Insomnia / circadian

In placebo-controlled RCTs of peri/postmenopausal women with hot flashes, low-dose oral/transdermal estradiol modestly reduced insomnia severity (ISI) and improved sleep quality (PSQI).

DSIP, an endogenous nonapeptide, promotes slow-wave sleep and shortens sleep latency in animal insomnia models, with early human data linking endogenous DSIP to delta sleep; rigorous modern controlled trials are lacking.

Pineal peptide bioregulators (Epithalon/Epithalamin/Pineamin) increased nocturnal melatonin (urinary 6-sulfatoxymelatonin) in melatonin-deficient elderly, suggesting circadian restoration; evidence is limited to small, low-quality studies.

Orexin A/B are neuroexcitatory arousal peptides that promote wakefulness and suppress sleep; agonism is contraindicated for insomnia, where orexin-receptor antagonists are the therapeutic strategy.

PACAP is co-expressed with melanopsin in retinal ganglion cells and conveys light to the SCN clock; PACAP-deficient mice show impaired photic entrainment and abnormal activity onset, rescued by PACAP-38.

Fezolinetant, a nonhormonal NK3-receptor antagonist, reduced menopausal vasomotor symptoms and significantly improved PROMIS sleep-disturbance scores versus placebo in pooled SKYLIGHT 1/2 RCT data.

Micronized progesterone, via GABA-A-active metabolites, is associated with improved subjective sleep quality (PSQI) in menopausal women with insomnia and is a component of menopausal hormone therapy that reduces sleep complaints; direct placebo-controlled evidence isolating progesterone is limited.