Primary Congenital Hypogonadism

Klinefelter syndrome (KS), classically associated with the 47, XXY karyotype, is the most common cause of congenital hypogonadism, affecting one in 660 men and is characterized typically by small, firm testes (<2 mL), low testosterone levels, eunuchoidal proportions, gynecomastia, elevated LH and FSH levels, and impaired spermatogenesis. However, there is considerable phenotypic variation due to mosaicism, variable polyglutamine tract length in exon 1 of the androgen receptor or other polymorphisms in the androgen receptor, other genetic factors, and variable testosterone levels; KS may present with learning difficulties and behavioral problems in childhood and with infertility, gynecomastia, or sexual dysfunction in adulthood. Registries of patients with KS have reported higher overall mortality and increased risk of breast cancer, non-Hodgkin lymphomas, lung cancer, and autoimmune diseases, such as systemic lupus erythematosus and Sjögren syndrome, and lower incidence of prostate cancer. Although most men with 47, XXY karyotype are azoospermic, pregnancies have been achieved by testicular sperm extraction combined with intracytoplasmic sperm injection.

Up to 15% to 20% of patients with KS demonstrate 46, XY/47, XXY mosaicism, which is associated with a milder phenotype. Patients with KS with more than one extra X chromosome have a more severe phenotype, increased risk of congenital malformations, and lower intelligence than individuals with 47, XXY. The true prevalence of KS, especially KS mosaicism, may be underestimated as many men with KS remain undiagnosed; a Danish study found that only 25% of adult men with KS had received a diagnosis; of these, less than 10% were diagnosed before puberty.

Structural chromosomal aberrations, including deletions, duplications, and translocations, and other rearrangements can lead to hypogonadism. For example, Noonan syndrome, an autosomal dominant disorder, is caused by a mutation in the PTPN11 gene and is characterized by dysmorphic facial features, short stature, and heart disease and is associated with abnormal Sertoli and Leydig cell function. Leydig cell hypoplasia as a result of LH receptor mutations leads to testosterone deficiency during the first trimester of pregnancy and complete lack of virilization of the external genitalia at birth. Additional diagnoses to consider in newborns with 46, XY with ambiguous genitalia include defects of testosterone biosynthesis, 5α-reductase deficiency, or androgen insensitivity due to mutations of the androgen receptor.

Cryptorchidism, if left uncorrected by 2 years of age, predisposes men to an increased risk of infertility, androgen deficiency, and testicular cancer. Cryptorchidism may also be associated with an increased risk of inguinal hernias and testicular torsion. Even unilateral cryptorchidism, corrected before puberty, is associated with decreased sperm count, possibly reflecting unrecognized damage to the fully descended testis or other genetic factors. A growing body of evidence suggests that cryptorchidism, hypospadias, impaired spermatogenesis, and testicular cancer may be related to common genetic and environmental perturbations and are components of the testicular dysgenesis syndrome.

In children with congenital anorchia, the testicular tissue is presumed to have been functioning during fetal life until at least the 16th week of gestation with gonadal regression occurring later; so at birth, sexual differentiation is normal, but the testes are absent and hypogonadism is severe. In children presenting as phenotypic boys, in whom testes cannot be palpated in the scrotum, bilateral cryptorchidism can be distinguished from congenital anorchia by the testosterone response to human chorionic gonadotropin (hCG) administration, the measurement of antimüllerian hormone level, and by magnetic resonance of the pelvis and abdomen.

Primary Acquired Hypogonadism

The testes are vulnerable to injury from trauma, torsion, surgery, toxins, infections, inflammation, and systemic diseases. The manifestations of primary acquired hypogonadism depend on the timing of the testicular injury and also on whether spermatogenesis and testosterone secretion are both affected. In general, there is a larger decrease in sperm production than in testosterone secretion because the seminiferous tubules are generally more susceptible to toxins than the Leydig cells. Testicular torsion, which results from twisting of one or both testes on the spermatic cord, leads to acute loss of the blood supply and permanent damage to the seminiferous tubules if not corrected within a few hours. In a nationwide study in the United States, the incidence of testicular torsion among males aged 1 to 25 years was reported to be 4.5 cases per 100,000 persons per year.

