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A variety of drugs are available for the treatment of androgen deficiency. Preparations for sublingual or oral administration such as methyltestosterone, oxymetholone, and fluoxymesterone have the advantage of ease of administration but the disadvantage of erratic absorption, potential for cholestatic jaundice, and decreased effectiveness when compared to the intramuscular preparations. Testosterone propionate is a short-acting androgen. Its main use is in initiating therapy in older men, whose prostate glands may be exquisitely sensitive to testosterone. A dose of 50 mg two or three times per week is adequate. Obstructive symptoms due to benign prostatic hypertrophy following therapy with this androgen usually resolve rapidly because of its short duration of action.
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Androgen deficiency may be treated with testosterone enanthate or cyclopentylpropionate (cypionate) given intramuscularly. Unlike the oral androgen preparations, both of these agents are capable of completely virilizing the patients. Therapy may be initiated with 50 mg intramuscularly every 4 weeks and gradually increased to a maintenance dose of 75 to 100 mg every week or 150 to 200 mg every 2 weeks. Testosterone undecanoate, a long-acting form of testosterone given intramuscularly every 3 months, is available in many countries, but is not yet approved by the FDA for use in the United States. Testosterone pellets may be implanted subcutaneously for a longer duration of effect. However, this therapy has not enjoyed much popularity. Transdermal delivery via membranes impregnated with testosterone (Androderm) is another method of replacement therapy. The patches can be placed on the skin of the back, shoulder, or abdomen and provide normal androgen concentrations. A testosterone gel (AndroGel 1%; Testim 1%) that is applied daily to the abdomen, shoulders, or upper arms also results in physiologic concentrations of testosterone. A buccal preparation (Striant) applied twice daily under the upper lip also is available, but is not widely used due to gum irritation.
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Androgens, both oral and intramuscular, have been used (illegally) by some athletes to increase muscle mass and strength. Although this may achieve the anticipated result in some individuals, adverse effects include oligospermia and testicular atrophy—in addition to some of the complications noted below.
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Androgen therapy is currently contraindicated in patients with prostatic carcinoma. About 1% to 2% of patients receiving oral methyltestosterone or fluoxymesterone develop intrahepatic cholestatic jaundice that resolves when the drug is discontinued. Rarely, these methylated or halogenated androgens have been associated with benign and malignant hepatocellular tumors.
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Androgen therapy also may cause premature fusion of the epiphyses in an adolescent, and this may result in some loss of potential height. Therefore, androgen therapy is usually withheld until a hypogonadal male reaches 13 years of age. Sodium and water retention may induce hypertension or congestive heart failure in susceptible individuals. Because androgens stimulate erythropoietin production, erythrocytosis may occur during therapy. This is not usually clinically significant. Inhibition of spermatogenesis is mediated through suppression of gonadotropins by the androgens. Gynecomastia may develop during initiation of androgen therapy but usually resolves with continued administration of the drug. Sleep apnea may be precipitated. Priapism, acne, and aggressive behavior are dose-related adverse effects and generally disappear after reduction of dosage. Androgens decrease the production of thyroxine-binding globulin and corticosteroid-binding globulin by the liver. Therefore, total serum thyroxine and cortisol concentrations may be decreased, although the free hormone concentrations remain normal. High-density lipoprotein concentrations may also be reduced with oral androgens.
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In patients with hypogonadism due to inadequate gonadotropin secretion, spermatogenesis and virilization may be induced by exogenous gonadotropin injections. Because the gonadotropins are proteins with short half-lives, they must be administered parenterally two or three times a week.
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The expense and inconvenience of this type of therapy preclude its routine use for the treatment of androgen deficiency. The two major indications for exogenous gonadotropins are treatment of cryptorchidism (see later) and induction of spermatogenesis in hypogonadal males who wish to father children.
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To induce spermatogenesis, 2000 IU of chorionic gonadotropin may be given intramuscularly three times a week for 9 to 12 months. In some individuals with partial gonadotropin deficiencies, this may induce adequate spermatogenesis. In patients with more severe deficiencies, menotropins, available in vials containing 75 IU each of FSH and LH, or highly purified urinary FSH (urofollitropin) or FSH produced by recombinant DNA technology (follitropin beta), each containing 75 IU of FSH, is added to chorionic gonadotropin therapy after 9 to 12 months and is administered in a dosage of one vial intramuscularly three times a week.
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Adverse reactions with such therapy are minimal. Acne, gynecomastia, or prostatic enlargement may be noted as a result of excessive Leydig cell stimulation. Reduction of the chorionic gonadotropin dosage or a decrease in the frequency of chorionic gonadotropin injections generally results in resolution of the problem.
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Gonadotropin-Releasing Hormone
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GnRH (gonadorelin acetate), administered in pulses every 60 to 120 minutes by portable infusion pumps, effectively stimulates the endogenous release of LH and FSH in hypogonadotropic hypogonadal patients. This therapy does not currently appear to offer any major advantage over the use of exogenous gonadotropins for induction of spermatogenesis or the use of testosterone enanthate or cypionate for virilization, and is no longer available in the United States. A long-acting analog of GnRH, leuprolide acetate, is available for the treatment of advanced prostatic carcinoma. Daily subcutaneous administration of 1 mg or monthly intramuscular injections of 7.5 mg of a depot preparation—22.5 mg for 3 months or 30 mg for 4 months—results in desensitization of the pituitary GnRH receptors, which reduces LH and FSH levels and so ultimately testosterone concentrations. Similar results are produced with a subcutaneous injection of the depot form of the GnRH analog goserelin or monthly intramuscular injections of triptorelin. With these therapies, initial remission rates for prostatic carcinoma are similar to those found with orchiectomy or treatment with diethylstilbestrol (about 70%). A long-acting GnRH antagonist, abarelix, also is an effective means of inducing medical castration by reducing LH, FSH, and testosterone secretion. Although GnRH agonists may produce an initial rise in LH, FSH, and testosterone levels, no such rise is seen with GnRH antagonists, making them better agents to use in the presence of metastasis in sensitive areas such as the spinal cord.
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Nafarelin acetate is a GnRH agonist that is administered intranasally for the treatment of endometriosis and central precocious puberty. Central precocious puberty also may be treated with leuprolide acetate and another analog, histrelin acetate. Long-acting GnRH agonists also are used to suppress endogenous gonadal steroid production as part of the endocrine treatment of transsexual persons. Long-acting GnRH agonists combined with testosterone have been studied as a possible male contraceptive, but they do not uniformly induce azoospermia.
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Clinical Male Gonadal Disorders
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Hypogonadism may be subdivided into three general categories (Table 12–3). A thorough discussion of the hypothalamic–pituitary disorders that cause hypogonadism is presented in Chapters 4 and 15. The defects in androgen biosynthesis and androgen action are described in Chapter 14. The following section emphasizes the primary gonadal abnormalities.
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Klinefelter Syndrome (XXY Seminiferous Tubule Dysgenesis)
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Klinefelter syndrome is the most common genetic cause of male hypogonadism, occurring in one of 600 male births. An extra X chromosome is present in about 0.2% of male conceptions and 0.1% to 0.2% of live-born males. Sex chromosome surveys of mentally retarded males have revealed an extra X chromosome in 0.45% to 2.5% of such individuals. Patients with an XXY genotype have classic Klinefelter syndrome; those with an XXXY, XXXXY, or XXYY genotype or with XXY/chromosomal mosaicism are considered to have variant forms of the syndrome.
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Etiology and Pathophysiology
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The XXY genotype is usually due to meiotic nondisjunction during parental gametogenesis, which results in an egg with two X chromosomes or a sperm with an X and a Y chromosome. After fertilization, nondisjunction during mitotic division results in mosaicism.
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At birth there are generally no physical stigmas of Klinefelter syndrome, and during childhood there are no specific signs or symptoms. The chromosomal defect is expressed chiefly during puberty. As the gonadotropins increase, the seminiferous tubules do not enlarge but rather undergo fibrosis and hyalinization, which results in small, firm testes. Obliteration of the seminiferous tubules results in azoospermia.
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In addition to dysgenesis of the seminiferous tubules, the Leydig cells are also abnormal. They are present in clumps and appear to be hyperplastic on initial examination of a testicular biopsy. However, the Leydig cell mass is not increased, and the apparent hyperplasia is actually due to the marked reduction in tubular volume. Despite the normal mass of tissue, the Leydig cells are functionally abnormal. The testosterone production rate is reduced, and there is a compensatory elevation in serum LH. Stimulation of the Leydig cells with exogenous chorionic gonadotropin results in a subnormal rise in testosterone. The clinical manifestations of androgen deficiency vary considerably from patient to patient and may be related to the degree of diminished testosterone production and alterations in the androgen receptor. Exon 1 of the androgen receptor gene contains a polymorphism with a variable number of CAG repeats. As the number of repeats increases, there is a progressive decrease in androgen action and more phenotypic abnormalities. Thus, some individuals have virtually no secondary sexual developmental changes, whereas others are indistinguishable from healthy individuals.
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The elevated LH concentrations also stimulate the Leydig cells to secrete increased quantities of estradiol and estradiol precursors. The relatively high estradiol: testosterone ratio is responsible for the variable degrees of feminization and gynecomastia seen in these patients. The elevated estradiol also stimulates the liver to produce SHBG. This may result in total serum testosterone concentrations that are within the low-normal range for adult males. However, the free testosterone level may be lower than normal.
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The pathogenesis of the eunuchoid proportions, personality, and intellectual deficits and associated medical disorders is presently unclear.
