AgRP neurons as an integrative node linking the somatotropic and reproductive axes

Growth hormone (GH) signaling contributes to pubertal development and reproductive function, yet the hypothalamic circuits mediating these effects remain incompletely understood. Kisspeptin and agouti-related protein (AgRP) neurons are key integrators of metabolic and reproductive cues and exhibit GH-responsive signaling pathways. We therefore investigated their contributions to the reproductive consequences of altered somatotropic signaling. Using genetic mouse models of chronic GH excess or deficiency, we examined the impact of altered GH signaling on pubertal maturation, fertility, and hypothalamic neuroendocrine function. Pubertal onset was unaffected in female mice, whereas males with either GH excess or GH deficiency exhibited delayed puberty. In contrast, GH hypersecretion selectively disrupted estrous cyclicity and impaired fertility in females. Female reproductive dysfunction occurred despite preserved kisspeptin signaling, as evidenced by the preservation of intrinsic electrophysiological properties of kisspeptin neurons and unaltered hypothalamic Kiss1 mRNA expression. Chronic GH excess increased hypothalamic Agrp mRNA expression and reduced Pomc and Tac2 mRNA expression compared to control mice; these transcriptional changes were prevented by AgRP-specific GH receptor (GHR) deletion, which also improved ovarian function. Notably, selective deletion of the GHR in AgRP cells markedly improved fertility in GH-hypersecreting females. Together, these findings identify AgRP neurons as a critical hypothalamic target through which chronic GH excess impairs female reproductive function. Our results further demonstrate that GH-induced infertility occurs independently of canonical kisspeptin-GnRH dysfunction, revealing a sexually dimorphic mechanism linking somatotropic signaling to reproductive competence. Significance Statement Reproductive dysfunction is a common consequence of chronic alterations in growth hormone (GH) secretion, but the underlying neural mechanisms remain poorly defined. We show that chronic GH excess induces a sexually dimorphic reproductive phenotype characterized by profound impairment of female fertility despite largely preserved kisspeptin neuronal function. In contrast, GH excess altered hypothalamic AgRP-associated pathways, and the selective deletion of GH receptors in AgRP neurons significantly improved fertility in GH-hypersecreting females. These findings identify AgRP neurons as key mediators of GH-induced reproductive dysfunction and reveal a previously unrecognized sexually dimorphic neuroendocrine mechanism linking somatotropic signaling, metabolic circuits, and female fertility.