Pavinetant

Objectives: Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored. Methods: Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration. Results: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, <i>p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, <i>p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist. Conclusions: The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.

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.

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.

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.

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.

Wellcome Trust through the Scottish Translational and Therapeutics Initiative.