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Most of the seminiferous tubules are fibrotic and hyalinized, although occasional Sertoli cells and spermatogonia may be present in some sections. Absence of elastic fibers in the tunica propria is indicative of the dysgenetic nature of the tubules. The Leydig cells are arranged in clumps and appear hyperplastic, although the total mass is normal.
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There are usually no symptoms before puberty other than poor school performance in some affected individuals. Puberty may be delayed but not usually by more than 1 to 2 years. During puberty, the penis and scrotum undergo varying degrees of development, with some individuals appearing normal. Most patients (80%) have diminished facial and torso hair growth. The major complaint is often persistent gynecomastia, which is clinically present in over half of patients. The testes are uniformly small (<2 cm in longest axis and <4 mL in volume) and firm as a result of fibrosis and hyalinization. Other complaints include infertility or insufficient libido and potency. The patient may have difficulty putting into words his embarrassment in situations where he must disrobe in the presence of other men, and the subnormal development of the external genitalia along with gynecomastia may lead to feelings of inadequacy that may be partly responsible for the maladjusted social behavior some patients exhibit. Bone mineral density may be dramatically reduced in patients with long-standing androgen deficiency.
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Patients with Klinefelter syndrome have abnormal skeletal proportions that are not truly eunuchoid. Growth of the lower extremities is relatively greater than that of the trunk and upper extremities; therefore, pubis-to-floor height (which represents appendicular bone growth) is greater than crown-to-pubis height (which predominantly represents axial bone growth), and span is less than total height. Thus, the abnormal skeletal proportions are not the result of androgen deficiency per se (which results in span greater than height).
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Intellectual impairment is noted in many patients with Klinefelter syndrome, but the true proportion of affected individuals with subnormal intelligence is not known. Deficits in language and higher intellectual functions, such as concept formation and problem solving, have been noted. Poor social skills also are common (see earlier). Patients generally show lack of ambition and difficulties in maintaining permanent employment.
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Several clinical and genotypic variants of Klinefelter syndrome have been described. In addition to small testes with seminiferous tubular hyalinization, azoospermia, deficient secondary sexual development, and elevated gonadotropins, patients with three or more X chromosomes uniformly have severe mental retardation. The presence of more than one Y chromosome tends to be associated with aggressive antisocial behavior and macronodular acne. Skeletal deformities such as radioulnar synostosis, flexion deformities of the elbows, and clinodactyly are more commonly seen in Klinefelter variants. Patients with sex chromosome mosaicism (XX/XXY) may have only a few of the Klinefelter stigmas. These patients may have normal testicular size and may be fertile if their testes contain the XY genotype.
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Medical disorders found to be associated with Klinefelter syndrome with more than chance frequency include chronic pulmonary disease (emphysema, chronic bronchitis), varicose veins, extragonadal germ cell tumors, cerebrovascular disease, glucose intolerance, primary hypothyroidism, and taurodontism—with early tooth decay. Some studies suggest that there is a 20-fold increased risk of breast cancer, while others do not.
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Serum testosterone is low or normal, and FSH and LH concentrations are elevated. Azoospermia is present. The buccal smear is chromatin-positive (20% of cells having a Barr body), and chromosomal analysis reveals a 47,XXY karyotype.
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Differential Diagnosis
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Klinefelter syndrome should be distinguished from other causes of hypogonadism. Small, firm testes should suggest Klinefelter syndrome. Hypothalamic-pituitary hypogonadism may be associated with small, rubbery testes if puberty has not occurred or atrophic testes if normal puberty has occurred. The consistency of the testes in Klinefelter syndrome is also different from that noted in acquired forms of adult seminiferous tubular damage. The elevated gonadotropins place the site of the lesion at the testicular level, and chromosomal analysis confirms the diagnosis. Chromosomal analysis is also required to differentiate classic Klinefelter syndrome from the variant forms.
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Androgen deficiency should be treated with testosterone replacement. Patients with personality defects should be virilized gradually to decrease the risk of aggressive behavior. Testosterone enanthate or cypionate, 100 mg intramuscularly, may be given every 2 to 4 weeks initially and increased to 200 mg every 2 weeks if well tolerated. Patients with low–normal androgen levels may not require androgen replacement therapy. For those desiring fertility, sperm may be extracted directly from the testes in about half of the patients and used for ICSI with a live birth rate of up to 20%.
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If gynecomastia presents a cosmetic problem, mastectomy may be performed.
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Patients generally feel better after androgen replacement therapy has begun. However, the personality defects do not improve, and these patients often require long-term psychiatric counseling. Life expectancy is not affected.
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Bilateral Anorchia (Vanishing Testes Syndrome)
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Approximately 3% of phenotypic boys undergoing surgery to correct unilateral or bilateral cryptorchidism are found to have absence of one testis, and in about 1% of cryptorchid males both testes are absent. Thus, bilateral anorchia is found in approximately one out of every 20,000 males.
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Etiology and Pathophysiology
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Functional testicular tissue must be present during the first 14 to 16 weeks of embryonic development in order for Wolffian duct growth and Müllerian duct regression to occur and for the external genitalia to differentiate along male lines. Absence of testicular function before this time results in varying degrees of male pseudohermaphroditism with ambiguous genitalia. Prenatal testicular injury occurring after 16 weeks of gestation as a result of trauma, vascular insufficiency, infection, or other mechanisms may result in loss of testicular tissue in an otherwise normal phenotypic male; hence the term vanishing testes syndrome.
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In most instances, no recognizable testicular tissue has been identified despite extensive dissections. Wolffian duct structures are generally normal, and the vas deferens and testicular vessels may terminate blindly or in a mass of connective tissue in the inguinal canal or scrotum.
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At birth, patients appear to be normal phenotypic males with bilateral cryptorchidism. Growth and development are normal until secondary sexual development fails to occur at puberty. The penis remains small; pubic and axillary hair does not fully develop despite the presence of adrenal androgens; and the scrotum remains empty. If the patient does not receive androgens, eunuchoid proportions develop. Gynecomastia does not occur.
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An occasional patient undergoes partial spontaneous virilization at puberty. Although anatomically no testicular tissue has been identified in such patients, catheterization studies have demonstrated higher testosterone concentrations in venous blood obtained from the spermatic veins than in the peripheral venous circulation. This suggests that functional Leydig cells are present in some patients, although they are not associated with testicular germinal epithelium or stroma.
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Serum testosterone concentrations are generally quite low, and both LH and FSH are markedly elevated. Serum testosterone concentrations do not rise following a chorionic gonadotropin stimulation test. Serum Müllerian duct inhibitory factor levels are low. Chromosomal analysis discloses a 46,XY karyotype.
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Testicular artery arteriograms, spermatic venograms, and gadolinium-infusion magnetic resonance venography show vessels that taper and end in the inguinal canal or scrotum without an associated gonad.
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Thorough inguinal and abdominal laparoscopic examination or retroperitoneal examination at laparotomy may locate the testes. If testicular vessels and the vas deferens are identified and found to terminate blindly together, it may be assumed that the testis is absent.
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Differential Diagnosis
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Bilateral cryptorchidism must be differentiated from congenital bilateral anorchia. A normal serum testosterone concentration that rises following stimulation with chorionic gonadotropin is indicative of functional Leydig cells and probable bilateral cryptorchidism. Elevated serum LH and FSH and a low testosterone that fails to rise after administration of exogenous chorionic gonadotropin indicate bilateral absence of functional testicular tissue.
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Androgen replacement therapy is discussed in the section on pharmacology (see "Androgens," earlier in the chapter).
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Implantation of testicular prostheses for cosmetic purposes may be beneficial after the scrotum has enlarged in response to androgen therapy.
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Defective development of testicular Leydig cells is a rare cause of male pseudohermaphroditism with ambiguous genitalia.
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Etiology and Pathophysiology
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Testes are present in the inguinal canal and contain prepubertal-appearing tubules with Sertoli cells and spermatogonia without germinal cell maturation. The interstitial tissue has a loose myxoid appearance with an absence of Leydig cells. The syndrome is caused by inactivating mutations in the LH receptor that alters receptor signal transduction. The presence of a vas deferens and epididymis in these patients indicates that the local concentration of testosterone was high enough during embryogenesis to result in differentiation of the Wolffian duct structures. However, the ambiguity of the genitalia indicates that the androgen concentration in these patients was insufficient to bring about full virilization of the external genitalia. The absence of Müllerian duct structures is compatible with normal fetal secretion of Müllerian duct inhibitory factor from the Sertoli cells.
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These patients may present in infancy with variable degrees of genital ambiguity, including a bifid scrotum, clitoral phallus, urogenital sinus, and blind vaginal pouch. Alternatively, they may appear as normal phenotypic females and escape detection until adolescence, when they present with primary amenorrhea, with or without normal breast development. The gonads are generally located in the inguinal canal. Axillary and pubic hair, although present, may be sparse. Mild defects may result in Leydig cell hypoplasia, a disorder whose clinical manifestations include micropenis, hypospadias, and variable suppression of fertility.
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Serum gonadotropins are elevated, and testosterone levels are below normal limits for a male and within the low-normal range for females. There is no increase in testosterone following chorionic gonadotropin administration.
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Differential Diagnosis
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Leydig cell aplasia should be differentiated from the vanishing testes syndrome, testosterone biosynthetic defects, disorders of androgen action, and 5α-reductase deficiency. The differential diagnostic features of these disorders are discussed in Chapter 14.
