Glenn D. Braunstein MD
The testes contain two major components which are structurally separate and serve different functions. The Leydig cells, or interstitial cells, comprise the major endocrine component. The primary secretory product of these cells, testosterone, is responsible either directly or indirectly for embryonic differentiation along male lines of the external and internal genitalia, male secondary sexual development at puberty, and maintenance of libido and potency in the adult male. The seminiferous tubules comprise the bulk of the testes and are responsible for the production of approximately 30 million spermatozoa per day during male reproductive life (puberty to death).
Both of these testicular components are interrelated, and both require an intact hypothalamic-pituitary axis for initiation and maintenance of their function. In addition, several accessory genital structures are required for the functional maturation and transport of spermatozoa. Thus, disorders of the testes, hypothalamus, pituitary, or accessory structures may result in abnormalities of androgen or gamete production, infertility, or a combination of these problems.
ANATOMY & STRUCTURE-FUNCTION RELATIONSHIPS (Figure 12-1)
The adult testis is a prolate spheroid with a mean volume of 18.6 ą 4.8 mL. The average length is 4.6 cm (range, 3.6–5.5 cm), and the average width is 2.6 cm (range, 2.1–3.2 cm). The testes are located within the scrotum, which not only serves as a protective envelope but also helps to maintain the testicular temperature approximately 2°C (3.6°F) below abdominal temperature. Three layers of membranes—visceral tunica vaginalis, tunica albuginea, and tunica vasculosa—comprise the testicular capsule. Extensions of the tunica albuginea into the testicle as fibrous septa result in the formation of approximately 250 pyramidal lobules each of which contains coiled seminiferous tubules. Within each testis there are almost 200 m of seminiferous tubules, and these structures account for 80–90% of the testicular mass. The approximately 350 million androgen-producing Leydig cells, as well as the blood and lymphatic vessels, nerves, and fibroblasts, are interspersed between the seminiferous tubules.
The blood supply to the testes is derived chiefly from the testicular arteries, which are branches of the internal spermatic arteries. After traversing a complicated capillary network, blood enters multiple testicular veins that form an anastomotic network, the pampiniform plexus. The pampiniform plexuses coalesce to form the internal spermatic veins. The right spermatic vein drains directly into the vena cava; the left enters the renal vein.
The seminiferous tubules in the adult average 165 ľm in diameter and are composed of Sertoli cells and germinal cells. The Sertoli cells line the basement membrane and form tight junctions with other Sertoli cells. These tight junctions prevent the passage of proteins from the interstitial space into the lumens of the seminiferous tubules, thus establishing a “blood-testis barrier.” Through extension of cytoplasmic processes, the
Sertoli cells surround developing germ cells and provide an environment essential for germ cell differentiation. In addition, these cells have been shown to be responsible for the movement of germ cells from the base of the tubule toward the lumen and for the release of mature sperm into the lumen. These cells also actively phagocytose damaged germ cells and residual bodies, which are portions of the germ cell cytoplasm not used in the formation of spermatozoa. Finally, in response to follicle-stimulating hormone (FSH) or testosterone, the Sertoli cells secrete androgen-binding protein, a molecule with high affinity for androgens. This substance, which enters the tubular lumen, provides a high concentration of testosterone to the developing germinal cells during the process of spermatogenesis.
Figure 12-1. Male genital system. A: The testis and the epididymis are in different scales from the other parts of the reproductive system. Observe the communication between the testicular lobules. B: Structural organization of the human seminiferous tubule and interstitial tissue. This figure does not show the lymphatic vessels frequently found in the connective tissue. (A and B reproduced, with permission, from Junqueira LC, Carneiro J, Kelley RO: Basic Histology, 9th ed. McGraw-Hill, 1999.) C: Section of human testis. (Creproduced, with permission, from Ganong WF: Review of Medical Physiology, 20th ed. McGraw-Hill, 2001.)
More than a dozen different types of germ cells have been described in males. Broadly, they can be classified as spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids, and spermatozoa. Spermatogenesis occurs in an orderly fashion, with the spermatocytes being derived from the spermatogonia via mitotic division. Through meiotic (or reduction) division, the spermatids are formed; they contain a haploid number of chromosomes (23). The interval from the beginning of spermatogenesis to release of mature spermatozoa into the tubular lumen is approximately 74 days. Although there is little variation in the duration of the spermatogenic cycle, a cross section of a seminiferous tubule will demonstrate several stages of germ cell development.
The seminiferous tubules empty into a highly convoluted anastomotic network of ducts called the rete testis. Spermatozoa are then transported through efferent ductules and into a single duct, the epididymis, by testicular fluid pressure, ciliary motion, and contraction of the efferent ductules. During the approximately 12 days required for transit through the epididymis, spermatozoa undergo morphologic and functional changes essential to confer upon the gametes the capacity for fertilizing an ovum. The epididymis also serves as a reservoir for sperm. Spermatozoa stored in the epididymis enter the vas deferens, a muscular duct 35–50 cm long that propels its contents by peristaltic motion into the ejaculatory duct.
In addition to the spermatozoa and the secretory products of the testes, retia testis, and epididymides, the ejaculatory ducts receive fluid from the seminal vesicles. These paired structures, 10–20 cm long, are composed of alveolar glands, connective tissue, and muscle. They are the source of seminal plasma fructose, which provides nourishment to the spermatozoa. In addition, the seminal vesicles secrete phosphorylcholine, ergothioneine, ascorbic acid, flavins, and prostaglandins. About 60% of the total volume of seminal fluid is derived from the seminal vesicles.
The ejaculatory ducts terminate in the prostatic urethra. There additional fluid (approximately 20% of total volume) is added by the prostate, a tubuloalveolar gland with a fibromuscular stroma that weighs about 20 g and measures 4 × 2 × 3 cm. The constituents of the prostate fluid include spermine, citric acid, cholesterol, phospholipids, fibrinolysin, fibrinogenase, zinc, acid phosphatase, and prostate-specific antigen, a 34-kDa kallikrein-like serine protease. Fluid is also added to the seminal plasma by the bulbourethral (Cowper) glands and urethral (Littre) glands during its transit through the penile urethra.
