Peter J. Snyder M.D.1
1Professor of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Medical School
The author has received research support from, and has been a consultant to, Solvay Pharmaceuticals, Inc., during the past year.
The testes begin to function early in utero and continue to function into senescence, but the consequences of their function differ at different stages of life. Diseases that affect testicular function, therefore, also have different consequences at different stages of life. Testicular function can be affected by diseases of the hypothalamus and pituitary, as well as by diseases of the testes themselves. The diseases may be either congenital or acquired [see Tables 1 and 2].
Table 1 Causes of Primary Hypogonadism
Table 2 Causes of Secondary Hypogonadism
Normal Testicular Function
The testes have two functions, the secretion of testosterone by the Leydig cells and the production of sperm by the seminiferous tubules. The cumulative effect of testosterone is to produce and maintain a phenotypic male. Testicular function is stimulated by the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are secreted by the gonadotroph cells of the pituitary gland, which in turn are stimulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus.
GONADOTROPIN SYNTHESIS AND SECRETION
GnRH is a decapeptide cleaved from a larger precursor peptide that is synthesized in the arcuate nucleus of the hypothalamus. FSH and LH are synthesized in the gonadotroph cells of the pituitary. Each is a heterodimeric glycopeptide consisting of a common α subunit and a unique β subunit.
GnRH travels via the hypothalamic-pituitary portal circulation to the pituitary, where it binds to G protein-coupled receptors on the surface of the gonadotroph cell. This triggers a cascade of intracellular signaling pathways and stimulates LH and FSH release. Although GnRH cannot be measured readily in the portal or peripheral circulation of humans, its secretion is thought to be pulsatile, because LH secretion is pulsatile. In addition, administration of GnRH to men who have GnRH deficiency increases LH secretion to normal only if GnRH is administered in pulses.1
Synthesis and Secretion
LH stimulates testosterone synthesis by binding to a surface receptor on the Leydig cells and activating a cyclic adenosine monophosphate-mediated mechanism that increases cholesterol side-chain cleavage and conversion to pregnenolone and eventually to testosterone. Testosterone is synthesized at a rate of 5 to 7 mg a day. Testosterone secretion is episodic, like that of LH, and follows a diurnal pattern. In normal young men, the highest concentrations of testosterone occur at about 8 A.M.; the lowest, at about 8 P.M.2
Circulating testosterone is 98% to 99% bound. About 40% is bound to sex hormone-binding globulin (SHBG) with high affinity; 60% is bound to albumin with low affinity. Testosterone bound to SHBG is not available to tissues, but that bound to albumin probably is available. SHBG synthesis is stimulated by estrogens and decreased by androgens and obesity.
Testosterone has many different effects in many different tissues, at least partly because it can act on a cellular level as three distinct hormones: testosterone itself and its two metabolites, dihydrotestosterone (DHT) and estradiol. Both testosterone and DHT act by binding to the androgen receptor, which is encoded by a gene that is located on the X chromosome and belongs to the steroid-retinoid-thyroid hormone superfamily of receptors.3 Although there is only one androgen receptor, the presence of coactivators or corepressors of transcription in certain types of cells could explain why the effects of testosterone vary in different tissues.4
The direct effect of testosterone on cells is mediated by its passive diffusion into cells, its binding to the androgen receptor, the binding of the testosterone-androgen receptor complex to DNA, and subsequent stimulation of messenger RNA (mRNA) and protein synthesis. This mechanism appears to be responsible for testosterone's stimulation of the wolffian ducts to become the male internal genitalia during embryonic development5 and for testosterone's inhibition of gonadotropin secretion. Testosterone has a probable role in the stimulation of erythropoiesis; the growth of muscle; an increase in linear bone growth; and, to some degree, an increase in bone mineral density.
In tissues that express the enzyme 5α-reductase, testosterone is irreversibly converted to DHT in the target cell cytoplasm. Two forms of 5α-reductase have been identified: type 1, which is found predominantly in nongenital skin and the liver; and type 2, which is found predominantly in urogenital tissue in both men and women. DHT binds to the androgen receptor with greater affinity than does testosterone and so has a greater effect than testosterone. After DHT binds to the androgen receptor, the DHT-receptor complex binds to DNA, stimulating mRNA and protein synthesis. This mechanism appears to be responsible for male differentiation of the external genitalia in utero,5 enlargement of the male external genitalia during puberty, and the development of sexual hair during puberty.
In tissues that express the enzyme complex aromatase—especially some hypothalamic nuclei, adipose tissue, liver, and perhaps bone—testosterone is converted to estradiol, which binds to an estrogen receptor. This mechanism appears to mediate several effects of testosterone. One effect is on bone: in males who have mutations of the gene coding for the estrogen receptor6 or the aromatase enzyme,7the epiphyses do not close and the bones are osteoporotic. Another effect is on libido, as suggested by the case report of a man who lacked aromatase and had poor libido until he was treated with estradiol.8 Aromatase appears to partially mediate the inhibition of LH secretion by testosterone and to entirely mediate the inhibition of FSH secretion by testosterone.9
Spermatogenesis occurs in the seminiferous tubules, stimulated principally by testosterone. The concentration of testosterone within the testes is 100 times that in the peripheral circulation. This high concentration, which is essential for spermatogenesis, probably results from both the LH-stimulated production of testosterone in the nearby Leydig cells and the FSH-stimulated binding of testosterone by androgen-binding protein, produced by the Sertoli cells of the seminiferous tubules. FSH also stimulates the Sertoli cells to secrete activin, which stimulates spermatogenesis. In addition, the Sertoli cells secrete inhibin, which inhibits FSH secretion by the pituitary.