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Patients with Leydig cell aplasia respond well to the exogenous administration of testosterone, and it would be anticipated that they would be fully virilized and even develop some degree of spermatogenesis with exogenous testosterone administration. However, because the few patients who have been reported have been discovered either late in childhood or as adolescents and have been raised as females, it would be inappropriate to attempt a gender reversal at such a late period. Removal of the cryptorchid testes and feminization with exogenous estrogens would appear to be the most prudent course of therapy.
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Cryptorchidism is unilateral or bilateral absence of the testes from the scrotum because of failure of normal testicular descent from the genital ridge through the external inguinal ring. Between 2% and 4% of full-term and 20% to 25% of premature male infants have cryptorchidism. In most cases of cryptorchidism noted at birth, spontaneous testicular descent occurs during the first year of life, reducing the incidence to 0.2% to 0.8% by 1 year of age. Approximately 0.75% of adult males are cryptorchid. Unilateral cryptorchidism is 5 to 10 times more common than bilateral cryptorchidism.
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Almost 50% of cryptorchid testes are located at the external inguinal ring or in a high scrotal position; 19% lie within the inguinal canal between the internal and external inguinal rings (canalicular); 9% are intra-abdominal; and 23% are ectopic (ie, located away from the normal pathway of descent from the abdominal cavity to the scrotum). Most ectopic testes are found in a superficial inguinal pouch above the external inguinal ring.
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Etiology and Pathophysiology
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Testicular descent usually occurs between the 12th week of fetal development and birth. Both mechanical and hormonal factors appear to be important for this process. Cryptorchidism is common in patients with congenital defects in androgen synthesis or action and in patients with congenital gonadotropin deficiency, and experimental studies have demonstrated that DHT is required for normal testicular descent. These observations suggest that prenatal androgen deficiency may be of etiologic importance in the development of cryptorchidism. Environmental endocrine disruptors with estrogen or antiandrogen activity, such as phthalates or bisphenol A, have been proposed as a cause of the increased incidence of cryptorchidism seen in recent years.
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It is not known whether pathologic changes in the testes are due to the effects of cryptorchidism or to intrinsic abnormalities in the gonad. Experimental studies in animals have shown that an increase in the temperature of the testes by 1.5°C to 2°C (34.7°F-35.6°F) (the temperature differential between the abdomen and scrotum) results in depression of spermatogenesis. Serial testicular biopsies in cryptorchid patients have demonstrated partial reversal of the histologic abnormalities following surgical correction, suggesting that the extra-scrotal environment is partly responsible for the observed pathologic abnormalities.
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An intrinsic abnormality in the testes in patients with unilateral cryptorchidism is suggested by the observation that such patients are at increased risk for development of germ cell neoplasms in the scrotal testis. Similarly, the observation that adults with unilateral cryptorchidism surgically corrected before puberty had low sperm counts, high basal serum LH and FSH concentrations, and an exaggerated FSH response to GnRH suggests either that both testes are intrinsically abnormal or that the cryptorchid gonad somehow suppresses the function of the scrotal testis.
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Histologic studies on cryptorchid testes have demonstrated a decrease in the size of the seminiferous tubules and number of spermatogonia and an increase in peritubular tissue. The Leydig cells usually appear normal. It is unclear at what age these changes first appear. Abnormalities have been detected as early as 6 months. It is well established that the longer a testis remains cryptorchid, the more likely it is to show pathologic changes. More severe changes are generally found in intra-abdominal testes than in canalicular testes.
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There are usually no symptoms unless a complication such as testicular torsion, trauma, or malignant degeneration occurs. School-age children may have gender identity problems. Adults may complain of infertility, especially if they have a history of bilateral cryptorchidism.
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Absence of one or both testes is the cardinal clinical finding. This may be associated with a small scrotum (bilateral cryptorchidism) or hemiscrotum (unilateral cryptorchidism). Signs of androgen deficiency are not present.
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Basal or stimulated serum FSH, LH, and testosterone concentrations are not helpful in evaluating prepubertal unilaterally cryptorchid males. However, serum FSH and LH concentrations and the testosterone response to exogenous chorionic gonadotropin are useful in differentiating cryptorchid patients from those with congenital anorchia. The latter have high basal gonadotropins, low serum testosterone, and absent or diminished testosterone rise following chorionic gonadotropin stimulation. Alternatively, measurement of the serum concentration of Müllerian duct inhibitory factor can be used; children with no testicular tissue have very low levels in comparison to those with bilateral cryptorchidism.
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Postpubertal adults may have oligospermia, elevated basal serum FSH and LH concentrations, and an exaggerated FSH increase following GnRH stimulation. Such abnormalities are more prevalent in patients with a history of bilateral cryptorchidism than with unilateral cryptorchidism.
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Gadolinium-infusion magnetic resonance venography is a sensitive method for localizing the nonpalpable cryptorchid testes. Intravenous urography discloses an associated abnormality of the upper urinary tract in 10% of cases—horseshoe kidney, renal hypoplasia, ureteral duplication, hydroureter, and hydronephrosis.
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Differential Diagnosis
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Retractile testis (pseudocryptorchidism) is due to a hyperactive cremasteric reflex, which draws the testicle into the inguinal canal. Cold temperature, fear, and genital manipulation commonly activate the reflex, which is most prominent between the ages of 5 and 6 years. The child should be examined with warm hands in a warm room. The testis can usually be milked into the scrotum with gentle pressure over the lower abdomen in the direction of the inguinal canal.
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Bilateral anorchia is associated with elevated gonadotropins, decreased testosterone, and an absent or subnormal response to stimulation with chorionic gonadotropin.
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The virilizing forms of congenital adrenal hyperplasia may result in prenatal fusion of the labial-scrotal folds and clitoral hypertrophy (Chapter 14). Severely affected females have the appearance of phenotypic males with bilateral cryptorchidism. Because of the potentially disastrous consequences (acute adrenal insufficiency) if this diagnosis is missed, a chromosomal analysis should be performed on bilaterally cryptorchid phenotypic male infants.
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Complications and Sequelae
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Approximately 90% of cryptorchid males have associated ipsilateral inguinal hernia resulting from failure of the processus vaginalis to close. This is rarely symptomatic.
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Because of the abnormal connection between the cryptorchid testis and its supporting tissues, torsion may occur. This should be suspected in any patient with abdominal or pelvic pain and an ipsilateral empty scrotum.
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Testes that lie above the pubic tubercle are particularly susceptible to traumatic injury.
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A cryptorchid testis is four to six times more likely to undergo malignant degeneration than a normal testis. The incidence of such tumors is greater in patients with intra–abdominal testes than in patients with canalicular testes. Seminomas are the neoplasms most commonly associated with maldescended testes. In addition, there is an increased risk for development of testicular intraepithelial neoplasia (carcinoma in situ). Orchiopexy before or during puberty decreases the risk of malignancy. Because of the increased risk of neoplasia, many urologists recommend orchiectomy for a unilaterally undescended testicle in a patient first seen after puberty. Patients who present with bilateral cryptorchidism after puberty should have bilateral orchiopexy and testicular biopsies to preserve testicular endocrine function and to make palpation for detection of neoplasia easier.
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Over 75% of untreated bilaterally cryptorchid males are infertile. About 30% to 50% of bilaterally cryptorchid patients who undergo prepubertal orchiopexy have been found to be fertile. About half of patients with untreated unilateral cryptorchidism are infertile, whereas infertility is found in less than one-fourth of such patients whose cryptorchidism is surgically repaired before puberty.
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Although cryptorchidism cannot be prevented, the complications can be avoided. It is clear that the adverse changes that take place in the testes are related in part to the location of the maldescended testis and the duration of the cryptorchidism. Most testes that are undescended at birth enter the scrotum during the first year of life. However, it is rare for a cryptorchid testis to descend spontaneously after the age of 6 months. Because adverse histologic changes have been noted around the age of 2 years, hormonal or surgical correction should be undertaken at or before that time, ideally between 6 and 12 months.
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Intramuscular chorionic gonadotropin therapy—Because growth of the vas deferens and testicular descent are at least partially dependent on androgens, stimulation of endogenous testosterone secretion by chorionic gonadotropin may correct the cryptorchidism. Cryptorchidism is corrected in less than 25% of patients treated with a course of chorionic gonadotropin, and recent studies suggest that patients with conditions that respond to hormonal therapy may actually have retractile testes rather than true cryptorchidism. Nevertheless, this therapy may be tried prior to orchiopexy, because it is innocuous and may avoid the need for surgery. For bilateral cryptorchidism, give a short course of chorionic gonadotropin consisting of 3300 U intramuscularly every other day over a 5-day period (three injections). For unilateral cryptorchidism, give 500 U intramuscularly three times a week for 6½ weeks (20 injections).
Intranasal GnRH therapy—GnRH given three times a day for 28 days by nasal spray has been shown to be as effective as chorionic gonadotropin injections in correcting cryptorchidism in some patients. This therapy is not approved for treatment of cryptorchidism in the United States.
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Several procedures have been devised to place the maldescended testis into the scrotum (orchiopexy). The operation may be performed in one or two stages. Inguinal hernia should be repaired if present. As noted earlier, the surgery is best performed between 6 and 12 months of age.