PHYSIOLOGY OF THE MALE REPRODUCTIVE SYSTEM
GONADAL STEROIDS (Figure 12-2)
The three steroids of primary importance in male reproductive function are testosterone, dihydrotestosterone, and estradiol. From a quantitative standpoint, the most important androgen is testosterone. Over 95% of the testosterone is secreted by the testicular Leydig cells. In addition to testosterone, the testes secrete small amounts of the potent androgen dihydrotestosterone and the weak androgens dehydroepiandrosterone (DHEA) and androstenedione. The Leydig cells also secrete small quantities of estradiol, estrone, pregnenolone, progesterone, 17α-hydroxypregnenolone, and 17α-hydroxyprogesterone. The steps in testicular androgen biosynthesis are illustrated inFigure 12-2.
Dihydrotestosterone and estradiol are derived not only by direct secretion from the testes but also by conversion in peripheral tissues of androgen and estrogen precursors secreted by both the testes and the adrenals. Thus, about 80% of the circulating concentrations of these two steroids is derived from such peripheral conversion. Table 12-1 summarizes the approximate contributions of the testes, adrenals, and peripheral tissues to the circulating levels of several sex steroid hormones in men.
In the blood, androgens and estrogens exist in either a free (unbound) state or bound to serum proteins. Although about 38% of testosterone is bound to albumin, the major binding protein is sex hormone-binding
globulin (SHBG), which binds 60% of the testosterone. This glycosylated dimeric protein is homologous to, yet distinct from, the androgen-binding protein secreted by the Sertoli cells. SHBG is synthesized in the liver, with the gene located on the short arm of chromosome 17. The serum concentrations of this protein are increased by estrogen, tamoxifen, phenytoin, or thyroid hormone administration and by hyperthyroidism and cirrhosis and are decreased by exogenous androgens, glucocorticoids, or growth hormone and by hypothyroidism, acromegaly, and obesity. About 2% of the circulating testosterone is not bound to serum proteins and is able to enter cells and exert its metabolic effects. In addition, some of the protein-bound testosterone may dissociate from the protein and enter target tissues; thus, the amount of bioavailable testosterone may be greater than just the amount of non-protein-bound testosterone.
Figure 12-2. Pathways for testicular androgen and estrogen biosynthesis. Heavy arrows indicate major pathways. Circled numbers represent enzymes as follows: ①, 20,22-desmolase (P450scc); ②, 3β-hydroxysteroid dehydrogenase and Δ5,Δ4-isomerase; ③, 17-hydroxylase (P-450c17); ④, 17,20-desmolase (P450c17); ⑤, 17-ketoreductase; symbol, 5α-reductase; symbol, aromatase. (See also Figures 9-4, 13-4, and 14-13.)
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Table 12-1. Relative contributions (approximate percentages) of the testes, adrenals, and peripheral tissues to circulating levels of sex steroids in men.
As noted below, testosterone may be converted to dihydrotestosterone within specific androgen target tissues. Most circulating testosterone is converted primarily by the liver into various metabolites such as androsterone and etiocholanolone, which, after conjugation with glucuronic or sulfuric acid, are excreted in the urine as 17-ketosteroids. However, it should be noted that only 20–30% of the urinary 17-ketosteroids are derived from testosterone metabolism. The majority of the 17-ketosteroids are formed from the metabolism of adrenal steroids. Therefore, 17-ketosteroid determinations do not reliably reflect testicular steroid secretion.
Testosterone leaves the circulation and rapidly traverses the cell membrane (Figure 12-3). In most androgen target cells, testosterone is enzymatically converted to the more potent androgen dihydrotestosterone by the microsomal isoenzyme 5α-reductase-2, which has a pH optimum of 5.5. Another isoenzyme, 5α-reductase-1, has a pH optimum near 8.0 and may involve androgen action in the skin, but it is not active in the urogenital tract. Dihydrotestosterone as well as testosterone then binds to the same specific intracellular receptor protein (Rcin Figure 12-3) that is distinct from both androgen-binding protein and SHBG. The genes that encode for this protein are located on the X chromosome. The androgen receptor, a phosphoprotein of about 110 kDa, is a member of the steroid-thyroid hormone nuclear superfamily. It is synthesized in the cytoplasm and is associated with several heat shock proteins. When testosterone or dihydrotestosterone binds to the carboxyl terminal androgen-binding portion of the receptor, the heat shock proteins dissociate and conformational changes in the receptor take place that allow it to be translocated into the nucleus (Rn in Figure 12-3). Some studies suggest that androgen binding to the receptor takes place only in the nucleus and not in the cytoplasm. In the nucleus, the androgen-androgen receptor complex binds to DNA through the DNA-binding domain of the receptor, which allows the polymorphic transactivating domain of the receptor to initiate transcriptional activity. This results in the synthesis of messenger RNA (mRNA), which is eventually transported
to the cytoplasm, where it directs new protein synthesis and other changes that together constitute androgen action.
Figure 12-3. Mechanisms of androgen action. (T, testosterone; DHT, dihydrotestosterone; Rn, activated nuclear receptor; mRNA, messenger RNA; Rc, inactive receptor.)
A variety of biologic effects of androgens have been defined in males. As discussed in Chapter 14, they are essential for appropriate differentiation of the internal and external male genital system during fetal development. During puberty, androgen-mediated growth of the scrotum, epididymis, vas deferens, seminal vesicles, prostate, and penis occurs. The functional integrity of these organs requires androgens. Androgens stimulate skeletal muscle growth and growth of the larynx, which results in deepening of the voice; and of the epiphysial cartilaginous plates, which results in the pubertal growth spurt. Both ambisexual (pubic and axillary) hair growth and sexual (beard, mustache, chest, abdomen, and back) hair growth are stimulated, as is sebaceous gland activity. Other effects include stimulation of erythropoiesis and social behavioral changes.
