Abstract:
OBJECTIVE : Patients with mutations of neurokinin B (NKB) and its receptor show hypogonadotrophic
hypogonadism, but there is little evidence for the importance of this pathway
in reproductive function in normal men, or its functional hierarchy with kisspeptin.
DESIGN : An open label study wherein men (n = 6) were administered the NK3R antagonist
MLE4901 40 mg orally twice a day for 7 days. Kisspeptin-10
(0.3 μg/kg iv bolus)
was given before and on day 7 of NK3R antagonist treatment.
PATIENTS : Subjects were healthy men.
MEASUREMENTS : Reproductive hormones were measured before and during the NK3R
antagonist administration, including frequent sampling on two occasions for analysis
of pulsatile LH secretion.
RESULTS : LH, FSH and testosterone secretion were decreased during NK3R antagonist
administration. LH showed a biphasic response, being reduced after 24 hours of treatment
(4.5 ± 0.6 IU/L pretreatment to 1.7 ± 0.2 IU/L, P < .05), with partial recovery thereafter,
but it was again decreased on day 7 (2.5 ± 0.6 IU/L, P < .05 vs pretreatment). FSH
secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone
secretion was decreased from 24 hours (18.4 ± 1.6 pretreatment vs 5.6 ± 1.5 nmol/L,
P < .01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility
showed that both basal and pulsatile LH secretion were markedly suppressed but
there was no detected change in LH pulse frequency. Kisspeptin-10
stimulated LH secretion,
with similar responses before and during NK3R antagonist administration.
CONCLUSIONS : These data demonstrate a central role for NKB/NK3R in the physiological
regulation of reproductive function in men, and that this is functionally upstream of kisspeptin-mediated
GnRH secretion.
