II. ETIOLOGIC CATEGORIES OF TESTICULAR ENDOCRINE DISORDERS
A. Hypothalamic Disease
In 1944, Kallmann described a hereditary syndrome of hypogonadotropic hypogonadism associated with anosmia. A failure of GnRH secretion by the hypothalamus is responsible for the gonadotropin deficiency leading to secondary testicular failure. Anosmia may be complete or partial. Kallmann's syndrome occurs in both sporadic and familial forms. The familial part of inheritance is autosomal dominant inheritance with variable penetrance as the most common pattern. Some patients who have Kallmann's syndrome have absent olfactory lobes. Interestingly, anosmia may be transmitted without hypogonadotropism or the hypogonadotropic syndrome may be encountered without anosmia in families with Kallmann's syndrome. Multiple other associated anomalies include cranial facial asymmetry, cleft palate, hairlip, color blindness, congenital deafness, cryptorchidism, and renal anomalies. Delayed pubertal development is the hallmark of this syndrome and is the reason that patients present for medical evaluation. As a result of a delay in the androgen dependent closure of the epiphyseal plates, the length of the arms and legs may be greater than that of the trunk. In addition, the testes remain prepubertal, with testicular size smaller than 2 cm in diameter.
In the prepubertal male, differentiating between Kallmann's syndrome and delayed sexual maturation may be very difficult. A family history of Kallmann's syndrome or the presence of somatic midline defects or anosmia may help in the prepubertal diagnosis. Because the first sign of puberty is testicular growth, a patient who has testes greater than 2 cm is experiencing delayed puberty rather than hypogonadotropic hypogonadism. Delayed pubertal males, but not patients with Kallmann's syndrome, respond to clomiphene citrate with a rise in serum LH levels. Although patients who have Kallmann's syndrome have an absent or blunted rise in gonadotropins following GnRH administration, repeated GnRH injections may prime the pituitary resulting in rises of both LH and FSH. Unfortunately, this pattern of response is also found in prepubertal boys. Finally, following doses of 5000 IU of human chorionic gonadotropin (hCG), prepubertal and pubertal boys demonstrate larger rises in
testosterone levels than patients with Kallmann's syndrome.
Androgen replacement with
testosterone or
hCG is adequate treatment for the teenager and usually results in virilization. Exogenous androgens, however, suppress intratesticular testosterone production and consequently, spermatogenesis and testicular growth are not stimulated in these patients. Androgen therapy should be given in parenteral form as
testosterone enanthate or cypionate. Intramuscular injections of 200 mg every other week is usually sufficient to induce full virilization in most patients. Although oral androgens are available as fluoxymesterone and fluoxymesterone and 17 a-methyl testosterone, they are less potent and may result in a higher incidence of hepatic abnormalities. Reversible intrahepatic cholestasis resulting in elevations of plasma transaminases, lactate dehydrogenase, and bilirubin may be noted. The development of hepatomas and peliosis hepatis, a cystic dilatation of the liver venules, has been noted after high androgen dosages. Other side effects include prostatic hypertrophy, acne, priapism, gynecomastia and erythrocytosis.
Gonadotropin therapy is required for the initiation of spermatogenesis. Given as 2000 IU IM three times per week, hCG initiates spermatogenesis in most patients, but only 20% of patients complete spermatogenesis with
hCG therapy alone. FSH is required in most patients and is commonly given after 6 months of hCG therapy. FSH is usually given in the form of human menopausal gonadotropin [hMG (Pergonal)], which contains 75 IU of FSH and 75 IU of LH per vial. The intramuscular administration of one-half vial three times per week usually results in the completion of spermatogenesis. Stimulation of the testes with FSH and LH results in testicular growth, although the final testis volume may remain below normal. Although semen motility parameters are usually quite good, oligospermia with counts below 10 million sperm per milliliter are common. In contrast to patients with idiopathic oligospermia who are often infertile with these sperm densities, many patients with hypogonadotropic hypogonadism are able to conceive despite these low sperm densities.