CONTROL OF TESTICULAR FUNCTION
Hypothalamic-Pituitary-Leydig Cell Axis (Figure 12-4)
The hypothalamus synthesizes a decapeptide, gonadotropin-releasing hormone (GnRH), and secretes it in pulses every 90–120 minutes into the hypothalamohypophysial portal blood. After reaching the anterior pituitary, GnRH binds to the gonadotrophs and stimulates the release of both luteinizing hormone (LH) and, to a lesser extent, FSH into the general circulation. LH is taken up by the Leydig cells, where it binds to specific membrane receptors. The LH receptor is a G protein-coupled receptor containing seven transmembrane domains with a serine and threonine-rich cytoplasmic region containing a phosphorylation site and a 350- to 400-amino-acid extracellular hormone-binding domain. The binding of LH to the receptor leads to activation of adenylyl cyclase and generation of cAMP and other messengers that ultimately result in the secretion of androgens. In turn, the elevation of androgens inhibits the secretion of LH from the anterior pituitary through a direct action on the pituitary and an inhibitory effect at the hypothalamic level. Both the hypothalamus and the pituitary have androgen and estrogen receptors. Experimentally, pure androgens such as dihydrotestosterone (DHT) reduce LH pulse frequency, while estradiol reduces LH pulse amplitude. However, the major inhibitory effect of androgen on the hypothalamus appears to be mediated principally by estradiol, which may be derived locally through the aromatization of testosterone. Leydig cells also secrete small quantities of oxytocin, renin, corticotropin-releasing factor, insulin-like growth factor I, transforming growth factors α and β, interleukin-1, lipotropin, β-endorphin, dynorphin, angiotensin, inhibin, gastrin-releasing peptide, stem cell factor, substance P, and prostaglandins, which may be important for paracrine regulation of testicular function.
Figure 12-4. Hypothalamic-pituitary-testicular axis. (GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; T, testosterone; DHT, dihydrotestosterone; ABP, androgen-binding protein; E2, estradiol; +, positive influence; -, negative influence.)
Hypothalamic-Pituitary-Seminiferous Tubular Axis (Figure 12-4)
After stimulation by GnRH, the gonadotrophs secrete FSH into the systemic circulation. This glycoprotein hormone binds to specific receptors in the Sertoli cells
and stimulates the production of androgen-binding protein. FSH is necessary for the initiation of spermatogenesis. However, full maturation of the spermatozoa appears to require not only an FSH effect but also testosterone. Indeed, the major action of FSH on spermatogenesis may be via the stimulation of androgen-binding protein production, which allows a high intratubular concentration of testosterone to be maintained.
In addition to androgen-binding protein, the Sertoli cell secretes several other substances including GnRH-like peptide, insulin-like growth factor-1, transferrin, plasminogen activator, ceruloplasmin, m˙llerian duct inhibitory factor, H-Y antigen, and inhibin. At least three genes have been found to direct inhibin synthesis. Two forms of inhibin have been identified, inhibin A and inhibin B. Both are 32-kDa proteins composed of the same alpha subunit cross-linked with different beta subunits, and each can selectively inhibit FSH release from the pituitary without affecting LH release. FSH directly stimulates the Sertoli cells to secrete inhibin. There is a reciprocal relationship between serum inhibin B and FSH levels, and inhibin B is therefore probably a physiologic regulator of pituitary FSH secretion, possibly together with the gonadal steroids. Inhibin levels decline with advancing age.
Two additional inhibin-related proteins that have been identified in porcine follicular fluid may also be present in the testes. These factors, designated follicle regulatory protein and activin, are composed of inhibin beta subunit dimers and can selectively stimulate pituitary FSH secretion in vitro. They are structurally similar to transforming growth factor β (TGFβ), which can also stimulate pituitary FSH release. The physiologic role, if any, that follicle regulatory protein, activin, and TGFβ have in the regulation of FSH secretion is unknown.
EVALUATION OF MALE GONADAL FUNCTION
The clinical presentation of patients with deficient testosterone production or action depends upon the age at onset of hypogonadism. Androgen deficiency during the second to third months of fetal development results in varying degrees of ambiguity of the genitalia and male pseudohermaphroditism. If the deficiency develops during the third trimester, defects in testicular descent leading to cryptorchidism as well as micropenis may occur. These topics are covered in Chapter 14 and 15.
Prepubertal androgen deficiency leads to poor secondary sexual development and eunuchoid skeletal proportions. The penis fails to enlarge, the testes remain small, and the scrotum does not develop the marked rugae characteristic of puberty. The voice remains high-pitched and the muscle mass does not develop fully, resulting in less than normal strength and endurance. The lack of appropriate stimulation of sexual hair growth results in sparse axillary and pubic hair (which receive some stimulation from adrenal androgens) and absent or very sparse facial, chest, upper abdominal, and back hair. Although the androgen-mediated pubertal growth spurt will fail to take place, the epiphysial plates of the long bones will continue to grow under the influence of insulin-like growth factor-I and other growth factors. Thus, the long bones of the upper and lower extremities will grow out of proportion to the axial skeleton. Healthy white men have an average upper segment (crown to pubis) to lower segment (pubis to floor) ratio of > 1, whereas prepubertal hypogonadism results in a ratio of < 1. Similarly, the ratio of total arm span to total height averages 0.96 in white men. Because of the relatively greater growth in the upper extremities, the arm span of eunuchoid individuals exceeds height by 5 cm or more.
If testosterone deficiency develops after puberty, the patient may complain of decreased libido, erectile dysfunction, and low energy. Patients with mild androgen deficiency or androgen deficiency of recent onset may not note a decrease in facial or body hair growth; it appears that although adult androgen levels must be achieved to stimulate male sexual hair growth, relatively low levels of androgens are required to maintain sexual hair growth. With long-standing hypogonadism, the growth of facial hair will diminish, and the frequency of shaving may also decrease (Figure 12-5). In addition, fine wrinkles may appear in the corners of the mouth and eyes and, together with the sparse beard growth, result in the classic hypogonadal facies.
Adequate assessment of the genitalia is essential in the evaluation of male hypogonadism. The examination should be performed in a warm room in order to relax the dartos muscle of the scrotum. The penis should be examined for the presence of hypospadias, epispadias, and chordee (abnormal angulation of the penis due to a fibrotic plaque), which may interfere with fertility. The fully stretched dorsal penile length should be measured in the flaccid state from the pubopenile skin junction to the tip of the glans. The normal range in
adults is 12–16 cm (10th and 90th percentiles, respectively).
Figure 12-5. A: Hypogonadal habitus. Note absence of body and facial hair as well as feminine body distribution. B: Hypogonadal facies. Note absence of facial hair and fine wrinkles around the corners of the eyes and lips.
