Causes of primary hypogonadism in males

INTRODUCTION — Hypogonadism in a man refers to a decrease in one or both of the two major functions of the testes: sperm production and testosterone production. These abnormalities usually result from disease of the testes (primary hypogonadism) or disease of the pituitary or hypothalamus (secondary hypogonadism). (See "Diagnosis and treatment of disorders of the androgen receptor" and "Steroid 5-alpha-reductase 2 deficiency".)

The distinction between primary and secondary hypogonadism is made by measurement of the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH):

●The patient has primary hypogonadism if the serum testosterone concentration and the sperm count are below normal and the serum LH and FSH concentrations are above normal.

●The patient has secondary hypogonadism if the serum testosterone concentration and the sperm count are subnormal and the serum LH and FSH concentrations are not elevated.

Primary hypogonadism differs from secondary hypogonadism in two ways:

●Primary hypogonadism is more likely to be associated with a decrease in sperm production than in testosterone production. Although many testicular diseases damage both the seminiferous tubules and the Leydig cells, they usually damage the seminiferous tubules to a greater degree. As a consequence, the sperm count may be low and the serum FSH concentration normal or high, yet the serum testosterone concentration remains normal. In contrast, in secondary hypogonadism, there is a proportionate reduction in testosterone and sperm production.

●Primary hypogonadism is more likely to be associated with gynecomastia, presumably due to the stimulatory effect of the supranormal serum FSH and LH concentrations on testicular aromatase activity. This results in increased conversion of testosterone to estradiol and enhanced testicular secretion of estradiol relative to testosterone.

The major causes of primary hypogonadism in males will be reviewed here (table 1). The causes of secondary hypogonadism and of male infertility, which may or may not be associated with hypogonadism, and the manifestations and diagnosis of hypogonadism in males are discussed separately. (See "Causes of secondary hypogonadism in males" and "Causes of male infertility" and "Clinical features and diagnosis of male hypogonadism".)

CONGENITAL ABNORMALITIES — The clinical features of primary hypogonadism vary greatly, depending upon the specific cause and whether or not testosterone secretion is affected and when this occurs. (See "Clinical features and diagnosis of male hypogonadism".)

●If testosterone production is reduced during the first trimester in utero, the fetus will not be completely virilized.

●If testosterone production is normal during the first trimester but reduced during the third trimester in utero, male sexual differentiation will be normal, but the newborn infant will have a small penis, called micropenis.

●If testosterone production is reduced before the expected onset of puberty, full pubertal development will not occur.

Klinefelter syndrome — Klinefelter syndrome is the most common congenital abnormality causing primary hypogonadism, occurring in approximately 1 in 1000 live male births [1]. This syndrome is the clinical manifestation of a male who has an extra X chromosome. The most common genotype is 47,XXY (figure 1), but greater and lesser numbers of X chromosomes have also been reported, resulting in karyotypes such as 48,XXXY and 46,XY/47,XXY mosaicism [2]. The clinical features, diagnosis, and management of Klinefelter syndrome are reviewed in detail separately. (See "Clinical features, diagnosis, and management of Klinefelter syndrome".)

Other chromosomal abnormalities — A large number of other chromosomal abnormalities that result in testicular hypofunction have been reported. Included in this group of rare disorders are the 46,XY/XO and the 47,XYY karyotypes [3].

●The 46,XY/XO karyotype leads to a syndrome characterized by short stature and features typical of Turner syndrome. The gonads vary from streak to dysgenetic to normal testes; as a result, the sexual phenotype varies from complete female to complete male. If the patient has both a streak gonad and a dysgenetic testis ("mixed gonadal dysgenesis"), the risk of gonadoblastoma is approximately 20 percent [3]. Gonadectomy should therefore be performed in these patients.

●The 47,XYY karyotype was initially thought to be associated with hypogonadism, but subsequent reports have not confirmed this relationship.

●Microdeletions in specific regions of the long arm of the Y chromosome are occur in up to 20 percent of men with azoospermia or severe oligospermia. Some of these men have no other testicular lesions, but others have cryptorchidism [4]. (See "Causes of male infertility", section on 'Y chromosome and related defects'.)

Mutation in the FSH and LH receptor genes — Another rare cause of primary hypogonadism is a mutation in the follicle-stimulating hormone (FSH) receptor gene [5,6]. One report described five men found to be homozygous for an inactivating mutation of the FSH receptor [5]. These subjects had variably low sperm counts and inhibin B concentrations and high serum FSH concentrations. Luteinizing hormone (LH) receptor mutations result in Leydig cell hypoplasia and testosterone deficiency in the first trimester in utero [7]. XY patients with mutations in LHCGR characteristically have female external genital appearance but lack a uterus and fallopian tubes; the epididymis and vas deferens may be present. (See "Causes of differences of sex development", section on 'Conditions affecting androgen synthesis or response'.)

