Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists. IntroductionHyperprolactinemia is the most common cause of hypogonadotropic anovulation (WHO Group I) and represents a major etiology of infertility, with highest incidence in women aged 25-34 years (1). In men, hyperprolactinemia is also frequently associated with hypogonadotropic hypogonadism. This gonadotropic deficiency has been proposed to result from direct suppression of prolactin (PRL) on gonadotrophin-releasing hormone (GnRH) release, but evidence supporting this mechanism has never been provided. PRL is synthesized and secreted by the lactotrope cells of the pituitary, and high levels of circulating PRL are mainly caused by lactotroph adenomas, which account for approximately 40% of all pituitary tumors. Pulsatile GnRH replacement can reverse hypogonadotropic hypogonadism and infertility induced by hyperprolactinemia in women as well as men (2, 3), suggesting that PRL excess in humans affects hypothalamic release of GnRH rather than directly affecting pituitary or gonad function. However, very few GnRH neurons in mice express PRL receptors (PRLRs) (4), suggesting that PRL exerts its actions on upstream neurons regulating the GnRH neuron. Because GnRH neurons are stimulated by kisspeptin (Kp) neurons (5, 6), which unequivocally express PRLR (7), we hypothesized that GnRH deficiency resulting from hyperprolactinemia is caused by reduced Kp input, which is now considered to be a primary gatekeeper governing reproduction (8,9). Here, we show that hyperprolactinemia in mice induces hypogonadotropic anovulation and diminished Kp expression and that peripheral Kp administration restores GnRH and gonadotropin secretion and ovarian cyclicity. Therefore, we suggest that hyperprolactinemic women resistant or intolerant to dopamine agonists could take advantage of this therapeutic approach as a treatment for their infertility.

Keywords cell growth; cell metabolism; Grb7/10/14 adaptor proteins; insulin; insulin-like growth factor 1; insulin receptor; insulin signaling and action; insulin-like growth factor 1 receptor; SH2B adaptor proteins; tyrosine kinase activity

Stimulating conversion of white fat to metabolically active adipocytes (beige fat) constitutes a promising strategy against weight gain and its deleterious associated-disorders. We provide direct evidence that prolactin (PRL), best known for its actions on the mammary gland, plays a pivotal role in energy balance through the control of adipocyte differentiation and fate. Here we show that lack of prolactin receptor (PRLR) causes resistance to high-fat-diet-induced obesity due to enhanced energy expenditure and increased metabolic rate. Mutant mice displayed reduced fat mass associated with appearance of massive brown-like adipocyte foci in perirenal and subcutaneous but not in gonadal fat depots under a high-fat diet. Positron emission tomography imaging further demonstrated the occurrence of these thermogenic brown fat depots in adult mice, providing additional support for recruitable brown-like adipocytes (beigeing) in white fat depots. Consistent with the activation of brown adipose tissue, PRLR inactivation increases expression of master genes controlling brown adipocyte fate (PRDM16) and mitochondrial function (PGC1α, UCP1). Altered pRb/Foxc2 expression suggests that this PRL-regulated pathway may contribute to beige cell commitment. Together, these results provide direct genetic evidence that PRLR affects energy balance and metabolic adaptation in rodents via effects on brown adipose tissue differentiation and function.

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