Hypofunction of the Testes

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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.

Table 577-1 ETIOLOGIC CLASSIFICATION OF MALE HYPOGONADISM

HYPOGONADOTROPIC HYPOGONADISM

HYPERGONADOTROPIC HYPOGONADISM: TESTES

I Genetic defects

A FSH and LH resistance

B Mutations in steroid synthetic pathways

C Gonadal dysgenesis

D Klinefelter syndrome (47,XXY)

E Noonan syndrome (PTPN-11 gene mutation in many cases)

F Cystic fibrosis (infertility)

II Acquired defects

A Cryptorchidism (some cases)

B Vanishing testes

C Chemotherapy

D Radiation

E Infection (e.g., mumps)

F Infarction (testicular torsion)

G Trauma

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.

Clinical Manifestations

The most common abnormalities are short stature, webbing of the neck, pectus carinatum or pectus excavatum, cubitus valgus, right-sided congenital heart disease, and characteristic facies. Hypertelorism, epicanthus, downward slanting palpebral fissures, ptosis, micrognathia, and ear abnormalities are common. Other abnormalities such as clinodactyly, hernias, and vertebral anomalies occur less frequently. The mean IQ of school-aged children with the condition is 86, with a range of 53 to 127. Verbal IQ tends to be better than performance IQ. High-frequency sensorineural hearing loss is common. The cardiac defect is most often pulmonary valvular stenosis, hypertrophic cardiomyopathy, or atrial septal defect. Hepatosplenomegaly and several hematologic diseases, including low clotting factors XI and XII, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia, are noted. Noonan-like features can be part of the phenotypic variation of the NF1 (neurofibromatosis) gene mutation, possibly due to common involvement of the RAS-MAPK pathway in both diseases. Males frequently have cryptorchidism and small testes. Testosterone secretion may be low or normal, but spermatogenesis may be affected even in those with normal testosterone (and normal secondary sexual characteristics). Serum inhibin-B may be a useful marker of Sertoli cell function in these patients. Puberty is delayed and adult height is achieved by the end of the 2nd decade and usually reaches the lower limit of the normal population. Prenatal diagnosis should be suspected in fetuses with normal karyotype, edema, or hydrops and short femur length.

Treatment

Human growth hormone has resulted in improvement in growth velocity comparable to that seen in patients with Turner syndrome without adverse effects on cardiac ventricular wall thickness. Increased adult height after growth hormone treatment has been reported in a few patients. Patients with Noonan syndrome and demonstrable PTNP11 mutations grow less well and are less responsive to growth hormone treatment than those without mutations. They have lower insulin-like growth factor-1 and higher growth hormone levels, suggesting the possibility of partial growth hormone resistance due to postreceptor signaling defects. Treatment of hypogonadism is discussed later.

Klinefelter Syndrome (Chapter 76)

Etiology

Klinefelter syndrome (KS) is the most common sex chromosomal aneuploidy in males, with an incidence of 0.1 to 0.2% in the general population (1/500 to 1/1,000) and rising to 4% among infertile males and 10-11% in those with oligospermia or azoospermia. Approximately 80% of them have a 47,XXY chromosome complement, while mosaics and higher degrees of polyX are seen in the remaining 20%. Even with as many as 4 X chromosomes, the Y chromosome determines a male phenotype. The chromosomal aberration most often results from meiotic nondisjunction of an X chromosome during parental gametogenesis; the extra X chromosome is maternal in origin in 54% and paternal in origin in 46% of patients. A national study in Denmark revealed a prenatal prevalence of 213 per 100,000 male fetuses but in adult men, the prevalence was only 40/100,000, suggesting that only 1 in 4 of adult males with Klinefelter syndrome was diagnosed.