Cryptorchidism — Cryptorchidism refers to testes that are undescended, specifically, to testes that are in the abdominal cavity or in the inguinal canal and cannot be manipulated manually to within the scrotum by the age of one year. In comparison, testes that can be manipulated manually into the scrotum are called retractile. The topic of cryptorchidism will be summarized very briefly here, but it is reviewed in detail elsewhere. (See "Undescended testes (cryptorchidism) in children: Clinical features and evaluation" and "Undescended testes (cryptorchidism) in children: Management" and "Causes of male infertility", section on 'Cryptorchidism'.)

Cryptorchidism may affect one or both testes. Some clinical consequences of cryptorchidism depend upon whether one or both testes are cryptorchid:

●If only one testis is undescended, the sperm count will be subnormal in 25 to 33 percent and the serum FSH concentration will be slightly elevated. The presence of these abnormalities suggests that both testes are abnormal, perhaps congenitally, even though only one fails to descend.

●If both testes are undescended, the sperm count will usually be severely subnormal and the serum testosterone may also be reduced.

Men with a history of undescended testis also have an increased risk of developing testicular cancer compared with men in the general population in whom the age adjusted incidence is approximately 5.4 per 100,000. However, the magnitude of increased risk is poorly quantified. (See "Undescended testes (cryptorchidism) in children: Management", section on 'Testicular cancer'.)

Treatment of cryptorchidism is also discussed in detail elsewhere. (See "Undescended testes (cryptorchidism) in children: Clinical features and evaluation" and "Undescended testes (cryptorchidism) in children: Management".)

Disorders of androgen biosynthesis — A congenital decrease in testosterone synthesis and secretion can result from mutations of the genes that encode the enzymes necessary for testosterone biosynthesis. These mutations, all rare, involve the cholesterol side-chain cleavage enzyme, 3 beta-hydroxysteroid dehydrogenase, and 17 alpha-hydroxylase, both of which are present in the adrenal glands as well as the testes, and 17 beta-hydroxysteroid dehydrogenase, which is present only in the testes. Each of these mutations results in decreased testosterone secretion, beginning in the first trimester of pregnancy, and therefore in incomplete virilization. (See "Causes of differences of sex development", section on 'Reduced androgen synthesis'.)

Myotonic dystrophy — Myotonic dystrophy, an autosomal dominant disorder that leads to muscle atrophy, is accompanied by hypogonadism that is usually not recognized until adulthood. Small testes and decreased sperm production are more common than decreased serum testosterone levels. In one study of 39 men with myotonic dystrophy, as an example, all had supranormal serum FSH concentrations, and approximately one-half had subnormal serum testosterone and supranormal serum LH concentrations [8]. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

Congenital anorchia — This form of testicular regression occurs after 20 weeks of gestation, so that at birth, male sexual differentiation is normal but testes are absent and hypogonadism is severe. (See "Causes of differences of sex development", section on 'Testicular dysfunction without atypical genital appearance'.)

Varicocele — Varicosity of the venous plexus within the scrotum, called a varicocele, has long been considered a possible cause of damage to the seminiferous tubules and thereby of infertility. As a result, ligation of varicoceles has long been practiced as a treatment for infertile men, although available data do not support this practice. This topic is discussed in detail elsewhere. (See "Treatments for male infertility", section on 'Surgical repair of varicocele'.)

ACQUIRED DISEASES — The manifestations of acquired causes of primary hypogonadism also depend upon whether sperm production, testosterone secretion, or both are impaired and, if testosterone secretion is diminished, when this occurs. (See "Clinical features and diagnosis of male hypogonadism".)

●Decreased sperm production results in infertility

●Reduced testosterone secretion during childhood is associated with incomplete pubertal changes

●Diminished testosterone secretion during adulthood leads to decreases in energy, libido, sexual hair, muscle mass, and bone mineral density

Infections — Mumps orchitis is the infection most closely associated with testicular damage. Orchitis is a much more common manifestation when mumps occurs in adulthood than in childhood. The median age of men with mumps orchitis in one study was 29 years, compared with age eight of all patients with mumps [9]. The incidence of mumps orchitis should decrease because of the widespread use of the mumps vaccine.

