Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men

Abstract

Context: Kisspeptins stimulate GnRH and thus gonadotropin secretion. Kisspeptin-10 is the minimal kisspeptin sequence with full intrinsic bioactivity, but it has not been studied in man.

Objective: We investigated our hypothesis that kisspeptin-10 increases GnRH and thus LH pulse frequency.

Design and participants: The dose response of kisspeptin-10 was investigated by administering iv bolus doses (0.01-3.0 μg/kg) and vehicle to healthy men. Effects on LH pulse frequency and size were determined by deconvolution analysis during infusion of kisspeptin-10 for up to 22.5 h.

Results: Intravenous bolus kisspeptin-10 resulted in a rapid and dose-dependent rise in serum LH concentration, with maximal stimulation at 1 μg/kg (4.1 ± 0.4 to 12.4 ± 1.7 IU/liter at 30 min, P < 0.001, n = 6). Administration of 3 μg/kg elicited a reduced response vs. 1 μg/kg (P < 0.05). Infusion of kisspeptin-10 at 4 μg/kg · h for 22.5 h elicited an increase in LH from a mean of 5.4 ± 0.7 to 20.8 ± 4.9 IU/liter (n = 4; P < 0.05) and serum testosterone increased from 16.6 ± 2.4 to 24.0 ± 2.5 nmol/liter (P < 0.001). LH pulses were obscured at this high rate of secretion, but a lower dose infusion of kisspeptin-10 (1.5 μg/kg · h) increased mean LH from 5.2 ± 0.8 to 14.1 ± 1.7 IU/liter (n = 4; P < 0.01) and increased LH pulse frequency from 0.7 ± 0.1 to 1.0 ± 0.2 pulses/h (P < 0.05) and secretory burst mass from 3.9 ± 0.4 to 12.8 ± 2.6 IU/liter (P < 0.05).

Conclusions: Kisspeptin-10 boluses potently evoke LH secretion in men, and continuous infusion increases testosterone, LH pulse frequency, and pulse size. Kisspeptin analogues have therapeutic potential as regulators of LH and thus testosterone secretion.

Figures

Fig. 1.

Gonadotropin response to acute administration of kisspeptin-10 to normal men (n = 6). A, Serum LH concentration in response to 1 μg/kg kisspeptin-10 (filled circles), 3 μg/kg kisspeptin-10 (filled triangles), or vehicle (open circles) administered to healthy volunteers at time 0. B, Δ AUC (60 min) of LH after kisspeptin-10 and vehicle administration. C, Δ AUC (60 min) of FSH after kisspeptin-10 and vehicle administration. Mean ± sem. *, P < 0.05 vs. vehicle.

Fig. 2.

Serum LH profiles of four individual subjects receiving 4 μg/kg · h kisspeptin-10 infusion (black bar) after 9 h baseline sampling and 3 μg/kg iv bolus administered at 9 h (black arrow). Serum samples were obtained at 10 min intervals except overnight when samples were obtained hourly. Note the difference in scale between individual subjects.

Fig. 3.

Gonadotropin and testosterone response to infusions of 4 μg/kg of kisspeptin-10 (n = 4). A, Mean serum LH before and during kisspeptin-10 infusion. B, Mean serum FSH before and during kisspeptin-10 infusion. C, Mean serum testosterone before and during kisspeptin-10 infusion. Error bars represent sem. *, P < 0.05; ***, P < 0.001.

Fig. 4.

Gonadotrophin response to 9-h iv infusion of 1.5 μg/kg kisspeptin-10 (n = 4). A–D, LH profiles from individual subjects during baseline (closed circles) and kisspeptin-10 infusion (open triangles) visits. Note the difference in scale between individual subjects. E, Mean LH pulse frequency during baseline and kisspeptin-10 infusion visits. F, Secretory mass of LH per pulse during baseline and kisspeptin infusion visits. Error bars represent sem. *, P < 0.05.