Assessment of testicular volume is also vital to the evaluation of hypogonadism. Careful measurement of the longitudinal and transverse axes of the testes may be made and testicular volume (V) calculated from the formula for a prolate spheroid: V = 0.52 × length × width2. The mean volume for an adult testis is 18.6 ą 4.8 mL. Alternatively, volume may be estimated with the Prader orchidometer, which consists of a series of plastic ellipsoids ranging in volume from 1 mL to 25 mL (Figure 12-6). Each testis is compared with the appropriate ellipsoid. Adults normally have volumes greater than 15 mL by this method.
Since 80–90% of testicular volume is composed of seminiferous tubules, decrease in volume indicates lack of tubular development or regression of tubular size. The consistency of the testicle should be noted. Small, firm testes are characteristic of hyalinization or fibrosis, as may occur in Klinefelter's syndrome. Small, rubbery testes are normally found in prepubertal males; in an adult, they are indicative of deficient gonadotropin stimulation. Testes with a mushy or soft consistency are characteristically found in individuals with postpubertal testicular atrophy.
The epididymis and vas deferens should also be examined. One of the most important parts of the examination is evaluation for the presence of varicocele resulting from incompetence of the internal spermatic vein. As will be discussed later, this is an important and potentially correctable cause of male infertility. The patient should be examined in the upright position while performing the Valsalva maneuver. The examiner should carefully palpate the spermatic cords above the testes. A varicocele can be felt as an impulse along the posterior portion of the cord. About 85% of
varicoceles are located on the left side, and 15% are bilateral.
Figure 12-6. Prader orchidometer.
LABORATORY TESTS OF TESTICULAR FUNCTION
With some exceptions, a normal semen analysis excludes gonadal dysfunction. However, a single abnormal semen analysis is not a sufficient basis for a diagnosis of disturbance of testicular function, since marked variations in several of the parameters may be seen in normal individuals: At least three semen samples must be examined over a 2- to 3-month interval in order to evaluate this facet of male gonadal function. As noted above, approximately 3 months are required for completion of the spermatogenic cycle and movement of the mature spermatozoa through the ductal system. Therefore, when an abnormal semen sample is produced, one must question the patient about prior fever, trauma, drug exposure, and other factors that may temporarily damage spermatogenesis.
The semen should be collected by masturbation after 1–3 days of sexual abstinence and examined within 2 hours after collection. Normal semen has a volume of 2–5 mL, with 20 × 106 or more sperms per milliliter. Over half of the spermatozoa should exhibit progressive motility, and 30% or more should have normal morphology.
Each of the gonadal steroids may be measured by immunoassay. Although single determinations may distinguish between normal individuals and patients with severe hypogonadism, mild defects in androgen production may be missed. In normal individuals, there are frequent, rapid pulsatile changes in serum testosterone concentration as well as a slight nocturnal elevation. Therefore, at least three separate blood samples should be collected at 20- to 40-minute intervals during the morning for testosterone measurement. The testosterone may be measured in each of the serum samples, or equal aliquots of each of the three serum samples may be combined, mixed, and subjected to testosterone analysis. The latter procedure provides a savings in cost as well as a mean serum testosterone concentration that takes into account the pulsatile release of testosterone.
Androgen and estrogen immunoassays measure total serum steroid concentrations. This is the sum of the free, biologically active hormone and the protein-bound moiety. Although in most circumstances it is not necessary to determine the actual quantity of free steroid hormones, in some situations alterations in the binding protein concentration may occur. Lowered concentrations of SHBG are seen in patients with hypothyroidism, obesity, and acromegaly. In these circumstances, the free testosterone concentration should be directly measured, since it may be normal when the total serum testosterone level is decreased. The normal male serum concentrations of gonadal steroids collected in the basal state are given in Table 12-2.
Table 12-2. Normal ranges for gonadal steroids, pituitary gonadotropins, and prolactin in men.
Gonadotropin & Prolactin Measurements
LH and, to a lesser extent, FSH are released in pulsatile fashion throughout the day. Therefore, as with testosterone, at least three blood samples should be obtained at 20- to 40-minute intervals during the day. FSH and LH may be measured in each of the samples or in a single pooled specimen. Although many laboratories give a numerical value for the lower limits of normal for gonadotropins, some normal males have concentrations of FSH and LH undetectable by presently available immunoassay techniques. Furthermore, the concentrations of gonadotropins measured in one laboratory may not be directly comparable to those measured in another because of differences in the reference preparations used. The primary use of basal FSH and LH concentrations is to distinguish between hypergonadotropic hypogonadism, in which either or both of the gonadotropins are elevated, and hypogonadotropic hypogonadism, in which the gonadotropins are low or inappropriately normal in the presence of decreased androgen production.
Elevations of serum prolactin (PRL) inhibit the normal release of pituitary gonadotropins (shown by a reduced LH pulse frequency), probably through an effect on the hypothalamus. Thus, serum PRL measurements should be performed in any patient with hypogonadotropic hypogonadism. Serum PRL concentrations are generally stable throughout the day; therefore, measurement of this hormone in a single sample is usually sufficient. However, the patient should abstain from eating for 3 hours before the blood sample is obtained, since a protein meal may acutely stimulate the release of PRL from the pituitary. The normal ranges for serum PRL and gonadotropins are shown in Table 12-2.
Human chorionic gonadotropin (hCG) is a glycoprotein hormone with biologic actions similar to those of LH. Following an injection of chorionic gonadotropin, this hormone binds to the LH receptors on the Leydig cells and stimulates the synthesis and secretion of testicular steroids. Therefore, the Leydig cells may be directly assessed by the intramuscular injection of 4000 IU of chorionic gonadotropin daily for 4 days. A normal response is a doubling of the testosterone level following the last injection. Alternatively, a single intramuscular dose of chorionic gonadotropin (5000 IU/1.7 m2 in adults or 100 IU/kg in children) may be given, with blood samples taken for testosterone measurements 72 and 96 hours later. Patients with primary gonadal disease will have a diminished response following administration of chorionic gonadotropin, while patients with Leydig cell failure secondary to pituitary or hypothalamic disease will have a qualitatively normal response.
