Neurokinin B Regulates Gonadotropin Secretion, Ovarian Follicle Growth, and the Timing of Ovulation in Healthy Women

Context: Neurokinin B (NKB) is obligate for human puberty, but its role in adult female gonadotropin secretion and ovarian follicle growth is unknown. Objective: To investigate antagonism of NKB on pulsatile gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion and ovarian follicle development in healthy women. Design: Open investigation of the effects of a neurokinin-3 receptor (NK3R) antagonist (NK3Ra) vs a no-treatment control cycle. Setting: Clinical research facility. Patients or other participants: Healthy women with regular menses (n = 13). Intervention(s): NK3Ra MLE4901 40 mg taken orally twice daily from cycle day 5 to 6 for 7 days. Main outcome measure(s): LH secretion, ovarian follicle growth, and timing of ovulation. Results: NK3Ra administration reduced basal LH secretion without a change in pulse frequency and delayed the LH surge by 7 days, the duration of treatment [mean cycle day +/- standard error of the mean (SEM), 22 +/- 1 days vs 15 +/- 1 days in control cycles; P = 0.0006]. Follicle growth (mean diameter at the end of administration of NK3Ra administration +/- SEM, 9.3 +/- 0.4 mm vs 15.1 +/- 0.9 mm in control cycles; P < 0.0001) and rising estradiol concentrations (mean +/- SEM, 166 +/- 29 pmol/L vs 446 +/- 86 pmol/L in control cycles; P < 0.0001) were prevented. After treatment, follicle development resumed and normal preovulatory follicle diameter and estradiol concentrations were demonstrated. Postovulatory progesterone risewas similarly delayed (peak cycle day, 30 +/- 2 vs 22 +/- 1; P = 0.002) and cycle length was prolonged (35 6 1 days vs 29 6 1 days in control cycles; P = 0.0003) but luteal progesterone excretion was unaffected by the NK3Ra (LH surge day + 7 mean urinary progesterone levels +/- SEM, 58 +/- 10 pmol/mol vs 48 +/- 7 pmol/mol creatinine in control cycles; nonsignificant). Conclusion: These data demonstrate the involvement of NKB-NK3R signaling in the physiological regulation of GnRH/LH secretion, determining normal follicle development in women.