Orexin signaling across the female lifespan: developmental, reproductive, and aging perspectives from humans and animal models

Orexin-A and orexin-B are hypothalamic neuropeptides that coordinate arousal, metabolic, and reproductive functions through orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). This review synthesizes evidence from humans, experimental models, and domestic species to examine how orexin signaling modulates female physiology across the lifespan. Perinatally, orexin activation supports neonatal survival by stabilizing respiration, feeding, and sleep-wake organization. During puberty, orexins integrate metabolic and circadian cues to regulate gonadotropin-releasing hormone output and reproductive onset. In pregnancy and lactation, central and peripheral adaptations coordinate maternal metabolism, uteroplacental communication, and prolactin-dependent lactation. In aging, reduced orexin tone contributes to sleep fragmentation, metabolic dysregulation, and cognitive decline. Therapeutically, dual orexin receptor antagonists and intranasal orexin delivery illustrate stage-specific intervention strategies. Evidence across life stages derives from human, rodent, and large-animal models and must be interpreted within species-, sex-, and stage-specific biological constraints. Collectively, orexin signaling represents a conserved integrative network with health relevance.