Molecular clues in the regulation of mini‐puberty involve neuronal DNA binding transcription factor NHLH2

Gonadotropin releasing hormone agonist (GnRHa) treatment following surgery to correct cryptorchidism restores mini-puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. Several genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed in both the brain and testis. However, the expression of these genes in prepubertal gonads has not been studied systematically, and little is known about the effect of hormone therapy on their testicular and neuronal expression levels. In this review, we interpret histological sections, data on hormone levels, and RNA profiling data from adult normal testes compared to pre-pubertal low infertility risk (LIR) and high infertility risk (HIR) patients randomly treated with surgery in combination with GnRHa or only surgery. We organize 31 target genes relevant for idiopathic hypogonadotropic hypogonadism and cryptorchidism into five classes depending on their expression levels in HIR versus LIR samples and their response to GnRHa treatment. Nescient-helix-loop-helix 2 (NHLH2) was the only gene showing a decreased mRNA level in HIR patients and an increase after GnRHa treatment. This phenomenon may reflect a broader effect of hormone treatment on gene expression in both testicular and central nervous system tissues, which could explain why the hypothalamus-pituitary-testicular axis is permanently restored by the administration of GnRHa.