Spermatogenesis takes approximately 3 months. Maturation of a spermatogonium to a mature spermatozoon takes approximately 75 days; passage through the epididymis, where motility is acquired, takes another 14 days.
TESTICULAR FUNCTION THROUGHOUT LIFE
Testicular function begins in utero, increases briefly in the first few months of infancy, develops fully during puberty, and declines gradually during adulthood.
Sexual differentiation occurs during the first trimester in utero.10 In the presence of the SRY gene, which is the sex-determining region of the Y chromosome, the undifferentiated gonads become testes. The Sertoli cells of the testes secrete antimüellerian hormone, which suppresses the müllerian ducts, thereby preventing the development of female internal genitalia.11 Human chorionic gonadotropin (hCG) from the placenta stimulates the Leydig cells of the testes to secrete testosterone, which in turn stimulates the nearby wolffian ducts to become the male internal genitalia—the vas deferens and seminal vesicles. In addition, testosterone is converted to DHT by the anlage of the external genitalia, and DHT influences the anlage to become the penis, scrotum, and prostate. During the third trimester, LH from the fetal pituitary stimulates the fetal testes to secrete testosterone, which results in penile growth. During the first few months post partum, there is a third testosterone elevation, to levels approximating that of a midpubertal boy. The consequences of this elevation are not known. Thereafter, the serum testosterone concentration falls to relatively low values until puberty.
Puberty in boys begins with an increase in the secretion of LH and FSH by the pituitary, which is presumably stimulated by an increase in GnRH secretion by the hypothalamus. This takes place at a mean age of 11.4 years (with a standard deviation of ± 1.1 years). The initial consequence is an increase in testicular volume, from 2 ml toward its adult volume of 20 to 25 ml. Rising levels of circulating testosterone cause an increase in the size of the phallus and promote the growth of pubic, axillary, and eventually body and facial hair, along with regression of temporal scalp hair. Testosterone also causes an increase in long bone growth and body height, thickening of the vocal cords and lowering of the voice, and an increase in hemoglobin concentration. Most of these changes are completed within 4 to 5 years, but full development of body hair and beard may take several more years, and temporal scalp hair regression continues for decades.
As men age, their serum total testosterone concentration decreases [see Figure 1].12,13,14 The decrease in the serum concentration of total testosterone is very gradual and of relatively small magnitude. SHBG, however, increases with increasing age, so the free-testosterone concentration decreases to a greater degree than the total. By 80 years of age, according to cross-sectional studies, the free-testosterone concentration is one half to one third that at 20 years of age.15,16 The decrease in testosterone appears to result from both decreased LH secretion and decreased responsiveness of the Leydig cells.17 The parallels between male senescence and male hypogonadism—both of which are marked by decreases in libido, energy, muscle mass and strength, and bone mineral density—suggest that testosterone deficiency could be a cause of the changes in male senescence.17 Serum estradiol concentration also decreases with increasing age, however. Several studies show a better correlation of some consequences of aging, such as the decrease in bone mineral density, with the estradiol level than with the testosterone level. Nevertheless, there is preliminary evidence that increasing the serum testosterone concentration of elderly men to that of young men increases bone mineral density18 and muscle mass and decreases fat mass,19 which supports the notion that the decrease in testosterone does have adverse consequences.
Figure 1. Serum Testosterone Concentration
Serum concentration of testosterone (a) and the free-testosterone index (b) versus age in healthy men who were followed longitudinally.12 Each line represents the mean for a cohort of men, and the numbers in parentheses represent the number of men in each cohort.
Male hypogonadism can occur as a consequence of a disease of the testes (primary hypogonadism) or as a consequence of a disease of the pituitary or hypothalamus (secondary hypogonadism). Certain clinical findings suggest hypogonadism, but these are usually nonspecific, so the diagnosis must be confirmed by laboratory tests.
The clinical findings of hypogonadism result from either decreased spermatogenesis or decreased testosterone secretion. The sole clinical finding of decreased spermatogenesis is infertility. In contrast, decreased testosterone secretion causes a wide variety of clinical findings; specific findings depend on the stage of life in which the deficiency occurs. When testosterone deficiency occurs in the first trimester in utero, male sexual differentiation is incomplete. Complete lack of testosterone during this period results in female external genitalia (i.e., clitoris and labia). Incomplete testosterone deficiency causes partial virilization, ranging from posterior labial fusion when testosterone deficiency is severe to hypospadias when testosterone deficiency is mild. Testosterone deficiency that begins in the third trimester in utero results in normal male sexual differentiation but microphallus at birth. When testosterone deficiency occurs in childhood but before puberty, the result is incomplete puberty. When testosterone deficiency develops after puberty, some pubertal changes regress; such changes usually occur slowly, and the effects can occur at different rates. Energy and libido diminish within days to weeks of the fall in testosterone, and the hemoglobin concentration and hematocrit decline within a few months. Decreases in sexual hair, muscle mass, and bone mineral density are usually not recognized for several years.
