Hypogonadism: Pathogenesis, Diagnosis, and Treatment

Male hypogonadism is a clinical syndrome arising from the failure of the testes to produce sufficient testosterone to maintain secondary sexual, reproductive and other androgen-dependent physiological functions. Consequences and clinical features of testosterone deficiency vary according to the stage of sexual development: fetal onset - ambiguous genitalia development, childhood onset - delayed puberty and adult onset – sexual dysfunction, infertility and alterations in adipose and musculo-skeletal mass and function. Klinefelter syndrome is the most common cause of hypogonadism; it is often undiagnosed due in part to the extremely variable clinical features. The complex genetic architecture of GnRH neuronal development and action underlying congenital isolated hypogonadotropic hypogonadism (IHH) is being gradually unraveled with up to 50% of cases now having identifiable monogenic or oligogenic mutations. Functional hypogonadism associated with obesity/diabetes, opiate and anabolic steroid abuse, and advanced age is becoming increasingly prevalent; some of these cases may be reversible. The diagnosis of hypogonadism should be made only in men with symptoms and signs consistent with androgen deficiency abetted by consistently and unequivocally low serum testosterone concentrations in fasting morning blood, measured by an accurate and reliable method. Free testosterone measurement is indicated in the presence of sex hormone binding globulin alterations, e.g. in obese and older men, and when testosterone is in the borderline low range. Measurement of gonadotropins can differentiate secondary from primary hypogonadism, direct further investigations to identify underlying etiologies and optimize specific treatment, e.g. for pituitary tumor or fertility promotion. Testosterone replacement therapy for confirmed organic hypogonadism is well-established and highly efficacious; a new generation of testosterone preparations have largely replaced legacy products from the 1950s. Patient-important efficacy outcomes and long-term safety of testosterone treatment in men with functional (potentially reversible) hypogonadism have not yet been clearly demonstrated. Gonadotropin induction of spermatogenesis with luteinizing hormone-like and follicle stimulating hormone preparations allow the majority of IHH men to achieve natural fertility or assisted conception. If fertility is not an immediate issue, patients with IHH can be treated with testosterone for failure to undergo puberty and other manifestations of androgen deficiency Appropriate efficacy assessment and safety monitoring should be performed during maintenance of testosterone treatment.