medscape.com/viewarticle/535162
- If you can’t access article from above URL, use this
google.ca/search?hl=en&q=med … dism&meta=
…and click the first result
Endocrinology
Testes and Testicular Disorders: Male Hypogonadism
From ACP Medicine Online
Posted 06/07/2006
Peter J. Snyder, M.D.
Etiology
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.
Diagnosis
Clinical Findings
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.
Physical Examination
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.
Laboratory Findings
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.
Spermatogenesis
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 concentration. 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.
Gonadotropins. 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 – omitted] is more common than secondary hypogonadism [see Table 2 – omitted]. Once a patient’s hypogonadism has been identified as primary or secondary, the specific etiology can be sought.
Primary Hypogonadism
Primary hypogonadism may be congenital or acquired. Many cases of primary hypogonadism have no identifiable cause, however. Presumably, many causes are yet unknown.
Congenital. 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
Acquired. 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 – omitted]. 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.
Secondary Hypogonadism
Like primary hypogonadism, secondary hypogonadism (also called hypogonadotropic hypogonadism) has both congenital and acquired causes in men [see Table 2 – omitted]. 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.
Treatment
Testosterone Replacement
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 – omitted].29 These fluctuations are noticed by some patients as fluctuations in energy, mood, and libido.
Transdermal testosterone is now available in both patch30 and gel31 form [see Figure 2 – omitted]. 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.
Click here to subscribe or purchase the full chapter. Snyder, Peter J, 3 Endocrinology, II Testes and Testicular Disorders, ACP Medicine Online, Dale DC; Federman DD, Eds. WebMD Inc., New York, 2000. acpmedicine.com/
Disclaimer
Figures, tables, references and sidebars are available in the subscription edition of ACP Medicine .
Peter J. Snyder, M.D., Professor of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Medical School
ACP Medicine Online. 2002; ©2002 WebMD Inc.