Other Congenital Hypothalamic Hypogonadal Syndromes:
The Prader-Willi syndrome consists of obesity, hypotonic musculature, mental retardation, small hands and feet, short stature, micropenis, and hypogonadism. The syndrome may be associated with abnormalities of chromosome 15. Patients demonstrate LH and FSH deficiencies because of a lack of GnRH. Treatment is identical to that for Kallmann's syndrome. A similar picture is found in Laurence-Moon Bardet-Biedl syndrome, which consists of hypogonadotropic hypogonadism, retinitis pigmentosa, and polydactyly.
B. Pituitary Disease
Pituitary function may be impaired in cases of pituitary surgery, infarction, tumors, radiation, or infectious diseases. Patients with prepubertal onset of pituitary disease are usually diagnosed prior to a fertility evaluation as a result of growth retardation or adrenal or thyroid deficiency. Infertility, impotence, visual field abnormalities, and severe headaches may be presenting symptoms in the adult male with pituitary dysfunction. Normal male secondary sexual characteristics are usually present unless adrenal insufficiency exists. Small, soft testes may be demonstrated on physical examination. This is in contrast to cases of primary testicular failure with tubular and peritubular sclerosis, in which case the testes are small and firm to palpation. Plasma testosterone levels are low and gonadotropin levels are low or normal. Thus, a normal LH value associated with a low serum testosterone value is abnormal and further evaluation is required. Evaluation of other pituitary hormones and endocrine functions should be performed in appropriate cases.
1. Fertile Eunuch Syndrome
Isolated LH deficiency occurs rarely in patients with normal FSH levels. These men demonstrate a variably eunuchoid habitus, large testes, and small volume ejaculates containing few spermatozoa. Plasma testosterone and LH levels are low, but FSH levels are in the normal range. Testicular biopsy specimens demonstrate maturation of the germinal epithelium with Leydig Cell hypoplasia because of insufficient LH stimulation. A rise in serum testosterone following hCG therapy supports normal Leydig function in these patients. Sufficient intratesticular testosterone is produced for spermatogenesis, but inadequate peripheral androgen levels lead to poor virilization.
2. Isolated FSH Deficiency
This is a rare disorder in which patients have adequate virilization, normal LH- and testosterone levels, and normal-sized testes. Because of a lack of FSH, oligospermia or azoospermia is present. Administration of hMG improves spermatogenesis, but a more specific treatment may be given in the form of pure FSH (Metrodin).
3. Hyperprolactinemia
Hyperprolactinemia interferes with reproductive functions lowering serum testosterone levels resulting in classic symptoms of hypogonadism. The mechanisms by which hyperprolactinemia induces testosterone deficiency are complex. Serum LH levels are suppressed or inappropriately low indicating that the hypothalamic-pituitary axis fails to respond to reduced testicular testosterone production. Prolactin inhibits GnRH secretion. Prompt and dramatic improvement in sexual function occurs in many hyperprolactinemic men treated with
bromocriptine (dopamine agonist with PRL- lowering activity). There is evidence to suggest that hyperprolactinemia may impair sexual function in men both by direct effect on the CNS and by inhibition of androgen secretion. The direct CNS effect is supported by clinical data demonstrating that androgen replacement therapy of hyperprolactinemic hypoandrogenized men did not return libido to normal as long as PRL levels remained elevated. Finally, it must be recognized that some patients with prolactinomas will have hypogonadotropic hypogonadism produced by the mass lesion itself.