Clomiphene citrate is a nonsteroid compound with weak estrogenic activity. It binds to estrogen receptors in various tissues, including the hypothalamus. By preventing the more potent estrogen estradiol from occupying these receptors, the hypothalamus in effect “sees” less estradiol. As noted above, most if not all of the hypothalamic-pituitary feedback control by testicular androgens is mediated by estradiol, which is derived from the peripheral conversion of androgens. The apparent estradiol deficiency leads to an increase of GnRH release the net result of which is stimulation of the gonadotrophs to secrete increased quantities of LH and FSH.
The test is performed by giving clomiphene citrate, 100 mg orally twice daily for 10 days. Three blood samples are collected at 20-minute intervals (see comments above, under Steroid Measurements) 1 day before the drug is administered and again on days 9 and 10 of drug administration. LH, FSH, and testosterone should be measured in pooled aliquots from each of these samples. Healthy men have a 50–250% increase in LH, a 30–200% increase in FSH, and a 30–220% increase in testosterone on day 10 of the test. Patients with pituitary or hypothalamic disease do not show a normal increment in LH or FSH.
The decapeptide GnRH (gonadorelin) directly stimulates the gonadotrophs of the anterior pituitary to secrete LH and FSH. It was expected that measurement of LH and FSH following the administration of GnRH would be useful in distinguishing between hypothalamic and pituitary lesions, but this has not proved to be the case. Patients with destructive lesions of the pituitary and those with long-standing hypogonadism due to hypothalamic disorders may not show a response to a GnRH test. However, if the releasing factor is administered by repeated injections every 60–120 minutes or by a programmable pulsatile infusion pump for 7–14 days, patients with hypothalamic lesions may have their pituitary responsiveness to GnRH restored, whereas patients with pituitary insufficiency do not. Conversely, a normal LH and FSH response to GnRH in a hypogonadal male does not eliminate hypopituitarism as the cause of the gonadal failure, since patients with mild hypogonadotropic hypogonadism may demonstrate a normal response.
The test is performed by administering 100 ľg of gonadorelin by rapid intravenous bolus. Blood is drawn at -15, 0, 15, 30, 45, 60, 90, 120, and 180 minutes for LH and FSH measurements. Normal adult males have
a two- to fivefold increase in LH over baseline concentrations and an approximately twofold rise of FSH. However, some normal males fail to have an increase in FSH following GnRH. Patients with primary testicular disease may respond with exaggerated increases in LH and FSH. If seminiferous tubule damage alone is present, abnormal FSH rise and normal LH response may be seen.
Testicular biopsy in hypogonadal men is primarily indicated in patients with normal-sized testes and azoospermia in order to distinguish between spermatogenic failure and ductal obstruction. Although germinal aplasia, hypoplasia, maturation arrest, and other abnormalities of spermatogenesis may be diagnosed by examination of testicular tissue in oligospermic males, knowledge of the type of defect does not alter therapy. Therefore, testicular biopsy is not usually indicted for evaluation of mild to moderate oligospermia.
Evaluation for Male Hypogonadism
Figure 12-7 outlines an approach to the diagnosis of male gonadal disorders. Semen analysis and determination of the basal concentrations of testosterone, FSH, and LH allow the clinician to distinguish patients with primary gonadal failure who have poor semen characteristics, low or normal testosterone, and elevated FSH or LH from those with secondary gonadal failure and abnormal semen analysis, decreased testosterone, and low or inappropriately normal gonadotropins.
In patients with elevations of gonadotropins resulting from primary testicular disease, chromosomal analysis will help to differentiate between genetic abnormalities and acquired testicular defects. Since no therapy exists that will restore spermatogenesis in an individual with severe testicular damage, androgen replacement is the treatment of choice. Patients with isolated seminiferous tubule failure may have normal or elevated FSH concentrations in association with normal LH and testosterone levels and usually severe oligospermia. Patients with azoospermia require evaluation for the possible presence of ductal obstruction, since this defect may be surgically correctable. Fructose is added to seminal plasma by the seminal vesicles, and an absence of fructose indicates that the seminal vesicles are absent or bilaterally obstructed. The combination of a poor semen analysis with low testosterone, FSH, and LH is indicative of a hypothalamic or pituitary defect. Such patients need further evaluation of anterior and posterior pituitary gland function with appropriate pituitary function tests, as well as neuroradiologic and neuro-ophthalmologic studies (Chapter 5).
PHARMACOLOGY OF DRUGS USED TO TREAT MALE GONADAL DISORDERS
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.
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 200 mg intramuscularly every 1–2 weeks for 1–2 years. After adequate virilization has been achieved, the androgen effect may be maintained by doses of 100–200 mg every 2–3 weeks. 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 is another method of replacement therapy. One variety (Testoderm) is placed on the scrotum. The patches, which are placed daily, provide physiologic levels of testosterone that closely mimic the normal diurnal testosterone fluctuation. Elevated serum concentrations of dihydrotestosterone—a finding of unknown clinical significance—have been noted in patients using these patches. Another type of transdermal patch (Androderm; Testoderm TTS) can be placed on the skin of the back, shoulder, or abdomen and provides normal androgen concentrations without elevation in dihydrotestosterone. A testosterone gel (Andro Gel 1%; Testim 1%) that is applied daily to the abdomen, shoulders, or upper arms also results in physiologic concentrations of testosterone.
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.
Figure 12-7. Scheme for evaluation of clinical hypogonadism. (ART, assisted reproductive technologies such as in vitro fertilization and sperm injection into ova.)
Androgen therapy is contraindicated in patients with prostatic carcinoma. About 1–2% 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.
Androgen therapy may also 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. Since 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 though the free hormone concentrations remain normal. High-density lipoprotein concentrations may also be reduced.
In patients with hypogonadism due to inadequate gonadotropin secretion, spermatogenesis and virilization may be induced by exogenous gonadotropin injections. Since the gonadotropins are proteins with short half-lives, they must be administered parenterally two or three times a week.
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 below) and induction of spermatogenesis in hypogonadal males who wish to father children.
To induce spermatogenesis, 2000 IU of chorionic gonadotropin may be given intramuscularly three times a week for 9–12 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 9-12 months and is administered in a dosage of one vial intramuscularly three times a week.
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.
