Principles of the Androgen Treatment of Hypogonadism

The indications for androgen treatment are shown in Table: Indications for Androgen Therapy. Primary Leydig cell failure must be treated with androgens to relieve clinical symptoms and signs. Response to androgen replacement therapy is monitored by checking for improvement in the clinical features of hypogonadism. Typically, an improvement in sexual function, frequency of shaving, secondary sexual characteristics, and general well being occurs rapidly after the initiation of treatment. It is often useful to monitor minimum and peak testosterone levels during the start of therapy and in patients who do not show adequate clinical response.

Table: Indications for Androgen Therapy

Definite Male hypogonadism
Probable or possible Micropenis in children

Constitutional delayed puberty

Aging men (with evidence of androgen deficiency)

Male contraception

Hereditary angioneurotic edema

Dubious or controversial Hematological disorders such as aplastic anemia, myelofibrosis with myeloid metaplasia hemolytic anemia, autoimmune thrombocytopenia, and leucopenia

Improvement of nitrogen balance in non-androgen-deficient catabolic state

Improvement of libido in hypogonadal women

Not indicated Anemia associated with renal failure

Improvement of muscle strength and endurance in athletes, body builders

Androgen treatment does not reverse infertility. Secondary Leydig cell dysfunction can be corrected by normalizing blood luteinizing hormone (luteinizing hormone) levels. Until patients with hypothalamic-pituitary disorders associated with hypogonadotropic hypogonadism are desirous of a pregnancy, however, they are also treated with androgens because of the ease of administration and low cost. When a patient with hypogonadotropic hypogonadism desires fertility, the testes must be stimulated with luteinizing hormone- and follicle-stimulating hormone (follicle-stimulating hormone)-like hormones. This is usually done with human chorionic gonadotropin (human chorionic gonadorropin) or recombinant human luteinizing hormone, followed by combined human chorionic gonadotropin or luteinizing hormone and human menopausal gonadotropin or purified follicle-stimulating hormone. As an alternate method, pulsatile gonadotropin-releasing hormone (gonadotropin-releasing hormone) injections may be given to induce spermatogenesis and fertility.

Pulsatile treatment requires the patient to continuously wear a micropump device for delivering small amounts of gonadotropin-releasing hormone every two hours. Prior treatment with testosterone does not jeopardize the chances of fertility in patients with hypogonadotropic hypogonadism.

In young children with micropenis, a short course of low-dose androgen therapy is often tried. In adolescent boys with constitutional delay of puberty in whom the psychological effects of delayed puberty are significant, short-term treatment with testosterone for three to four months may be indicated.

As described in earlier sections, total and free testosterone levels decrease with age. This decline in Leydig cell function occurs at a time when various androgen-responsive end organs show signs of abnormal function (i.e., penis, bone, and muscle). Although a decrease in sexual function is often observed in older men, many aged men have other causes for erectile dysfunction (ED), and thus do not experience a reversal of impotence when treated with testosterone alone. Combined PDE-5 inhibitors and testosterone may be beneficial on sexual function when decreased libido and erectile dysfunction are present in hypogonadal, older men. Although it has not been proved that androgen therapy in older men with borderline or normal range testosterone levels will improve sexual function, prevent bone and muscle loss, or improve the quality of life, clinical trials are underway to determine its efficacy in symptomatic men with definitely low serum testosterone levels. The possible beneficial effect of androgens must be balanced against the possible adverse effects on lipids, prostate, and sleep-related breathing disorders.

Testosterone has been given alone or in conjunction with other steroids and gonadotropin-releasing hormone analogs as experimental male contraceptives. Recent data indicate that pharmacologic doses of testosterone will successfully suppress sperm counts to levels incompatible with fertility. These effects are reversible. In these regimens, androgens function both to suppress sperm production by inhibiting gonadotropins and to replace endogenous androgen levels. The dosage of testosterone used in successful male contraceptive trials is higher than replacement, and long-term data on possible adverse effects on the prostate and cardiovascular system are not yet available.

In hereditary angioneurotic edema, anabolic steroids have been used to prevent attacks. These anabolic steroids increase the synthesis of complement 1 inhibitor, which is deficient in these patients. Because of the known side effects of these agents, they are not recommended for use in pregnant women and in children.

