Chapter 577 Hypofunction of the Testes

Testicular hypofunction during fetal life can be a component of various disorders of sexual development (Chapter 582.2). Since prepubertal children normally do not produce significant amounts of testosterone and are not yet producing sperm, there are no discernible effects of testicular hypofunction in this age group. Testicular hypofunction from the age of puberty onward may lead to testosterone deficiency, infertility, or both. Such hypofunction may be primary in the testes (primary hypogonadism) or secondary to deficiency of pituitary gonadotropic hormones (secondary hypogonadism). Both types may be due to inherited genetic defects or acquired causes, and in some cases the etiology may be unclear, but the level of the lesion (primary or secondary) is usually well defined; patients with primary hypogonadism have elevated levels of gonadotropins (hypergonadotropic); those with secondary hypogonadism have inappropriately low or absent levels (hypogonadotropic). Table 577-1 details the etiologic classification of male hypogonadism.

577.1 Hypergonadotropic Hypogonadism in the Male (Primary Hypogonadism)

Omar Ali, Patricia A. Donohoue

Etiology

Some degree of testicular function is essential in the development of phenotypically male infants. After sex differentiation has taken place, by the 14th wk of intrauterine life, hypogonadism may occur for a variety of reasons. Genetic or chromosomal anomalies may lead to testicular hypofunction that does not become apparent until the time of puberty, when these boys may have delayed or incomplete pubertal development. In other cases, normally developed testes may be compromised by infarction, trauma, radiation, chemotherapy, infections, infiltration, and other causes. In some cases, genetic defects may predispose to maldescent; torsion or infarction or may lead to progressive testicular damage and atrophy after a period of normal development. If testicular compromise is global, both testosterone secretion and fertility (sperm production) are likely to be effected. Even when the primary defect is in testosterone production, low levels of intratesticular testosterone will frequently lead to infertility. The reverse may not be true. Defects in sperm production and in the storage and transit of sperm may not be associated with low testosterone levels; infertility may thus be seen in patients with normal testosterone levels, normal libido, and normal secondary sexual characteristics.

Various degrees of primary hypogonadism also occur in a significant percentage of patients with chromosomal aberrations such as in Klinefelter syndrome, males with more than 1 X chromosome and XX males. These chromosomal anomalies are associated with other characteristic findings. Noonan syndrome is associated with cryptorchidism and infertility but other features dominate its clinical picture.

Congenital Anorchia: Boys in whom the external genitalia have developed normally (or near normally) and müllerian duct derivatives (uterus, fallopian tubes, etc.) are absent have obviously had testicular function for at least some part of gestation. If their testes cannot be palpated at birth, they are said to have cryptorchidism. In most such cases, the testes are undescended or retractile, but in a small number of cases, no testes are found in any location even after extensive investigation. This syndrome of absence of testes in a phenotypic male (indicating some period of testicular function in intrauterine life) is known as “vanishing testes,” “congenital anorchia,” or “testicular regression syndrome.”

Congenital anorchia occurs in 0.6% of boys with nonpalpable testes (1/20,000 males). It is thought that many cases are due to infarction of the testes that occurs in late fetal life or at some point after birth. But the condition has been reported in monozygotic twins; familial occurrence also suggests a genetic etiology. Some cases are associated with micropenis and in these cases the testicular loss probably occurred after the 14th wk, but well before the time of birth, or this may indicate a pre-existing dysfunction of the male hormonal development. Low levels of testosterone (<10 ng/dL) and markedly elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are found in the early postnatal months; thereafter, levels of gonadotropins tend to decrease even in agonadal children, rising to very high levels again as the pubertal years approach. Stimulation with human chorionic gonadotropin (hCG) fails to evoke an increase in the level of testosterone. Serum levels of antimüllerian hormone (AMH) are undetectable or low. All patients with undetectable testes should undergo these tests and if the results indicate that no testicular tissue is present, then the diagnosis of testicular regression syndrome is confirmed. If testosterone secretion is demonstrated, surgical exploration is indicated. Treatment of hypogonadism is discussed later. There is no possibility of normal fertility in these patients.