GnRH (gonadorelin acetate), administered in pulses every 60-120 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. A long-acting analog of GnRH, leuprolide acetate, is available for the treatment of 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. With these therapies, initial remission rates for prostatic carcinoma are similar to those found with orchiectomy or treatment with diethylstilbestrol (about 70%). In patients with benign prostatic hypertrophy, prostate size has been reduced with this therapy. Another potent intranasally administered GnRH analog, nafarelin acetate, is available 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 combined with testosterone have been studied as a possible male contraceptive, but they do not uniformly induce azoospermia.
CLINICAL MALE GONADAL DISORDERS
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 Chapter 5 and 15. The defects
in androgen biosynthesis and androgen action are described in Chapter 14. The following section emphasizes the primary gonadal abnormalities.
Table 12-3. Classification of male hypogonadism.
KLINEFELTER's SYNDROME (XXY Seminiferous Tubule Dysgenesis)
Klinefelter's syndrome is the most common genetic cause of male hypogonadism, occurring in one of 500 male births. An extra X chromosome is present in about 0.2% of male conceptions and 0.1% of live-born males. Sex chromosome surveys of mentally retarded males have revealed an extra X chromosome in 0.45–2.5% of such individuals. Patients with an XXY genotype have classic Klinefelter's syndrome; those with an XXXY, XXXXY, or XXYY genotype or with XXY/chromosomal mosaicism are considered to have variant forms of the syndrome.
Etiology & Pathophysiology
The XXY genotype is usually due to maternal meiotic nondisjunction, which results in an egg with two X chromosomes. The frequency of meiotic errors correlates positively with maternal age. Meiotic nondisjunction may also occur during spermatogenesis.
At birth there are generally no physical stigmas of Klinefelter's 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.
In addition to dysgenesis of the seminiferous tubules, the Leydig cells are also abnormal. They are present in clumps and appear to be hyperplastic upon 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. Thus, some individuals have virtually no secondary sexual developmental changes, whereas others are indistinguishable from healthy individuals.
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.
The pathogenesis of the eunuchoid proportions, personality, and intellectual deficits and associated medical disorders is presently unclear.
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.
Clinical Features (Figure 12-8)
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 1–2 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 dyssocial behavior some patients exhibit. Osteopenia may be severe in patients with long-standing androgen deficiencies.
Figure 12-8. Klinefelter's syndrome in a 20-year-old man. Note relatively increased lower/upper body segment ratio, gynecomastia, small penis, and sparse body hair with a female pubic hair pattern.
Patients with Klinefelter's 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 is greater than crown-to-pubis height, 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).
Intellectual impairment is noted in many patients with Klinefelter's syndrome, but the true proportion of affected individuals with subnormal intelligence is not known. Dyssocial behavior is common (see above). Patients generally show want of ambition, difficulties in maintaining permanent employment, and a tendency to ramble in conversations.
Several clinical and genotypic variants of Klinefelter's 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.
Medical disorders found to be associated with Klinefelter's 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. There is a 20-fold increased risk of breast cancer.
Serum testosterone is low or normal; 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.
Klinefelter's syndrome should be distinguished from other causes of hypogonadism. Small, firm testes should suggest Klinefelter's 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's 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's syndrome from the variant forms.
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 2–4 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.
If gynecomastia presents a cosmetic problem, mastectomy may be performed.
Course & Prognosis
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.
BILATERAL ANORCHIA (Vanishing Testes Syndrome)
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.
Etiology & Pathophysiology
Functional testicular tissue must be present during the first 14–16 weeks of embryonic development in order for wolffian duct growth and m˙llerian duct regression to occur and for the external genitalia to differentiate along male lines. Absence of testicular function before this time will result 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.”
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.
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.
An occasional patient will undergo 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.
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 m˙llerian duct inhibitory factor levels are low. Chromosomal analysis discloses a 46,XY karyotype.
Testicular artery arteriograms and spermatic venograms show vessels that taper and end in the inguinal canal or scrotum without an associated gonad.
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.
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.
Androgen replacement therapy is discussed in the section on pharmacology (see Androgens, above).
Implantation of testicular prostheses for cosmetic purposes may be beneficial after the scrotum has enlarged in response to androgen therapy.
LEYDIG CELL APLASIA
Defective development of testicular Leydig cells is a rare cause of male pseudohermaphroditism with ambiguous genitalia.
Etiology & Pathophysiology
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 m˙llerian duct structures is compatible with normal fetal secretion of m˙llerian duct inhibitory factor from the Sertoli cells.
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.
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.
Leydig cell aplasia should be differentiated from the vanishing testes syndrome, from testosterone biosynthetic defects, from disorders of androgen action, and from 5α-reductase deficiency. The differential diagnostic features of these disorders are discussed in Chapter 14.
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, since the few patients that 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.
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. About 5% of full-term 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 0.2–0.8% by 1 year of age. Approximately 0.75% of adult males are cryptorchid. Unilateral cryptorchidism is five to ten times more common than bilateral cryptorchidism.
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.
Etiology & Pathophysiology
Testicular descent usually occurs between the twelfth 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 dihydrotestosterone is required for normal testicular descent. These observations suggest that prenatal androgen deficiency may be of etiologic importance in the development of cryptorchidism.
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 1.5–2°C (2.7–3.6°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 extrascrotal environment is partly responsible for the observed pathologic abnormalities.
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.
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.
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.
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.
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.
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.
Intravenous urography will disclose an associated abnormality of the upper urinary tract in 10% of cases—horseshoe kidney, renal hypoplasia, ureteral duplication, hydroureter, and hydronephrosis.
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.
Bilateral anorchia is associated with elevated gonadotropins, decreased testosterone, and an absent or
subnormal response to stimulation with chorionic gonadotropin.
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.
Complications & Sequelae
Approximately 90% of cryptorchid males have associated ipsilateral inguinal hernia resulting from failure of the processus vaginalis to close. This is rarely symptomatic.
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.
Testes that lie above the pubic tubercle are particularly susceptible to traumatic injury.
A cryptorchid testis is 20–30 times more likely to undergo malignant degeneration than are normal testes. 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. Because of the increased risk of neoplasia, many urologists recommend orchiectomy for a unilaterally undescended testicle in a patient first seen during or 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.
Over 75% of untreated bilaterally cryptorchid males are infertile. About 30–50% 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.
Although cryptorchidism cannot be prevented, the complications can. 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 1 year. Since adverse histologic changes have been noted around the age of 2 years, hormonal or surgical correction should be undertaken at or before that time.
