Role of a neurokinin B receptor antagonist in the regulation of ovarian function in healthy women

BACKGROUND: Patients with loss-of-function mutation in neurokinin B (NKB) and its receptor show hypogonadotropic hypogonadism characterised by failure to progress through puberty, indicating the involvement of this newly described hypothalamic peptide in human reproduction. However the role of NKB in regulating ovarian function in adult women is unknown. We tested the hypothesis that a NKB antagonist would decrease gonadotropin secretion and inhibit folliculogenesis in healthy women. METHODS: Six healthy women with regular menstrual cycles were administered the NKB antagonist AZD4901 (AstraZeneca, London, UK) 40 mg orally twice daily for 5 days from cycle days 4-5. Transvaginal ultrasonography was performed at the end of drug administration, and serum gonadotropins and oestradiol measured. Cycle-day-matched results were compared with seven women who received no treatment (controls). The study received ethics committee approval, and all women gave written informed consent. FINDINGS: The diameter of the largest follicle was significantly smaller in women treated with NKB antagonist than in controls (mean 8·8 mm [SD 1·2] vs 11·9 [2·1], p=0·01). Serum oestradiol concentrations were also significantly reduced in the NKB antagonist group (mean 112·7 pmol/L [SD 56·0] vs 240·1 [73·6], p=0·005): in keeping with this finding endometrial thickness was also reduced (mean 3·5 mm [SD 0·5] vs 6·4 [3·2], p=0·05). Concentrations of luteinising hormone were not significantly altered after 5 days of NKB antagonist (mean pretreatment luteinising hormone 5·2 IU/L [SD 2·1] vs post-treatment 6·7 [3·8], p=0·2) or when compared with control women (6·0 [2·4], p=0·7). One woman had minimal vaginal bleeding; there were no adverse events. INTERPRETATION: We have shown for the first time, to our knowledge, that NKB antagonist is a potent suppressor of follicle development and oestradiol secretion in women. This effect is likely to be mediated by reduced secretion of gonadotropin-releasing hormone and our results support the involvement of NKB in the control of human reproduction: further analysis will explore in detail effects on secretion of follicle-stimulating hormone and luteinising hormone. Our findings have potential for translational application, for example in endometriosis and contraception. FUNDING: Wellcome Trust through the Scottish Translational and Therapeutics Initiative.