Hypogonadism in Infertile Men: A Clinical Minefield

Male hypogonadism is one of the most prevalent endocrinologic problems for the infertile male, with up to 40% of infertile men presenting with some degree of hypogonadism. Depending on where the defect is within the hypothalamus-pituitary-testicular (HPT) axis, hypogonadism can be categorized as a primary (hypergonadotropic) or secondary (hypogonadotropic) hypogonadism. A newer classification of hypogonadism termed “organic” and “functional” hypogonadism is also used to describe the etiology. Functional hypogonadism is mainly related to age-related comorbidities and metabolic disease, with an intact HPT axis, and is potentially reversible by addressing the underlying comorbidities. The diagnosis of hypogonadism requires clinical signs and symptoms as well as laboratory confirmation of low serum testosterone levels from at least two tests from a reliable assay. Clinical manifestations and the effect of hypogonadism on fertility largely depend on the onset of hypogonadism, the type of hypogonadism, any associated genetic abnormalities, and any previous hormonal therapy. The fundamental laboratory parameters evaluated for the hypogonadal infertile male include concentrations of total testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Primary and secondary hypogonadism can be distinguished by the LH and FSH concentrations. When an alteration in sex hormone-binding globulin concentration is suspected, free testosterone will provide a more accurate depiction of serum testosterone levels. Additional laboratory tests, imaging, and genetic testing are performed when indicated. The treatment of hypogonadal infertile men is different from men who are hypogonadal and not interested in fertility. The treatment options are generally limited as exogenous testosterone may halt fertility potential. Each hormonal therapy should be discussed with the patient according to its cost, availability, and pharmacologic action. Until now, the hormonal therapeutic option for primary testicular failure is limited and generally ineffective in improving spermatogenesis. On the other hand, for secondary hypogonadism, gonadotropin formulations, antiestrogens, and aromatase inhibitors can serve as an option. A return to normal sperm production may still be achievable within a year of stopping the testosterone in certain patients who have already taken testosterone therapy. Future advances in reproductive technology, with assisted reproductive technologies, tissue grafting, and stem cell therapy, may solve reproductive issues in hypogonadal infertile men.