Male hypogonadism: childhood diagnosis and future therapies

Abstract

Male hypogonadism results from inadequate testicular function manifested by the impairment of both testosterone secretion and spermatogenesis. Hypogonadism has several etiologies. Hypogonadotropic hypogonadism (HH) results from hypothalamic–pituitary disorders leading to a complete or partial deficiency in gonadotropin-releasing hormone (GnRH) secretion from hypothalamic neurons, or gonadotropin secretion from anterior pituitary, or defects in GnRH receptor at the pituitary. All situations result in low or normal serum gonadotropin levels and low serum testosterone levels. Congenital HH can occur isolated (idiopathic HH) or in association with olfactory dysfunction (Kallmann’s syndrome). Gonadotropin deficiency can also occur with other pituitary hormone deficiencies. Most of the congenital isolated HH are still idiopathic. However, defects in more than ten genetic loci with multiple modes of inheritance, accounting for monogenic and occasionally oligogenic presentations were found in approximately 30% of cases. Acquired HH results from a hypothalamic–pituitary structural lesion as well as from tumors, trauma, autoimmunity or radiation. Hypergonadotropic hypogonadism is characterized by elevated serum gonadotropin levels due to testicular disorders, chromosomal abnormalities (Klinefelter syndrome), genetic syndromes as well as acquired conditions (autoimmunity, chemotherapy or radiation therapy). The main clinical feature of a male infant with hypogonadism is micropenis associated with or without cryptorchidism. The diagnosis of HH at childhood is difficult and usually postponed until adult age. At pubertal age, the differential diagnosis between the constitutional delay of growth and puberty, and HH is tricky and no hormonal test can consistently distinguish between these two disorders with 100% sensitivity and specificity; therefore, clinical follow-up is essential. Optimal management of male hypogonadism depends of the underlying etiology. Genetic tests are now available to detect genetic mutations in candidate genes essential for hypothalamic–pituitary axis function. Infants with micropenis require testosterone or dihydrotestosterone therapy to increase penile length. The first-line therapy for cryptorchidism is orchiopexy. Puberty should be induced with a low dose of testosterone and fertility could be achieved with chorionic gonadotropin hormone, recombinant luteinizing hormone and follicle stimulating hormone preparations or pulsatile GnRH injection. A small subset of HH patients may have a reversible phenotype enabling the withdrawal of medication in up to 10% of cases.