Modulation of lactose synthesis and orexinergic‐glucose pathway by sex steroid hormones

Sex steroid hormones play a regulatory role in various metabolic processes, including glucose homeostasis via the orexinergic system and lactose synthesis. This review consolidates experimental findings on the mechanisms by which these hormones regulate these two pathways. A systematic search of PubMed, Scopus, and Web of Science identified 15 controlled studies involving animals and humans that investigated the effects of sex steroid hormones on both pathways. Estradiol enhanced orexin neuron excitability and increased orexin-1 receptor expression in a cyclical, phase-dependent manner within the orexinergic-glucose axis, promoting glucose utilization during estrogen-dominant phases. Progesterone reduced this activity, which is consistent with the conservation of energy during the luteal phase. Testosterone diminished orexin-A neuronal activation during glucose deficit, suggesting a suppressive effect on orexin-driven glucose mobilization. Also, estradiol promoted lactogenesis after progesterone withdrawal, whereas progesterone sustained prepartum inhibition of α-lactalbumin and casein gene transcription. In conclusion, the influence of sex steroid hormones on orexinergic-glucose regulation is hormone-specific and phase-dependent, with estradiol acting as a stimulant, progesterone as an inhibitor, and testosterone having a largely suppressive effect. The postpartum decrease in progesterone level triggers estradiol to support milk production. Studies are needed to investigate the role of sex steroid hormones on lactase expression, activity, and lactose tolerance.