Interactions between neurokinin B and kisspeptin in mediating estrogen feedback in healthy women

Abstract

CONTEXT : 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.