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Medical Article on Anabolic Steroids discussing side effect.

grwoo

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This is a nice article off Uptodate containing the most recent medical literature physicians are using to guide the detection and treatment of anabolic steroids.

Last literature review for version 16.2: May 31, 2008 | This topic last updated: June 4, 2008

INTRODUCTION — Some athletes take medications to attempt to improve their performance. They are motivated by a desire to win and the perception that certain medications improve performance. The focus of the general news media is on the athletes who are caught using these medications in popular sporting events, such as the Olympics, baseball, and the Tour de France bicycle race [1] . In comparison, the emphasis of the sports medicine literature is on methods of detection of the newest medications that athletes are using. The focus of this review is on the effects of these compounds that might be encountered by a physician who sees an athlete, competitive or noncompetitive, as a patient. Physicians might also see patients who are taking androgens to improve their appearance [2] .

The United States Preventive Services Task Force found insufficient evidence to recommend for or against routine screening for drug abuse in adolescents, including abuse of anabolic steroids [3] . The American Academy of Family Physicians, American Medical Association Guidelines for Adolescent Preventive Services, and the American Academy of Pediatrics all suggest that clinicians discuss the dangers of drug abuse with children and adolescents and include questions about substance abuse as a part of routine adolescent visits. Physicians may also suspect abuse of androgens in adolescents who have problem behavior (eg, fighting, other substance abuse, sexual risk) [4] .

HOW THIS AREA OF MEDICINE IS DIFFERENT — This area of medicine differs from most others because athletes who take medications to improve their performance do so surreptitiously. There are several consequences of the clandestine nature of this use:

* Athletes often obtain the medications from sources other than physicians.

* Athletes obtain their information about the medications from other athletes, trainers, magazines, underground publications, and the Internet.

* Athletes often take several medications simultaneously in an attempt to increase the overall effect on performance, or to counter a side effect of one medication with another medication. As an example, an athlete might take human chorionic gonadotropin (hCG) to counteract the decrease in testicular size resulting from high-dose androgen use, and take an aromatase inhibitor or estrogen receptor antagonist to counteract the gynecomastia from administration of high doses of hCG.

* Athletes discontinue the medications periodically, often to avoid detection when they know they will be tested just before a competition.

* Physicians who see these athletes are often unaware that they are taking these medications.

* Physicians' knowledge of the possible effects of these medications is poor because the doses and even the medications used have rarely been studied in a controlled fashion.

EPIDEMIOLOGY — It is difficult to know how commonly athletes take these medications since they are so often taken surreptitiously. In fact, athletes use elaborate schemes to avoid detection.

Available information about prevalence comes from unannounced testing during training, testing at the time of competitions, and surveys of athletes.

* In 2005, the United States Anti-Doping Agency (USADA) (http://www.usantidoping.org/files/active/who/annual_report_2005.pdf) reported performing over 8000 tests in Olympic, Paralympic and Pan American sports and identifying 22 potential doping cases.

* In a mail survey of 26 members of the United States Power Lifting Team, 10 replied that they had taken androgens, and 5 stated that they had been able to circumvent the International Olympic Committee's detection procedures [5] .

* In a survey at 21 gymnasia in England, Scotland, and Wales, 9 percent of 1310 men and 2 percent of 349 women reported taking androgens [6] .

* A large CDC survey found that 4 percent of adolescents in high school reported taking androgenic steroids without a doctor's prescription [7] .

* The Monitoring the Future survey of the National Institute of Drug Abuse conducted in found that in 2007, 0.8 percent of eighth graders, 1.1 percent of tenth graders, and 1.4 percent of twelfth graders had used steroid drugs during the previous year. These prevalence values are approximately half of those five years earlier [monitoringthefuture.org].

ANDROGENS

Kinds of androgens — Virtually all androgens produced for human or veterinary purposes have been taken by athletes (show figure 1). These include testosterone esters, which are usually taken by injection, the 17-alpha-alkylated androgens, which are usually taken orally, and androgen precursors.

* The testosterone esters include the enanthate and cypionate, which are also used for hormone replacement. (See "Testosterone treatment of male hypogonadism").

* Synthetic androgens, eg, oral 17-alpha-alkylated androgens (eg, stanozolol) or parental 19-nortestosterone derivatives (eg, nandrolone), were originally developed to have a greater anabolic to androgenic effect than testosterone, specifically a greater trophic effect on the levator ani muscle than on the ventral prostate in rats [8] . They were therefore given the name "anabolic steroids," which persists today. However, whether these compounds have a higher ratio of anabolic to androgenic activity than testosterone in humans is uncertain. Although there is only one androgen receptor [9] , which is present in genital tissue, muscle, and many other tissues, there are many cofactors that influence the transcriptional activity of the androgen receptor, and these, called coactivators or corepressors, differ from tissue to tissue [10] . These coactivators and corepressors provide a theoretical basis for a compound to affect the androgen receptor in one tissue differently from the receptor in other tissues. Nevertheless, no compound has yet been found to have a greater anabolic effect than androgenic effect in humans, and therefore they will all be referred to here simply as androgens.