C. Primary Testicular Disorders
Approximately 6% of infertile men are found to have chromosomal abnormalities, with the incidence increasing as the sperm count decreases. The highest incidence is found in azoospermic patients, with up to 21 % of cases demonstrating abnormalities of the karyotype. The majority of these cases are associated with Klinefelter's syndrome or XXY syndrome. One gene locus localized to the long arm of the Y chromosome is a region referred to as AZF (Azoospermic Factor). This locus is subdivided into a, b and c, of which AZFc contains the gene DAZ (deleted in azoospermia). Men with complete deletions of the entire AZFa region uniformly show a Sertoli cell only pattern (see below). The AZFa region contains a gene DBY, a transcriptional regulator. The AZFb region appears to be critical for completion of spermatogenesis. No patients with AZFb deletion have shown completely developed spermatozoa present on testicular biopsy.
1. Klinefelter's Syndrome
The presence of an extra X chromosome is the genetic hallmark of Klinefelter's syndrome. This is due to nondysjunction of the meiotic chromosomes of the gametes from either parent. Hypogonadism, with the classic triad of small, firm testes, gynecomastia, and elevated urinary gonadotropins, has an incidence of 1 of every 600 male births, but clinically may not be identifiable until puberty. Although secondary sexual characteristics begin developing at the appropriate time, the completion of puberty is usually delayed with features of eunuchoidism, gynecomastia, and impotence. Virilization may be complete in some patients and the diagnosis for them delayed until adulthood, at which point the patient may present with infertility (azoospermia) with associated gynecomastia and small, firm testes. Mental retardation and various psychiatric disturbances may also occur. Testicular biopsy reveals seminiferous tubular sclerosis and an occasional Sertoli cells or spermatozoa. Owing to the absence of normal seminiferous tubules, Leydig cells may appear hyperplastic. Plasma FSH levels are usually markedly elevated as a result of the severe seminiferous tubular injury, whereas LH levels may be elevated or normal. Total plasma testosterone levels are decreased in 60% of patients and normal in 40%. The physiologically active free testosterone concentrations are usually decreased. In addition, plasma estradiol levels are usually increased, stimulating increased levels of testosterone-binding globulin and resulting in a decreased testosterone to estrogen ratio resulting in gynecomastia. The diagnosis may be made with a chromatin-positive buccal smear, indicating the presence of an extra X chromosome. Karyotypes usually demonstrate 47 XXY or, less commonly, a mosaic pattern 46 XY/47 XXY. Less severe abnormalities are present in patients with the mosaic form of Klinefelter's syndrome, and occasional patients are fertile.
2. XYY Syndrome
This karyotype occurs in 0.1 % to 0.4% of newborn infants. This karyotype has been linked to aggressive and criminal behavior. Not all investigators agree that this behavior is secondary to the karyotype, but feel it may be secondary to tall stature, which may predispose individuals to this behavior. Patients are characteristically tall, whereas semen analyses typically reveal severe oligospermia or azoospermia. Testicular biopsy specimens reveal patterns of maturation arrest to complete germinal aplasia as well as occasional cases demonstrating seminiferous tubular sclerosis. Plasma gonadotropins and testosterone levels are most often within the normal range in these patients. However, elevations of plasma FSH levels may be found in association with more severe patterns of testicular dysfunction.
3. XX Disorder
Patients with the XX male syndrome (sex reversal syndrome) have findings similar to those of Klinefelter's syndrome. These patients demonstrate small, firm testes, frequent gynecomastia, small to normal-sized penises, and azoospermia. Testicular biopsy may demonstrate seminiferous tubule sclerosis, resulting in elevated gonadotropins and decreased testosterone levels. In contrast to Klinefelter's syndrome, these individuals have average heights to shorter than normal heights, no mental deficiency, and hypospadias. Although karyotypes are 46 XX, molecular biologic mapping has suggested that portions of the Y chromosome including the testis determining gene SRY are present in some but not all of these individuals. Because none of the AZF region is present, it is unlikely that sperm could be recovered from testicular tissue.
4. Noonan's Syndrome
The appearance of these patients is similar to that of Turner's syndrome (XO). They have short stature, hypertelorism, webbed neck, low-set ears, cubitus valgus, ptosis, and cardiovascular abnormalities. Chromosomal analysis reveals a 46 XY karyotype. A gene on chromosome 12 has been linked to this defect. Cryptorchidism and testicular atrophy results in elevations of gonadotropins. Androgens may be given to complete virilization, but these patients remain infertile.
