine regulation of PRL at the pituitary level.…”

Correlation between Levels of Serum Prolactin and Total Sialic Acids Concentrations in Fertile and Infertile Women

“…Hyperprolactinemia is one of a major causes of infertility, brought about by inhibition of gonadotropin-releasing hormone (GnRH) or pulsatile GnRH secretion from the hypothalamus and impairment of LH output from the pituitary gland (27). PRL within gonadotroph cells are controlled by dopamine, the main hypothalamic inhibitory regulator of PRL release in vivo, this specific actions of PRL within the gonadotroph and the cell signaling interactions that ultimately underlie hyperprolactinemia-induced infertility (27); hyperprolactinemia can occur in physiological and pathological conditions (28) such as psychotic stress, severe mental illness or other causes, and the reproductive dysfunction affecting about one third of infertile women (29).…”