The physical examination focuses primarily on whether sexual development is consistent with the patient's age. If the patient is an adult, he should have facial, chest, and other body hair; temporal scalp hair should be receding appropriately for the patient's age and family pattern; and pubic hair should be dense and in a diamond pattern. The voice should be appropriately deep. Musculature should be normal for a man. Subcutaneous fat should be less than that of a boy or a woman. The testes should be 4 to 7 cm in length (20 to 25 ml in volume). If the patient is an adolescent, development should be appropriate for his age. If the patient is a child, the testes should be descended, and no hypospadias should be present.
The physical examination should also include evaluation for possible eunuchoid proportions and gynecomastia. An adult male usually has an upper body segment approximately equal to his lower segment and an arm span equal to his height. The absence of testosterone and the continued presence of growth hormone during puberty, as occurs in primary hypogonadism and isolated secondary hypogonadism, causes a delay in epiphyseal closure and an increase in the length of the long bones. In such patients, the lower body segment becomes longer than the upper and the arms become longer than the legs—a relationship known as eunuchoid proportions. This relationship persists even after testosterone treatment. Consequently, a man of any age who has a heel-to-pubis measurement more than 2 cm longer than his pubis-to-crown measurement and an arm span more than 2 cm longer than his height was probably hypogonadal during adolescence. Gynecomastia often occurs in hypogonadism; it is especially common in patients with primary hypogonadism.
Once the diagnosis of hypogonadism has been suspected on the basis of symptoms and signs, the diagnosis must be confirmed by documenting decreased production of sperm or testosterone. If hypogonadism is confirmed, the next step is to measure LH and FSH. Elevated serum concentrations of LH and FSH indicate primary hypogonadism, whereas subnormal or normal values indicate secondary hypogonadism.
Sperm production can be assessed most readily by counting the sperm in an ejaculated semen specimen. Generally accepted normal values for ejaculated sperm are a density of greater than 20 × 106 sperm/ml of ejaculate and a total count of more than 40 × 106 sperm/ejaculate. More than 60% of the sperm should be motile, and more than 30% should be normal in morphology. A recent study of the male partners in 765 infertile couples and 696 fertile couples showed that fertility was associated with a sperm density of greater than 48 × 106 sperm/ml, sperm motility of greater than 63%, and normal morphology in more than 12% of sperm.20 Low fertility was associated with a sperm density of less than 13.5 × 106 sperm/ml, sperm motility of less than 32%, and normal morphology in less than 9%. Indeterminate fertility was associated with intermediate values. A severely subnormal sperm count (e.g., < 5 times; 106 sperm/specimen) can result from either primary or secondary hypogonadism. A normal or mildly subnormal sperm count (e.g., 35 × 106 sperm/specimen) associated with markedly abnormal sperm motility more likely indicates a primary spermatogenic abnormality and less likely indicates secondary hypogonadism.
Testicular biopsy usually provides no more information about spermatogenesis than a semen analysis, because the variety of histologic responses to testicular injury is very limited. Testicular biopsy is likely to be helpful only when the ejaculated semen contains no sperm but the testicular size is normal and the serum concentrations of testosterone, LH, and FSH are normal. Such a patient may have obstruction of the ejaculatory outflow, or he may have suffered damage to the seminiferous tubules sufficient to impair spermatogenesis but not sufficient to cause an elevation in the serum FSH concentration. A testicular biopsy showing normal seminiferous tubules would favor the former diagnosis.
Testosterone secretion is best evaluated by measuring the serum concentration of total testosterone, because the total testosterone level is usually an accurate reflection of the free-testosterone level. Also, most of the current assay techniques for free testosterone are not as accurate as those for total testosterone. Testosterone is secreted into the circulation episodically, in a diurnal pattern; the serum testosterone concentration is highest at about 8 A.M. and lowest at about 8 P.M.2 Therefore, the serum testosterone concentration should be measured at 8 A.M. If the result is low or borderline, the test should be repeated. Measurement of free testosterone and SHBG may be helpful in situations in which the total testosterone level does not accurately reflect the free-testosterone level, such as would be the case with obese patients. If free testosterone is measured, the assay method should be equilibrium dialysis.
If the testosterone concentration is low, serum LH and FSH concentrations should be measured. If those values are high, the patient has primary hypogonadism; otherwise, he has secondary hypogonadism. In a patient with a distinctly subnormal sperm count but a normal serum testosterone concentration, the combination of an elevated FSH concentration and a normal LH concentration indicates that there has been damage to the seminiferous tubules but that the Leydig cells have not been affected.
In patients with secondary hypogonadism, magnetic resonance imaging of the sellar region is indicated. The MRI scan will show whether the patient has a mass lesion and, if so, whether it is in the pituitary, the hypothalamus, or the parasellar region. Pituitary and hypothalamic lesions cannot be distinguished on the basis of the LH response to a single dose of exogenous GnRH. Administration of repeated doses of exogenous GnRH, however, will result in a normal LH response to an individual dose of GnRH in patients who have hypothalamic disease, but not in patients who have pituitary disease. In patients with hypothalamic disease, the length of time required for LH response to become normal varies widely.