The role of androgens in the treatment of hematological disorders remains controversial; and newer, more specifically targeted treatments are available. Treatment of refractory hypoplastic anemia with androgens may be tried for three to six months, but in responders, treatment must be continued for a much longer period. Because of the availability of recombinant human erythropoietin, with its more specific action and its lack of side effects, androgens are no longer the primary treatment for patients with anemia associated with chronic renal failure.

Androgens have been used in clinical situations such as severe trauma or chronic illness, in which the patient is in long-term negative nitrogen balance. The long-term results are generally disappointing, but trials in cancer and HIV-infected patients are underway.

There is an increasing trend toward the use of androgenic steroids by athletes and body builders. The pattern of androgen use by athletes involves the intermittent and cyclical administration of pharmacological doses of a combination of oral and parenteral agents. These unprescribed androgens may include huge doses of drugs, including veterinary agents that either are potentially toxic or have not been tested in humans. Androgens increase muscle mass and strength in women and prepubertal children. In normal adult men, it has been debated whether the administration of additional androgens enhances athletic performance. Most information is anecdotal; however, a number of studies including several well-controlled protocols have been performed. Results of double-blind studies are contradictory; there are reports indicating both positive and nonbeneficial effects on athletic performance in postpubertal males. A careful dose-response study was performed in which normal men were given a gonadotropin-releasing hormone antagonist to markedly suppress serum luteinizing hormone levels. Groups of men were then given increasing doses of testosterone from subphysiological to markedly pharmacological amounts. The effect on muscle size and strength was progressive, indicating that the performance-enhancing effects of androgens are dose related. Even in those studies in which increased strength and performance was seen, the changes induced by these agents were small; thus, documentation of clinically significant improvement in muscle strength and endurance has not been obtained. Despite the controversy, some athletic trainers and physicians have argued that even small changes in performance justify the use of these agents by high-performance, competitive athletes. Nevertheless, the policies of all international and U.S. athletic regulatory agencies are unambiguously opposed to “doping” with androgens or other medicines to improve performance. Furthermore, physicians believe that the unsupervised use of androgens and high-dose androgen treatment impose some risk of undesired toxic effects. The long-term abuse of supraphysiological doses of androgens in men may lead to gynecomastia, hepatic toxicity (caused by 17-alkylated androgens), polycythemia, lipid changes (lowering of high-density cholesterol), and suppression of spermatogenesis (due to decreased luteinizing hormone and follicle-stimulating hormone secretion and decreased testosterone biosynthesis by the Leydig cells). These toxic side effects are suffcient to discourage the use of androgens for nonmedical reasons in people of all ages, even adult men.

Adverse Effects of Androgen Treatment

In general, testosterone and its esters have fewer side effects than the synthetic 17-alkylated androgens (8,. Acne and increased oiliness of skin are frequently experienced by patients at the initiation of androgen supplementation. Because testosterone is metabolized to estradiol, gynecomastia may develop. The gynecomastia is often mild, and treatment is usually unnecessary. Most patients gain weight when administered androgens. The weight gain is due to water retention, increased blood volume, and increased lean body mass. With the exception of severely hypogonadal men with preexisting azoospermia and decreased testicular volume, patients given exogenous androgen therapy have suppression of spermatogenesis and a decrease in testicular size. The decreases in sperm production and seminiferous tubule volume are consequences of the suppression of gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone.

Androgens cause virilization in women and prepubertal children. In addition, androgens promote premature epiphyseal closure of the long bones in children and will result in reduced ultimate height. There have been several studies on androgen effects on hypodesire states in women. The results indicate positive effects over placebo. Androgens are not approved in the United States for this condition, presumably because of the sparseness of safety data. For these reasons, androgens should not be used in women and in children of either sex except for the specific indications discussed previously.

Changes in liver function and hepatic disorders are dependent on the type of androgen given. Liver dysfunction is not observed with testosterone or its esters. In contrast, the 17-alkylated androgens can produce liver dysfunction, including cholestasis, elevation of plasma alkaline phosphatase, and conjugated bilirubin. Methyltestosterone causes cholestaric jaundice with minimal parenchymal liver damage. Recovery is usually rapid after drug discontinuation. Two more serious liver problems, peliosis hepatis and hepatic tumors, may occur rarely after androgen therapy, and only when high pharmacological doses of androgens are used to treat conditions such as refractory aplastic anemia. Because most of these reports involved patients with preexisting conditions that are associated with increased evidence of neoplasms, the implications of such reports in the treatment of hypogonadal men remain controversial. The majority of studies in which testosterone was given in physiologic doses for hypogonadism or pharmacologic doses for male contraception have not demonstrated evidence of hepatic toxicity.