Chemotherapy and Radiation-Induced Hypogonadism: Testicular damage is a frequent consequence of chemotherapy and radiotherapy for cancer. The frequency and extent of damage depend on the agent used, total dose, duration of therapy, and post-therapy interval of observation. Another important variable is age at therapy; germ cells are less vulnerable in prepubertal than in pubertal and postpubertal boys. Chemotherapy is most damaging if more than 1 agent is used. The use of alkylating agents such as cyclophosphamide in prepubertal children does not impair pubertal development, even though there may be biopsy evidence of germ cell damage. High doses of cyclophosphamide and ifosfamide are associated with infertility. Cisplatin causes transient azoospermia or oligospermia at lower doses, while higher doses (400-600 mg/m²) can cause permanent infertility. Interleukin-2 can depress Leydig cell function, whereas interferon-α does not seem to affect gonadal function. Most chemotherapeutic agents produce azoospermia and infertility; Leydig cell damage (leading to low testosterone levels) is less common. In many cases, the damage is transient and sperm counts recover after 12-24 mo. Both chemotherapy and radiotherapy are associated with increase in the percentage of abnormal gametes, but data concerning the outcomes of pregnancies after such therapy has NOT shown any increase in genetically mediated birth defects, possibly due to selection bias against abnormal sperm.

Radiation damage is dose dependent. Temporary oligospermia can be seen with doses as low as 0.1 Gy, with permanent azoospermia seen with doses greater than 2 Gy. Recovery of spermatogenesis can be seen as long as 5 yr (or more) after irradiation, with higher doses leading to slower recovery. Leydig cells are more resistant to irradiation. Mild damage as determined by elevated LH levels can be seen with up to 6 Gy; doses greater than 30 Gy cause hypogonadism in most. Whenever possible, testes should be shielded from irradiation. Testicular function should be carefully evaluated in adolescents after multimodal treatment for cancer in childhood. Replacement therapy with testosterone and counseling concerning fertility may be indicated. The storage of sperm prior to chemotherapy or radiation treatment in postpubertal males is an option. Even in those cases where sperm counts are abnormal, recovery is possible, though the chances of recovery decline with increasing dose of radiation. If sperm counts remain low, fertility is still possible with testicular sperm extraction and intracytoplasmic sperm injection.

Sertoli Cell–Only Syndrome: Small testes and azoospermia are seen in patients with the Sertoli cell–only syndrome (germ cell aplasia, or Del Castillo syndrome). These patients have no germ cells in the testes, but usually have normal testosterone production, and present as adults with the complaint of infertility. The cause is unknown.

Other Causes of Testicular Hypofunction: Atrophy of the testes may follow damage to the vascular supply as a result of manipulation of the testes during surgical procedures for correction of cryptorchidism or as a result of bilateral torsion of the testes. Acute orchitis in pubertal or adult males with mumps may occasionally damage the testes; though usually, only the reproductive function of the testes is impaired. The routine immunization of all prepubertal males with mumps vaccine may reduce the incidence of this complication. Autoimmune polyendocrinopathy may be associated with primary hypogonadism (associated with anti-P450scc antibodies) but this appears to be more common in females.

Testicular Dysgenesis Syndrome: The incidence of cryptorchidism, hypospadias, low sperm counts, and testicular cancer has increased in many developed societies. For example, 8% of all births in Europe are estimated to involve assisted reproductive techniques and 20% of Danish adult males have sperm counts below the World Health Organization standard of 20 × 10⁶ per mL. Incidence of testicular cancer also appears to be rising and in some cases seems to parallel the higher incidence of hypofertility. There is evidence that the incidence of hypospadias and cryptorchidism has increased in several countries in the last few decades. It has been proposed that all these trends are linked by prenatal testicular dysgenesis. The hypothesis is that some degree of testicular dysgenesis develops in intrauterine life due to genetic as well as environmental factors, and is associated with increased risk of cryptorchidism, hypospadias, hypofertility, and testicular cancer. The environmental influences that have been implicated in this syndrome include environmental chemicals that act as endocrine disruptors, such as bisphenol A and phthalates (components of many types of plastics), several pesticides, phytoestrogens or mycoestrogens, and other chemicals. The fact that these lesions can be reproduced in some animal models by environmental chemicals has led to efforts to remove these chemicals from products used by infants and pregnant mothers, and from the environment in general. Nonetheless, the evidence is only suggestive and is not conclusive.

