Male Hypogonadism. Part II: Etiology, Pathophysiology, and Diagnosis

A. Seftel


Int J Impot Res. 2006;18(3):223-228. 

In This Article

Abstract and Etiology


Male hypogonadism has a multifactorial etiology that includes genetic conditions, anatomic abnormalities, infection, tumor, and injury. Defects in the hypothalamic-pituitary-gonadal axis may also result from type II diabetes mellitus and treatment with a range of medications. Circulating testosterone levels have been associated with sexual function, cognitive function, and body composition. Apart from reduced levels of testosterone, clinical hallmarks of hypogonadism include absence or regression of secondary sex characteristics, reduced fertility (oligospermia, azoospermia), anemia, muscle wasting, reduced bone mass (and bone mineral density), and/or abdominal adiposity. Some patients, particularly those with partial androgen deficiency of the aging male, also experience sexual dysfunction, reduced sense of vitality, depressed mood, increased irritability, difficulty concentrating, and/or hot flushes in certain cases of acute onset. As many patients with male hypogonadism—like patients with erectile dysfunction—do not seek medical attention, it is important for clinicians to be acquainted with the signs and symptoms of hypogonadism, and to conduct appropriate laboratory testing and other assessments to determine the causes and inform the treatment of this condition.


Hypogonadism is characterized by low serum testosterone (T) levels (<300 ng/dl) together with ≥1 clinical symptom or sign. Symptoms of postpubertal hypogonadism include[1,2,3] (1) sexual dysfunction, such as reduced libido, erectile dysfunction (ED), diminished penile sensation, difficulty attaining orgasm, as well as reduced ejaculate with orgasm; (2) reduced energy, vitality, or stamina; (3) depressed mood or diminished sense of well-being; (4) increased irritability; (5) difficulty concentrating and other cognitive problems; and/or (6) hot flushes in some cases of acute onset.

Signs of hypogonadism include (1) anemia; (2) muscle wasting (sarcopenia); (3) reduced bone mass or bone mineral density (BMD); (4) absence or regression of secondary sex characteristics; (5) abdominal adiposity (i.e. 'pot belly' obesity); and/or (6) oligospermia or azoospermia.

A number of hypothalamic-pituitary-gonadal (HPG) axis defects may induce hypogonadism ( Table 1 ).[2,4] The term primary (hypergonadotropic) hypogonadism refers to testicular disorders and is characterized by low serum T despite high levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Causes of primary hypogonadism include (1) genetic conditions (e.g. Klinefelter syndrome, gonadal dysgenesis); (2) anatomic defects; (3) infection; (4) tumor; (5) injury; (6) iatrogenic causes (surgery or certain medications); and/or (7) alcohol abuse.[3]

The term secondary (hypogonadotropic) hypogonadism denotes deficient release of gonadotropin-releasing hormone (GnRH) and is characterized by low-normal or low levels of FSH, LH, and T. Causes or manifestations of secondary hypogonadism include (1) hyperprolactinemia (often secondary to pituitary adenoma); (2) GnRH deficiency with anosmia (Kallmann syndrome); (3) hypothalamic lesions or disorders; and (4) pituitary lesions or disorders. The term normogonadotropic hypogonadism denotes symptoms or signs of hypogonadism together with low serum T and normal LH levels.

Conditions that may be associated with hypogonadism include type II diabetes mellitus (DM); cancer; acquired immune deficiency syndrome; cirrhosis of the liver; renal failure; hyperthyroidism or hypothyroidism; Cushing syndrome; protein-calorie malnutrition (and anorexia nervosa); morbid obesity; hemochromatosis or sickle-cell anemia; paraplegia and myotonia dystrophica; as well as certain psychiatric disorders, including depressive disorders.[5] In addition, several agents are associated with low circulating testosterone[3] ( Table 2 ).