Continuously Administered Kisspeptin as a Pseudo-antagonist of the Kisspeptin Receptor

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 134-163-GnRH & Gonadotroph Biology & Signaling
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-151
Margaret Flynn Lippincott*, Yee-Ming Chan, Valerie F Sidhoum and Stephanie Beth Seminara*
Massachusetts General Hospital, Boston, MA
Kisspeptin is a powerful stimulus for GnRH induced LH secretion. Like long acting GnRH analogues, it may have the potential to selectively and reversibly induce hypogonadism. Although single bolus administration of kisspeptin stimulates LH release across species, continuous administration results in 1) desensitization of the kisspeptin receptor in the rhesus macaque (doses of 33-40 ug/kg/h x 4 d) but 2) sustained elevations of LH in healthy male volunteers (doses of 1.5-4 ug/kg/h x 22.5h). We hypothesized that a higher dose of continuous kisspeptin in the human would result in LH suppression.

Three healthy men and one post-menopausal woman received an infusion of kisspeptin (12 ug/kg/h x 24 h). Blood sampling was performed q 10-60 min starting 6 h before the start of the infusion and continuing for 6 h after the infusion stopped. All samples were assayed for LH. Mean LH levels during 3 time windows were compared using one-way ANOVA and Bonferroni corrected post-hoc tests: 1) PRE: the 3 h before the infusion; 2) PEAK: the 3 h with the highest mean LH during the infusion; 3) END: the final 3 h of the infusion.

All men demonstrated a robust increase in LH at the start of the kisspeptin infusion with each subject showing a statistically significant rise in LH from PRE to PEAK. As a group, mean LH levels rose from a PRE value of 3.19 ± 0.52 to a PEAK value of 24.05 ± 5.88 (p< 0.001). After this initial rise, LH levels plateaued in each subject for several hours and then started to fall before the infusion stopped (group PEAK: 24.05 ± 5.8 vs. group END: 16.66 ± 5.1, p< 0.001). In contrast, the single post-menopausal female demonstrated a markedly different LH pattern from the healthy men with no significant change in LH levels from PRE (12.53±1.38) to PEAK (12.03±0.92, P = NS) or from PEAK to END (11.23±0.42, P = NS).

The drop in LH levels at the end of the kisspeptin infusion (12 ug/kg/h) in healthy men stands in contrast to the LH patterns observed at lower doses. While the degree of LH suppression is less than that observed in non–human primates, this may reflect the three fold lower dose used in the current study. Moreover, in a healthy post-menopausal woman, LH levels appeared to be unaffected across the 24 hour kisspeptin infusion. This difference in kisspeptin responsiveness may be related to (but not limited to) differences in the sex steroid milieu, endogenous kisspeptin tone, or receptor expression and signaling.

Nothing to Disclose: MFL, YMC, VFS, SBS

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Sources of Research Support: NIH Grant 5R01 HD043341