Glucocorticoids inhibit kisspeptin-stimulated LH secretion by disrupting KISS1R signaling

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-18
Le Min*1, Victor Manuel Navarro2, Oluwaseun Adeola3, Shuyun Xu4, Jiangfeng Mao5, Rona S. Carroll6 and Ursula B Kaiser7
1Brigham and Women's, Boston, MA, 2Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 3Brigham and Womenís Hospital, Boston, MA, 4Brigham & Womens Hosp, Boston, MA, 5Peking Union Medical College Hospital, Beijing, China, 6Brigham and Women's Hospital, Boston, MA, 7Brigham and Women's Hospital and Harvard Medical School, Division of Endocrinology/Diabetes, Boston, MA, Boston, MA
Hypercortisolemia, as occurs in in a wide variety of medical conditions such as Cushing syndrome, depression, anorexia nervosa, metabolic syndrome and chronic glucocorticoid use, can lead to hypogonadism, irregular menses, and infertility.  The mechanisms by which hypercortisolemia results in impaired reproductive function are largely unknown, but independent inhibitory actions on hypothalamic Kiss1 mRNA expression, on pulsatile GnRH release, and on GnRH-stimulated LH release have all been implicated.  Glucocorticoid receptors (GR) are expressed in GnRH neurons, but the mechanisms by which glucocorticoids act at the level of the GnRH neurons to regulate GnRH release remain to be determined.  Kisspeptin receptors (KISS1R) are expressed in GnRH neurons as well and play a critical role in the regulation of GnRH secretion. Disruption of KISS1R signaling results in dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis.  Glucocorticoids have been shown to inhibit cellular signaling pathways; for example, blunting insulin receptor signaling to contribute to insulin resistance. Hence, we hypothesized that glucocorticoids may similarly inhibit KISS1R signaling to contribute to hypercortisolemia-associated hypogonadotropic hypogonadism. We tested this hypothesis through a series of pharmacological and functional in vitro and in vivo studies.  Using the immortalized GT1-7 GnRH neuronal cell line, with stable expression of KISS1R, we found that treatment with 100 nM dexamethasone for 48 hours blunted the kisspeptin-10 (KP10)-stimulated intracellular calcium response. Furthermore, mice pretreated with dexamethasone (1 mg/kg intraperitoneally for 24 hours) showed decreased KP10-stimulated (50 pmol, intracerebroventricularly) LH release compared to controls.  This effect was reversed by co-administration of the GR antagonist, mifepristone (25 mg/kg intraperitoneally). In summary, our data suggest that glucocorticoid-induced dysregulation of the HPG axis occurs in part through an inhibitory effect on KISS1R signaling. This study will help to elucidate the mechanisms underlying reproductive dysfunction in patients with hypercortisolemic states.

Nothing to Disclose: LM, VMN, OA, SX, JM, RSC, UBK

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