Neurokinin 3 Receptor Antagonists Do Not Increase FSH or Estradiol Secretion in Menopausal Women

Julia K Prague; Ali Abbara; Alexander N Comninos; Channa N Jayasena; Claire E Higham; Jo Adaway; Brian G Keevil; Johannes D Veldhuis; Waljit S Dhillo

doi:10.1210/jendso/bvz009

Neurokinin 3 Receptor Antagonists Do Not Increase FSH or Estradiol Secretion in Menopausal Women

J Endocr Soc. 2019 Nov 14;4(2):bvz009. doi: 10.1210/jendso/bvz009. eCollection 2020 Feb 1.

Authors

Affiliations

¹ Section of Endocrinology & Investigative Medicine, Imperial College, London, UK.
² Department of Endocrinology, The Christie NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
³ Biochemistry Department, Wythenshawe Hospital, Wythenshawe, UK.
⁴ School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁵ Mayo Clinic, Rochester, MN, UK.

Abstract

Background: Neurokinin 3 receptor (NK3R) antagonism is a promising novel treatment for menopausal flashes. However, 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.

Implication: NK3R antagonists do not increase serum estradiol or FSH despite their reduction in hot flashes. This is clinically significant and highly reassuring for women who have a contraindication to conventional hormone therapy such as prior/existing breast cancer and/or thromboembolism.

Keywords: NK3R antagonists; breast cancer; estradiol; flashes; menopause.

Associated data

ClinicalTrials.gov/NCT02668185

Abstract

Associated data

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