Clinical Manifestations

In patients who do not have a prenatal diagnosis, the diagnosis is rarely made before puberty because of the paucity or subtleness of clinical manifestations in childhood. Behavioral or psychiatric disorders may often be apparent long before defects in sexual development. These children tend to have learning disabilities and deficits in “executive function” (concept formation, problem solving, task switching, and planning), and the condition should be considered in boys with psychosocial, learning, or school adjustment problems. Affected children may be anxious, immature, or excessively shy and tend to have difficulty in social interactions throughout life. In a prospective study, a group of children with 47,XXY karyotypes identified at birth exhibited relatively mild deviations from normal during the 1st 5 yr of life. None had major physical, intellectual, or emotional disabilities; some were inactive, with poorly organized motor function and mild delay in language acquisition. Problems often first become apparent after the child begins school. Full-scale IQ scores may be normal, with verbal IQ being somewhat decreased. Verbal cognitive defects and underachievement in reading, spelling, and mathematics are common. By late adolescence, many boys with KS have generalized learning disabilities, most of which are language based. Despite these difficulties, most complete high school.

The patients tend to be tall, slim, and underweight and have a specific tendency to have long legs (out of proportion to the arms, and longer than those seen with other causes of hypogonadism), but body habitus can vary markedly. The testes tend to be small for age, but this sign may become apparent only after puberty, when normal testicular growth fails to occur. The phallus tends to be smaller than average, and cryptorchidism is more common than in the general population. Bone mineral density may be low in adults with KS and this correlates with lower testosterone levels.

Pubertal development may be delayed, although some children may undergo almost normal virilization. Despite normal testosterone levels, serum LH and FSH concentrations and their responses to gonadotropin-releasing hormone (GnRH) stimulation are elevated starting at around 13 yr of age. About 80% of adults have gynecomastia; they have sparser facial hair, most shaving less often than daily. The most common testicular lesions are spermatogenic arrest and Sertoli cell predominance. The sperm have a high incidence of sex chromosomal aneuploidy. Azoospermia and infertility are usual, although rare instances of fertility are known. It is now clear that germ cell numbers and sperm counts are higher in early puberty and decline with age. Testicular sperm extraction followed by intracytoplasmic sperm injection can result in the birth of healthy infants, with success rates declining with increasing age. In nonmosaic Klinefelter patients, most testicular sperm (94%) have a normal pattern of sex chromosome segregation, indicating that meiotic checkpoints can remove most aneuploid cells. Antisperm antibodies have been detected in 25% of tested specimens.

There is an increased incidence of pulmonary disease, varicose veins, and cancer of the breast. Among 93 unselected male breast cancer patients, 7.5% were found to have KS. Mediastinal germ cell tumors have been reported; some of these tumors produce hCG and cause precocious puberty in young boys. They may also be associated with leukemia, lymphoma, and other hematologic neoplasia. The highest cancer risk (relative risk 2.7) occurs in the 15-30 yr age group. A large cohort study in Britain demonstrated an overall significantly increased standardized mortality ratio (1.5), with particular increases in deaths due to diabetes, epilepsy, peripheral and intestinal vascular sufficiency, pulmonary embolism, and renal disease. Mortality from ischemic heart disease was decreased. In adults, structural brain abnormalities correlate with cognitive deficits.

In adults with XY/XXY mosaicism, the features of KS are decreased in severity and frequency. Children with mosaicism have a better prognosis for virilization, fertility, and psychosocial adjustment.