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.
NOONAN's SYNDROME (Male Turner's Syndrome)
Phenotypic and genotypic males with many of the physical stigmas of classic Turner's syndrome have been described under a variety of names, including Noonan's
syndrome and male Turner's syndrome. It may occur sporadically or may be familial, inherited in an autosomal dominant fashion with variable penetrance. Approximately half of the patients have a mutation in the PTPN11 gene on chromosome 12. 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.
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.
Cryptorchidism is frequently present. Although some affected individuals are fertile, with normal testes, most have small testes and mild to moderate hypogonadism.
Serum testosterone concentrations are usually low or low normal, and serum gonadotropins are high. The karyotype is 46,XY.
The clinical features of Noonan's 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.
If the patient is hypogonadal, androgen replacement therapy is indicated.
Myotonic dystrophy type 1 is one of the familial forms of muscular dystrophy. There are two types of myotonic dystrophy, but 80% of affected males with myotonic dystrophy type 1 have some degree of primary testicular failure.
The disorder is transmitted in an autosomal dominant fashion, with marked variability in expression. The underlying lesion is an expansion CTG repeat of the 3′ untranslated region of a gene that encodes a serine-threonine protein kinase located on chromosome 19.
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.
The testes are normal in affected prepubertal individuals, and puberty generally proceeds normally. Testosterone secretion is normal, and secondary sexual characteristics develop. 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.
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.
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.
Associated features include mental retardation, cataracts, cranial hyperostosis, diabetes mellitus, and primary hypothyroidism.
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.
Myotonic dystrophy type 1 should be distinguished from proximal myotonic myopathy, and myotonic dystrophy type 2. All may be associated with primary hypogonadism but have different clinical features and do not exhibit myotonic dystrophy type 1 mutations.
There is no therapy that will prevent progressive muscular atrophy in this disorder. Testosterone replacement therapy is not indicated unless the serum testosterone levels are subnormal.
ADULT SEMINIFEROUS TUBULE FAILURE
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.
Etiology, Pathology, & Pathophysiology
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. In many patients, no etiologic factors can be identified, and the condition is referred to as “idiopathic.”
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.
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 or 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's syndrome.
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. Since 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.
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's maneuver with the patient in the upright position. The patients are fully virilized, and gynecomastia is not present.
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.
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.
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.
Attempts to treat oligospermia and infertility medically have included testosterone rebound therapy, low-dose testosterone, exogenous gonadotropins, thyroid hormone therapy, vitamins, 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.
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.
Course & Prognosis
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.
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.
Improvement in the quality of the semen is found in 60–80% of patients following successful repair of varicocele. Restoration of fertility has been reported in about half of such patients.
The prognosis for spontaneous improvement of idiopathic oligospermia due to infection or infarction is poor.
ADULT LEYDIG CELL FAILURE (ANDROPAUSE)
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 25). It is not known how many men develop symptoms directly attributable to this phenomenon.
Etiology, Pathology, & Pathophysiology
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.
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.
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.
Serum testosterone may be low or low normal; serum LH concentration is usually high normal or slightly high. Oligospermia is usually present. Bone mineral density may be decreased.
Because many men with complaints compatible with Leydig cell failure have testosterone and LH concentrations within the normal adult range, a diagnostic trial of testosterone therapy 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, 200 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 of adult Leydig cell failure is substantiated. If the patient experiences no subjective improvement following testosterone, of if improvement is noted following both placebo and testosterone injections, Leydig cell failure is effectively ruled out.
Erectile dysfunction from vascular, neurologic, or psychologic causes must be distinguished from Leydig cell failure. A therapeutic trial of androgen therapy will not help erectile dysfunction that is not due to androgen deficiency.
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 HDL cholesterol and urine hydroxyproline.
About 15% of married couples are unable to produce offspring. Male factors are responsible in about 40% of cases, female factors in about 40%, and couple factors in 20%.
Etiology & Pathophysiology
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.
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 4-5% 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 25-40% of patients classified as having idiopathic infertility. The significance of this finding is uncertain, since 8-20% of males in the general population have varicoceles.
Table 12-4. Causes of male infertility.
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.
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's 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, since these defects may prevent the deposit of sperms in the vagina.
A carefully collected and performed semen analysis is mandatory. A normal report indicates normal endocrine function and spermatogenesis and an intact transport system. Semen analysis should be followed by a postcoital test, which consists of examining a cervical mucus sample obtained within 2 hours after intercourse. The presence of large numbers of motile spermatozoa in mucus obtained from the internal os of the cervix rules out the male factor as a cause of infertility. If a postcoital test reveals necrospermia (dead sperms), asthenospermia (slow-moving sperms), or agglutination of sperms, examination of the female partner for the presence of sperm-immobilizing antibodies or cervical mucus abnormalities should be carried out.
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 12-7.
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 done even in the presence of a male factor abnormality, since infertility is due to a combination of male and female factors in about 20% of cases.
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 12–18 months if sperms do not appear in the ejaculate, will restore 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 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.
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 density. In some patients with maturation arrest, severe hypospermatogenesis or incomplete Sertoli cell only, retrieval of sperms through testicular aspiration or testicular biopsy followed by IVF or ICSI have resulted in pregnancies.
Localized obstruction of the vas deferens may be treated by vasovasotomy. Sperm are detected in the ejaculate of 60–80% of patients following this procedure. However, the subsequent fertility rate is only 30–35%; the presence of antisperm antibodies that agglutinate or immobilize sperms probably accounts for the high failure rate.
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.
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. 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.
The presence of varicocele in an infertile male with oligospermia is an indication for surgical ligation of the incompetent spermatic veins. Improvement in the semen is noted in 60–80% of treated patients, and about half are subsequently fertile.
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.
Antibodies in the female genital tract that agglutinate or immobilize sperms 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, in vitro fertilization, and gamete intrafallopian transfer are considered the most effective treatments.
Patients with hypospadias, epispadias, or severe chordee may collect semen by masturbation for use in insemination.
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.
Course & Prognosis
The prognosis for fertility depends upon 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 artificial donor insemination, in vitro fertilization, or adoption.
ERECTILE DYSFUNCTION (IMPOTENCE)
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 are completely impotent 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.