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Noonan Syndrome (Male Turner Syndrome)
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Phenotypic and genotypic males with many of the physical stigmas of classic Turner syndrome have been described under a variety of names, including Noonan syndrome and male Turner syndrome. It has an incidence of 1:1000 to 1:2500 live births and may occur sporadically or may be familial—inherited in an autosomal dominant fashion with variable penetrance. Approximately half of the patients have a gain-of-function mutation in the protein-tyrosine phosphatase, nonreceptor type II (PTPN11) gene on chromosome 12, which encodes for Src homology region two-domain phosphatase (SHP-2), a signaling protein that modulates cellular proliferation, differentiation, and migration. A number of pathologic features have been noted, including reduced seminiferous tubular size with or without sclerosis, diminished or absent germ cells, and Leydig cell hyperplasia.
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The most common clinical features are short stature, webbed neck, hypertelorism, cubitus valgus, and bleeding diathesis. Other somatic defects are variably observed in these patients. Congenital cardiac anomalies are common and involve primarily the right side of the heart—in contrast to patients with XO gonadal dysgenesis.
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Cryptorchidism is frequently present. Although some affected individuals are fertile, with normal testes, most have small testes and mild to moderate hypogonadism.
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Serum testosterone concentrations are usually low or low-normal, and serum gonadotropins are high. The karyotype is 46,XY.
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Differential Diagnosis
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The clinical features of Noonan syndrome are sufficiently distinct so that confusion with other causes of hypogonadism is usually not a problem. However, a rare individual with XY/XO mosaicism may have similar somatic anomalies requiring chromosomal analysis for differentiation. Some of the phenotypic features are shared with the Costello and cardiofaciocutaneous syndromes.
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If the patient is hypogonadal, androgen replacement therapy is indicated.
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Myotonic dystrophies types 1 (DM1) and 2 (DM2) are autosomal dominant disorders of muscle with multisystem clinical features including primary hypogonadism. The underlying lesion in DM1is an expansion of the CTG repeat in the 3′ untranslated region of a gene that encodes a serine-threonine protein kinase located on chromosome 19. The cause of DM2 is expansion of a CCTG repeat in intron 1 of the zinc finger protein-9 gene on chromosome 3.
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Testicular histology varies from moderate derangement of spermatogenesis with germinal cell arrest to regional hyalinization and fibrosis of the seminiferous tubules. The Leydig cells are usually preserved and may appear in clumps.
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The testes are normal in affected prepubertal individuals, and puberty generally proceeds normally. Testosterone secretion is normal, and secondary sexual characteristics develop appropriately. After puberty, seminiferous tubular atrophy results in a decrease in testicular size and change of consistency from firm to soft or mushy. Infertility is a consequence of disrupted spermatogenesis. If testicular hyalinization and fibrosis are extensive, Leydig cell function may also be impaired.
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The disease usually becomes apparent in adulthood. Progressive weakness and atrophy of the facial, neck, hand, and lower extremity muscles is commonly observed. Severe atrophy of the temporalis muscles, ptosis due to weakness of the levator muscles of the eye with compensatory wrinkling of the forehead muscles, and frontal baldness comprise the myopathic facies characteristic of the disorder. Myotonia is present in several muscle groups and is characterized by inability to relax the muscle normally after a strong contraction.
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Testicular atrophy is not noted until adulthood, and most patients develop and maintain normal facial and body hair growth and libido. Gynecomastia is usually not present.
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Associated features include mental retardation (type 1 disease only), cataracts, diabetes mellitus, cardiac arrhythmias, and primary hypothyroidism.
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Serum testosterone is normal to slightly decreased. FSH is uniformly elevated in patients with atrophic testes. LH is also frequently elevated, even in patients with normal serum testosterone levels. Leydig cell reserve is generally diminished, with subnormal increases in serum testosterone following stimulation with chorionic gonadotropin. An excessive rise in FSH and, to a lesser extent, LH is found following GnRH stimulation.
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There is no therapy that will prevent progressive muscular atrophy in this disorder. Testosterone replacement therapy is not indicated unless serum testosterone levels are subnormal.
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Adult Seminiferous Tubule Failure
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Adult seminiferous tubule failure encompasses a spectrum of pathologic alterations of the seminiferous tubules that results in hypospermatogenesis, germinal cell arrest, germinal cell aplasia, and tubular hyalinization. Almost half of infertile males exhibit some degree of isolated seminiferous tubule failure.
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Etiology, Pathology, and Pathophysiology
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Etiologic factors in seminiferous tubule failure include mumps or gonococcal orchitis, leprosy, cryptorchidism, irradiation, uremia, alcoholism, paraplegia, lead poisoning, and therapy with antineoplastic agents such as cyclophosphamide, chlorambucil, vincristine, methotrexate, and procarbazine. Vascular insufficiency resulting from spermatic artery damage during herniorrhaphy, testicular torsion, or sickle cell anemia may also selectively damage the tubules. Similar pathologic changes may be found in oligospermic patients with varicoceles. Deletions of portions of the Y chromosome may also present as adult seminiferous tubule failure. In many patients, no etiologic factors can be identified, and the condition is referred to as idiopathic.
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The rapidly dividing germinal epithelium is more susceptible to injury than are the Sertoli or Leydig cells. Thus, pressure necrosis (eg, mumps or gonococcal orchitis), increased testicular temperature (eg, cryptorchidism and perhaps varicocele and paraplegia), and the direct cytotoxic effects of irradiation, alcohol, lead, and chemotherapeutic agents primarily injure the germ cells. Although the Sertoli and Leydig cells appear to be morphologically normal, severe testicular injury may result in functional alterations in these cells.
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Several different lesions may be found in testicular biopsy specimens. The pathologic process may involve the entire testes or may appear in patches. The least severe lesion is hypospermatogenesis, in which all stages of spermatogenesis are present but there is a decrease in the number of germinal epithelial cells. Some degree of peritubular fibrosis may be present. Cessation of development at the primary spermatocyte or spermatogonial stage of the spermatogenic cycle is classified as germinal cell arrest. More severely affected testes may demonstrate a complete absence of germ cells with maintenance of morphologically normal Sertoli cells (Sertoli cell–only syndrome). The most severe lesion is fibrosis or hyalinization of the tubules. This latter pattern may be indistinguishable from that seen in Klinefelter syndrome.
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Irrespective of the etiologic factors involved in damage to the germinal epithelium, the alterations in spermatogenesis result in oligospermia. If the damage is severe, as in the Sertoli cell–only syndrome or tubular hyalinization, azoospermia may be present. Because testicular volume consists chiefly of tubules, some degree of testicular atrophy is often present in these patients. Some patients have elevations in basal serum FSH concentrations and demonstrate a hyperresponsive FSH rise following GnRH, suggesting that the Sertoli cells are functionally abnormal despite their normal histologic appearance.
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Infertility is usually the only complaint. Mild to moderate testicular atrophy may be present. Careful examination should be made for the presence of varicocele by palpating the spermatic cord during Valsalva maneuver with the patient in the upright position. The patients are fully virilized, and gynecomastia is not present.
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Semen analysis shows oligospermia or azoospermia, and serum testosterone and LH concentrations are normal. Basal serum FSH levels may be normal or high, and an excessive FSH rise following GnRH may be present. Serum inhibin B levels generally are low, but they add little information beyond that of the serum FSH measurement.
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Differential Diagnosis
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Patients with hypothalamic or pituitary disorders may have oligospermia or azoospermia and testicular atrophy. The serum FSH and LH concentrations are often in the low-normal range, and the testosterone level is usually (not always) diminished. The presence of neurologic and ophthalmologic abnormalities, diabetes insipidus, anterior pituitary trophic hormone deficiencies, or an elevated serum PRL concentration distinguishes these patients from those with primary seminiferous tubule failure. Other causes of primary testicular failure are associated either with clinical signs and symptoms of androgen deficiency or with enough somatic abnormalities to allow differentiation from isolated seminiferous tubule failure.
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In many instances, damage to the seminiferous tubules cannot be prevented. Early correction of cryptorchidism, adequate shielding of the testes during diagnostic radiologic procedures or radiotherapy, and limitation of the total dose of chemotherapeutic agents may prevent or ameliorate the adverse effects.
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Attempts to treat oligospermia and infertility medically have included low-dose testosterone, exogenous gonadotropins, thyroid hormone therapy, vitamins, bromocriptine, aromatase inhibitors, tamoxifen, and clomiphene citrate. None of these agents have been found to be uniformly beneficial, and several may actually lead to a decrease in the sperm count.
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Some of the pathologic changes in the testes have been reversed by early orchiopexy in cryptorchid individuals. If a varicocele is found in an oligospermic, infertile male, it should be ligated.
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Patients who have received up to 300 cGy of testicular irradiation may show partial or full recovery of spermatogenesis months to years following exposure. The prognosis for recovery is better for individuals who receive the irradiation over a short interval than for those who are exposed over several weeks. Radiation therapy for prostate cancer may cause an acute reduction in spermatogenesis and testosterone followed in most patients by partial or full recovery.
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Recovery of spermatogenesis may also occur months to years following administration of chemotherapeutic agents. The most important factor determining prognosis is the total dose of chemotherapy administered.
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Improvement in the quality of the semen is found in 60% to 80% of patients following successful repair of varicocele. Restoration of fertility has been reported in about half of such patients.
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The prognosis for spontaneous improvement of idiopathic oligospermia due to infection or infarction is poor.
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Adult Leydig Cell Failure (Andropause)
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In contrast to the menopause in women, men do not experience an abrupt decline or cessation of gonadal function. However, a gradual diminution of testicular function does occur in many men as part of the aging process (see Chapter 23). It is not known how many men develop symptoms directly attributable to this phenomenon.