Stimulation of testosterone secretion by hCG — HCG, which acts as LH and stimulates the Leydig cells to secrete testosterone, has also been used by athletes, because what is produced is native testosterone and in normal ratio to epitestosterone, making its use more difficult to distinguish from normal secretion.

Androgen precursors — The androgen precursors include androstenedione and dehydroepiandrosterone.

* Androstenedione is available as an over-the-counter nutritional supplement, it is not regulated as are many other androgens, and it is widely promoted in body-building magazines. Administration of 300 mg of androstenedione once daily for one week to normal young men increased their mean serum testosterone concentration [11] , but administration of 100 mg three times a day for eight weeks did not [12] . In a third study, in which 100 mg of androstenedione or placebo was given to normal men three times a day in a double-blind fashion for four weeks, the total testosterone concentration did not increase in the androstenedione-treated men, but free testosterone (measured by an analog assay, which may not be accurate), dihydrotestosterone, and estradiol did [13] .

* DHEA is also available as a "nutritional supplement" and is widely touted in body building magazines as an agent that will increase muscle strength. It is not androgenic itself, but is converted to testosterone. When healthy young men were given either a placebo (n=5) or 50 mg (n=4) or 100 mg (n=5) daily for six months, serum concentrations of testosterone did not change, but serum concentrations of DHEA, DHEA-sulfate, and androstanediol glucuronide, a metabolite of dihydrotestosterone, did increase [14] . The clinical implications of these changes are as yet unknown.

* In a randomized, double-blind trial, 40 trained men (>1 year of weight training) were given DHEA (100 mg/day), androstenedione (100 mg/day), or placebo [15] . There were no changes in lean body mass or muscle strength in either treatment group when compared to placebo.

Other uses of DHEA are discussed elsewhere. (See "Dehydroepiandrosterone and its sulfate" and see "Initial treatment of depression in adults" section on Dehydroepiandrosterone).

Efficacy — It seems intuitive that androgens increase muscle mass and muscle strength, given the obvious differences between men and women. While exogenous testosterone administration results in increases in serum testosterone concentrations and muscle strength, there is no evidence that androstenedione increases muscle strength.

* In one placebo-controlled, double-blind study of exogenous testosterone, 43 normal men were randomly assigned to one of four groups: strength training exercise with either 600 mg of testosterone enanthate once per week (about six times a replacement dose) or with placebo; or no exercise with either testosterone or placebo [16] . Testosterone treatment increased fat-free mass and muscle strength, both in men who exercised and in men who did not, but more so in those who exercised simultaneously.

* In contrast, in a double-blind, placebo-controlled study in normal men, administration of 100 mg androstenedione three times daily for eight weeks did not increase muscle strength; however, serum testosterone concentrations were not increased by this regimen [12] . Similarly, in a placebo-controlled study of 50 healthy men ages 35 to 65 years receiving androstenedione or androstanediol (200 mg/day), neither hormone altered body composition or muscle strength compared with placebo [17] .

Side effects — All androgens have some side effects when taken in high doses; other side effects depend upon the structure of the androgen or the steroids it is converted to. Some side effects occur only in women.

Suppression of endogenous testicular function — All androgens suppress gonadotropin secretion and therefore suppress endogenous testicular function. Spermatogenesis and fertility are greatly diminished by high doses of androgens, although the sperm count usually returns to normal within four months after discontinuation [18] . Testicular size may decrease if androgen administration continues for many years. Gonadotropin and testosterone secretion remain suppressed for a few months after androgens are discontinued.

Gynecomastia — Gynecomastia occurs because testosterone is converted to estradiol via the action of the aromatase enzyme complex, so that high doses of testosterone result in high serum estradiol concentrations. Androgens that have been 5 alpha-reduced, such as dihydrotestosterone and synthetic androgens in which the A ring has been modified, cannot be aromatized and therefore cannot be converted to estrogens and do not cause gynecomastia.

Erythrocytosis — Erythrocytosis is a common side effect of pharmacologic doses of all androgens, probably due largely to direct androgen stimulation of erythropoiesis.

Hepatotoxicity — Hepatic side effects occur only with oral 17-alpha-alkylated androgens and include high serum concentrations of liver enzymes [19] , cholestatic jaundice, and peliosis hepatitis, characterized by blood-filled hepatic cysts [20] . Hepatomas have also been reported, but the number of cases is few and causality is uncertain.

