Skorupskaite, KarolinaGeorge, Jyothis T.Veldhuis, Johannes D.Millar, Robert P.Anderson, Richard A.2017-01-172017-01-172016-12Skorupskaite, K, George, JT, Veldhuis, JD, Millar, RP & Anderson, RA 2016, 'Interactions between Neurokinin B and kisspeptin in mediating estrogen feedback in healthy women', Journal of Clinical Endocrinology and Metabolism, vol. 101, no. 12, pp. 4628-4636.0021-972X (print)1945-7197 (online)10.1210/jc.2016-2132http://hdl.handle.net/2263/58533CONTEXT : Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. Objective: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. DESIGN : Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study. SETTING : Clinical research facility. PATIENTS OR OTHER PARTICIPANTS : Healthy females with regular menses. INTERVENTION (S) : NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4–6 for 6 days (n 10, with 10 no treatment controls). Transdermal estradiol patches (200 g/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 g/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. MAIN OUTCOME MEASURE(S) : Plasma gonadotropin and estradiol secretion.RESULTS : After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 0.2 vs 0.7 0.2 pulses/h, P .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 11.0 vs 5.0 3.6 IU/L, P .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 4.8 vs 15.0 11.4 IU/L, P .05). CONCLUSIONS : These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women,and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.en© 2016 The Endocrine Society. This article has been published under the terms of the Creative Commons Attribution License (CC-BY : https://creativecommons.org/licenses/by/4.0/).KisspeptinGnRHEstrogen feedbackLH pulsatilityNeurokinin B (NKB)Neurokinin-3 receptor (NK3R)Article