Abstract
STUDY QUESTIONWhat is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)?SUMMARY ANSWERAdministration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained.WHAT IS KNOWN ALREADYPCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear.STUDY DESIGN, SIZE, DURATIONThe NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSSubjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion.MAIN RESULTS AND THE ROLE OF CHANCENK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment.LIMITATIONS, REASONS FOR CAUTIONThe study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects.WIDER IMPLICATIONS OF THE FINDINGSThese data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback.STUDY FUNDING/COMPETING INTEREST(S)Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose.TRIAL REGISTRATION NUMBERN/A.
Highlights
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and the leading cause of anovulatory infertility (Sirmans and Pate, 2013)
Analysis of LH at hourly intervals for 8 h after the last neurokinin 3 receptor antagonist (NK3Ra) dose showed that overall LH secretion was lower in NK3Ra-treated women compared to no treatment (P < 0.0001, Fig. 2D), post hoc analysis indicated no significant differences in LH levels at any individual hourly time point
These data confirm that NK3Ra treatment in women with PCOS reduced LH secretion, indicative of suppressed hypothalamic GnRH pulsatile secretion
Summary
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and the leading cause of anovulatory infertility (Sirmans and Pate, 2013). In a randomized controlled trial, neurokinin 3 receptor antagonist (NK3Ra) administration in women with PCOS decreased the frequency of LH pulses (indicative of pulsatile GnRH release) and LH and testosterone concentrations (George et al, 2016) This is in concordance with a suppressive action of NKB antagonism on pulsatile LH secretion shown in postmenopausal women with hot flushes (Skorupskaite et al, 2018b), in a model of the mid-cycle LH surge in healthy women (Skorupskaite et al, 2016) and in gonadectomized animals (Fraser et al, 2015; Li et al, 2015). These findings clearly illustrate NKB modulation of LH secretion via GnRH, and it is possible that dysregulation of NKB signalling may play a role in the neuroendocrine pathogenesis of PCOS
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