DISEASES THAT CAUSE HYPOGONADISM
Overall, primary hypogonadism [see Table 1] is more common than secondary hypogonadism [see Table 2]. Once a patient's hypogonadism has been identified as primary or secondary, the specific etiology can be sought.
Primary hypogonadism may be congenital or acquired. Many cases of primary hypogonadism have no identifiable cause, however. Presumably, many causes are yet unknown.
Of the congenital abnormalities that cause primary hypogonadism, the most common is Klinefelter syndrome,21 which occurs in approximately 0.2% of newborns. It is the phenotypic presentation of a male with more than one X chromosome. The most common genotype is 47 XXY, but additional X chromosomes (e.g., 48 XXXY) and mosaics (e.g., 46 XY/47 XXY) have also been reported. The 47 XXY genotype results from nondisjunction of the sex chromosomes of either parent during meiotic division. Mosaicism probably results from nondisjunctive mitotic division after conception. The severity of the phenotypic consequences usually increases with the number of extra X chromosomes. The gonadal consequences are usually severe damage to the seminiferous tubules and variable damage (minimal to severe) to the Leydig cells. Consequently, men with Klinefelter syndrome usually have very small testes, no sperm in their ejaculate, infertility, and markedly high serum FSH concentrations. Their serum testosterone concentrations vary from normal to subnormal; correspondingly, their virilization varies from normal to low and their serum LH concentrations vary from normal to elevated. Klinefelter syndrome is also usually marked by abnormalities of behavior and of the long bones. These abnormalities are not directly related to the gonadal abnormalities. The behavioral abnormality is manifested as difficulty in social interactions that is recognized in childhood, and it leads to problems in school and eventually in work. The long-bone abnormality is increased length of the legs but not the arms; this abnormality occurs independently of increased length of both the arms and legs as a result of testosterone deficiency.
The diagnosis of Klinefelter syndrome can usually be made by determining the karyotype of the peripheral leukocytes. Testosterone deficiency, if present, can be treated with testosterone replacement (see below). The behavioral abnormality cannot be treated satisfactorily, but a support group can be helpful for the patient's family, and school counselors should be advised of the diagnosis.
Cryptorchidism, or undescended testes, is also associated with damage to the testes and with greater damage to the seminiferous tubules than to the Leydig cells. More than one mechanism may be involved: testosterone deficiency in utero may inhibit descent, and the heat of the abdomen may cause further damage to the undescended testis. The clinical consequences depend partly on whether one or both testes are undescended. If only one testis is undescended, there is a 25% to 33% likelihood that the sperm count will be subnormal and the serum FSH level slightly high.22 If both testes are undescended, the sperm count will likely be severely subnormal and the patient infertile; the serum testosterone concentration may be subnormal, and the patient may be undervirilized as well. Neoplasms are two to five times more likely to develop in cryptorchid testes.23 The diagnosis is made in patients younger than 1 year by failure to palpate a testis that either is within the scrotum or can be manipulated manually from the inguinal canal into the scrotum.
Varicocele—a varicosity of the venous plexus within the scrotum—has for decades been considered a possible cause of infertility. The proposed mechanism is that varicocele causes an increase in blood flow, which impairs spermatogenesis by raising scrotal temperature above normal. However, scrotal temperatures are similar in infertile men with and without varicoceles, and varicoceles are not much more common in infertile than fertile men, so it is not certain that varicocele can cause infertility. More important, in a randomized trial of the surgical treatment of varicocele in men who were infertile, fertility was not found to be improved as a result of treatment.24 Therefore, surgical treatment of a varicocele cannot be recommended as a means of improving fertility.
Congenital deficiency of testosterone production can also result from mutations of genes that encode enzymes necessary for androgen biosynthesis. These disorders are rare. The cholesterol side-chain cleavage enzymes 3β-hydroxysteroid dehydrogenase and 17α-hydroxylase occur in the adrenal as well as in the testes, so deficiencies of either of these enzymes lead to deficient cortisol secretion as well. Deficiency of 17β-hydroxysteroid oxidoreductase affects only the testes. All of these disorders result in deficient testosterone secretion, beginning in the first trimester in utero, and subsequent incomplete virilization. The degree of incompleteness, especially of phallic development, influences whether these babies are raised as boys or girls. The testosterone deficiency itself can be treated in the same way as testosterone deficiency from any other cause.
Deletions on the long arm of the Y chromosome appear to be associated with infertility. Azoospermia is more common than oligospermia in such cases.25
Many acquired illnesses can cause primary hypogonadism. These include infections—notably, mumps orchitis. Orchitis is an uncommon complication of mumps and may be unilateral. In bilateral cases, both testes initially become markedly swollen and severely painful, then gradually atrophy. Diminished sperm production is common; decreased testosterone secretion is less common. The diagnosis is made by eliciting a history of painful swelling of the testes during systemic mumps infection.
