Neuroendocrine crosstalk between sex and metabolic hormones: mechanisms and implications across the female reproductive spectrum

Energy metabolism and fertility are intricately linked across the female lifespan, from puberty through pregnancy, lactation, and menopause, ensuring that nutrition aligns with reproductive demands. We review here the nature of the synergistic crosstalk between sex hormones (notably estradiol) and metabolic hormones (including insulin, leptin, adiponectin, GLP‑1, ghrelin) within the brain, across the female reproductive spectrum. Estradiol amplifies metabolic signaling via shared pathways such as PI3K/Akt and JAK/STAT and enhances receptor sensitivity and secretion of multiple metabolic hormones, supporting the regulation of appetite, energy expenditure, and glucose homeostasis. Menopause disrupts this integrated network as estradiol declines, resulting in metabolic imbalances characterized by impaired hormone sensitivity, weight gain, and insulin resistance. In contrast, pregnancy enhances hormonal crosstalk through placental hormones, triggering metabolic realignments necessary for fetal energy demands. However, excessive or dysregulated adaptations may contribute to disorders like gestational diabetes. Understanding these synergies, and how estrogen receptor-associated co‑transcription factors can modulate them, represents a promising therapeutic direction to restore metabolic and reproductive health during hormonal transitions such as menopause and pregnancy.