Neurokinin 3 Receptor Antagonists Do Not Increase Fsh Or Estradiol Secretion In Menopausal Women

Background: Neurokinin 3 receptor (NK3R) antagonism is a promising novel treatment for menopausal flashes. IIowever, to avoid adverse hormonal effects it is clinically important to first confirm whether gonadotropin and estradiol concentrations change as a result of their administration.Methods: Single-center, randomized, double-blind, placebo-controlled, crossover trial of an oral NK3R antagonist (MLE4901) in 28 women aged 40 to 62 years, experiencing >7 hot flashes/24 h; some bothersome or severe (Clinicaltrials.gov, NCT02668185). Weekly serum gonadotropins and estradiol levels were measured using commercially available automated immunoassays a priori. Serum estradiol was also measured post hoc using a highly sensitive direct assay by liquid chromatography tandem mass spectrometry. Hormone levels were compared by the paired sample t tests or by the Wilcoxon matched-pairs signed rank test, as appropriate for the distribution of the data.Results: Mean (standard deviation) serum follicle-stimulating hormone (FSH) concentration was not significantly increased when taking MLE4901 (72.07 +/- 19.81 IU/L) compared to placebo (70.03 +/- 19.56 IU/L), P= .26. Serum estradiol was also not significantly altered, irrespective of which assay method was used (median interquartile range of serum estradiol by immunoassay: placebo 36 +/- 3 pmol/L, MLE4901 36 +/- 1 pmol/L, P = .21; median serum highly sensitive estradiol: placebo 12 +/- 16 pmol/L, MLE4901 13 +/- 15 pmol/L, P = .70). However, mean (standard deviation) serum luteinizing hormone concentration significantly decreased with MLE4901 (27.63 +/- 9.76 IU/L) compared to placebo (30.26 +/- 9.75 IU/L), P= .0024. (C) Endocrine Society 2019.