Treatment of neoplasms with chemotherapeutic drugs (especially alkylating agents) or with radiation therapy to the inguinal lymph nodes often damages the seminiferous tubules; less often, it damages the Leydig cells. Radiation causes damage despite shielding of the testes, because of radiation scatter. The degree of damage is usually proportionate to the radiation dose. In cases of less extensive treatment, the damage may be reversible. No specific remedy for such damage is available, however.
Medications and drugs of abuse can produce hypogonadism. The antifungal agent ketoconazole impairs testosterone production. Heavy alcohol ingestion damages the testes.
HIV infection and AIDS wasting are commonly associated with hypogonadism.26 Several mechanisms appear to be involved in these cases. Some men with HIV infection and subnormal serum testosterone concentrations have inappropriately low serum concentrations of LH. This may be the result of conditions such as malnutrition, opiate abuse, and megestrol acetate administration, all of which are known to cause secondary hypogonadism. Other men with HIV infection lack known risk factors for secondary hypogonadism but have elevated serum concentrations of LH, indicating primary hypogonadism. Hypogonadism in HIV-infected men has been observed less commonly since the introduction of retroviral therapy.
Testicular torsion can cause permanent damage if not treated promptly. Trauma to the testes can sometimes be sufficiently severe to damage them.
Hypogonadism may be induced (surgically or chemically) as a therapeutic strategy in cases of advanced prostate cancer [see 12:IX Prostate Cancer]. Bilateral orchiectomy is used as a treatment for bilateral testicular cancer. In testicular cancer patients, however—unlike those treated with castration for prostate cancer—there is no reason to withhold testosterone replacement.
Like primary hypogonadism, secondary hypogonadism (also called hypogonadotropic hypogonadism) has both congenital and acquired causes in men [see Table 2]. Unlike primary hypo gonadism, secondary hypogonadism often has a cause that is amenable to specific treatment. For that reason, finding the cause carries particular importance. Pituitary adenomas, other benign tumors and cysts of the sellar area, and malignancies that arise in the sellar region or metastasize there can usually be detected by MRI. Infiltrative diseases (e.g., sarcoidosis, hemochromatosis) usually produce manifestations in other organ systems that suggest the diagnosis. Tumors, cysts, and infiltrative lesions are often accompanied by deficiencies of other hypothalamic or pituitary hormones.
Some cases of secondary hypogonadism are not associated with any other hormonal abnormalities and are called isolated. Some cases appear to be caused by a deficiency of GnRH secretion by the hypothalamus; such cases can be congenital or acquired. When congenital, they may or may not be a part of Kallmann syndrome.27 Patients with Kallmann syndrome have deficient GnRH secretion, variably associated with anosmia, cryptorchidism, red-green color blindness, and long-bone and urogenital tract abnormalities. Kallmann syndrome may occur sporadically or in families; familial cases can be inherited in an autosomal dominant pattern, with expression mostly limited to males, or in an X-linked recessive pattern. The genetic defect responsible both for the deficiency in GnRH secretion and for anosmia in some patients who have the X-linked recessive form of Kallmann syndrome is a mutation in the KAL-1 gene, which encodes a neural cell adhesion protein, anosmin. When this protein is not present during embryogenesis, GnRH-secreting neurons do not migrate from the olfactory placode to the olfactory bulb and then to the hypothalamus, resulting in both anosmia and hypogonadotropic hypogonadism.
Another cause of isolated secondary hypogonadism is a mutation of the GnRH receptor. In these cases, GnRH is secreted by the hypothalamus but does not stimulate LH secretion by the pituitary. A third cause is a mutation of the DAX-1 gene, which leads to hypogonadotropic hypogonadism and to adrenal hypoplasia congenita.
Gonadotropin secretion can be reversibly inhibited by any systemic illness or by hyperprolactinemia. Inhibition from medications, such as glucocorticoids, suramin, and opiates, is also reversible. Since the introduction and widespread use of controlled-release forms of opioids for chronic-pain management, hypogonadism from these medications has become more common.28 Heroin addicts may experience hypogonadism by the same mechanism. Damage to the pituitary from surgery or radiation, in contrast, usually results in permanent inhibition of gonadotropin secretion.
Delayed puberty is diagnosed in any boy whose pubertal development does not begin by more than two standard deviations past the mean age. In some cases, this delay represents a normal variant; these patients eventually enter puberty spontaneously. In other cases, the delay is caused by secondary hypogonadism. Distinguishing a normal variant from pathologic delay can be difficult. The degree of hypogonadism is usually not helpful in making this distinction, nor is any biochemical test. A family history of delayed puberty or constitutional short stature increases the likelihood of physiologic delayed puberty. Anosmia, symptoms of a chiasmal lesion, or other signs of a specific hypothalamic or pituitary disease increase the likelihood of an organic lesion as the cause. In many cases, the diagnosis can be made only by continued observation.
In an otherwise healthy elderly man, an unequivocally subnormal serum testosterone concentration, along with an LH concentration that is not elevated, can be considered a form of secondary hypogonadism.