5. Androgen Insensitivity Syndrome
Androgens act by binding to androgen receptors that travel to the cell nucleus and interact with the nuclear matrix, stimulating messenger RNA synthesis. Abnormalities in this process result in androgen-resistant syndromes. Karyotypically, these patients are 46 XY males, with phenotypes ranging from pseudohermaphroditism to a normal male phenotype with infertility. Since there was a defect in testosterone action, these patients were found to have elevated serum levels of LH and testosterone.
6. Bilateral Anorchia (Vanishing Testes Syndrome)
Vanishing testis syndrome is bilateral anorchia found in genetic XY males with nonpalpable testes. Patients have prepubertal male phenotypes, suggesting that testicular tissue capable of secreting androgens must have been present at one time in utero. It is theoretical that the testes may have been lost in utero secondary to vascular injury or testicular torsion. Low plasma testosterone and elevated gonadotropin levels are present in these males. Virilization may be induced with testosterone administration but the infertility is not treatable.
7. Cryptorchidism
Cryptorchidism is present in about 3% of full term boys. By 1 year of age, approximately 1% of boys demonstrate undescended testes and approximately 0.8% of adult males have undescended testes. After 1 year of age, the undescended testis is unlikely to descend. Two thirds of cases are unilateral, whereas one third of cases are bilateral. Sperm concentrations below 12 to 20 million per milliliter are found in 50% of patients with bilateral cryptorchidism and in 25% of patients with unilateral cryptorchidism. Testicular biopsy of the cryptorchid testis reveals decreased numbers of Leydig cells. Within the first 6 months of life, the number of germ cells in the cryptorchid testis is within the normal range. By 2 years of age, 38% of unilateral and bilaterally cryptorchid testes will have lost their germ cells. The descended testis, in cases of unilateral cryptorchidism, also may demonstrate abnormalities with low numbers of germ cells. The higher the cryptorchid testis, the more severe the testicular dysfunction. Absence of germ cells is found in 20% to 40% of inguinal or prescrotal testes in contrast to 90% of intra-abdominal testes. Both mechanical and hormonal etiologic factors have been suggested to explain the mechanism of cryptorchidism. Increasing evidence points to a defect in the hypothalamic-pituitary-gonadal axis in these patients. Histologic changes in cryptorchid testis within the first year of life has supported the therapy directed toward correction of cryptorchidism by 12 months of age. Retrospective studies report reasonably high fertility rates in patients with surgically corrected unilateral cryptorchidism.
8. Sertoli Cell-Only Syndrome
Although the etiology of Sertoli Cell-Only Syndrome is unknown, patients usually present with bilaterally small testes and azoospermia. Phenotypically, these patients have normal secondary characteristics. Seminiferous tubules are lined by Sertoli cells with a complete absence of germ cells. The testes of patients with Sertoli Cell Only Syndrome are reasonably normal in consistency. Plasma FSH levels are often but not invariably elevated. Plasma testosterone and LH levels are normal.
9. Myotonic Dystrophy
Patients who have myotonic dystrophy have myotonia, a condition of delayed muscle relaxation after contraction. In addition, patients demonstrate premature frontal baldness, posterior subcapsular cataracts, and cardiac conduction defects. Testicular atrophy may develop in up to 80% of patients. Testicular damage usually occurs in adulthood; Leydig cells typically are uninvolved, with biopsy specimens demonstrating severe tubular sclerosis. Serum FSH is elevated with severe tubular atrophy. disease is transmitted as an autosomal dominant trait with variable penetrance. There is no therapy for the testicular dysfunction in these patients.
10. Gonadotoxic Agents
Many physical and chemical agents may injure the germinal epithelium. Since the seminiferous epithelium consists of rapidly dividing cells, it is susceptible to agents that interfere with cell division. In addition, since spermatogenesis is an androgen dependent process, drugs that interfere with androgen production or action may adversely affect fertility.
