ESPE Abstracts

Minipuberty, a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis during early infancy, plays a critical role beyond reproductive development. Recent evidence suggests that minipuberty, in addition to facilitating the process by which the capacity for sexual reproduction is achieved and maintained, may also influence neurodevelopmental programming and the maintenance of sensory (e.g., olfaction and hearing) and cognitive performance throughout life. During minipuberty, there is a surge in gonadotropins—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—that activates neuronal networks, including those responsible for the production of nitric oxide (NO), a significant regulator in central hormonal pathways. Studies using animal models of NO deficiency have demonstrated that NO is essential for the maturation of neuroendocrine functions. Nos1-deficient mice, which lack the enzyme necessary for neuronal NO production, show not only impaired sexual maturation but also notable deficits in olfaction, hearing, and cognitive abilities. Preclinical studies have shown that therapeutic interventions targeting NO levels can be promising. Restoring NO levels in Nos1 -deficient mice during minipuberty has been shown to rescue reproductive functions and improve sensory and cognitive abilities. The underlying mechanisms of minipuberty may involve NO’s role in regulating Gnrh1 expression and GnRH production through the activation of specific miRNA-transcription factor micro-networks in GnRH neurons. During minipuberty, NO potentially facilitates proper communication between hypothalamic GnRH neurons and neurons expressing the GnRH receptor in extrahypothalamic areas such as the hippocampus and cortex, which are crucial for sensory and cognitive functions. These insights have profound implications for understanding the developmental challenges faced by preterm infants, who often experience altered minipuberty with abnormal hormone levels. Such infants are at increased risk for non-reproductive comorbidities, including intellectual disabilities and sensory impairments, which resemble the phenotypic traits seen in Nos1 -deficient animal models. Elevated FSH levels during minipuberty may contribute to these adverse outcomes, highlighting the critical importance of this developmental window. Therapeutic strategies aimed at normalizing hormonal levels in individuals with disrupted minipuberty could potentially improve long-term outcomes and enhance quality of life. The established safety of NO-based treatments, such as inhaled NO and sildenafil, in neonatal care supports the exploration of these interventions as viable options for promoting brain development and mitigating long-term non-reproductive deficits in premature infants. This hypothesis is currently under investigation by the European miniNO consortium (https://minino-project.com), which aims to further validate the potential benefits of NO-based therapies in this vulnerable population.