Testosterone can be replaced whether the hypogonadism is primary or secondary. Unlike estrogen, testosterone itself is not suitable for oral replacement, because it is catabolized rapidly during its first pass through the liver. Derivatives of testosterone that are alkylated in the 17α position do not undergo this rapid hepatic catabolism; however, these agents appear to lack the full virilizing effect of testosterone, and they may cause hepatic toxicity, including cholestatic jaundice, a cystic condition of the liver called peliosis, and, possibly, hepatocellular carcinoma. Consequently, the 17α-alkylated androgens should not be used to treat testosterone deficiency.
Currently, replacement therapy is instead delivered by the intramuscular or transdermal routes. The intramuscular formulations, testosterone enanthate and testosterone cypionate, are long-acting esters of testosterone produced by esterifying the hydroxyl group in the 17β position with a fatty acid. These do produce full virilization. They are usually administered in doses of 150 to 200 mg by deep intramuscular injection every 2 weeks. With this regimen, serum testosterone values peak within 1 to 2 days after the injection and fall to a nadir just before the next injection [see Figure 2].29 These fluctuations are noticed by some patients as fluctuations in energy, mood, and libido.
Figure 2. Serum Testosterone Concentration During Administration of Testosterone Preparations
Serum testosterone concentrations during the course of chronic administration of three different testosterone preparations to hypogonadal men. (a) Concentrations during 14 days after the injection of 200 mg of testosterone enanthate.29 (b) Concentrations during the 24 hours after application of a testosterone patch that delivers approximately 5 mg of testosterone.41 (c) Concentrations during the 24 hours after application of a testosterone gel containing 50 or 100 mg of testosterone.31
Transdermal testosterone is now available in both patch30 and gel31 form [see Figure 2]. In most hypogonadal men, these preparations usually produce serum testosterone concentrations that are within the normal range and that fluctuate no more than physiologically, resulting in reasonable stability of energy, mood, and libido. The relatively physiologic pattern of serum testosterone concentrations and the infrequency of side effects make transdermal preparations the best means of testosterone replacement for most hypogonadal men.
During replacement therapy, clinicians should monitor patients for the efficacy and side effects of testosterone. Efficacy is determined by measurement of the serum testosterone concentration, which should be in the middle of the normal range midway between injections of testosterone esters and at any time after application of a transdermal preparation. Serum testosterone concentrations can vary with any of these preparations, however, so testosterone should be measured more than once to determine whether the initial dose is optimal. Serum testosterone should be measured again after a dose is changed and then once or twice a year. If the serum testosterone concentration is maintained within the normal range, the patient should experience reversal of the consequences of testosterone deficiency. Specifically, energy, libido, hemoglobin concentration, muscle mass, and bone density will increase.32
Men older than 40 years who are receiving testosterone replacement should be monitored for testosterone-dependent diseases, such as prostate cancer, benign prostatic hyperplasia, and erythrocytosis. However, there is as yet no evidence that exogenous testosterone is more likely to exacerbate any of these conditions than is endogenous testosterone.
Stimulation of Spermatogenesis
When sperm production is impaired by damage to the seminiferous tubules, no treatment can improve fertility. However, if some mature sperm are produced, they may be used for in vitro fertilization. When the sperm count is low because of pituitary or hypothalamic disease, sperm production can often be stimulated to within the normal range by administration of exogenous gonadotropins. If the hypogonadism occurred postpubertally, usually only LH need be replaced. If the hypogonadism occurred prepubertally, usually both LH and FSH need to be replaced.33 In hypogonadism secondary to hypothalamic disease, spermatogenesis can also be stimulated by pulsatile administration of GnRH.
Generalized tissue insensitivity to the action of androgens results in abnormalities similar to those of testosterone deficiency. Such insensitivity can be caused by abnormalities of either the androgen receptor 34 or 5α-reductase type 2 enzyme.35 Both conditions result from genetic mutations, both are rare, and both result in incomplete virilization of the external genitalia.
Many different mutations of the androgen receptor gene have been described. Some of these mutations interfere with binding of androgen to the receptor, and others interfere with binding of the androgen-receptor complex to the DNA of the androgen-responsive cell.
The clinical presentations of the different receptor abnormalities also vary. In the most severe clinical presentation, called complete androgen insensitivity, the affected person is born with testes in the inguinal canals, no internal genitalia, and female external genitalia. At puberty, the serum testosterone concentration increases to a high-normal or slightly above-normal value, but sexual hair does not develop. Breasts do develop, because testosterone can still be converted to estradiol. In incomplete androgen insensitivity, there is variable partial fusion of the labial folds: a lesser degree of fusion results in genitalia that are still more female than male, and a greater degree results in genitalia that are more, but still incompletely, male. The least severe form of androgen resistance is manifested only by infertility and sometimes gynecomastia. Serum testosterone and LH concentrations are high normal to slightly high in all of these forms of androgen resistance.
Kennedy disease consists of a relatively mild form of androgen insensitivity but progressively severe spinal bulbar neuropathy. It is caused by a mutation leading to doubling of the number of N-terminal glutamines in the androgen receptor.