Clinical Manifestations

Primary hypogonadism may be suspected at birth if the testes and penis are abnormally small. Normative data are available for different populations. The condition often is not noticed until puberty, when secondary sex characteristics fail to develop. Facial, pubic, and axillary hair is scant or absent; there is neither acne nor regression of scalp hair; and the voice remains high-pitched. The penis and scrotum remain infantile and may be almost obscured by pubic fat; the testes are small or not palpable. Fat accumulates in the region of the hips and buttocks and sometimes in the breasts and on the abdomen. The epiphyses close later than normal; therefore, extremities are long. The span may be several inches longer than the height, and the distance from the symphysis pubis to the soles of the feet (lower segment) is much greater than that from the symphysis to the vertex (upper segment). The proportions of the body are described as eunuchoid. The upper to lower segment ratio is considerably less than 0.9. Many individuals with milder degrees of hypogonadism may be detected only by appropriate studies of the pituitary-gonadal axis. Examination of the testes should be performed routinely by pediatricians; testicular volumes as determined by comparison with standard orchidometers or by measurement of linear dimensions should be recorded.

Diagnosis

Levels of serum FSH and, to a lesser extent, of LH are elevated to greater than age-specific normal values in early infancy (when “minipuberty” normally occurs and the gonadotropins are normally disinhibited). This is followed by a period of time when even agonadal children may not exhibit significant elevation in gonadotropins, indicating that the gonadotropins are also suppressed at this stage by some mechanism independent of feedback inhibition by gonadal hormones. In the latter half of childhood and several years prior to onset of puberty, this inhibition is released and gonadotropin levels again rise above age-matched normals in subjects with primary hypogonadism. These elevated levels indicate that even in the prepubertal child there is an active hypothalamic-gonadal feedback relationship. After the age of 11 yr, FSH and LH levels rise significantly, reaching the castrate range. Measurements of random plasma testosterone levels in prepubertal boys are not helpful because they are ordinarily low in normal prepubertal children, rising during puberty to attain adult levels. During puberty, these levels correlate better with testicular size, stage of sexual maturity, and bone age than with chronological age. In patients with primary hypogonadism, testosterone levels remain low at all ages. There is an attenuated rise or no rise after administration of hCG, in contrast to normal males in whom hCG produces a significant rise in plasma testosterone at any stage of development.

AMH (antimüllerian hormone) is secreted by the Sertoli cells and this secretion is suppressed by testosterone. As a result, AMH levels are elevated in prepubertal boys and suppressed at onset of puberty. Boys with primary hypogonadism continue to have elevated AMH levels in puberty. Detection of AMH may be used in prepubertal years as an indicator of the presence of testicular tissue (e.g., in patients with bilateral cryptorchidism). Inhibin B is also secreted by the Sertoli cells, is present throughout childhood, and rises at onset of puberty (more in boys than in girls). It may be used as another marker of the presence of testicular tissue in bilateral cryptorchidism and as a marker of spermatogenesis (e.g., in delayed puberty, cancer survivors, and patients with Noonan syndrome). Bone age x-rays are useful to document delayed bone age in patients with constitutional growth delay as well as primary hypogonadism.

Noonan Syndrome

Etiology

The term Noonan Syndrome (NS) has been applied to males and females with normal karyotypes who have certain phenotypic features that occur also in females with Turner syndrome. Noonan syndrome occurs in 1 : 1,000-2,500 live births. About 20% of the cases are familial and exhibit autosomal dominant inheritance. Males and females are equally affected. Missense mutations in PTPN11—a gene on chromosome 12q24.1 encoding the nonreceptor protein tyrosine phosphatase SHP-2—are seen in about half the cases. It is now thought that several mutations in the RAS-MAPK pathway can cause Noonan syndrome and other related disorders. These include mutations in the KRAS gene and SOS1 gene as well as duplications of the 12q24 region. Phenotypic features of NS therefore overlap with other syndromes involving the RAS-MAPK pathway, such as Leopard syndrome and cardio-facio-cutaneous syndrome.

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