Testosterone treatment influences cholesterol and apolipoprotein synthesis and metabolism. When a 17-alkylated androgen, stanozolol, is administered to normal men, high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I and A-II levels are decreased, and low-density lipoprotein cholesterol and apolipoprotein B levels are increased. These changes in lipid profiles have been identified as risk factors for coronary atherosclerosis. Such changes in lipid profile occur to a much lower extent with testosterone esters such as testosterone enanthate, perhaps because some of the testosterone is converted to estrogens that have effects on lipid profile opposite those of androgens. Another explanation for the difference in lipid profiles may be that the orally active anabolic steroids (17-alkylated androgens) have a first-pass effect on the liver, leading to effects on lipids not apparent with the parenterally administered testosterone esters. More data are needed in larger groups of men to quantify the degree to which testosterone esters are associated with adverse effects on lipid profiles and to determine if these small effects are associated with an increased risk of atherosclerosis. The findings of decreased high-density lipoprotein cholesterol after high-dose testosterone and 17-alkylated androgens need to be balanced by the failure to document these changes in many replacement studies.

Androgens cause small increases in hemoglobin, hematocrit, and total red cell count when administered to normal or hypogonadal men. Androgens both stimulate erythropoietin production by the kidneys and have a direct effect on the bone-marrow stem cells. Clinically significant polycythemia is uncommon in hypogonadal men given androgen replacement except in patients who are likely to develop polycythemia — for example, those with chronic obstructive pulmonary disease or sleep apnea.

The 17-alkylated androgens have been given to men with coagulation disorders. Although small increases of clotting factors have been recorded, these anabolic steroids increase fibrinolysis and antithrombin III levels (a natural anticoagulant). The net effect is that increased bleeding episodes occur. The increase in fibrinolysis may counterbalance the negative effects of lipid profiles on the risk of coronary heart disease.

In hypogonadal men treated with androgen replacement, sleep-related breathing disorders (sleep apnea) have been reported. In obese patients and those with chronic obstructive airway disease, the physician should question the patient about sleep-related breathing disorders before the commencement of androgen replacement.

Although reports of androgen-induced mild resistance to insulin action exist, the usual doses of testosterone esters, when given to normal men, are not associated with changes in glucose or insulin levels. Although adverse effects on glucose control in diabetic patients given androgen replacement have been reported, many studies now suggest that testosterone may benefit the metabolic syndrome by reducing body and visceral fat.

Benign prostatic hypotrophy and prostate cancer rarely occur in men who developed androgen deficiency prior to puberty. Despite this fact, no clear evidence indicates that androgen replacement given to men who become hypogonadal after puberty increases the risk of prostatic disease. For all adult men, especially older men on long-term androgen therapy, regular digital rectal examination must be performed and prostate-specific antigen levels should be monitored. If there is a suspicion of prostatic enlargement, a transrectal prostatic ultrasound should be performed and / or final needle biopsy of a suspicious nodule.

The effects of androgen on behavior and cognitive function have been topics of broad public interest. Anecdotal reports of androgen rage or increased aggressive behavior after androgen therapy have not been substantiated by controlled studies. A recent report has shown improved mood, lessened depression, and general well being when hypogonadal men are treated with testosterone.

Androgen Replacement Therapy: Conclusion

Disorders of Leydig cell function can be primary or secondary to abnormal secretion of luteinizing hormone and follicle-stimulating hormone. These disorders can be congenital or acquired. The clinical manifestations depend on the following: (i) location of the defect (hypothalamic, pituitary, and gonadal) or mimicking by abnormalities of androgen-responsive end organs; (ii) age at onset of the disorder; and (iii) the nature of associated nonreproducrive problems. Because of the actual role of intratesticular testosterone in germ cell maturation, Leydig cell dysfunction usually leads to infertility. Testosterone replacement therapy is required for androgen-deficient males with primary Leydig cell underfuncrion. Males with hypo-gonadotropic hypogonadism may be treated with either luteinizing hormone (human chorionic gonadorropin) or testosterone to normalize serum testosterone levels, but reversal of infertility requires gonadotropic hormone treatment.

 

Selections from the book: “Male Reproductive Dysfunction. Pathophysiology and Treatment”, Edited by Fouad R. Kandeel, 2007.

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