Other mutations of the androgen receptor have been described in metastatic prostate cancer that has become resistant to androgen deprivation. These mutations may allow ligands other than testosterone to bind to the receptor and stimulate receptor-dependent functions even in the absence of testosterone. Mutations of the 5α-reductase type 2 gene also lead to incomplete virilization of the external genitalia because virilization requires conversion of testosterone to DHT by this enzyme.35 At birth, most males with 5α-reductase type 2 deficiency have external genitalia that are predominantly female, so the sex of rearing is usually female. At puberty, the serum testosterone concentration increases and overcomes the lack of DHT to some degree; binding of testosterone to the androgen receptor causes phallic enlargement and hair growth in an adult male pattern. If the patient is being raised as a female, the testes can be removed before puberty to prevent these events.
Gynecomastia is the development of glandular breast tissue in a man. In most cases of gynecomastia, the stimulation of glandular tissue appears to result from an increased ratio of estrogen to androgen.
Gynecomastia is common at all ages of life but is more common in infancy, puberty, and from middle age on. In most large series, gynecomastia can be detected in 10% to 20% of midpubertal boys and in more than 50% of men older than 50 years. These high rates probably reflect the hormonal changes that typically occur at those ages and do not represent disease.
ETIOLOGY AND PATHOGENESIS
The common mechanism for gynecomastia appears to be an increased estrogen-to-androgen effect on the breast. This may involve an increase in estrogen effect or a decrease in androgen effect, or both, and may result from changes in hormonal production or in hormonal action at the cellular level. Normally, most of the estrogen in the peripheral circulation in men is produced by the conversion of testosterone to estradiol or of androstenedione to estrone by the enzyme complex aromatase, which is concentrated in adipose tissue and the liver.
Exposure to Exogenous Estrogen
Gynecomastia from exogenous estrogens is uncommon. Reported cases have involved exposure to a partner's vaginal cream, application of antibalding creams, dietary intake, and occupational exposure.
Increased Estrogen Secretion
The most common cause of increased endogenous estrogen secretion is increased gonadotropin stimulation of the testes, which increases intratesticular aromatase levels and thereby increases the amount of estradiol secreted relative to testosterone. This is the likely mechanism by which gynecomastia occurs in normal males during puberty; with refeeding after starvation; and after successful treatment of severe illness, such as chronic cardiac, hepatic, or renal disease. In these situations, a period of secondary hypogonadism is followed by normal gonadotropin secretion. Increased gonadotropin (specifically, LH) secretion is also the cause of gynecomastia in primary hypogonadism. Increased secretion of hCG is the cause in patients who have tumors of the testes or liver. Administration of hCG therapeutically (e.g., to stimulate spermatogenesis) acts similarly, especially when the dose is excessive.
Increased Peripheral Conversion of Androgens to Estrogens
Increased peripheral conversion of testosterone to estradiol or of androstenedione to estrone can occur via several mechanisms: (1) an increased rate of conversion, as in hyperthyroidism or cirrhosis of the liver; (2) an increase in the amount of aromatase, as occurs in obesity; and (3) an increased substrate for aromatization, as occurs when an adrenal carcinoma secretes large amounts of androstenedione or when an aromatizable androgen, such as a long-acting testosterone ester, is administered in excessive doses.
Inhibition of Androgen Binding
Many drugs that cause gynecomastia appear to do so by binding to the androgen receptor and thereby blocking endogenous testosterone. As a consequence, endogenous androgens have less androgenic action but are still converted to estrogens. Drugs that can block the androgen receptor include spironolactone, cimetidine, flutamide, bicalutamide, and cyproterone acetate. Inherited disorders of the androgen receptor produce similar results, although in these cases, the inhibition of binding is, of course, irreversible.
The diagnosis of gynecomastia is confirmed by physical examination. The examiner places a spread thumb and forefinger above and below the patient's nipple and draws them together, like calipers, toward the nipple, hugging the chest wall. Subcutaneous tissue feels soft as the fingers are drawn together, whereas gynecomastia feels firm. The diameter of the gynecomastia can be measured with a ruler. Mammography is usually unnecessary. Gynecomastia is generally bilateral, although it is occasionally unilateral. It is often asymmetrical. If the tissue is tender, the gynecomastia is more likely to be of recent origin.
Having confirmed that gynecomastia exists, the clinician then needs to find the cause. This involves inquiring about medications and searching for diseases known to cause gynecomastia [see Etiology and Pathogenesis, above].36
Gynecomastia must be distinguished from carcinoma of the male breast, which is rare, and from adiposity, which is common. Breast cancer should be suspected when the breast enlargement is unilateral, nontender, not centered directly under the nipple, and hard. The diagnosis can be confirmed by mammography. Breast adiposity is bilateral and can usually be distinguished from gynecomastia by the absence of palpable glandular tissue on physical examination.
Gynecomastia is not physically harmful, and it usually regresses once the cause has been removed, although regression may take many years. Therefore, treatment is indicated only if the gynecomastia is causing psychological distress. The only accepted treatment is surgical removal, which is best performed by a plastic surgeon. Small series suggest that the antiestrogen drug tamoxifen and the aromatase inhibitor testolactone can reduce gynecomastia. Anastrozole is a more potent aromatase inhibitor than testolactone, but no results of its efficacy in treating gynecomastia have been published. None of these drugs have been approved by the Food and Drug Administration for this purpose.
