Nesfatin-1 across human reproduction and early life: implications for infertility, pregnancy complications, and lactation.

Nesfatin-1, a peptide derived from nucleobindin-2 (NUCB2), is a widely expressed neuroendocrine factor originally identified for its anorexigenic effects in the central nervous system. Beyond energy homeostasis, accumulating evidence implicates nesfatin-1 in the regulation of glucose metabolism, stress-axis activity, inflammation, and reproductive function. These properties make nesfatin-1 particularly relevant to human reproduction and early life, physiological states characterized by profound metabolic and endocrine adaptations. The objective of this review is to examine whether nesfatin-1 functions as an integrative endocrine signal linking metabolic, stress-related, and reproductive pathways across the reproductive life course. We synthesize current human evidence on nesfatin-1 in infertility, assisted reproductive technologies, pregnancy adaptations and complications, the maternal-fetal interface, lactation, and postpartum metabolic recovery. Nesfatin-1 has been detected in several biological compartments relevant to reproductive physiology, including maternal plasma, follicular fluid, amniotic fluid, cord blood, and human breast milk. Clinical studies investigating these compartments report heterogeneous findings, with nesfatin-1 levels described as increased, decreased, or unchanged across similar clinical conditions. This variability likely reflects the context-dependent regulation of nesfatin-1 by metabolic status, stress-axis activation, inflammatory signaling, and reproductive stage. In this review, we synthesize current human evidence on nesfatin-1 across the continuum of reproduction, pregnancy, early development, and lactation, and propose a framework to reconcile these inconsistent findings. We argue that nesfatin-1 should be viewed as a context-dependent endocrine integrator reflecting the interaction of metabolic, stress-related, inflammatory, and reproductive axes rather than as a unidirectional biomarker. We further highlight key methodological challenges, including assay variability, timing of sampling, and population heterogeneity, and discuss the potential of nesfatin-1 as a longitudinal or stratification biomarker in reproductive endocrinology. Finally, we outline priorities for future research to clarify its physiological role and translational relevance in human reproduction and early life.