ICEECE2012 Oral Communications Female Reproductioin Basic (6 abstracts)
GnRH release failure in hyperprolactinemia is caused by a Kisspeptin deficiency
C. Sonigo 1 , J. Bouilly 1 , N. Carré 1 , V. Tolle 2 , P. Zizzari 2 , A. Caraty 3 , J. Tello 4 , F. Simony 4 , R. Millar 4, , J. Young 1, & N. Binart 1
1Univ Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France; 2Centre de Psychiatrie et Neurosciences, Univ Paris Descartes, Paris, France; 3Univ. de Tours, Nouzilly, France; 4University of Edinburgh, Edinburgh, EH8 9XD, UK; 5University of Cape Town, Pretoria, South Africa; 6Hôpital du Kremlin Bicêtre, Le Kremlin Bicêtre, France.
Hyperprolactinemia is the most common cause of hypogonadotropic anovulation in women. It is related to an alteration of pulsatile GnRH secretion. This gonadotropic deficiency has been proposed to result from direct suppression of prolactin (PRL) on GnRH release but its mechanism remains unknown. Because GnRH neurons do not express unequivocally the PRL receptor, and are stimulated by kisspeptin (Kp) neurons which do express PRL receptors, we hypothesized that GnRH deficiency in this condition could be due to a decrease in Kp secretion. To test this we developed and characterized a hyperprolactinemic female mouse model mimicking the human pathology and analyzed the ability of Kp10 i.p. administration to restore gonadotropin secretion and cyclicity
We demonstrated that 28 days administration of PRL by micropumps, significantly inhibited mouse ovarian cyclicity evaluated by vaginal smears, and decrease corpora lutea (CL) number, reflecting ovulation rate impairment. This anovulation was related to a significant downregulation of pituitary LHβ and FSHβ transcripts indicating a gonadotropin deficiency in this model. Hypothalamic GnRH expression was not altered while there was, a significant decrease of Kp mRNA and peptide (hypothalamic staining) suggesting a role of Kp decrease in GnRH release alteration in hyperprolactinemic female mice. We then demonstrated that Kp-10 administration restored cyclicity, ovulation and pituitary gonadotropin expression in hyperprolactinemic mice. Using hypothalamic explants, we also demonstrated that in vitro decrease of GnRH release induced by PRL was rescued by Kp-10 administration.
Together with the recent demonstration that Kp neurons express high levels of PRL receptor, our data suggest that PRL excess acts directly on Kp neurons to suppress Kp secretion and downstream GnRH secretion. Kp neurons appear, therefore, to be the missing link between hyperprolactinemia and GnRH deficiency in mammals.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Volume 29
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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