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Etiology, Pathology, and Pathophysiology
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After age 50, there is a gradual decrease in the total serum testosterone concentration, although the actual values remain within the normal range. The levels of free testosterone decrease to a greater extent because of an increase in SHBG. The testosterone production rate declines and Leydig cell responsiveness to hCG also decreases. A gradual compensatory increase in serum LH levels has also been noted. Aging also is associated with alterations in the hypothalamic-pituitary portion of the axis.
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Histologic studies of the aging testes have shown patchy degenerative changes in the seminiferous tubules with a reduction in number and volume of Leydig cells. The pathologic changes are first noted in the regions most remote from the arterial blood supply. Thus, microvascular insufficiency may be the etiologic basis for the histologic tubular changes and the decrease in Leydig cell function noted with aging. In addition, virtually all of the conditions that cause adult seminiferous tubule failure may lead to Leydig cell dysfunction if testicular injury is severe enough.
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A great many symptoms have been attributed to the male climacteric (andropause), including decreased libido and potency, emotional instability, fatigue, decreased strength, decreased concentrating ability, vasomotor instability (palpitations, hot flushes, diaphoresis), and a variety of diffuse aches and pains. There are usually no associated signs unless the testicular injury is severe. In such patients, a decrease in testicular volume and consistency may be present as well as gynecomastia.
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Serum testosterone may be low or low-normal. Serum LH concentration is usually high-normal or slightly high, but a number of men have a normal LH and borderline low total and free testosterone. Oligospermia is usually present. Bone mineral density may be decreased.
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Because many men with complaints compatible with Leydig cell failure have borderline low testosterone concentrations and LH concentrations within the normal adult range, a therapeutic testosterone/placebo trial may be attempted. The test is best performed double-blind over an 8-week period. During the first or last 4 weeks, the patient receives testosterone enanthate, 100 mg intramuscularly per week; during the other 4-week period, placebo injections are administered. The patient is interviewed by the physician 2 weeks after the last course of injections. After the interview, the code is broken; if the patient notes amelioration of symptoms during the period of androgen administration but not during the placebo period, the diagnosis or adult Leydig cell failure is substantiated. If the patient experiences no subjective improvement following testosterone, or if improvement is noted following both placebo and testosterone injections, Leydig cell failure is effectively ruled out.
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Differential Diagnosis
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Erectile dysfunction from vascular, neurologic, or psychologic causes must be distinguished from Leydig cell failure. A therapeutic trial of androgen therapy does not help erectile dysfunction that is not due to androgen deficiency.
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Androgen replacement therapy is the treatment of choice for both symptomatic and asymptomatic Leydig cell failure. This results in increases in lean body mass, bone mineral density, hemoglobin, libido, strength, and sense of well-being and decreases in total and high-density lipoprotein cholesterol and markers of bone resorption.
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About 15% of married couples are unable to produce off spring. Male factors are responsible in about 30% of cases, female factors in about 45%, and couple factors in 25%.
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Etiology and Pathophysiology
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In order for conception to occur, spermatogenesis must be normal, the sperm must complete its maturation during transport through patent ducts, adequate amounts of seminal plasma must be added to provide volume and nutritional elements, and the male must be able to deposit the semen near the female's cervix. Any defect in this pathway can result in infertility due to a male factor problem. The spermatozoa must also be able to penetrate the cervical mucus and reach the uterine tubes, where conception takes place. These latter events may fail to occur if there are female reproductive tract disorders or abnormalities of sperm motility or fertilizing capacity.
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Table 12–4 lists the identified causes of male infertility. Disturbances in the function of the hypothalamus, pituitary, adrenals, or thyroid are found in approximately 4% of males evaluated for infertility. Sex chromosome abnormalities, cryptorchidism, adult seminiferous tubule failure, and other forms of primary testicular failure are found in 15% of infertile males. Congenital or acquired ductal problems are found in approximately 6% of such patients, and poor coital technique, sexual dysfunction, ejaculatory disturbances, and anatomic abnormalities such as hypospadias are causative factors in 4% to 5% of patients evaluated for infertility. Idiopathic infertility, in which no cause can be identified with certainty, accounts for approximately 35% of patients. Some of these patients may have mild forms of androgen receptor defects, microdeletions of the Y chromosome, or mutations in the cystic fibrosis gene. Autoimmune disturbances that lead to sperm agglutination and immobilization causes infertility in only a small fraction of patients. Varicoceles are found in 25% to 40% of patients classified as having idiopathic infertility, and experimental studies have shown an adverse effect of varicoceles on spermatogenesis. However, it is unclear why some individuals appear to be more susceptible to testicular problems from varicoceles, as the presence of a varicocele is not uniformly associated with infertility and they are found in 8% to 20% of healthy males in the general population.
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The clinical features of the hypothalamic-pituitary, thyroid, adrenal, testicular, and sexual dysfunctional disorders have been discussed in preceding sections of this chapter. Evaluation for the presence of varicocele has also been described.
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Patients with immotile cilia syndrome have associated mucociliary transport defects in the lower airways that result in chronic pulmonary obstructive disease. Some patients with this disorder also have Kartagener syndrome, with sinusitis, bronchiectasis, and situs inversus. Infections of the epididymis or vas deferens may be asymptomatic or associated with scrotal pain that may radiate to the flank, fever, epididymal swelling and tenderness, and urethral discharge. The presence of thickened, enlarged epididymis and vas is indicative of chronic epididymitis. Chronic prostatitis is usually asymptomatic, although a perineal aching sensation or low back pain may be described. A boggy or indurated prostate may be found on rectal palpation. A careful examination for the presence of penile anatomic abnormalities such as chordee, hypospadias, or epispadias should be made, because these defects may prevent the deposit of sperm in the vagina.
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A carefully collected and performed semen analysis is mandatory. A normal report indicates normal endocrine function and spermatogenesis and an intact transport system. Sperm function can be further evaluated through sperm penetration assays, the inducibility of the acrosome reaction, and motility evaluation on a postcoital test. Immunologic infertility can be examined with a mixed antiglobulin reaction test for antisperm antibodies.
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If semen analysis shows abnormalities, at least two more specimens should be obtained at monthly intervals. Persistent oligospermia or azoospermia should be evaluated by studies outlined in Figure 12–6. Patients with severe oligospermia or azoospermia should undergo chromosome analysis and testing for Yq microdeletions. If congenital absence of the vas deferens is present, testing for cystic fibrosis transmembrane conductance regulator gene mutations should be performed.
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The female partner should be thoroughly examined to verify patency of the uterus and uterine tubes, normal ovulation, and normal cervical mucus. This examination must be performed even in the presence of a male factor abnormality, because infertility is due to a combination of male and female factors in about 20% of cases.
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In patients with azoospermia or severe oligospermia, transscrotal ultrasound allows an assessment of the seminal vesicles and ejaculatory ducts. Patency of the ducts can be examined with scrotal vasography or seminovesiculography.
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Correction of hyperthyroidism, hypothyroidism, adrenal insufficiency, and congenital adrenal hyperplasia generally restores fertility. Patients with hypogonadotropic hypogonadism may have spermatogenesis initiated with gonadotropin therapy. Chorionic gonadotropin (2000 units intramuscularly three times per week) with urofollitropin or follitropin beta (75 units intramuscularly three times per week) added after 12 to 18 months if sperm cells do not appear in the ejaculate, restores spermatogenesis in most hypogonadotropic men. The sperm count following such therapy usually does not exceed 10 million/mL but may still allow impregnation. Patients with isolated deficiency of LH may respond to chorionic gonadotropin alone. There is no effective therapy for adult seminiferous tubule failure not associated with varicocele or cryptorchidism. However, if the oligospermia is mild (10-20 million/mL), cup insemination of the female partner with concentrates of semen may be tried. In vitro fertilization (IVF) and other assisted reproductive techniques, including direct injection of a spermatozoon into an egg (intracytoplasmic sperm injection; ICSI), are increasingly being utilized as a method for achieving pregnancy in couples in which the male is oligospermic.
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Defects of Spermatogenesis
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There is no treatment for immotile cilia syndrome or for chromosomal abnormalities associated with defective spermatogenesis. Drugs that interfere with spermatogenesis should be discontinued. These include the antimetabolites, phenytoin, marijuana, alcohol, monoamine oxidase inhibitors, sulfasalazine, and nitrofurantoin. Discontinuing use of these agents may be accompanied by restoration of normal sperm production. In some patients with maturation arrest, severe hypospermatogenesis or incomplete Sertoli cell only, retrieval of sperm through testicular aspiration or testicular biopsy followed by IVF or ICSI have resulted in pregnancies.
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Localized obstruction of the vas deferens may be treated by vasovasostomy. Sperm are detected in the ejaculate of 60% to 80% of patients following this procedure. However, the subsequent fertility rate is only 40% to 50%; the presence of antisperm antibodies that agglutinate or immobilize sperms probably accounts for the high failure rate.
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Epididymovasostomy may be performed for epididymal obstruction. Sperm in the postoperative ejaculate have been found in approximately half of patients treated with this procedure, but subsequent fertility has been demonstrated in only 20% of cases.
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Genital Tract Infections
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Acute prostatitis may be treated with daily sitz baths, prostatic massage, and antibiotics. A combination of trimethoprim (400 mg) and sulfamethoxazole (2000 mg), twice a day for 10 days followed by the same dosage once a day for another 20 days, has been used with some success. Chronic prostatitis requires a longer period of treatment or a switch to a fluoroquinolone, such as ciprofloxacin 500 mg orally twice daily for 4 weeks. Acute epididymitis may respond to injections of local anesthetic into the spermatic cord just above the testicle. Appropriate antibiotic therapy should also be given. The prognosis for fertility following severe bilateral chronic epididymitis or extensive scarring from acute epididymitis is poor.
