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Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men

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Skorupskaite, Karolina, George, Jyothis T., Veldhuis, Johannes D, Millar, Robert P and Anderson, Richard A (2017) Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men. Clinical Endocrinology, 87 (6). pp. 748-756. doi:10.1111/cen.13445

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Official URL: http://dx.doi.org/10.1111/cen.13445

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Abstract

Objective

Patients with mutations of 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 40mg 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 pre-treatment to 1.7±0.2 IU/l, p<0.05), with partial recovery thereafter; but it was again decreased on day 7 (2.5±0.6 IU/l, p<0.05 vs pre-treatment). 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 pre-treatment vs 5.6±1.5 nmol/l, p<0.01) 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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Medicine > Warwick Medical School > Health Sciences
Faculty of Medicine > Warwick Medical School
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Tachykinins, Luteinizing hormone releasing hormone, Testosterone
Journal or Publication Title: Clinical Endocrinology
Publisher: Wiley-Blackwell Publishing Ltd
ISSN: 0300-0664
Official Date: December 2017
Dates:
DateEvent
December 2017Published
12 August 2017Available
Date of first compliant deposit: 17 August 2017
Volume: 87
Number: 6
Page Range: pp. 748-756
DOI: 10.1111/cen.13445
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: Wellcome Trust (London, England), Medical Research Council (Great Britain) (MRC)
Grant number: Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A (Wellcome Trust (London, England)), Grant G0701682 (MRC)
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/AWellcome Trusthttp://dx.doi.org/10.13039/100010269
G0701682[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265

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