Testicular involvement of mumps causes painful swelling of the testes, followed by atrophy. The seminiferous tubules are almost always severely affected, often resulting in infertility, especially when both testes are involved; the Leydig cells also may be damaged, resulting in decreased testosterone production [10]. (See "Mumps", section on 'Orchitis or oophoritis'.)

Radiation — Direct radiation to the testes, as in treatment for leukemia, will damage the testes [11]. Even indirect radiation to the testes that are shielded (as with radiation to the inguinal lymph nodes for lymphoma) will damage the seminiferous tubules [12]. The degree of damage is proportionate to the amount of radiation exposure.

Radioactive iodide has been reported to cause a decrease in the sperm count when doses of several hundred mCi are administered to treat thyroid cancer [13]. (See "Causes of male infertility", section on 'Drugs and radiation'.)

Alkylating and antineoplastic agents — Alkylating agents, such as cyclophosphamide, chlorambucil, cisplatin, and busulfan, can damage the seminiferous tubules to a degree sufficient to cause azoospermia and markedly elevated serum follicle-stimulating hormone (FSH) concentrations [14,15]. As with radiation, the damage is proportionate to the extent and duration of treatment. Long-term follow-up of men treated in childhood suggests that many patients recover normal spermatogenesis and fertility [15]. Less commonly, testosterone secretion is also impaired, leading to a decrease in the serum concentration of testosterone and increase in that of luteinizing hormone (LH) [16]. Concurrent administration of testosterone might protect against long-term gonadal injury in adults. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity' and "Effects of cytotoxic agents on gonadal function in adult men".)

Cisplatin or carboplatin also can decrease the sperm count, but the count typically recovers, at least partially. In one study, as an example, the changes in sperm count were assessed in 89 men with testicular germ-cell tumors who were treated with unilateral orchiectomy and either cisplatin- or carboplatin-based chemotherapy [17]. The sperm count was normal in 64 percent at one year and 80 percent at five years. Recovery was less likely when cisplatin was administered for more than four cycles.

Other chemotherapeutic agents can also cause some degree of seminiferous tubular damage, but the effect is less prominent than that of alkylating agents. (See "Effects of cytotoxic agents on gonadal function in adult men".)

Ketoconazole — The antifungal drug ketoconazole directly inhibits testosterone biosynthesis, thereby causing testosterone deficiency [18].

Glucocorticoids — Chronic glucocorticoid use can also lower testosterone levels by approximately one-third; the mechanism is not clear, but inhibition may occur at both the testis and pituitary [19].

Environmental toxins (endocrine-disrupting chemicals) — Many environmental toxins have been demonstrated to cause decreased spermatogenesis in laboratory animals or in vitro. The nematocide dibromochloropropane is known to decrease spermatogenesis in men in vivo and has been banned [20]. Although several toxins, referred to as endocrine-disrupting chemicals, have been associated with abnormalities in one semen parameter or another, no one agent has been consistently shown to affect any one parameter [21], and therefore, one cannot state that any one agent is a cause of testicular damage in men. (See "Endocrine-disrupting chemicals".)

Trauma — Trauma to the testes can be sufficiently severe to damage both seminiferous tubules and Leydig cells.

Testicular torsion — Testicular torsion is one of the most common reasons for the loss of a testicle before puberty. Testicular torsion is a twisting of the testis on the spermatic cord, which results in acute loss of the blood supply to the testis. The testis can die from lack of blood if the torsion does not remit spontaneously or is not corrected surgically within a few hours. The degree of damage depends upon the duration of the torsion. Torsion lasting more than eight hours can lead to sufficient damage to the seminiferous tubules to lower the sperm count [22]. Even when the torsion involves only one testis, both testes may be damaged. How this might occur is not known. (See "Causes of scrotal pain in children and adolescents", section on 'Testicular torsion'.)

Bilateral orchiectomy — Orchiectomy is standard treatment for testicular cancer, which is often bilateral, although it often occurs at different times on each side.

Autoimmune damage — Many men with idiopathic infertility have antisperm antibodies. It is not known, however, if these antibodies are the result of an autoimmune process or a response to damage by some other mechanism [23].

The hypogonadism that accompanies autoimmune polyglandular disease is also characterized by hypothyroidism and hypoadrenalism. It is much less common than idiopathic infertility, but it is more likely to be the result of an autoimmune process [24]. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 2 (polygenic)'.)

Chronic, systemic diseases — Many chronic, systemic illnesses cause hypogonadism both by a direct testicular effect and by decreasing gonadotropin secretion.