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The presence of varicocele in an infertile male with oligospermia is considered an indication for surgical ligation of the incompetent spermatic veins or radiographic embolization of the veins. Improvement in the semen is noted in 60% to 80% of treated patients, and about half are subsequently fertile.
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Retrograde Ejaculation
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Ejaculation of semen into the urinary bladder may occur following disruption of the internal bladder sphincter or with neuropathic disorders such as diabetic autonomic neuropathy. Normal ejaculation has been restored in a few patients with the latter problem following administration of phenylpropanolamine, 15 mg orally twice daily in timed-release capsules. Sperm can also be recovered from the bladder following masturbation for the purpose of direct insemination of the female partner.
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Antibodies to Sperm or Seminal Plasma
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Antibodies in the female genital tract that agglutinate or immobilize sperm may be difficult to treat. Older methods such as condom therapy or administration of glucocorticoids have not been uniformly successful. Currently, intrauterine insemination with washed spermatozoa, IVF, and gamete intrafallopian transfer are considered the most effective treatments.
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Anatomic Defects of the Penis
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Patients with hypospadias, epispadias, or severe chordee may collect semen by masturbation for use in insemination.
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Poor Coital Technique
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Couples should be counseled not to use vaginal lubricants or postcoital douches. In order to maximize the sperm count in cases of borderline oligospermia, intercourse should not be more frequent than every other day. Exposure of the cervix to the seminal plasma is increased by having the woman lie supine with her knees bent up for 20 minutes after intercourse.
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The prognosis for fertility depends on the underlying cause. It is good for patients with nontesticular endocrine abnormalities, varicoceles, retrograde ejaculation, and anatomic defects of the penis. If fertility cannot be restored, the couple should be counseled regarding intrauterine insemination with concentrated sperm, artificial insemination, IVF, ICSI, or adoption.
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Erectile dysfunction is the inability to achieve or maintain an erection of sufficient duration and firmness to complete satisfactory sexual activity in more than 25% of attempts. It may occur with or without associated disturbances of libido or ejaculation. Approximately 5% of men have complete erectile dysfunction by age 40 and 15% by age 70. Some degree of erectile dysfunction is present in about 50% of men between ages 40 and 70.
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Etiology and Pathophysiology
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Penile erection occurs when blood flow to the penile erectile tissue (corpora cavernosa and spongiosum) increases as a result of dilation of the urethral artery, the artery of the bulb of the penis, the deep artery of the penis, and the dorsal artery of the penis following psychogenic or sensory stimuli transmitted to the limbic system and then to the thoracolumbar and sacral autonomic nervous system. The relaxation of the cavernosal arterial and cavernosal trabecular sinusoidal smooth muscle occurs following stimulation of the sacral parasympathetic (S2-4) nerves, which results in the release of acetylcholine, vasoactive intestinal peptide, and an endothelial cell-derived nitric oxide, which activates guanylyl cyclase. As the sinusoids become engorged, the subtunical venous plexus is compressed against the tunica albuginea, preventing egress of blood from the penis. Contraction of the bulbocavernosus muscle through stimulation of the somatic portion of the S2 to S4 pudendal nerves further increases the intracavernosal pressure. These processes result in the distention, engorgement, and rigidity of the penis that constitute erection.
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Broadly speaking, erectile dysfunction may be divided into psychogenic and organic causes. Major epidemiologic factors that have been associated with erectile dysfunction include diabetes, hypertension, depression, smoking, aging, low high-density lipoprotein cholesterol, metabolic syndrome, cardiovascular disease, lower urinary tract symptoms of benign prostatic hyperplasia, and a low serum DHEA sulfate level. Table 12–5 lists various pathologic conditions and drugs that may be associated with erectile dysfunction.
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Most organic causes of erectile dysfunction result from disturbances in the neurologic pathways essential for the initiation and maintenance of erection or in the blood supply to the penis. Many of the endocrine disorders, systemic illnesses, and drugs associated with erectile dysfunction affect libido, the autonomic pathways essential for erection, or the blood flow to the penis. Venous incompetence because of anatomic defects in the corpora cavernosa or subtunical venous plexus is being recognized with increasing frequency. Local urogenital disorders such as Peyronie disease (idiopathic fibrosis of the covering sheath of the corpus cavernosum) may mechanically interfere with erection. In some patients, the cause of erectile dysfunction is multifactorial. For example, some degree of erectile dysfunction is reported by over 50% of men with diabetes mellitus. The basis of the erectile dysfunction is usually autonomic neuropathy. However, vascular insufficiency, antihypertensive medication, uremia, and depression may also cause or contribute to the problem in diabetics.
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Patients may complain of constant or episodic inability to initiate or maintain an erection, decreased penile turgidity, decreased libido, or a combination of these difficulties. The degree of erectile dysfunction can be assessed by questionnaires such as the International Index of Erectile Function or the Sexual Health Inventory for men. Besides the specific sexual dysfunction symptoms, symptoms and signs of a more pervasive emotional or psychiatric problem may be elicited. If an underlying neurologic, vascular, or systemic disorder is the cause of erectile dysfunction, additional symptoms and signs referable to the anatomic or metabolic disturbances may be present. A history of claudication of the buttocks or lower extremities should direct attention toward arterial insufficiency. Lower urinary tract disorders may be screened for through the use of the International Prostate Symptom Score questionnaire. A thorough history of medication, herb, illicit drug and alcohol use should be obtained.
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The differentiation between psychogenic and organic erectile dysfunction can usually be made on the basis of the history. Even though the patient may be selectively unable to obtain or maintain a satisfactory erection to complete sexual intercourse, a history of repeated normal erections at other times is indicative of psychogenic erectile dysfunction. Thus, a history of erections that occur nocturnally, during masturbation, or during foreplay or with other sexual partners eliminates significant neurologic, vascular, or endocrine causes of erectile dysfunction. Patients with psychogenic erectile dysfunction often note a sudden onset of sexual dysfunction concurrently with a significant event in their lives such as loss of a friend or relative, an extramarital affair, or the loss of a job.
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Patients with organic erectile dysfunction generally note a more gradual and global loss of potency. Initially, such individuals may be able to achieve erections with strong sexual stimuli, but ultimately they may be unable to achieve a fully turgid erection under any circumstances. In contrast to patients with psychogenic erectile dysfunction, patients with organic erectile dysfunction generally maintain a normal libido. However, patients with systemic illness may have a concurrent diminution of libido and potency. Hypogonadism should be suspected in a patient who has never had an erection (primary erectile dysfunction).
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During the physical examination, the patient's secondary sexual characteristics should be assessed and examination performed for gynecomastia, discordant or diminished femoral pulses, reduced testicular volume or consistency, penile plaques, and evidence of peripheral or autonomic neuropathy. The bulbocavernosus reflex tests the integrity of the S2 to S4 nerves. It is performed by inserting a finger into the patient's rectum while squeezing his glans penis. Contraction of the anal musculature represents a normal response.
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Laboratory Findings and Special Examinations
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Serum testosterone measurements may uncover a mild and otherwise asymptomatic androgen deficiency. If the testosterone level is low, serum PRL should be measured because hyperprolactinemia—whether drug-induced or due to a pituitary or hypothalamic lesion—may inhibit androgen production. Diabetes mellitus is a relatively common cause of erectile dysfunction and erectile dysfunction may be the presenting symptom of diabetes; therefore, fasting and 2-hour postprandial blood glucose measurements should be ordered.
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In a patient with a normal physical examination and screening blood tests, many clinicians elect to begin with a therapeutic trial of a type 5 phosphodiesterase (PDE5) inhibitor that potentiates the effects of nitric oxide by inhibiting the breakdown of cyclic guanosine monophosphate. The initial oral dose is usually 50 mg of sildenafil (Viagra), 10 mg of tadalafil (Cialis), or 10 mg vardenafil (Levitra). This should be tried only if the patient is not taking nitrates, has not had a myocardial infarction in the last 6 months, and does not have unstable angina, hypotension, severe congestive heart failure, or retinitis pigmentosa.
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The integrity of the neurologic pathways and the ability of the blood vessels to deliver a sufficient amount of blood to the penis for erection to occur may be objectively examined by placement of a strain gauge behind the glans penis and at the base of the penis at the time the patient retires for sleep. The occurrence of nocturnal penile tumescence can thus be recorded. Healthy men and those with psychogenic erectile dysfunction have three to five erections a night associated with rapid eye movement sleep. Absence or reduced frequency of nocturnal tumescence indicates an organic lesion. Penile rigidity as well as tumescence can be evaluated with an ambulatory monitor called RigiScan. The vascular integrity of the penis may be examined by Doppler ultrasonography with spectral analysis following intracorporeal injection of a vasoactive drug. This method allows detection of venous leaks with a sensitivity of 55% to 100% and specificity of 69% to 88%. Arterial problems are also detected with a sensitivity of 82% to 100% and specificity of 64% to 96%. The choice of other laboratory tests such as cavernosometry, cavernosography, or arteriography depends on associated organic symptoms or signs.