Klinefelter Variants and Other PolyX Syndromes

When the number of X chromosomes exceeds 2, the clinical manifestations, including mental retardation and impairment of virilization, are more severe. Height decreases with increasing number of X chromosomes. The XXYY variant is the most common variant (1/18,000 to 1/40,000 male births). In most, mental retardation occurs with IQ scores between 60 and 80, but 10% have IQs greater than 110. The XXYY male phenotype is not distinctively different from that of the XXY patient, except that XXYY adults tend to be taller than the average XXY patient. The 49,XXXXY variant is sufficiently distinctive to be detected in childhood. Its incidence is estimated to be 1/80,000 to 1/100,000 male births. The disorder arises from sequential nondisjunction in meiosis. Affected patients are severely retarded and have short necks and typical coarse facies with wide-set eyes with a mild upward slant of the fissures, epicanthus, strabismus, a wide and flat upturned nose, a large open mouth, and large malformed ears. The testes are small and may be undescended, the scrotum is hypoplastic, and the penis is very small. Defects suggestive of Down syndrome (short, incurved terminal 5th phalanges, single palmar creases, and hypotonia) and other skeletal abnormalities (including defects in the carrying angle of the elbows and restricted supination) are common. The most frequent radiographic abnormalities are radioulnar synostosis or dislocation, elongated radius, pseudoepiphyses, scoliosis or kyphosis, coxa valga, and retarded osseous age. Most patients with such extensive changes have a 49,XXXXY chromosome karyotype; several mosaic patterns have also been observed: 48,XXXY/49,XXXXY, 48,XXXY/49,XXXXY/50,XXXXXY; and 48,XXXY/49,XXXXY/50,XXXXYY. Prenatal diagnosis of a 49,XXXXY infant has been reported. The fetus had intrauterine growth retardation, edema, and cystic hygroma colli.

The 48,XXXY variant is relatively rare. The characteristic features are generally less severe than those of patients with 49,XXXXY and more severe than those of 47,XXY patients. Mild mental retardation, delayed speech and motor development, and immature but passive and pleasant behavior are associated with this condition.

Very few patients have been described with 49,XYYY and 49,XXYYY karyotypes. Dysmorphic features and mental retardation are common to both.

Laboratory Findings

Most males with this condition go through life undiagnosed. The chromosomes should be examined in all patients suspected of having KS, particularly those attending child guidance, psychiatric, and mental retardation clinics. In infancy, inhibin B and AMH levels are normal but testosterone levels are lower than in controls. Before 10 yr of age, boys with 47,XXY KS have normal basal plasma levels of FSH and LH. Responses to gonadotropin-stimulating hormone and to hCG are normal. The testes show normal growth early in puberty, but by mid-puberty the testicular growth stops, gonadotropins become elevated, and testosterone levels are slightly low. Inhibin B levels are normal in early puberty, decrease in late puberty, and are low in adults with the syndrome. Elevated levels of estradiol, resulting in a high estradiol to testosterone ratio, account for the development of gynecomastia during puberty. SHBG levels are elevated, further decreasing free testosterone levels. Long androgen receptor polyglutamine (CAG) repeat length is associated with the more severe phenotype including gynecomastia, small testes, and short penile length.

Testicular biopsy before puberty may reveal only deficiency or absence of germinal cells. After puberty, the seminiferous tubular membranes are hyalinized, and there is adenomatous clumping of Leydig cells. Sertoli cells predominate. Azoospermia is characteristic, and infertility is the rule.

Treatment

Replacement therapy with a testosterone preparation depends on the age of the patient. It usually begins no later than 11-12 yr of age, when testosterone levels are found to be lower than the normal range. While testosterone treatment will normalize testosterone levels and stimulate the development of secondary sexual characteristics, it will NOT improve fertility (and will, in fact, suppress spermatogenesis). Either long-acting testosterone injections or daily application of testosterone gel may be used (testosterone patches have a high incidence of skin rash and are not frequently used in pediatrics). Testosterone enanthate ester may be used in a starting dose of 25-50 mg injected intramuscularly every 3-4 wk, with 50-mg increments every 6-9 mo until a maintenance dose for adults (200-250 mg every 3-4 wk) is achieved. At that time, testosterone patches or testosterone gel may be substituted for the injections. Depending on patient and physician preference, transdermal testosterone may be used as initial treatment instead of injections. For older boys, larger initial doses and increments can achieve more rapid virilization.

Gynecomastia may be treated with aromatase inhibitors (which will also increase endogenous testosterone levels) but medical treatment is not always successful. Fertility may not be an issue in the pediatric age group, but adults can father children using testicular sperm extraction (TSE) followed by intracytoplasmic sperm injection. Because sperm counts actually decrease with time, sperm banking is an option for older adolescents. HCG treatment may be used to stimulate sperm counts prior to TSE. Therapy, counseling and psychiatric services should be provided as needed for learning difficulties and psychosocial disabilities.

