Interactions Between Neurokinin B and Kisspeptin in Mediating Estrogen Feedback in Healthy Women.
Skorupskaite. Karolina K; George. Jyothis T JT; Veldhuis. Johannes D JD; Millar. Robert P RP; Anderson. Richard A RA
Key Findings
- An NK3R antagonist (AZD4901) reduces LH pulse frequency and changes the LH response to kisspeptin.
- Kisspeptin‑10 infusion (4 µg/kg/h) increases LH secretion during the estrogen‑induced inhibitory phase, and the effect persists after the infusion stops.
- Blocking neurokinin B signaling blunts the duration of the LH response, indicating NKB is positioned before kisspeptin in the estrogen feedback loop.
Practical Outcomes
- For biohackers interested in hormone modulation, kisspeptin can acutely raise LH/FSH even under estrogen suppression, but its effectiveness may be reduced if neurokinin‑3 signaling is blocked. Current data do not define a safe, long‑term dosing regimen, so any experimentation should be cautious and limited to short‑term, supervised settings.
Summary
In healthy women, blocking the neurokinin‑3 receptor (NK3R) lowers the natural pulse of the hormone LH, while a short infusion of the peptide kisspeptin‑10 can still boost LH even when estrogen is trying to suppress it. The LH rise lasts beyond the infusion, and the interaction shows that neurokinin B works upstream of kisspeptin in controlling estrogen feedback.
Abstract
Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. 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. Clinical research facility. Healthy females with regular menses. 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 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. Plasma gonadotropin and estradiol secretion. 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). 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.
Study Information
pubmed
2016
2016-09-16T00:00:00.000Z
10.1210/jc.2016-2132