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Discontinuation of an offending drug usually results in a return of potency. Similarly, effective therapy of an underlying systemic or endocrine disorder may cure the erectile dysfunction. For psychogenic erectile dysfunction, simple reassurance and explanation, formal psychotherapy, and various forms of behavioral therapy have a reported 40% to 70% success rate. Sildenafil, 25 to 100 mg taken orally about 1 hour before anticipated intercourse is approximately 70% to 80% effective in patients with a wide variety of causes of erectile dysfunction, including psychogenic ones. This agent is absolutely contraindicated in men receiving oral or transdermal nitrates for vascular disease. Side effects include headache (16%) and visual disturbances (3%). Other PDE5 inhibitors that are available include vardenafil (2.5-20 mg) and tadalafil (2.5-20 mg).
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Vasoactive drugs including prostaglandin E1, papaverine hydrochloride, and phentolamine mesylate, either alone or in combination, may induce an erection following intracavernous injection. Of these, the only Food and Drug Administration-approved agent is prostaglandin E1 (alprostadil), which needs to be individualized within the dosage range of 2.5 to 60 μg per injection. In clinical studies, up to 90% of men with erectile dysfunction developed erections with intracavernosal injections. Side effects include penile pain (33% of patients), hematoma (3%), penile fibrosis (3%), and priapism (0.4%). Intraurethral insertion of a 1.4-mm pellet containing alprostadil leads to satisfactory erections in two-thirds of patients, with effects beginning within 10 minutes and lasting 30-60 minutes. The major side effects are penile pain (36%), urethral pain (13%), and dizziness (4%).
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Devices have been developed that use suction to induce penile engorgement and constrictive bands to maintain the ensuing erection. Erections are achieved in 90% of patients with an approximately 70% couple satisfaction rate. Alternatively, a surgically implanted semirigid or inflatable penile prosthesis provides satisfactory results in 85% to 90% of cases, but the device must be replaced every 5 to 10 years.
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Repair of venous leaks and microsurgical revascularization of arterial lesions have had variable success rates. Patients with permanent erectile dysfunction due to organic lesions that cannot be corrected should be counseled in noncoital sensate focus techniques.
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Gynecomastia is common during the neonatal period and is present in about 70% of pubertal males (Chapter 15). Clinically apparent gynecomastia has been noted at autopsy in almost 1% of adult males, and 40% of autopsied males have histologic evidence of gynecomastia.
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Etiology and Pathophysiology
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The causes of gynecomastia are listed in Table 12–6. Several mechanisms have been proposed to account for this disorder. All involve a relative imbalance between estrogen and androgen concentrations or action at the mammary gland level. Decrease in free testosterone may be due to primary gonadal disease or an increase in SHBG as is found in hyperthyroidism and some forms of liver disease (eg, alcoholic cirrhosis). Decreased androgen action in patients with the androgen insensitivity syndromes results in unopposed estrogen action on the breast glandular tissue. Acute or chronic excessive stimulation of the Leydig cells by pituitary gonadotropins alters the steroidogenic pathways and favors excessive estrogen and estrogen precursor secretion relative to testosterone production. This mechanism may be responsible for the gynecomastia found with hypergonadotropic states such as Klinefelter syndrome and adult Leydig cell failure. The rise of gonadotropins during puberty may lead to an estrogen-androgen imbalance by similar mechanisms. Patients who are malnourished or have systemic illness may develop gynecomastia during refeeding or treatment of the underlying disorder. Malnourishment and chronic illness are accompanied by a reduction in gonadotropin secretion, and during recovery the gonadotropins rise and may stimulate excessive Leydig cell production of estrogens relative to testosterone.
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Excessive stimulation of Leydig cells may also occur in patients with hCG-producing trophoblastic or nontrophoblastic tumors. In addition, some of these tumors are able to convert estrogen precursors into estradiol. Feminizing adrenocortical and Leydig cell neoplasms may directly secrete excessive quantities of estrogens. The mechanisms by which PRL-secreting pituitary tumors and hyperprolactinemia produce gynecomastia are unclear. Elevated serum PRL levels may lower testosterone production and diminish the peripheral actions of testosterone, which may result in an excessive estrogen effect on the breast that is not counteracted by androgens.
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Drugs may reduce androgen production (eg, spironolactone, ketoconazole), peripherally antagonize androgen action (spironolactone, cimetidine), or interact with breast estrogen receptors (spironolactone and phytoestrogens in marijuana).
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Finally, it has been proposed that patients with idiopathic and familial gynecomastia have breast glandular tissue that is inordinately sensitive to normal circulating levels of estrogen or excessively converts estrogen precursors to estrogens.
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Three histologic patterns of gynecomastia have been recognized. The florid pattern consists of an increase in the number of budding ducts, proliferation of the ductal epithelium, periductal edema, and a cellular fibroblastic stroma. The fibrous type has dilated ducts, minimal duct epithelial proliferation, no periductal edema, and a virtually acellular fibrous stroma. An intermediate pattern contains features of both types.
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Although it has been proposed that different causes of gynecomastia are associated with either the florid or the fibrous pattern, it appears that the duration of gynecomastia is the most important factor in determining the pathologic picture. Approximately 75% of patients with gynecomastia of 4 months' duration or less exhibit the florid pattern, whereas 90% of patients with gynecomastia lasting a year or more have the fibrous type. Between 4 months and 1 year, 60% of patients have the intermediate pattern.
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The principal complaint is unilateral or bilateral concentric enlargement of breast glandular tissue. Nipple or breast pain is present in one-fourth of patients and objective tenderness in about 40%. A complaint of nipple discharge can be elicited in 4% of cases. Histologic examination has demonstrated that gynecomastia is almost always bilateral, although grossly it may be detected only on one side. The patient often complains of discomfort in one breast despite obvious bilateral gynecomastia. Breast or nipple discomfort generally lasts less than 1 year. Chronic gynecomastia is usually asymptomatic, with the major complaint being the cosmetic one. Symptoms and signs of underlying disorders may be present. Gynecomastia may be the earliest manifestation of an hCG-secreting testicular tumor; therefore, it is mandatory that careful examination of the testes be performed in any patient with gynecomastia. Enlargement, asymmetry, and induration of a testis may be noted in such patients.
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Once pubertal and drug-induced gynecomastia have been excluded, a biochemical screen for liver and renal abnormalities should be performed. If those are normal and the gynecomastia is of recent onset, then serum hCG, LH, testosterone, and estradiol levels should be measured. The interpretation of the results is outlined in Figure 12–8. For chronic, asymptomatic gynecomastia detected on physical examination, measurement of a morning serum testosterone level is a reasonable screen for hypogonadism.
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Differential Diagnosis
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Gynecomastia should be differentiated from lipomas, neurofibromas, carcinoma of the breast, and obesity. Breast lipomas, neurofibromas, and carcinoma are usually unilateral, painless, and eccentric, whereas gynecomastia characteristically begins in the subareolar areas and enlarges concentrically. The differentiation between gynecomastia and enlarged breasts due to obesity may be difficult. The patient should be supine. Examination is performed by spreading the thumb and index fingers and gently palpating the breasts during slow apposition of the fingers toward the nipple. In this manner, a concentric ridge of tissue can be felt in patients with gynecomastia but not in obese patients without glandular tissue enlargement. The examination may be facilitated by applying soap and water to the breasts.
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Complications and Sequelae
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There are no complications other than possible psychologic damage from the cosmetic defect. With the possible exclusion of patients with Klinefelter syndrome, individuals with gynecomastia do not have an increased risk of development of breast carcinoma.
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The underlying disease should be corrected if possible, and offending drugs should be discontinued. Antiestrogens or selective estrogen receptor modulators, such as tamoxifen or raloxifene, have been found useful in relieving pain and reversing gynecomastia in some patients. Whether these therapies will be useful in most patients with gynecomastia remains to be seen. Aromatase inhibitors have also been tried but are not as beneficial as tamoxifen. Tamoxifen is also useful in preventing development of gynecomastia in many patients who are starting therapy for prostate cancer with antiandrogens.
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Reduction mammoplasty should be considered for cosmetic reasons in any patient with long-standing gynecomastia that is in the fibrotic stage.
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Patients with prostatic carcinoma may receive low-dose radiation therapy (900 cGy or less) to the breasts before initiation of antiandrogen monotherapy for prostate cancer. This may prevent or diminish the gynecomastia that usually results from such therapy, although tamoxifen is more effective. Radiotherapy should not be given to other patients with gynecomastia.
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Pubertal gynecomastia usually regresses spontaneously over 1 to 2 years. Patients who develop drug-induced gynecomastia generally have complete or near-complete regression of the breast changes if the drug is discontinued during the early florid stage. Once gynecomastia from any cause has reached the fibrotic stage, little or no spontaneous regression occurs, and medical therapy is ineffective.
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Testicular neoplasms account for 1% to 2% of all male-specific malignant neoplasms and 4% to 10% of all genitourinary neoplasms. They are the most frequent type of cancer in men between 20 and 34 years of age. The incidence is 5.4 per 100,000 men in the United States and 4.6 to 7.3 per 100,000 men in Europe. The incidence is lower in nonwhite than in white populations. Ninety-five percent of testicular tumors are of germ cell origin; 5% are composed of stromal or Leydig cell neoplasms.
