Primary Gonadal Failure

Primary hypogonadism is a more frequent cause of low serum testosterone in younger men than hypothalamic-pituitary disease. The list of specific etiological causes is long (Table but often definable by careful history, physical examination, and laboratory tests.

Klinefelter’s Syndrome

This most common form of congenitally induced primary male hypogonadism (500-1000 male births) was described by Klinefelter in nine men who had small testes with androgen deficiency, azoospermia, bilateral gynecomasria, and increased urinary gonadotropin excretion. Subsequently, eight of the nine men were shown to be positive for a Barr body, indicating an extra X chromosome.

Klinefelter’s males are usually shown to have an XXY karyotype. There are several genetic mechanisms that can lead to this karyotype. Most are due to nondisjunction of a maternal or paternal sex chromosome during the first meioric division. Although hypogonadism and infertility are the most common clinical signs that identify this disorder, other nonreproductive defects can also occur. These include cognitive disabilities, behavioral dysfunction, abnormalities of tooth structure, and atypical findings of relatively longer lower extremities when compared to upper extremities.

The phenotypic manifestations of Klinefelter’s syndrome are most classical in men with a 47, XXY karyotype. Some men with the clinical picture of Klinefelter’s syndrome have a mosaic pattern where some of the cells are XXY and others are normal XY. In other, less common situations, greater supernumerary X chromosomes may occur, producing a spectrum of XXY, XXXY, and mosaics of these two variants.

Diagnosis of Klinefelter’s syndrome prior to puberty is often difficult, although learning disabilities, attention deficits, and behavioral dysfunction may raise a suspicion of Klinefelter’s syndrome in early life. The testes are usually small in the neonatal period, failing to increase in size at puberty and remaining less than 1.5 mL in volume due to absence of germ cells in the seminiferous tubules. Interestingly, the few testicular biopsies available from prepubertal Klinefelter’s syndrome patients show either normal or minimal evidence of germ-cell loss. luteinizing hormone and follicle-stimulating hormone levels tend to be normal prior to puberty but rise above the normal range at the age of physiologic pubertal increases in reproductive hormones. Gynecomastia occurs in varying degrees during the postpubertal period, probably due to a relative increase in estradiol secretion from the hyperstimulated testes and decreased ratios of testosterone to estradiol. In Klinefelter’s syndrome, muscle mass may appear to be normal but is usually diminished and strength is decreased. Beard and body hair are reflective of the testosterone levels in the patient. The prostate is prepubertal and does not increase in size until androgen treatment is begun. Taurodontism (enlargement of the molar teeth by extension of the pulp) is said to be present in 40% of Klinefelter’s syndrome patients when compared to 1% with the general XY population. Other dental abnormalities including increased caries have been frequently seen in the authors’ experience.

Serum testosterone levels are usually low or low-normal, with free testosterone levels more predictably decreased due to increased sex hormone binding globulin levels. In many instances, a temporary state of compensated hypogonadism may be present (elevated serum, luteinizing hormone, and follicle-stimulating hormone with normal serum testosterone), but testosterone levels fall as the patient ages. Serum luteinizing hormone and follicle-stimulating hormone levels are uniformly elevated in adult Klinefelter’s syndrome patients even when serum testosterone falls within the low-normal range. Azoospermic infertility is the rule in Klinefelter’s syndrome, with typical testicular biopsies revealing Leydig cell hyperplasia, loss of germ cells, sclerosis of the germ-cell compartment, and thickened tubular basement membranes. Mosaic forms may have some degree of immature germ cells on biopsy, but almost all are azoospermic. The reasons for delayed Leydig cell failure and the relationship of spermatogenic failure to the Leydig cell abnormalities are unknown.

Lowered verbal IQ is commonly reported by age seven. The reasons for the cognitive dysfunction in Klinefelter’s syndrome are not known, but the selective learning (dyslexia) and behavioral difficulties suggest an integrarive disorder of the central nervous system (CNS) reminiscent of other frontal-temporal lobe disorders. An autopsy study of dyslexic brains with cognitive phenotypes similar to those seen in Klinefelter’s syndrome patients has revealed a loss of the typical leftward asymmetry seen in right-handed control subjects, particularly in the area of the first temporal gyri. This finding has been corroborated by functional neuroimaging, which showed anomalous cerebrum laterally, and by MRI, which showed significant reduction in the total left temporal gray matter volume in Klinefelter’s syndrome adults. Despite typical histories of poor school advancement and work habits, many Klinefelter’s syndrome patients perform well on global IQ testing, with some scoring in the superior range.

