Prague Julia K, Abbara Ali, Comninos Alexander N, Jayasena Channa N, Higham Claire E, Adaway Jo, Keevil Brian G, Veldhuis Johannes D, Dhillo Waljit S
Section of Endocrinology & Investigative Medicine, Imperial College, London, UK.
Department of Endocrinology, The Christie NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
J Endocr Soc. 2019 Nov 14;4(2):bvz009. doi: 10.1210/jendso/bvz009. eCollection 2020 Feb 1.
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.
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 tests or by the Wilcoxon matched-pairs signed rank test, as appropriate for the distribution of the data.
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), = .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, = .21; median serum highly sensitive estradiol: placebo 12 ± 16 pmol/L, MLE4901 13 ± 15 pmol/L, = .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), = .0024.
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.
神经激肽3受体（NK3R）拮抗剂是一种有前景的绝经潮热新疗法。然而，为避免不良激素影响，临床首先确认促性腺激素和雌二醇浓度是否会因使用该拮抗剂而发生变化至关重要。
对28名年龄在40至62岁、每日潮热超过7次的女性进行单中心、随机、双盲、安慰剂对照、交叉试验，使用口服NK3R拮抗剂（MLE4901）（Clinicaltrials.gov，NCT02668185）。预先使用市售自动免疫分析法每周测量血清促性腺激素和雌二醇水平。事后还使用液相色谱串联质谱法的高灵敏度直接检测法测量血清雌二醇。根据数据分布情况，采用配对样本检验或Wilcoxon配对符号秩检验比较激素水平。
与安慰剂组（70.03±19.56 IU/L）相比，服用MLE4901组（72.07±19.81 IU/L）的血清促卵泡激素（FSH）平均（标准差）浓度无显著升高，P = 0.26。无论采用哪种检测方法，血清雌二醇也无显著变化（免疫分析法血清雌二醇的中位数四分位间距：安慰剂组36±3 pmol/L，MLE4901组36±1 pmol/L，P = 0.21；血清高灵敏度雌二醇中位数：安慰剂组12±16 pmol/L，MLE4901组13±15 pmol/L，P = 0.70）。然而，与安慰剂组（30.26±9.75 IU/L）相比，MLE4901组的血清促黄体生成素平均（标准差）浓度显著降低（27.63±9.76 IU/L），P = 0.0024。
NK3R拮抗剂虽能减少潮热，但不会升高血清雌二醇或FSH。这在临床上具有重要意义，对于有传统激素治疗禁忌证（如既往/现有乳腺癌和/或血栓栓塞）的女性来说，极具安慰作用。