XX Males

This disorder is thought to occur in 1 in 20,000 newborn males. Affected individuals have a male phenotype, small testes, a small phallus, and no evidence of ovarian or müllerian duct tissue. They appear, therefore, to be distinct from the ovotesticular disorder of sexual development. Undescended testes and hypospadias occur in a minority of patients. Infertility occurs in practically all cases and the histologic features of the testes are essentially the same as in Klinefelter syndrome. Patients with the condition usually come to medical attention in adult life because of hypogonadism, gynecomastia, or infertility. Hypergonadotropic hypogonadism occurs secondary to testicular failure. A few cases have been diagnosed perinatally as a result of discrepancies between prenatal ultrasonography and karyotype findings.

In 90% of XX males with normal male external genitals, 1 of the X chromosomes carries the SRY gene. The exchange from the Y to the X chromosome occurs during paternal meiosis, when the short arms of the Y and X chromosomes pair. XX males inherit 1 maternal X chromosome and 1 paternal X chromosome containing the translocated male-determining gene. A few cases of 46,XX males with 9P translocations were identified. Most XX males who are identified before puberty have hypospadias or micropenis; this group of patients may lack Y-specific sequences, suggesting other mechanisms for virilization. Fluorescent in situ hybridization and primed in situ labeling (PRINS) have been used to identify small SRY DNA segments. Yp fragment abnormalities may result in sexually ambiguous phenotypes.

45,X Males

In a few male patients recognized with a 45,X karyotype, Yp sequences have been translocated to an autosomal chromosome. In 1 instance, the terminal short arm of the Y chromosome was translocated onto an X chromosome. In another, SRY/autosomal translocation was postulated. A male with 45,X karyotype and Leri-Weill dyschondrosteosis, SHOX gene loss, and SRY to Xp translocation was also described.

47,XXX Males

A Japanese male with poor pubic hair development, hypoplastic scrotal testes (4 mL), normal penis and normal height, gynecomastia, and severe mental retardation had 47,XXX karyotype due to abnormal X-Y interchange during paternal meiosis and X-X nondisjunction during maternal meiosis.

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577.2 Hypogonadotropic Hypogonadism in the Male (Secondary Hypogonadism)

Omar Ali, Patricia A. Donohoue

In hypogonadotropic hypogonadism, there is deficiency of 1 or both gonadotropins: follicle stimulating hormone (FSH) or luteinizing hormone (LH). The primary defect may lie either in the anterior pituitary or in the hypothalamus. Hypothalamic etiologies result in deficiency of gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone–releasing hormone (LHRH). The testes are normal but remain in the prepubertal state because stimulation by gonadotropins is lacking. The disorder may be recognized in infancy, around the time of puberty, or rarely, in adulthood.

Etiology

Hypogonadotropic hypogonadism (HH) may be genetic or acquired. Several different genes can cause inherited forms of hypogonadotropic hypogonadism; the affected genes may be upstream of GnRH, at the level of GnRH receptors, or at the level of gonadotropin production. In addition, various genetic defects in transcription factors like POUF-1, LHX-3, LHX-4, and HESX-1 lead to defects in pituitary development and multiple pituitary hormone deficiencies, including deficiency of gonadotropins. Acquired pituitary gonadotropin deficiency may develop due to various lesions in the hypothalamic-pituitary region (e.g., tumors, infiltrative disease, autoimmune disease, trauma, stroke).

Isolated Gonadotropin Deficiency

Isolated gonadotropin deficiency is more likely to be due to defects in the secretion of GnRH from the hypothalamus rather than defects in gonadotropin synthesis in the pituitary. It affects about 1/10,000 males and 1/50,000 females and encompasses a heterogeneous group of entities. Many cases are associated with anosmia and this combination of anosmia and hypogonadotropic hypogonadism defines Kallman syndrome.