The reasons why extra X chromosomes produce this clinical spectrum of events are unknown, but it may be related to the overexpression of genes that are not susceptible to inacrivarion in the supernumerary X chromosomes. This possibility seems to be supported by the observation that cognitive-behavioral dysfunctions are increased as the number of X chromosomes increases, for example, XXXY. The typical hypogonadal manifestations in patients with Klinefelter’s syndrome respond favorably to testosterone replacement, while the cognitive dysfunction seems to be immutable, or, at best, variable in its response. Many parents of adolescents with Klinefelter’s syndrome claim improved attention span and behavior

after testosterone treatment, while others complain of worsening of these manifestations. Several mouse models of XXY aneuploidy have been developed that show reproductive and cognitive deficits. These models may allow more insight into the molecular basis of the various phenotypic manifestations of Klinefelter’s syndrome.

XX Males

This chromosome disorder is much rarer than Klinefelter’s syndrome (1:10,000 births). Patients with this karyotype constitution and a male phenotype usually have a Y to X translocation, with a portion of the Y chromosome present on one of the X chromosomes. They may have partial defects in external genitalia development (i.e., hypospadias, an abnormal opening at the urethra on the ventral shaft of the penis or perineum), are androgen deficient, have small testes, and are infertile. Unlike Klinefelter’s syndrome patients, they tend to have short stature, and taurodontism is not present.

XX / XO individuals are a mixed variant of XX males with gonadal dysgenesis and a spectrum of hermaphroditic characteristics. They differ from XX males in that they have a higher incidence of dysgenetic testes and an increased susceptibility to testicular malignancy (20%).

XYY syndrome is another sex chromosomal disorder resulting from paternal meiotic nondisjunction or mitotic nondisjunction of the fertilized egg. These phenotypic men have decreased to low-normal testosterone levels, elevated gonadorropins, azoospermia with hyalinized seminiferous tubules, and increased height compared to the general male population, with a mean height of six feet four inches. The phenotypic similarities of XYY to XXY men are intriguing, perhaps suggesting overexpression of genes common to both the X and Y chromosomes.

Myotonic Dystrophy

This disorder presents later in life (after age, is often passed on from father to son, and is characterized by an inability to relax the striated muscles after recent contraction. It is associated with testicular atrophy, decreased fertility, and hypergonadotropic hypogonadism. Brain dysfunction of the frontal-temporal lobes may be present. The relationship of testicular dysfunction to the causative mutation is unknown.

Diabetes Mellitus and Obesity

Both obesity and diabetes mellitus are risks factors for low testosterone levels. The degree of suppression seems to correlate with the increase of blood sugar (hemoglobin A1C levels) and the severity of obesity.

Mumps Orchitis, Leprosy, Hematochromatosis, and HIV Disease

Following puberty, mumps will be associated with clinical orchitis in 25% of cases; 60% of men with clinically induced mumps orchitis will become infertile. Spermatogenic changes occur more often and earlier than Leydig cell dysfunction. Thus, patients with infertility may have normal testosterone and luteinizing hormone values with increased serum follicle-stimulating hormone. With increasing time, elevations in luteinizing hormone and lowered serum testosterone levels may appear.

Leprosy also produces orchitis, but with an apparent tendency to damage either the Leydig cells or spermatogenic tubules selectively, resulting in monotropic increases of luteinizing hormone or follicle-stimulating hormone. HIV infection is often associated with hypogonadism, which can be either hypogonadotropic or hypergonadorropic in classification. The pathogenesis of hypogonadism in this disorder is complicated since gonadal and hypothalamic infection with the HIV virus, infection by other organisms, stress, malnutrition, and malignancies may all coexist.

Cryptorchidism

Although the incidence of incomplete or undescended testes at birth is high (10%), most testes will descend to the appropriate scrotal location in early childhood. The incidence of bilateral undescended testes is 0.3% to 0.4% following puberty. Undescended testes may occur in many congenital syndromes, resulting in hypogonadotropic hypogonadism (see below). Bilateral cryptorchidism is associated with infertility 70% of the time. This is believed to be the result of heat-induced damage to the germinal tissues due to the absence of the normal cooling effect of the scrotal site for the testes. Unilateral cryptorchidism is associated with infertility to a lesser degree than bilateral cases. The reason(s) why unilateral cryptorchidism is associated with infertility is unclear; perhaps it reflects preexisting dysgeneric testes. Androgen deficiency (Leydig cell dysfunction) is less common but does occur. Cryptorchidism should be treated by bringing the testes into the scrotum in early childhood (before age five), thus decreasing the chances of permanent infertility and the testicular malignancies (8%) associated with abdominal testes.

Autoimmune Testicular Failure

Antibodies against the microsomal fraction of the Leydig cells may occur either as an isolated disorder or as part of a multiglandular disorder involving, to variable degrees, the thyroid, pituitary, adrenals, pancreas, and other organs.

Testicular Irradiation, Chemotherapy, and Toxins

Irradiation of the testes due to accidental exposure in the treatment of associated malignant disease will produce testicular damage. A dose as low as 15 rad will cause transient decreases in the sperm count; 50 rad exposure may cause azoospermia. After 500 rad, the infertility is usually irreversible. Doses above 800 rad can produce combined spermatogenic and Leydig cell failure characterized by low serum testosterone levels, oligozoospermia, and elevated serum luteinizing hormone and follicle-stimulating hormone. Chemotherapy for malignant disorders has a high association of irreversible germ-cell damage.

