OBJECTIVES: Neurokinin B (NKB) and kisspeptin are obligate for normal 
gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) 
pulsatility and vasomotor symptoms have been proposed. Using a selective NKB 
receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in 
menopausal women was explored.
METHODS: Eleven postmenopausal women were administered the NK3R antagonist 
MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 
h was performed before and on the last day of NK3R antagonist treatment for 
luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. 
bolus) administered at 6 h on both days. Hot flash frequency and severity were 
self-reported for 7 days before and during NK3R antagonist administration.
RESULTS: LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of 
NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). 
Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 
IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the 
group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 
8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These 
women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 
0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 
did not affect LH secretion with or without the NK3R antagonist.
CONCLUSIONS: The administration of an NK3R antagonist indicates a role for NKB 
in the regulation of LH/GnRH in postmenopausal women, whereas the lack of 
response to kisspeptin may reflect the hypo-oestrogenic state. These data 
support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R 
antagonism as a potential therapeutic approach.