Kallmann syndrome is the commonest form of hypogonadotropic hypogonadism and is genetically heterogeneous, with autosomal recessive, X-linked and autosomal dominant forms of inheritance (see Table 76-7). Clinically, it is characterized by its association with anosmia or hyposmia; 85% of the cases are autosomal while 15% are X-linked. The X-linked form (KAL1) is caused by mutations of the KAL1 gene at Xp22.3. This leads to failure of olfactory axons and GnRH-expressing neurons to migrate from their common origin in the olfactory placode to the brain. The KAL gene product anosmin-1, an extracellular 95 kDa matrix glycoprotein, facilitates neuronal growth and migration. The KAL gene is also expressed in various parts of the brain, facial mesenchyme, and mesonephros and metanephros, thus explaining some of the associated findings in patients with Kallmann syndrome, such as synkinesia (mirror movements), hearing loss, midfacial defects, and renal agenesis.

Some kindreds contain anosmic individuals with or without hypogonadism; others contain hypogonadal individuals who are anosmic. Cleft lip and palate, hypotelorism, median facial clefts, sensorineural hearing loss, unilateral renal aplasia, neurologic deficits, and other findings occur in some affected patients. When Kallmann syndrome is caused by terminal or interstitial deletions of the Xp22.3 region, it may be associated with other contiguous gene syndromes, such as steroid sulfatase deficiency, chondrodysplasia punctata, X-linked ichthyosis, or ocular albinism.

The autosomal dominant form of Kallman syndrome (KAL 2) occurs in up to 10% of patients, and is due to a loss of function mutation in the fibroblast growth factor receptor 1 (FGFR1) gene. Cleft lip and palate is associated with KAL2 but not with KAL1. Oligodontia and hearing loss may occur with both KAL1 and KAL2.

In a majority of patients with Kallman syndrome the affected gene remains undefined. Candidate genes include CHD7 (responsible for CHARGE syndrome, which includes hypogonadism in its phenotype), NELF (another olfactory axonal outgrowth gene), and PROK2 and its receptor PROKR2 (may be responsible for up to 10% of Kallman Syndrome patients). Fibroblast growth factor 8 has also been implicated as a possible HH gene.

Hypogonadotropic Hypogonadism without Anosmia: Most cases of isolated HH without anosmia are idiopathic, but some genetic disorders leading to normosmic HH are now known. Several patients with HH have been found to have defects in G-protein coupled receptor 54 (GPCR 54) and its ligand kisspeptin (KiSS-1 gene). These patients have intact GnRH-secreting neurons and are able to produce GnRH, but fail to initiate GnRH secretion to start pubertal development. It appears that kisspeptin and GPCR54 play an important role in triggering puberty in humans and act downstream of the leptin receptor in this pathway. Rare cases of leptin deficiency and leptin receptor defects are also associated with HH. In addition, starvation and anorexia are associated with hypogonadism, most likely acting via the leptin pathway.

There are no known human mutations of the GnRH gene, but several families with mutations in the GnRH receptor have been described. These mutations account for 2-14% of idiopathic HH without anosmia. The severity of the defect is variable and many patients will respond to high dose GnRH with increased gonadotropin secretion, indicating that the receptor defect is partial and not complete.

Mutations in gonadotropin genes are extremely rare. Mutations in the common alpha subunit are not known in humans. Mutations in the LH-β subunit have been described in a few individuals and may lead to low, absent, or elevated LH levels, depending on the mutation. Defects in the FSH-β subunit may be the cause of azoospermia in a few rare cases.

Children with X-linked congenital adrenal hypoplasia have associated HH due to impaired GnRH secretion. In these patients, there is a mutation of the DAX1 gene at Xp21.2-21.3. Conditions occasionally associated with these patients because of the contiguous gene syndrome include glycerol kinase deficiency, Duchenne muscular dystrophy, and ornithine transcarbamoyl transferase deficiency. Most boys with DAX1 mutations develop HH in adolescence, although a patient with adult-onset adrenal insufficiency and partial HH and 2 females with HH and delayed puberty have also been described, the latter as part of extended families with males with classic HH. The DAX1 gene defect is, however, rare in patients with delayed puberty or HH without at least a family history of adrenal failure (Chapter 570).