Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that SELENOT, a newly-described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuro-endocrine regulations in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome (PCOS)-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These alterations are reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a new redox effector of GnRH neuron activity impacting both male and female reproductive function.