Androgen deficiency can be due to either testicular failure (primary hypogonadism) or hypothalamic-pituitary defects (secondary hypogonadism).

Primary hypogonadism is diagnosed when testosterone levels are low and gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) are high. Klinefelter’s syndrome is the most common cause (∼1 in 1000 male births) and is due to the presence of one or more extra X chromosomes, usually a 47,XXY karyotype. Other genetic causes of testicular development, androgen biosynthesis, or androgen action are uncommon. Acquired primary testicular failure usually results from viral orchitis but may be due to trauma, testicular torsion, cryptorchidism, radiation damage, or systemic diseases such as amyloidosis, Hodgkin’s disease, sickle cell disease, or granulomatous diseases. Testicular failure can occur as a part of polyglandular autoimmune failure syndrome. Malnutrition, AIDS, renal failure, liver cirrhosis, myotonic dystrophy, paraplegia, and toxins such as alcohol, marijuana, heroin, methadone, lead, and antineoplastic and chemotherapeutic agents also can cause testicular failure. Testosterone synthesis may be blocked by drugs such as ketoconazole or abiraterone, and testosterone action may be blocked at the androgen receptor level by spironolactone or cimetidine.

Secondary hypogonadism is diagnosed when levels of both testosterone and gonadotropins are low (hypogonadotropic hypogonadism). Kallmann syndrome is due to maldevelopment of neurons producing gonadotropin-releasing hormone (GnRH) and is characterized by GnRH deficiency, low levels of LH and FSH, and anosmia. Several other types of GnRH deficiency or gonadotropin deficiency occur without anosmia. Acquired causes of isolated hypogonadotropic hypogonadism include critical illness, malnutrition, excessive stress, obesity, Cushing’s syndrome, opioid and marijuana use, hemochromatosis, and hyperprolactinemia (due to pituitary adenomas or drugs such as phenothiazines). Destruction of the pituitary gland by tumors, infection, trauma, or metastatic disease causes hypogonadism in conjunction with deficiency of other pituitary hormones (see Chap. 171: Disorders of the Anterior Pituitary and Hypothalamus). Normal aging is associated with a progressive decline of testosterone production, which is due to downregulation of the entire hypothalamo-pituitary-testicular axis.