Cirrhosis — Cirrhosis is occasionally associated with hypogonadism, as manifested by a reduction in the serum testosterone concentration. More than one mechanism appears to be involved. In some cases, primary gonadal injury appears to be more prominent, as suggested by increased serum FSH and LH concentrations [25,26]. In others, suppression of hypothalamic or pituitary function appears to play a primary role, as suggested by serum LH concentrations that are not elevated [26]. Hypogonadism due to cirrhosis is rapidly corrected following liver transplantation [27].

Acute alcohol ingestion also may cause secondary hypogonadism, as manifested by subnormal serum testosterone concentration levels without increases in either LH or FSH [28].

Chronic kidney disease — Severe chronic kidney disease may also be associated with hypogonadism. One study, as an example, evaluated 35 men with creatinine clearances of below 4 mL/min per 1.73 m²; the mean (±SE) serum testosterone concentration was 469±58 ng/dL (16.3±2.0 nmol/L), compared with 622±130 ng/dL (21.6±4.5 nmol/L) in normal men [29]. Several observations suggested that this was due to primary hypogonadism:

●Germinal cells, as seen on histologic sections of testicular biopsies in 15 of the men, were subnormal compared with normal men

●The mean serum FSH and LH concentrations were supranormal, while the serum testosterone response to exogenous human chorionic gonadotropin (hCG) was impaired

Another study evaluated men with chronic kidney disease who were being treated by hemodialysis and then underwent renal transplantation [30]. Some of the patients had similar findings to the previous study consisting of abnormalities in testicular biopsy, a low sperm count, and high serum FSH and LH concentrations. These findings, which were consistent with primary hypogonadism, were corrected by renal transplantation. However, the improvement in sperm count and testosterone concentration was preceded by a surge in FSH release, suggesting that transplantation corrected a concurrent impairment in hypothalamic or pituitary function. (See "Causes of secondary hypogonadism in males", section on 'Chronic, systemic illness'.)

HIV — Men who have human immunodeficiency virus (HIV) infection may be hypogonadal to some degree, as judged by generally lower serum testosterone concentrations than men without HIV [31]. However, the serum FSH and LH can be elevated or not, indicating both primary and secondary hypogonadism. The frequency with which hypogonadism accompanies HIV infection and its severity appear to have diminished since the introduction of antiretroviral therapy. (See "Hypogonadism in males with HIV".)

Idiopathic — Primary hypogonadism is often idiopathic, whether it is severe, resulting in testosterone deficiency and azoospermia, or mild, resulting only in oligospermia/azoospermia and an elevated FSH.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Male infertility or hypogonadism".)

SUMMARY — Hypogonadism in a male refers to a decrease in either of the two major functions of the testes: sperm production and testosterone production. These abnormalities usually result from disease of the testes (primary hypogonadism), disease of the pituitary or hypothalamus (secondary hypogonadism), or, more rarely, a defect in the ability to respond to testosterone. (See "Causes of secondary hypogonadism in males" and "Diagnosis and treatment of disorders of the androgen receptor".)

The distinction between primary and secondary hypogonadism is made by measurement of the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH):

●The patient has primary hypogonadism if the serum testosterone concentration and the sperm count are below normal and the serum LH and FSH concentrations are above normal.

●The patient has secondary hypogonadism if the serum testosterone concentration and the sperm count are subnormal and the serum LH and FSH concentrations are normal or reduced.

Primary hypogonadism differs from secondary hypogonadism in two ways:

●Primary hypogonadism is more likely to be associated with a decrease in sperm production than in testosterone production. Although many testicular diseases damage both the seminiferous tubules and the Leydig cells, they usually damage the seminiferous tubules to a greater degree.

●Primary hypogonadism is more likely to be associated with gynecomastia, presumably due to the stimulatory effect of the supranormal serum FSH and LH concentrations on testicular aromatase activity. This results in increased conversion of testosterone to estradiol and enhanced testicular secretion of estradiol relative to testosterone.

Primary hypogonadism may be due to congenital abnormalities or acquired diseases.

●Congenital abnormalities include: Klinefelter syndrome (the most common congenital cause), FSH and LH receptor mutations, cryptorchidism, disorders of androgen biosynthesis, and myotonic dystrophy.

●Acquired diseases include: infection (mumps orchitis); radiation and chemotherapy; trauma; testicular torsion; chronic, systemic diseases; environmental toxins; suramin; ketoconazole; glucocorticoids; autoimmune damage; and human immunodeficiency virus (HIV). Unfortunately, many cases of primary hypogonadism remain unexplained (idiopathic).