Psychological disorders — Many psychological abnormalities have been described, both in the medical literature and anecdotally, in men taking high doses of androgens. Most descriptions are uncontrolled, although in one study an attempt was made to compare men taking and not taking androgens [21] . One hundred sixty men recruited from gymnasia responded to a questionnaire about androgen use and psychiatric symptoms. Psychiatric symptoms, including major mood disorders and aggressive behavior, were more common in the men who had taken androgens than in those who had never taken androgens, and among the former the symptoms were more common when they were taking androgens.

Cardiac disease — The effect of high doses of androgens on cardiac function is uncertain. Several case reports describe sudden death in young athletes who had no previously known heart disease but who were taking androgens; cardiac hypertrophy or myocarditis were found at autopsy [22,23] . It is not possible to establish causality in these sporadic cases. (See "Risk of sudden cardiac death in athletes").

There are also reports of left ventricular hypertrophy in body builders and power lifters, but most of these studies have not been randomized or controlled for degree of exercise, which itself can affect the degree of cardiac hypertrophy [24] . In one randomized, placebo-controlled trial, eight body builders treated with nandrolone decanoate showed no difference in several echocardiographic parameters at the end of eight weeks from those treated with placebo, but this study was limited by the small numbers of subjects and short duration [25] .

Serum lipids — Although physiologic doses of testosterone have no consistent effects upon serum lipid concentrations, pharmacologic doses of androgens, especially 17-alpha-alkylated androgens, decrease serum high-density-lipoprotein (HDL) cholesterol and increase low-density-lipoprotein (LDL) cholesterol concentrations [26] .

In a study of normal men aged 30 to 56 years given androstenedione (300 mg/day for 28 days), serum HDL cholesterol concentrations decreased by 15 percent, a change that, in the general population, would predict an increase in risk of coronary heart disease [13] .

Coagulation activation — Androgen administration is associated with activation of the hemostatic system. As an example, in one study of 49 weight lifters in whom androgen use was ascertained by history and urine testing. The confirmed steroid users had a higher percentage of abnormally high thrombin–antithrombin complexes in plasma than nonusers (16 versus 6 percent, p=0.01), higher plasma concentrations of prothrombin fragment 1 (44 versus 24 percent, p<0.001), antithrombin III (22 versus 6 percent, p=0.005), and protein S (19 versus 0 percent), and lower plasma concentrations of tissue plasminogen activator and its inhibitor [27] . The importance of hemostatic system activation with regard to risk of thrombosis is unclear.

Virilization — Because men are maximally virilized by physiologic amounts of testosterone, only women athletes are virilized by taking androgens. Specifically, they have facial and body hirsutism, temporal hair recession in a male pattern, acne, and clitoral enlargement.

Premature epiphyseal fusion and stunting of growth — Pharmacologic doses of testosterone or other androgens that can be aromatized to estrogens hasten epiphyseal closure if taken by adolescents whose epiphyses have not yet closed naturally. The number at risk is illustrated by a survey of 873 Indiana high school football players randomly selected from 27 high schools throughout the state [28] . Six percent reported that they were current or former users of androgens; 50 percent first used the drugs before age 14 years and 15 percent before age 10 years.

Infections — Sporadic case reports describe infections due to injection of androgens, including local abscess at the site of injection, septic arthritis, hepatitis B and C, and HIV infection from sharing of needles [29] .

Detection of use — Exogenous administration of pharmacologic doses of androgens might be suspected in a man who competes in a sport in which excess androgens are perceived as improving performance and who have small testes, low sperm counts, high hematocrit and hemoglobin values, and low serum sex hormone-binding globulin concentrations. In a woman, androgen abuse might be suspected in an athlete with hirsutism, balding, or acne. The diagnosis can be confirmed by one of several tests, depending upon the compound to be tested.

* Androgens other than testosterone can be detected by gas chromatography and mass spectroscopy if the athlete is still taking the compound(s) at the time of the testing.

* Testosterone taken exogenously cannot be distinguished from that produced endogenously, so other methods must be used. The conventional method is to determine the urinary ratio of testosterone glucuronide to its endogenous epimer, epitestosterone glucuronide (T/E ratio). Normally the ratio is 1 to 3:1, but subjects taking exogenous testosterone, which suppresses the production of both testosterone and epitestosterone and replaces it only with testosterone, have higher ratios, usually >6:1, which rarely occurs naturally [30] . However, a T/E ratio of >4:1 is considered evidence of doping by the World Anti-Doping Agency (WADA).

The limitation of the T/E ratio is shown by the much greater between, than within, subject variability [31] . The reason for this difference has recently been shown to result from heterozygosity in the uridine diphosphoglucuronosyl transferase that converts testosterone to testosterone glucuronide [32] . No such heterozygosity apparently exists in the glucuronosyl transferase that converts epitestosterone to epitestosterone glucuronide. The consequence is that a man who has a deletion of both copies of this enzyme converts testosterone to testosterone glucuronide poorly, so after an injection of exogenous testosterone, his T/E ratio is much lower than a man who has two copies of the gene. Conventional monitoring by this ratio, therefore, is much less likely to detect the athlete who has both copies deleted and who takes exogenous testosterone than the athlete who has two normal copies of the gene. The investigators who elucidated this heterozygosity proposed setting normal ranges for the T/E ratio depending on whether or not the athlete has two, one or no copies of this gene.