Toxins may also directly damage the testes. Many agents such as fungicides and insecticides (e.g., 1,2-dibromo-3-chloropropane), heavy metals (lead and cadmium), and cottonseed oil (gossypol) produce damage to the germ cells. Leydig cell function is relatively less susceptible to most chemotherapeuric drugs and toxins than the Sertoli germ cells, with serum testosterone levels usually normal despite infertility in the exposed men. Some medications interfere with testosterone biosynthesis (e.g., ketoconazole and spironolactone), thus producing Leydig cell underproduction of testosterone.

Trauma, torsion of the testes, and vascular injury may produce hypogonadism. Of interest is the observation that unilateral torsion may be associated with subsequent infertility. Trauma during scrotal surgery can result in vascular insults and panhypogonadism (Leydig cell and germ-cell abnormalities).

Androgen End-Organ Failure

Certain conditions have clinical phenotypes mimicking Leydig cell dysfunction (androgen deficiency) in the absence of lowered testosterone secretion and serum concentrations. These are usually congenital due to decreased end-organ responsiveness to circulating testosterone. This category includes androgen receptor defects, postreceptor signal rransducrion defects, and 5α-reductase deficiency.

Androgens Receptor Defects

Androgens normally induce their effects either directly on their target organs or after conversion to a 5α-reduced metabolite, dihydrotestosterone. Both androgens bind to the C-terminal portion of an intranuclear androgen receptor (member of the steroid receptor family). Subsequently, androgen actions are generated by the transcription of specific genes initiated by the binding of the DNA binding domain of the testosterone (or dihydrotestosterone) androgen receptor complex to the androgen response element of the target gene. A number of androgen receptor defects have been reported, producing a spectrum of clinical manifestations (described below), from “complete” forms (testicular feminization) to “incomplete” forms (Reifenstein’s syndrome) and to “minimal” forms (hypospadias).

In testicular feminization, there is essentially no binding of testosterone and dihydrotestosterone to a mutant androgen receptor. The patients are phenotypically female, with normal-appearing breasts and external genitalia but have blind vaginal pouches; the absence of the uterus results in amenorrhea. The testes are present in the labial canal or intra-abdominally. Serum testosterone levels are normal to elevated, and serum luteinizing hormone and follicle-stimulating hormone levels may be elevated due to the lack of normal feedback of testosterone on the hypothalamic-piruitary axis. Breast development and female fat distribution reflects increased estradiol levels and unimpeded estrogen effects. The testes should be removed because of increased risk of malignancy, and estrogen replacement therapy will be needed, as these patients should be treated as though they were hypogonadal women.

Reifenstein’s syndrome is a form of partial androgen resistance. The receptor defects appear to be heterogenous, with variable inheritance, including X-linked and autosomal recessive forms. Decreased receptor number, decreased receptor stability, and postreceptor response defects are responsible for the hypogonadal state and varying degrees of defective external genitalia differentiation (including bifid scrotum and hypospadias) due to incomplete midline fusion of the urethra and labial folds. Gynecomastia frequently occurs at puberty when luteinizing hormone, testosterone, and estradiol levels rise. More subtle defects, limited to hypospadias and / or impaired spermatogenesis, have also been described. Despite their pseudohermaphrodirism, these patients are phenotypically assigned to the male gender. Treatment of incomplete androgen receptor deficiency with testosterone has been only partially successful.

androgen receptor polymorphisms involving differences in the length of CAG repeats (CAGn) is inversely associated with androgen action. There is a racial distribution with Asian men having longer CAGn and African-American men having shorter CAGn. Studies of phenotype (social and physical defects, genotype) and CAGn showed that XXY men (Klinefelter’s syndrome) with longer CAGn had more clinical manifestations of testosterone deficiency and were less responsive to testosterone therapy.

5α-Reductase Deficiency

5α-reductase deficiency is a fascinating disorder characterized by diminished levels of the enzyme responsible for conversions of testosterone to dihydrotestosterone. Since dihydrotestosterone is required in males for the normal development of the external genitalia, including growth of the phallus and prostate, these patients have severe pseudohermaphroditism at birth. Because the defect is incomplete, the patients undergo partial masculinization due to the high levels of testosterone secreted at puberty. At that time, muscle mass increases, body fat decreases, and phallic growth occurs, while the rudimentary prostate and severe hypospadias, small testes, and infertility persist. luteinizing hormone, follicle-stimulating hormone, and testosterone levels are normal in these patients, but the ratio of dihydrotestosterone to testosterone is decidedly low. Since the disorder is variable in severity and age at detection, management depends on the gender assignment given. Intra-abdominal testes are usually removed, and androgen or estrogen treatment will be given depending on the assigned gender management of the hypogonadal genetic male.

Hypogonadotropic Hypogonadism

Organic Hypothalamic-Pituitary Disorders

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