Erectile dysfunction is the inability to achieve or maintain an erection sufficient for intercourse. Although occasional erectile dysfunction does not indicate disease, its occurrence on most attempts to engage in sexual activity may indicate disease and is usually very troubling to the patient and his partner. Erectile dysfunction is not the same as a decrease in libido, which is decreased sexual interest. The two usually have different causes and, therefore, different treatments.
In a cross-sectional survey of noninstitutionalized men 40 to 70 years of age, all degrees of erectile dysfunction, from minimal to complete, occurred in 50% of men. Older men were more commonly affected, however. For example, impotence occurred in 5% of 40-year-old men and in 15% of 70-year-old men.37 When men from the same population were followed longitudinally, the incidence of new cases was 2.5% a year.38
Development of an erection requires intact psychological, neurologic, and vascular mechanisms.39,40 Erotic stimuli result in neural impulses that are carried from the cerebral cortex to the penis via the spinal cord, and stimulation of the penis results in neural impulses that loop to the spinal cord and back to the penis via parasympathetic nerves. These stimuli trigger blood flow into the corpora cavernosa. The inflow of blood is mediated by relaxation of arteriolar smooth muscle under the influence of nitric oxide, the production of which is catalyzed by the enzyme nitric oxide synthetase. Nitric oxide, in turn, promotes the production of cyclic guanosine monophosphate (cGMP), which also relaxes arteriolar smooth muscle and increases blood flow. Outflow of blood from the engorged corpora cavernosa is impeded by an increase in venous resistance.
Disruption of any of these steps can lead to erectile dysfunction. The neural mechanisms can be disrupted mechanically (such as by radical prostatectomy, surgery for an abdominal aortic aneurysm, or spinal cord trauma) or pathologically (such as by diabetic autonomic neuropathy or autonomic insufficiency syndromes). They also can be disrupted functionally, such as by drugs. The vascular mechanism can be disrupted by large vessel (atherosclerotic) or small vessel (diabetic) disease. The mechanism by which hyperprolactinemia causes impotence is not known, although it does not appear to be via hypogonadism.
History, physical examination, and laboratory testing all contribute to finding the cause of erectile dysfunction. From the history, the physician can determine whether the patient is taking a drug or has a disease associated with this disorder. Several drugs that are used to treat hypertension may occasionally cause erectile dysfunction; these include thiazide diuretics and alpha- and beta-blocking agents. Other drugs include tranquilizers and antidepressants. Excessive alcohol ingestion can also cause erectile dysfunction. The physician should ask about a history of diabetes of long duration, including other manifestations of diabetic neuropathy, and explore psychogenic factors, including depression, anxiety, fatigue, interpersonal stresses, and chronic illness. It is useful to ask whether the patient can obtain an erection under any circumstances. If the patient has an erection on awakening in the morning or can get an erection on some occasions but not others, the cause is more likely to be psychogenic than organic.
On physical examination, the absence of peripheral pulses and the presence of femoral bruits indicate vascular disease. Neurologic disease is indicated by diminished touch sensation and proprioception and a diminished cremasteric reflex (retraction of the testis on stroking of the ipsilateral inner thigh).
Laboratory evaluation should include measurement of the serum prolactin concentration, because hyperprolactinemia can be detected in no other way. The serum testosterone concentration should be measured in a man who has decreased libido as well as erectile dysfunction, but it will rarely be helpful in a man who has erectile dysfunction but normal libido.
Erectile dysfunction should be differentiated from decreased libido, if possible, because they often have different causes and different treatments. The two conditions may occur together, however. Decreased libido is decreased sexual interest, of which the principal hormonal cause is hypogonadism. Hypogonadism does not by itself impair erectile ability. A man who has a normal libido but has difficulty getting an erection probably does not have hypogonadism, whereas a man who has decreased libido and potency should be evaluated for hypogonadism as well as erectile dysfunction.
Treatment of erectile dysfunction depends on the cause. If a medication is the source of the problem, it may be possible to substitute a drug that does not affect erectile function. For example, if the patient is being treated for hypertension with a thiazide diuretic, it might be replaced with an angiotensin-converting enzyme inhibitor or a calcium channel blocker—agents that do not seem to interfere with erectile function.
Underlying disorders should be corrected whenever possible. Hyperprolactinemia can be treated with a dopamine agonist (e.g., cabergoline).
The most effective treatment for erectile dysfunction of psychogenic, vascular, or neurologic origin is sildenafil. This agent inhibits phosphodiesterase, the enzyme that degrades cGMP, and therefore enhances smooth muscle relaxation in the corpora cavernosa, increasing arteriolar blood flow and promoting erection. In one randomized study of 329 men with erectile dysfunction who were randomized to receive either sildenafil or placebo, the men who took sildenafil were eventually able to get an erection on 69% of attempts, compared with 22% of attempts in men who received placebo.39,40
Other treatments include intraurethral instillation of alprostadil, intracavernous injection of alprostadil or prostaglandin E1, and application of a vacuum pump to the penis. These are more cumbersome and therefore less popular than sildenafil, even when they are effective.
Editors: Dale, David C.; Federman, Daniel D.