Another proposed method uses the ratio of testosterone to LH in the urine, which is high (>30) in subjects taking testosterone because it suppresses LH secretion [33] .

* The method currently considered most accurate is determination of the ratio of 13C to 12C in urinary metabolites of testosterone. The rationale is that pharmacologic testosterone preparations are synthesized from plant sterols, which have a lower ratio of 13C to 12C than does endogenous testosterone [34] . This method will show a low 13C to 12C ratio even if an athlete takes epitestosterone to attempt to mask taking testosterone. News media reported that in the 2006 Tour de France, Floyd Landis had a high testosterone:epitestosterone ratio and a low 13C to 12C ratio.

* Athletes and those who supply them with androgens are ever attempting ways to avoid detection. The most common way is to discontinue the drug before testing will occur. Another way was first reported in the lay press in the fall of 2003 [35] . According to these reports, a private laboratory in the San Francisco area synthesized an androgenic steroid specifically designed to avoid detection. The drug was identified when a syringe filled with it was provided to the United States Anti-Doping Agency, which eventually determined that the drug was tetrahydrogestrinone. In February 2004, the president of the laboratory, a personal trainer of well-known athletes, and others were indicted by a grand jury for providing athletes with these drugs [36] .

* The World and the US Antidoping Agencies allow athletes to compete if they are taking a banned medication because they need it medically. In this situation, they grant a Therapeutic Use Exemption (TUE) after reviewing a TUE form completed by the athlete's physician. The physician must state that the athlete would experience a significant health problem if he did not take the prohibited medication; the medication would not produce significant enhancement of performance; and there is no reasonable therapeutic alternative. An example is an athlete who takes testosterone because he has had bilateral orchiectomy for testicular cancer.

hCG and antiestrogens — Another approach to increasing endogenous testosterone concentrations is by taking exogenous hCG, which stimulates Leydig cell testosterone secretion, or estrogen blockers: antiestrogens such as tamoxifen or raloxifene, or aromatase inhibitors. These drugs result in an increase in serum testosterone concentrations, and all are banned by the World Anti-Doping Agency [37] .

GROWTH HORMONE — Athletes take recombinant human growth hormone because of its demonstrated effects on body composition (more muscle, less fat) [38] . Efficacy has not been demonstrated either on strength [39,40] or endurance [41] . It would be expected to cause acromegaly if given in high doses long enough, but no such cases have been reported. In addition, epidemiologic data suggest an association between serum concentrations of insulin-like growth factor 1 (IGF-1) and cancer risk. (See "Risk factors for prostate cancer" section on Insulin like growth factor). A review of studies in which growth hormone was administered to normal men and women showed an increased incidence of soft tissue edema compared to those not treated [38] .

In spite of the possible risks, and in spite of the World Antidoping Agency (WADA) banning it, the lay press has reported that growth hormone use has been indirectly associated with athletes in such diverse sports as baseball, swimming and cycling during the past several years. Its use by high school athletes in Germany, according to a survey, was relatively low, 0.4 percent, compared to 15.1 percent who reported using other substances on the WADA list [42] .

Two methods have been proposed to detect use of growth hormone by athletes [43] .

* Markers of growth hormone action, such as IGF-1 and N-terminal extension peptide of procollagen type III (P-III-P). One study showed that when growth hormone in doses of 0.033 or 0.066 mcg/kg body was administered daily for four weeks to normal men and women, their serum concentrations of IGF-1 and P-III-P were readily distinguishable from subjects administered placebo [44] .

* Growth hormone isoforms. This method takes advantage of the fact that the human pituitary gland normally secretes a variety of growth hormone isoforms, including a 22 kDa form in monomers and dimers, a 20 kDa form, and desamidated and acetylated forms, but rhGH consists only of the 22 kDa monomer. Immunoassays have been developed that can recognize either the 22 kDa form selectively or all of the isoforms nonselectively. Because administration of rhGH suppresses endogenous GH secretion, an elevated ratio of GH measured by the selective 22 kDa assay to GH measured by the nonselective assay indicates administration of exogenous GH [43] .

OTHER DRUGS — Some athletes take several other drugs in addition to androgens and growth hormone to enhance performance.

Stimulants — Stimulants, including amphetamines and caffeine, have been taken for years, but are not used commonly in competitions in which testing occurs since they are detected by standard tests. They still may be taken in less regulated events. Ephedra, which is banned by the United States Food and Drug Administration, is discussed in detail elsewhere. (See "Drug therapy of obesity").