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Etiology and Pathophysiology
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The cause of germ cell testicular tumors is not known. Predisposing factors include testicular maldescent and dysgenesis. About 4% to 12% of testicular tumors are found in association with cryptorchidism, and such a testicle has a 20- to 30-fold greater risk of developing a neoplasm than does a normally descended one. Almost 20% of testicular tumors associated with cryptorchidism arise in the contralateral scrotal testis, suggesting that testicular dysgenesis may be of etiologic importance in the development of germ cell neoplasms. Although trauma is frequently cited as an etiologic factor in testicular tumors, no causal relationship has been established. What is more likely is that testicular trauma serves to call the patient's attention to the presence of a testicular mass. Familial predisposition is found in 1% to 2% of patients. An increased incidence has been noted in patients with Down and Klinefelter syndromes and prenatal exposure to exogenous estrogens. Increased risk also has been associated with smoking and possibly HIV infection. Extra copies of a portion of chromosome 12 (isochromosome 12p) have been found in testicular germ cell tumors.
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Bilateral gynecomastia is uncommon in patients who present with germ cell tumors. It is generally associated with production of hCG by the trophoblastic elements in the tumor. The hCG stimulates the Leydig cells to produce excessive estrogens relative to androgen production, resulting in estrogen-androgen imbalance and gynecomastia. In addition, the trophoblastic tissue in some of the germ cell tumors may convert estrogen precursors to estrogens, as can Leydig and Sertoli cell tumors.
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Seminomas account for 33% to 50% of all germ cell tumors. They are composed of round cells with abundant cytoplasm, prominent nuclei, and large nucleoli. The cells are arranged in cords and nests and have a thin delicate network of stromal connective tissue. Embryonal cell neoplasms comprise 20% to 33% of germ cell tumors. These tumors have multiple histologic patterns composed of cuboidal pleomorphic cells. One distinct pattern of cellular arrangement is the endodermal sinus tumor (yolk sac tumor), the most frequent germ cell neoplasm found in infants. Immunohistochemical techniques have localized alpha-fetoprotein to the embryonal cells. About 10% of germ cell tumors are teratomas, which are composed of well-differentiated cells derived from all three germ layers. When one or more of the teratoid elements are malignant or are mixed with embryonal carcinoma cells, the term teratocarcinoma is applied. These tumors account for one-tenth to one-third of germ cell neoplasms. Choriocarcinoma is the rarest form of germ cell tumor (2%) and is composed of masses of large, polymorphic, multinucleated syncytiotrophoblastic cells. Although pure choriocarcinoma is rare, many testicular tumors contain an occasional trophoblastic giant cell. Immunohistochemical techniques have shown that these cells are the source of hCG in such tumors.
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Leydig and Sertoli Cell Tumors
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Leydig cell (interstitial cell) tumors are rare. Most are benign and are composed of sheets of oval to polygonal cells arranged in lobules separated from one another by thin strands of connective tissue. Malignant Leydig cell tumor disseminates by both lymphatic and venous channels, with initial metastatic deposits being found in the regional lymph nodes, followed by metastases to liver, lung, and bone. Sertoli cell tumors also are rare, are generally benign, and are composed of large tubules, a thick basement membrane with enlarged cuboidal Sertoli cells. There may be extensive calcification within the tumors and the tumors may be multifocal and bilateral.
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Germ cell tumors—Testicular tumors usually present as painless enlargement of a testicle with an associated feeling of fullness or heaviness in the scrotum. Thus, about 80% of patients note a testicular swelling or mass, whereas only 25% complain of testicular pain or tenderness. About 6% to 25% of patients give a history of testicular trauma that brought the testicular mass to their attention. Gynecomastia may be present initially in 2% to 4% of patients and develops subsequently in another 10%. About 5% to 10% of patients present with symptoms of distant metastatic disease, including backache, skeletal pains, gastrointestinal symptoms and abdominal pains, inguinal adenopathy, cough, hemoptysis, and neurological dysfunction.
A testicular mass or generalized enlargement of the testis is often present on examination. In 5% to 10% of patients, a coexisting hydrocele may be present. In the presence of metastatic disease, supraclavicular and retroperitoneal lymph node enlargement may be present.
Leydig and Sertoli cell tumors—In children, Leydig cell tumors of the testes may produce sexual precocity, with rapid skeletal growth and development of secondary sexual characteristics. Adults with such tumors usually present with a testicular mass and occasionally gynecomastia. Decreased libido may also be present in such patients. Sertoli cell tumors are associated with gynecomastia and feminization due to excessive aromatase activity. In addition, these tumors are associated with the autosomal dominant Peutz-Jeghers syndrome (gastrointestinal polyposis and oval, irregularly pigmented lip macules) and the Carney complex (cardiac myxomas, spotty cutaneous pigmentation, primary pigmented nodular adrenocortical disease with hypercortisolism).
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Germ cell tumors—The tumor markers hCG, alpha-fetoprotein, and lactate dehydrogenase (LDH) should be measured in every male presenting with a testicular mass. hCG is found in the sera of 5% to 10% of males with seminoma, over half of patients with teratocarcinoma or embryonal cell carcinoma, and all patients with choriocarcinoma. hCG should be measured as the beta subunit or other hCG-specific immunoassay method. Elevated serum immunoreactive alpha-fetoprotein concentrations are found in almost 70% of patients with nonseminomatous forms of germ cell neoplasms. Both markers are elevated in over 50% of patients with nonseminomatous germ cell tumors, and at least one of the markers is elevated in 85% of such patients. These markers can also be used to monitor the results of therapy. LDH measurements have an independent prognostic significance and reflect tumor growth rate and cellular proliferation. It is increased in about 80% of patients with advanced seminomas and 60% of advanced nonseminomatous tumors. The results of the three marker measurements are included in the formal staging classification from the American Joint Committee on Cancer.
Leydig and Sertoli cell tumors—Serum DHEA sulfate, urinary 17-ketosteroid, and both urinary and serum estrogen levels may be increased, while serum testosterone concentrations tend to be low or within the normal adult range in patients with Leydig cell tumors. Individuals with Sertoli cell tumors have elevated estradiol levels.
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Testicular ultrasonography may be required to visualize small tumors. Staging of testicular tumors requires chest and abdominal CT scans and other radiologic procedures depending on the type of tumor and the symptoms.
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Differential Diagnosis
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Testicular tumors are sometimes misdiagnosed as epididymitis or epididymo-orchitis. An inflammatory reaction of the epididymis often involves the vas deferens. Therefore, both the vas and the epididymis are thickened and tender on examination during the acute disease. Pyuria and fever also help to differentiate between epididymitis and testicular tumor. Because hydrocele may coexist with testicular tumor, the testes should be carefully examined following aspiration of the hydrocele.
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Other conditions that can cause confusion with testicular tumors include inguinal hernia, hematocele, hematoma, torsion, spermatocele, varicocele, and (rarely) sarcoidosis, tuberculosis, and syphilitic gumma. Ultrasonic examination of the scrotum may help distinguish between testicular tumors and extratesticular disease such as acute or chronic epididymitis, spermatocele, or hydrocele.
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Benign Leydig cell tumors of the testes must be differentiated from adrenal rest tumors in patients with congenital adrenal hyperplasia. Because the testes and the adrenals are derived from the same embryologic source, ectopic adrenal tissue may be found to migrate with the testes. This tissue can enlarge under the influence of ACTH in patients with congenital adrenal hyperplasia or Cushing disease. Adrenal rest tumors tend to be bilateral, whereas patients with Leydig cell tumors generally have unilateral disease. Both may be associated with elevated urine 17-ketosteroids and elevated serum DHEA sulfate concentrations. Elevated serum and urinary estrogen concentrations are found with both disorders. However, patients with congenital adrenal hyperplasia or Cushing disease have a decrease in 17-ketosteroids, DHEA sulfate, and estrogen concentrations, as well as a decrease in tumor size, following administration of dexamethasone, while those with Leydig cell tumors do not.
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Seminomas are quite radiosensitive, and disease localized to the testes is usually treated with radical inguinal orchiectomy and 2000 to 4000 cGy of conventional radiotherapy delivered to the ipsilateral inguinal-iliac and bilateral para-aortic lymph nodes to the level of the diaphragm. For disease that has spread to the lymph nodes below the diaphragm, additional whole abdominal radiotherapy and prophylactic mediastinal and supraclavicular lymph node irradiation are usually given. Widely disseminated disease is generally treated with a combination of radiotherapy and chemotherapy, especially with bleomycin, etoposide, and cisplatin.
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Nonseminomatous tumors are treated with orchiectomy, retroperitoneal lymph node dissection, and, if necessary, radiotherapy or chemotherapy (or both). Although many chemotherapeutic agents have been used, combinations of etoposide, bleomycin, and cisplatin currently appear to produce the best overall results. Patients with nonseminomatous tumors treated by these means should be monitored with serial measurements of serum hCG and alpha-fetoprotein.
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Leydig and Sertoli Cell Tumors
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Leydig and Sertoli cell tumors of the testes are treated by unilateral radical inguinal orchiectomy. Objective remissions of malignant Leydig cell tumors have been noted following treatment with mitotane.
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In patients with seminoma confined to the testicle, the 5-year survival rates after orchiectomy and radiotherapy are 98% to 100%. Disease in the lymph nodes below the diaphragm also has an excellent prognosis, with 5-year survival rates of 80% to 85%. Disease above the diaphragm and disseminated disease have overall 5-year survival rates of about 70%.
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In patients with nonseminomatous germ cell tumors, aggressive surgery and combination chemotherapy have raised the 5-year survival rates from less than 20% to 60% to 90%.
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Leydig and Sertoli Cell Tumors
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Removal of a benign Leydig or Sertoli cell tumor is accompanied by regression of iso- or heterosexual precocious puberty in children or feminization in adults. The prognosis for malignant Leydig cell tumor is poor, with most patients surviving less than 2 years from the time of diagnosis.