Cancer chemotherapeutic agents, especially alkylating agents, such as cyclophosphamide and procarbazine, can cause Leydig cell impairment, damage to the seminiferous tubules, and hypogonadism. Testicular germ cells are very sensitive to radiation, and there is a clear relation between radiation dose and testicular damage. Radiation doses of 200 mGy (20 rad) or more are associated with damage to the spermatogonia, and a dose level of 800 mGy (80 rad) is associated with oligospermia or azoospermia; higher doses may completely destroy the germinal epithelium.

Viral orchitis may be caused by the mumps virus, echovirus, lymphocytic choriomeningitis virus, and group B arboviruses. Orchitis occurs in as many as 25% of postpubertal men with mumps; the orchitis is unilateral in about 60% and bilateral in the remainder. Orchitis typically develops a few days after the onset of parotitis. Although testicular function may recover completely in many men after a bout of orchitis, others may experience testicular atrophy. Semen analysis returns to normal in 75% of men with unilateral orchitis but in only about a third of men with bilateral orchitis. Many chronic, systemic diseases, such as cirrhosis, end stage renal disease, and human immunodeficiency virus (HIV) infection, can cause primary hypogonadism.

Secondary Congenital Hypogonadism

Congenital hypogonadotropic hypogonadism with anosmia (Kallmann syndrome) or without anosmia is a heterogeneous group of disorders that can result from one or more mutations in genes that contribute to the development and migration of the GnRH neurons, olfactory lobe organogenesis, regulation of GnRH secretion, gonadotrope development, or to the regulation of gonadotropin secretion ( Table 3 ). Varying patterns of inheritance and penetrance have been described. A substantial proportion of patients with idiopathic hypogonadotropic hypogonadism (IHH) may have an oligogenic rather than a monogenic disorder. Patients with complete GnRH deficiency may have complete absence of pubertal development, whereas others may manifest varying degrees of gonadotropin deficiency and pubertal delay; a subset that carries the same mutations as their affected family members may even have normal reproductive function. Complete reversal of gonadotropin deficiency may also occur in adult life after sex steroid therapy in a small proportion of patients with IHH. Further, some men with IHH may present with androgen deficiency and infertility in adult life after having gone through apparently normal pubertal development. Nutritional, emotional, or metabolic stressors may unmask gonadotropin deficiency in some patients who harbor mutations in the candidate genes but who previously had normal reproductive function, such as women with hypothalamic amenorrhea. The factors that contribute to the phenotypic variation in IHH are incompletely understood, but oligogenicity and gene-gene and gene-environment interactions are likely contributors.

The incidence of congenital hypogonadotropic hypogonadism is approximately 1 to 10:100,000 live births (IHH). Mutations in a large number of genes, including GnRH1/GnRHR , TAC3/TACR3 , FGF8/FGF17 , PROK2/PROKR2 , NELF , CHD7 , HS6ST1 , WDR11 , SEMA3A , SOX10 , IL17RD2 , DUSP6 , SPRY4 , and FLRT3 , have been implicated in the genesis of IHH; this list continues to grow. Mutations of the Dax1 gene lead to hypogonadism associated with congenital adrenal hypoplasia. Mutations in the prohormone convertase gene lead to hypogonadism in conjunction with severe obesity, hypocortisolism, and diabetes. Similarly, leptin or leptin receptor mutations lead to morbid obesity along with hypogonadotropic hypogonadism. The defect may rarely lie above the level of the hypothalamus; kisspeptin stimulates GnRH neurons in the hypothalamus to secrete GnRH, and mutations in the kisspeptin receptor lead to congenital hypogonadotropic hypogonadism. Mutations of the gonadotropins and their receptors have also been described with varying consequences on reproductive health. Mutations in homeodomain transcription factors, such as Prop1 , Pit1 , Hsx1 , and others may be associated with failure of differentiation of one or more pituitary cell lineage resulting in deficiency of one or more pituitary hormones.