Erythropoietin — Athletes have used recombinant erythropoietin because it increases hemoglobin concentrations and therefore oxygen-carrying capacity. They hope that it will also improve performance. It was reported to be the "booster of choice" during the 1998 Tour de France bicycling race [45] and has been reported in news media to have been used since then. Both erythropoietin administration and blood doping increase exercise performance [46,47] .

No side effects have yet been reported, but thrombotic events might be expected with long-term therapy, especially if the hematocrit is well above 50 percent, and is exacerbated by the dehydration associated with endurance sports [48] .

The use of recombinant erythropoietin should be suspected in athletes if the hematocrit is above 50 percent in males and above 47 percent in females; however, there is substantial overlap with healthy controls [49] . As a result, tests for confirming erythropoietin use have been proposed:

* Elevation of the serum ratio of the soluble transferrin receptor to ferritin [50]

* The glycosylation pattern of commercially available recombinant erythropoietin differs from that of human serum erythropoietin, and can be detected by a combination of electrophoretic and immunologic techniques, although false-positive results are possible under certain conditions [48,51-53] .

Insulin — Athletes have also begun to use insulin because of its anabolic effects on muscle. In one survey of 20 men who were recruited from gyms and admitted to using androgens, 5 reported that they also used insulin [54] . They reported ingesting large amounts of sugar after insulin injection, but there have been reports of hypoglycemia in athletes who have taken insulin.

Creatine — The nutritional supplement creatine is taken by many professional, collegiate, and high school athletes. At one university, 48 percent of male and 4 percent of female athletes were chronically ingesting creatine supplements [55] . In a study of 328 male and female high school athletes, 27 (8 percent) reported taking creatine [56] .

Some small studies suggest that creatine enhances performance in short-duration, high-intensity exercise, but other studies suggest it does not [57] . No studies suggest that it enhances performance in endurance sports. In a meta-analysis of 16 studies, creatine supplements combined with resistance training increased the maximal weight that young men (<36 years old) were able to lift (bench press and squat) [58] . There was no effect in women and older men, and performance of other types of muscular effort did not improve.

Side effects include weight gain, and possibly acute interstitial nephritis and more rapid progression of renal disease [59,60] .

Beta blockers — Beta blockers are used by those competing in areas in which reduction of tremors is useful, such as archery.

SUMMARY

* The use of androgens, growth hormone, and other drugs to improve athletic performance is common, even in adolescents. (See "Epidemiology" above).

* Virtually all androgens produced for human or veterinary purposes have been taken by athletes (show figure 1). These include testosterone esters, which are usually taken by injection, the 17-alpha-alkylated androgens, which are usually taken orally, and androgen precursors. (See "Androgens" above).

* Exogenous testosterone administration increases serum testosterone concentrations, fat-free mass and muscle strength. There is no evidence that androstenedione increases muscle strength. (See "Efficacy" above).

* Adverse effects of androgen use include suppression of endogenous testicular function, gynecomastia, erythrocytosis, hepatoxicity (with 17-alpha-akylated androgens), psychological disorders, a decrease in serum HDL (especially with 17-alpha-akylated androgens), coagulation activation, premature epiphyseal fusion (in adolescents), infections, and virilization (in women). (See "Side effects" above).

* Detection of androgen use by athletes is difficult. The conventional method used is the urinary ratio of testosterone glucuronide to its endogenous epimer, epitestosterone glucuronide (T/E ratio). Normally, the T/E ratio is 1 to 3:1; a T/E ratio of >4:1 is considered evidence of doping by the World Anti-Doping Agency (WADA). (See "Detection of use" above).

* The utility of the T/E ratio is limited by its significant between subject variability, due to genetically determined differences in the ability to convert testosterone to testosterone glucuronide. (See "Detection of use" above).

* Human growth hormone is also commonly used to enhance athletic performance. Clinical trial data suggest that while lean body mass may be increased by growth hormone use, strength and exercise capacity are not. (See "Growth hormone" above).

* Detection of exogenous growth hormone use by athletes is difficult. There are two approaches currently being used: measurement of markers of growth hormone action (IGF-1 and N-terminal extension peptide of procollagen type III (P-III-P)), and measurement of growth hormone isoforms that can distinguish exogenous growth hormone from rhGH. (See "Growth hormone" above).

* Other banned substances and dietary supplements that are often used by athletes include stimulants, erythropoietin, insulin, creatine, and beta blockers. (See "Other drugs" above).


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Testosterone treatment of male hypogonadism


AuthorPeter J Snyder, MD
Section Editor
Alvin M Matsumoto, MD
Deputy Editor
Kathryn A Martin, MD

Last literature review for version 16.2: May 31, 2008 | This topic last updated: November 20, 2007

INTRODUCTION — Hypogonadism in a male refers to a decrease in either of the two major functions of the testes: sperm production or testosterone production. These abnormalities can result from disease of the testes (primary hypogonadism) or disease of the pituitary or hypothalamus (secondary hypogonadism). The use of testosterone to treat male hypogonadism is reviewed here. The clinical manifestations and diagnosis of male hypogonadism are discussed elsewhere. (See "Clinical features and diagnosis of male hypogonadism").