Etiology & Pathophysiology
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 muscles 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 S2-4 pudendal nerves further increases the intracavernosal pressure. These processes result in the distention, engorgement, and rigidity of the penis that constitute erection.
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 HDL cholesterol, and a low serum DHEA sulfate level. Table 12-5 lists various pathologic conditions and drugs that may be associated with erectile dysfunction.
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's 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.
Table 12-5. Organic causes of erectile dysfunction.
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. 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.
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.
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).
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 S2-4 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.
Serum testosterone measurements may uncover a mild and otherwise asymptomatic androgen deficiency. If the testosterone level is low, serum PRL should be measured since hyperprolactinemia—whether drug-induced or due to a pituitary or hypothalamic lesion—may inhibit androgen production. Because diabetes mellitus is a relatively common cause of erectile dysfunction and because erectile dysfunction may be the presenting symptom of diabetes, fasting and 2-hour postprandial blood glucose measurements should be ordered.
In a patient with a normal physical examination and screening blood tests, many clinicians elect to begin with a therapeutic trial of 50 mg of oral sildenafil (Viagra), a type 5 phosphodiesterase inhibitor that potentiates the effects of nitric oxide by inhibiting the breakdown of cyclic guanosine monophosphate. 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.
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 (REM) 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 55–100% and specificity of 69–88%. Arterial problems are also detected with a sensitivity of 82–100% and specificity of 64–96%. The choice of other laboratory tests such as cavernosometry, cavernosography, or arteriography depends upon associated organic symptoms or signs.
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 40–70% success rate. Sildenafil taken about 1 hour before anticipated intercourse is approximately 70–80% 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%).
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 FDA-approved agent is prostaglandin E1 (alprostadil), which needs to be individualized within the dosage range of 2.5–60 ľg 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 effect beginning within 10 minutes and lasting 30–60 minutes). The major side effects are penile pain (36%), urethral pain (13%), and dizziness (4%).
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 85–90% of cases, but the device must be replaced every 5–10 years.
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.
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.
Etiology & Pathophysiology
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's 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.
Table 12-6. Causes of gynecomastia.
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.
Drugs such as phenothiazines, methyldopa, and reserpine may induce gynecomastia through elevations of PRL. Other drugs may reduce androgen production (eg, spironolactone), peripherally antagonize androgen action (spironolactone, cimetidine), or interact with breast estrogen receptors (spironolactone, digitoxin, phytoestrogens in marijuana).
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.
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.
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, while 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.
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 will often complain 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.
Once pubertal and drug-induced gynecomastia have been excluded, a biochemical screen for liver and renal abnormalities should be performed. If those are normal, then serum hCG, LH, testosterone, and estradiol levels should be measured. The interpretation of the results is outlined in Figure 12-9
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.
Complications & Sequelae
There are no complications other than possible psychologic damage from the cosmetic defect. Patients with gynecomastia may have a slightly increased risk of development of breast carcinoma.
The underlying disease should be corrected if possible, and offending drugs should be discontinued. Antiestrogens, such as tamoxifen, and aromatase inhibitors have
been found useful for relieving pain and reversing gynecomastia in a few patients. Whether these therapies will be useful in most patients with gynecomastia remains to be seen.
Figure 12-9. Diagnostic evaluation for endocrine causes of gynecomastia. (hCG, human chorionic gonadotropin; LH, luteinizing hormone; T, testosterone; E2, estradiol; T4, thyroxine; TSH, thyrotropic hormone.) (Reproduced, with permission, from Braunstein GD: Gynecomastia. N Engl J Med 1993;328:490.)
Reduction mammoplasty should be considered for cosmetic reasons in any patient with long-standing gynecomastia that is in the fibrotic stage.
Patients with prostatic carcinoma may receive low-dose radiation therapy (900 cGy or less) to the breasts before initiation of estrogen therapy. This may prevent or diminish the gynecomastia that usually results from such therapy. Radiotherapy should not be given to other patients with gynecomastia.
Course & Prognosis
Pubertal gynecomastia usually regresses spontaneously over 1–2 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.
Testicular neoplasms account for 1–2% of all male-related malignant neoplasms and 4–10% of all genitourinary neoplasms. They are the second most frequent type of cancer in men between 20 and 34 years of age. The incidence is 2–3 per 100,000 men in the USA and 4–6 per 100,000 men in Denmark. 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.
Etiology & Pathophysiology
The cause of testicular tumors is not known. Predisposing factors include testicular maldescent and dysgenesis. About 4–12% 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. In a few cases a genetic component is present and is associated with mutations in chromosome Xq27.
Bilateral gynecomastia is uncommon in patients who present with testicular cancer. 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 tumors may convert estrogen precursors to estrogens.
Seminomas account for 33–50% 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 20–33% 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.
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.
A testicular mass or generalized enlargement of the testis is often present on examination. In 5–10% of patients, a coexisting hydrocele may be present. In the presence of metastatic disease, supraclavicular and retroperitoneal lymph node enlargement may be present.
Staging of testicular tumors requires chest and abdominal CT scans and other radiologic procedures depending on the type of tumor and the symptoms.
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 will be 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.
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.
Benign Leydig cell tumors of the testes must be differentiated from adrenal rest tumors in patients with congenital adrenal hyperplasia. Since 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's 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's disease will have a decrease in 17-ketosteroids, DHEA sulfate, and estrogen concentrations, as well as a decrease in tumor size, following administration of dexamethasone.
Seminomas are quite radiosensitive, and disease localized to the testes is usually treated with orchiectomy and 2000–4000 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 alkylating agents.
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.
Benign Leydig cell tumors of the testes are treated by unilateral orchiectomy. Objective remissions of malignant Leydig cell tumors have been noted following treatment with mitotane.
Course & Prognosis
In patients with seminoma confined to the testicle, the 5-year survival rates after orchiectomy and radiotherapy are 98–100%. Disease in the lymph nodes below the diaphragm also has an excellent prognosis, with 5-year survival rates of 80–85%. Disease above the diaphragm and disseminated disease have 5-year survival rates as low as 18%.
In patients with nonseminomatous germ cell tumors, aggressive surgery and combination chemotherapy have raised the 5-year survival rates from less than 20% to 60–90%.
Removal of a benign Leydig cell tumor is accompanied by regression of 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.
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