TY - JOUR
T1 - Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men
AU - Skorupskaite, Karolina
AU - George, Jyothis T.
AU - Veldhuis, Johannes D.
AU - Millar, Robert P.
AU - Anderson, Richard A.
N1 - Funding Information:
Funding information This study was funded by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative STMTI and MRC grant G0701682 to RAA and RPM We thank the men who volunteered to take part in the studies and the staff at the Royal Infirmary of Edinburgh Clinical Research Facility. We are grateful to Cat Graham for statistical advice and to Forbes Howie and Kirsten Wilson for hormone measurements. We are grateful to AstraZeneca for the supply of AZD4901 (now known as MLE4901) used in this study.
Funding Information:
This study was funded by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A and Medical Research Council grant G0701682. JTG has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. RAA has undertaken consultancy work for AstraZeneca, Takeda Pharmaceuticals and Ferring Pharmaceuticals. RPM consults for Ogeda and is CEO of Peptocrine. JDV and KS have nothing to disclose.
Funding Information:
This study was funded by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative STMTI and MRC grant G0701682 to RAA and RPM
Publisher Copyright:
© 2017. The Authors Clinical Endocrinology Published by John Wiley & Sons Ltd
PY - 2017/12
Y1 - 2017/12
N2 - 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.
AB - 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.
KW - GnRH pulsatility
KW - gonadotrophins
KW - kisspeptin
KW - neurokinin B
KW - testosterone
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U2 - 10.1111/cen.13445
DO - 10.1111/cen.13445
M3 - Article
C2 - 28802064
AN - SCOPUS:85028803064
SN - 0300-0664
VL - 87
SP - 748
EP - 756
JO - Clinical Endocrinology
JF - Clinical Endocrinology
IS - 6
ER -