GENERAL PRINCIPLES — The means for replacing testosterone in hypogonadal men have been generally satisfactory for many years and are getting better as new pharmacologic preparations are developed and approved for general use. The following principles should guide testosterone therapy:

* Testosterone should be administered only to a man who is hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a distinctly subnormal serum testosterone concentration. In comparison, increasing the serum testosterone concentration in a man who has symptoms suggestive of hypogonadism, but whose testosterone concentration is already normal will not relieve those symptoms. (See "Clinical features and diagnosis of male hypogonadism").

* Testosterone can be replaced satisfactorily whether the testosterone deficiency is due to primary or secondary hypogonadism.

* The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range. It is not yet known if restoring the normal circadian rhythm of testosterone is important. (See "Male reproductive physiology").

* The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs with increasing frequency above age 60 in the absence identifiable pituitary or hypothalamic disease is uncertain. (See "Decline in testicular function with aging").

TESTOSTERONE PREPARATIONS — Choosing among the different testosterone preparations requires an understanding of their pharmacokinetics. Native testosterone is absorbed well from the intestine, but it is metabolized so rapidly by the liver that it is virtually impossible to maintain a normal serum testosterone concentration in a hypogonadal man with oral testosterone. The solutions to this problem that have been developed over many years involve modifying the testosterone molecule, changing the method of testosterone delivery, or both. The following testosterone preparations are currently available or are under development for treating testosterone deficiency:

Alkylated androgens — Decades ago, investigators discovered that adding an alkyl group in the 17-alpha position of the testosterone molecule retarded its catabolism by the liver (show figure 1). Since that time, several 17-alkylated androgens (eg, methytestosterone) have been available for oral use. Many endocrinologists who treat male hypogonadism think that these preparations are not fully effective in producing virilization, although no studies have tested these observations. In addition, several reports have described hepatic side effects with these preparations, including cholestatic jaundice, a hepatic cystic disease called peliosis hepatis, and hepatoma [1-5] . For both of these reasons, and because better preparations are available, the 17-alkylated androgens should generally not be used to treat testosterone deficiency.

Testosterone esters — Testosterone enanthate and testosterone cypionate are esters of testosterone that have been used for many years in the treatment of testosterone deficiency. The rationale for their use is that esterification of a lipophilic fatty acid to the 17-beta hydroxyl group of testosterone (show figure 1) makes testosterone even more lipophilic than the native molecule. Intramuscular injection of testosterone esters results in their storage in, and gradual release from the oil-based vehicle in which they are administered, thereby prolonging the presence of testosterone in the blood [6,7] .

The therapeutic characteristics of testosterone enanthate are relatively well described. In one report, for example, 100 mg of testosterone enanthate was administered once a week for 12 weeks to 12 men with primary hypogonadism [8] . The mean serum testosterone concentration increased to slightly higher than the upper limit of normal one to two days after the injection and gradually decreased to the mid-normal range by the time of the next injection (show figure 2).

When the dose of testosterone was increased to 200 mg in an attempt to prolong the dosing interval to every two weeks, the peak serum testosterone concentration increased further, and the nadir, just before the next injection, decreased to the low-normal range. Regimens of 300 mg every three weeks and 400 mg every four weeks increased the peaks and decreased the nadirs further.

The serum concentrations of luteinizing hormone (LH), which were initially above normal in all the men, decreased gradually after initiation of the 100 mg/week regimen, reaching the normal range by six to eight weeks and remaining in the normal range thereafter. Serum LH concentrations also decreased to normal with the 200 mg per two week regimen, barely to normal with the 300 mg per three week regimen, and remained supranormal with the 400 mg per four week regimen [8] .

These data suggest that testosterone enanthate doses from 100 mg per week to 300 mg per three weeks are biologically effective, but that 400 mg per four weeks is not. Less information is available for testosterone cypionate, but the few studies that have been performed suggest that its characteristics are similar to those of testosterone enanthate.

The advantage of testosterone enanthate and cypionate over other testosterone preparations is that they are biologically effective in initiating and maintaining normal virilization in all hypogonadal men. The disadvantages are the need for deep intramuscular administration of an oily solution every one to three weeks and fluctuations in the serum testosterone concentration, which result in fluctuations in energy, mood, and libido in many patients. These fluctuations are more pronounced as the dosing interval is increased.

An intramuscular formulation of another ester of testosterone, testosterone undecanoate, has been approved, under the trade name Nebido, in several countries for treatment of hypogonadism. When a 1000 mg dose is administered deep IM every three months, the serum testosterone concentration is maintained within the normal range [9] . An oral formulation of this ester is also available in some countries, but it does not keep the serum testosterone concentration normal in hypogonadal men.

