NK3 receptor antagonist alters the centrally controlled perception of menopausal flushing - a pilot study

Kisspeptin/neurokinin/dynorphin (KNDy) signaling links reproductive and thermoregulatory systems, and improvements in menopausal flushing are reported with neurokinin 3 receptor (NK3R) antagonists. A rise in brainstem activity preceding a flush has been proposed as its functional origin, with subsequent activity in the insula and prefrontal cortices reflecting individual perception. Using functional magnetic resonance imaging (fMRI), this study investigated the central effect of the NK3R antagonist MLE4901 during a flush, particularly functional connectivity changes in the salience network.

Five postmenopausal women with flushes completed a 1-week flush diary prior to baseline fMRI, during which hot flushes were triggered by heating. Diaries were continued during 7 days of treatment with the NK3R antagonist MLE4901, with repeat fMRI on day 7. Sternal monitors recorded objective flushing before each fMRI. Connectivity changes in the salience network post flush were assessed.

Treatment with MLE4901 reduced the subjective flush frequency (from median 6.9 to 1.1 per day; p = 0.02) without changes in objective flushes. Treatment decreased right anterior insula connectivity, which correlated significantly with decreased subjective flushing.

This pilot study demonstrates decreased connectivity in the salience network during NK3R antagonist treatment. This may indicate areas of interest for further targeted fMRI studies and mechanistic investigation of this novel treatment for flushing.