FP04-4 Non-Kisspeptin-Responsive GnRH Neurons in Patients With Idiopathic Hypogonadotropic Hypogonadism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP04-GnRH & Gonadotroph Biology & Signaling
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:15 AM
Room 135 (Moscone Center)

Poster Board SAT-138
Yee-Ming Chan*1, Valerie F Sidhoum2, Margaret Flynn Lippincott2 and Stephanie Beth Seminara*2
1Boston Children's Hospital, Boston, MA, 2Massachusetts General Hospital, Boston, MA
Kisspeptin potently stimulates GnRH secretion and thus can be used as an in vivoprobe of the GnRH neuron. We hypothesized that 1) patients with idiopathic hypogonadotropic hypogonadism (IHH) and complete absence of GnRH secretion (with low baseline LH and an “unprimed” pituitary gland with feeble LH responses to exogenous GnRH) would have no responses to kisspeptin, and 2) patients with some GnRH secretion (with measurable LH and a “primed” pituitary) would have detectable but subnormal responses to kisspeptin.

Seven men and one woman with IHH underwent 12-14 h of q10 min blood sampling and received kisspeptin-10 0.31 µg/kg IV x1 and later GnRH 75 ng/kg IV. Subjects then underwent pituitary “priming” with exogenous pulsatile GnRH x 6 d, then returned for q10 min blood sampling and IV boluses of kisspeptin and GnRH again. One subject returned for a third study in which she received five boluses of kisspeptin 0.31 µg/kg.

The subjects could be divided into two groups. Group I (n=5) had baseline serum LH near assay detection limits and small pre-priming responses to exogenous GnRH (ΔLH 0.5-2.6 mIU/mL) that could be enhanced by priming with exogenous GnRH (post-priming ΔLH 4.2-18.8 mIU/mL), demonstrating absence of endogenous GnRH secretion. Group II (n=3) had measurable serum LH and pre-priming responses to GnRH (ΔLH 4.6-6.8 mIU/mL) already in the range of post-priming responses, indicating endogenous GnRH stimulation of the pituitary gland. None of the subjects in Group I or Group II responded to kisspeptin (ΔLH 0-0.3 mIU/mL), either before or after priming with exogenous GnRH. To test the possibility that GnRH neurons themselves require “priming” with repeated exposure to kisspeptin, one subject in Group II received five boluses of kisspeptin, and still no responses to kisspeptin were seen. 

Consistent with Hypothesis 1, patients with IHH had no response to kisspeptin. Surprisingly, counter to Hypothesis 2, even patients with evidence of endogenous (albeit enfeebled) GnRH secretion failed to respond to kisspeptin. In other words, these patients have GnRH neurons that do not respond to kisspeptin, even after repeated exposure. It may be that sex steroids are required for these GnRH neurons to respond to kisspeptin. Alternatively, these patients may have lost the kisspeptin-responsive subset of GnRH neurons, and the remaining non-kisspeptin-responsive neurons secrete sufficient GnRH to achieve pituitary priming but not to sustain normal reproductive function.

Nothing to Disclose: YMC, VFS, MFL, SBS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Grant R01 HD043341 awarded to SBS; Pediatric Endocrine Society Clinical Scholars Award; Charles A. King Trust Postdoctoral Fellowship; Boston Children's Hospital Career Development Award awarded to Y-MC