Transdermal delivery — Transdermal delivery of testosterone first became available in 1994 with the introduction of a scrotal patch. Since then, body patches and gels have also become available, but the scrotal patch is no longer available in the United States. The major advantage of transdermal administration is maintenance of relatively stable serum testosterone concentrations, resulting in maintenance of relatively stable energy, mood, and libido.

Patch — One patch, Androderm, is currently available. Androderm relies upon chemical means to increase the absorption of testosterone across nonscrotal skin, and it is meant to be worn on the arm or torso. It delivers approximately 5 mg of testosterone per 24 hours and results in normal serum testosterone concentrations in the majority of hypogonadal men (show figure 2) [10-13] . Anecdotal reports suggest that as many as one third of men who try this preparation cannot continue it because of severe skin rash.

Testosterone gels — Testosterone in a hydroalcoholic gel (Androgel) [14] was approved by the FDA in February 2000. It is supplied in 2.5 g and 5.0 g packets, which contain 25 mg and 50 mg of testosterone, respectively [15] . A metered-dose pump that delivers 1.25 g of gel (containing 12.5 mg of testosterone) per pump depression is also available. When this preparation is applied to the skin once a day in doses of 50 to 100 mg, the serum testosterone concentrations reach the normal male range within a month and remain steady throughout 24 hours (show figure 2). The serum concentrations of testosterone throughout the 24 hours from one application to the next are similar at one, three, and six months [16] . Occasional local skin irritation occurs but usually does not necessitate discontinuation of therapy. A second testosterone gel preparation, Testim, has been approved at doses of 50 and 100 mg [17] . Anecdotal reports suggest that this preparation gives an odor.

Buccal tablet — A buccal tablet (Striant), 30 mg, was approved by the FDA in June, 2003. It is applied twice a day, and adheres, to a depression in the gum above the upper incisors and releases testosterone across the buccal mucosa into the systemic circulation [18] .

Human chorionic gonadotropin (hCG) — This preparation, while not an androgen, stimulates the testes to make testosterone and is especially useful in stimulating both testosterone and sperm production. (See "Induction of fertility in men with secondary hypogonadism").

MONITORING — Patients who are treated with testosterone should be monitored to determine that normal serum testosterone concentrations are being achieved. They should also be monitored for both desirable and undesirable effects.

Serum testosterone concentration — The timing of serum testosterone measurements varies with the preparation that is used.

* The serum testosterone should be measured midway between injections in men who are receiving testosterone enanthate, and the value should be mid-normal, eg, 600 to 700 ng/dL (20.8 to 24.3 nmol/L). The dose should be reduced if higher values are obtained.

* The serum testosterone can be measured at any time in men who are using any of the transdermal preparations, with the recognition that the peak values occur six to eight hours after application of the nonscrotal patch. The concentrations fluctuate when the gel is used, but not in a predictable way, so at least two measurements should be made at any dose of gel; the time of measurement does not appear to matter. The value should be well within the normal range (400 to 800 ng/dL [13.9 to 27.7 nmol/L]).

If the patient has primary hypogonadism, normalization of the serum LH concentration should also be used to judge the adequacy of the testosterone dose, no matter which testosterone preparation is used.

Desirable effects — Normalization of the serum testosterone concentration should lead to normal virilization in men who are not virilized and maintenance of virilization in those who already are. Men who become hypogonadal in adulthood and are still normally virilized, but whose hypogonadism is manifested by a decrease in libido and energy, should note a marked improvement in these symptoms. Failure of improvement when the serum testosterone concentration has been restored to normal suggests another cause of the symptoms.

Testosterone replacement also leads to substantial improvements in muscle strength and bone density. In one report, for example, the administration of 100 mg of testosterone enanthate once a week for ten weeks to hypogonadal men increased their strength in the bench press by 22 percent and their squat strength by 45 percent [19] . In another series, the effect of testosterone replacement on bone density was assessed in 72 hypogonadal men [20] . The increase in bone density averaged 39 percent in the first year of testosterone replacement and eventually reached and was maintained in the normal range. The response was greatest in the first year in previously untreated patients and was most pronounced in those with lowest bone density measurements at baseline. (See "Treatment of osteoporosis in men", section on testosterone therapy).

Undesirable effects — Testosterone enanthate and the testosterone patch and gels have few side effects unrelated to the action of testosterone.

* Testosterone enanthate rarely leads to infection at the injection site.

* The patch, Androderm, often causes skin rashes, some very mild and others quite severe, requiring discontinuation of this treatment. The rash may sometimes be prevented by pretreatment of the skin with a corticosteroid cream [21] . Local skin irritation occasionally occurs with testosterone gels (AndroGel and Testim), but usually is not severe and does not necessitate discontinuation of therapy.