Secondary Acquired Hypogonadism

Hypogonadotropic hypogonadism can be caused by any disease process that affects the HPG axis by suppressing GnRH secretion from the hypothalamus, preventing GnRH from reaching the pituitary by stalk injury, and damaging the pituitary itself, effectively lowering the secretion of the gonadotropins. Hyperprolactinemia can suppress GnRH secretion and gonadotropin response to GnRH secretion, resulting in suppressed LH and FSH secretion and consequently in low testosterone levels.

The HPG axis is sensitive to alterations in energy balance, emotional or physiologic stress, and illness. Hypogonadotropic hypogonadism may be the primary intent of a medication (ie, GnRH analogues used in the treatment of prostate cancer) or an undesired consequence of medications, including androgenic anabolic steroids, glucocorticoids, marijuana, and chronic opiates. SHBG levels are negatively associated with body mass index; therefore, men with mild to moderate obesity typically have low total testosterone levels but normal free testosterone levels. Severe obesity may be associated with true hypogonadotropic hypogonadism in which both total and free testosterone levels are suppressed. Eating disorders are less common in men than in women and can be associated with hypogonadism. Damage to the gonadotroph cells can result from both benign and malignant tumors, infiltrative diseases (ie, sarcoidosis, Langerhans cell histiocytosis, hemochromatosis), infection, and pituitary apoplexy, which may be spontaneous or due to trauma; the hypogonadism may be transient or permanent.

Chronic opioid use is emerging as an important cause of secondary hypogonadism and has been associated with an increased risk of sexual dysfunction, osteoporosis, and fractures in men. Typically, 20 mg of methadone or equivalent doses of other opiates are sufficient to suppress testosterone levels.

After prolonged use of large doses of anabolic-androgenic steroid (AAS), the recovery of HPT axis may take a long time, be incomplete, or may not occur at all leading to AAS withdrawal hypogonadism. In some men’s health clinics, AAS withdrawal hypogonadism has emerged as an important cause of androgen deficiency. In a retrospective review of 6033 patients attending a men’s health clinic in Texas, 43% of those with total testosterone less than 50 ng/dL reported prior AAS exposure. In another report, 21% of 382 hypogonadal men seeking testosterone replacement therapy had earlier AAS exposure.

Testosterone and Metabolic Disorders

In epidemiologic studies, low total testosterone levels have been associated with an increased risk of diabetes and metabolic syndrome. However, in longitudinal analyses of epidemiologic data, SHBG levels, but not total or free testosterone levels, are independently associated with incident diabetes and metabolic syndrome after adjusting for age, adiposity, and comorbid conditions. SHBG is being recognized as an important independent marker of metabolic risk.

The induction of severe acute deficiency of testosterone, such as that induced by withdrawal of testosterone therapy in men with IHH or that induced therapeutically in men with prostate cancer receiving androgen deprivation therapy, is associated with the worsening of insulin resistance. Furthermore, testosterone administration reduces whole-body, subcutaneous as well as visceral fat ; therefore, testosterone therapy would be expected to improve insulin resistance in androgen-deficient men. However, randomized clinical trials have not shown consistent improvements in insulin resistance or diabetes outcomes with testosterone therapy.

Although several randomized, placebo-controlled trials of testosterone have been conducted in men with diabetes, the results of only one such trial have been published. The TIMES2 (Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome) Study was a randomized trial in which men with type 2 diabetes and/or metabolic syndrome were randomized to either 2% testosterone gel or placebo gel for 6 months. The change in hemoglobin A1C between groups did not differ significantly between groups. Thus, this and other unpublished trials have failed to show significant improvements in diabetes outcomes with testosterone therapy, although some trials have reported improvements in homeostatic model assessment for insulin resistance (HOMA-IR).