11. Chemotherapy
Spermatogenesis is adversely affected by most chemotherapeutic agents. The most susceptible cells are those most actively dividing and consist of spermatogonia and spermatocytes up to the preleptotene stage. Nondividing spermatids and mature spermatozoa are less susceptible. Repopulation of the seminiferous tubules occurs as long as some spermatogonial stem cells remain. These cells slowly divide, eventually resulting in a resumption of spermatogenesis. The specific combination of drugs used for therapy, the dose administered, and the age of the patient at the time of treatment are determinants of the specific effect on the gonads. Studies of large groups of patients who survived cancers in childhood have demonstrated that fertility rates of patients treated with alkylating agents were 60% lower than in nontreated controls. As single drugs, alkylating agents and procarbazine seem to result in the greatest amount of testicular damage. The use of multidrug chemotherapeutic regimens has made it difficult to determine which specific agents are responsible for specific defects. A resumption of spermatogenesis occurs in 50-60% of testis cancer patients treated with combination chemotherapy such as cisplatin, vinblastine and bleomycin. During chemotherapy, most patients demonstrate elevations of serum FSH levels that correlate with azoospermia and then levels decline if and when spermatogenesis resumes.
12. Radiation
Germinal epithelium has a high rate of cell division making it very radiosensitive. Spermatids are more resistant than spermatogonia or spermatocytes. Leydig cells are reasonably radioresistant; and testosterone levels usually remain normal after radiation exposure. Serum FSH levels may increase and revert to normal after a return of spermatogenesis. Azoospermia results from dosages greater than 65 cGy. At dosages lower than 100 cGy, recovery takes approximately 12 months. Following dosages of 200 to 300 cGy, recovery may take 30 months; at dosages of 400 to 600 cGy, more than 5 years may be required for spermatogenesis to return. Semen quality will usually return to baseline within 2 years of radiation therapy for seminoma, however approximately 25% may become permanently infertile. After radiation therapy, most patients are advised to avoid conception for 2 years, although pregnancies after treatment have revealed no evidence of an increase in the prevalence of congenital anomalies.
13. Alcohol
Both the testes and the liver are directly affected by ethanol. Testicular atrophy is commonly found in chronic alcoholics. Free testosterone levels are often decreased, whereas total testosterone levels may be within the normal range secondary to elevated levels of testosterone-estradiol-binding globulin. Testicular specimens demonstrate peritubular fibrosis and a reduction in the number of germ cells. Patients may demonstrate impotence, gynecomastia, and feminization. Gonadotropin levels may be increased. Acute consumption of alcohol in nonalcoholics also demonstrates a fall in testosterone levels.
14. Systemic Illness
Uremia is associated with decreased libido, impotence, gynecomastia, and defects in spermatogenesis secondary to decreased plasma testosterone levels and elevated gonadotropins. These abnormalities persist even in patients undergoing chronic hemodialysis. The elevated gonadotropin levels and subnormal responses of the testes to hCG administration suggest an impairment of testosterone production. An improvement in spermatogenesis and testicular function occurs following renal transplantation. Testicular failure is also common in patients with cirrhosis of the liver also resulting in impotence, gynecomastia, and testicular atrophy. Patients with sickle cell disease may demonstrate delayed secondary characteristics, small testicles, and oligospermia.
15. Orchitis
Postpubertal mumps results in orchitis in approximately 30% of patients with bilateral involvement in 10% to 30% of cases. Permanent testicular atrophy may develop within several months to several years following infection. An intense interstitial edema and mononuclear infiltration is noted pathologically. This may result in hypergonadotropic hypogonadism and gynecomastia. This entity has become uncommon since the advent of the mumps vaccine. Syphilis may affect both the testis and epididymis, resulting in diffuse interstitial inflammation with endarteritis and gumma formation.