* The possibility of skin transfer to a woman or child appears to be low if package insert directions are followed to wash hands thoroughly after application and avoid skin contact until the gel has dried completely. In a study of healthy male volunteers receiving testosterone gel, intense skin contact with a second male volunteer (pretreated with norethisterone [400 mg IM] to suppress endogenous testosterone) did not result in an increase in serum testosterone concentrations [22] . A few reports describe transfer of topical testosterone products, but most involve compounded products; one report describes transfer of a regulatory-approved product [23] .

Some of the actions of testosterone itself, while not side effects, are undesirable.

* During the first few months after the initiation of testosterone replacement, some of the undesirable effects of normal puberty, such as acne and gynecomastia, can be seen.

* When testosterone is first administered to hypogonadal adolescent boys, physically aggressive behavior may increase [24] .

* Overtreatment of a boy whose epiphyses have not yet closed can cause premature closure and permanent short stature.

* Prostate volumes and serum prostate specific antigen (PSA) increase in response to testosterone treatment [25-27] . On average, values increase to those of age-matched eugonadal men [28] .

Some men, especially those over the age of 50, experience an exacerbation of benign prostatic hyperplasia (BPH), a testosterone-dependent disease [29] . Symptoms, predominantly urinary outflow obstruction, may increase.

* Because prostate cancer is, at least to some degree, testosterone dependent, it seems theoretically likely that the risk of prostate cancer is less in hypogonadal men than eugonadal men and the risk increases to normal, but not above, when testosterone is replaced. However, no data are available to support or refute this assumption. It seems prudent, nonetheless, to screen hypogonadal men for prostate cancer before beginning testosterone replacement and to monitor them for prostate cancer during treatment, just as one would monitor a eugonadal man. (See "Decline in testicular function with aging", section on Prostate cancer).

* Sleep apnea and erythrocytosis may be worsened [30] .

There is no reason to think that men who rely on medication to maintain a normal serum testosterone concentration are more likely to develop these conditions than men who produce their own testosterone. Nevertheless, the physician who prescribes testosterone for a man over age 50 should monitor him as follows:

* For BPH, the symptom score should be assessed [31] and, if warranted by symptoms, the urine flow rate [32] and post-void residual urine in the bladder by ultrasonography [33] should be measured. (See "Medical treatment of benign prostatic hyperplasia" and see "Surgical and other invasive therapies of benign prostatic hyperplasia").

* For prostate cancer, digital rectal examination and measurement of serum PSA should be performed three months after initiation of treatment and then annually. The patient should be referred for prostate biopsy if a prostate nodule is palpated at any time or if the serum PSA concentration, confirmed by a repeat value, is above 4.0 ng/mL initially [34,35] or if it rises by more than 1.4 ng/mL in any one-year period or, if data are available for two or more years, a PSA velocity of >0.4 ng/mL per year, beginning six months after initiation of testosterone therapy [36] . The latter recommendations assume that the patient does not have prostatitis and that the values are confirmed by repeat measurement. (See "Measurement of prostate specific antigen").

* For erythrocytosis, the hemoglobin and hematocrit should be measured initially after three months and then yearly.

* For sleep apnea, the physician should inquire about symptoms, such as excessive daytime sleepiness and witnessed apnea during sleep by a partner, and, if indicated, polysomnography should be performed. (See "Polysomnography in obstructive sleep apnea-hypopnea in adults").

Time course of effects — The time course of the effects of testosterone replacement is variable. This was illustrated in a three-year study of physiological transdermal testosterone replacement in 18 previously untreated hypogonadal men [37] . Increases in fat-free mass, prostate volume, erythropoiesis, energy, and sexual function occurred within the first three to six months. In contrast, the full effect on bone mineral density did not occur until 24 months.

RECOMMENDATIONS — The following recommendations are consistent with the Endocrine Society Clinical Practice Guidelines [36] :

We recommend testosterone therapy for symptomatic men with hypogonadism, and usually recommend transdermal testosterone to most hypogonadal men, especially a gel, because it usually produces normal serum testosterone concentrations, and most patients find it the most convenient. Some men, however, prefer injections of testosterone enanthate because of the freedom from daily application.

For patients, cost may be an issue. In general, the newest preparations, the gels, cost the most, patches somewhat less, and injectable esters the least.

Men who begin using a transdermal preparation need to be seen two to three months after the initiation of therapy to measure the serum testosterone concentration and evaluate the possibility of undesirable effects. Men who use the body patch or a 50 mg dose of the gel, but whose serum testosterone concentration is not high enough, can try wearing two patches or applying 75 or 100 mg of the gel.

The initial regimen of testosterone enanthate should be 200 mg every two weeks, which can be administered either by someone in the patient's household or by the patient himself. The patient should be seen approximately two to three months later and, if he is bothered by fluctuations in energy, mood, or libido, the regimen can be changed to 100 mg once a week or transdermal testosterone can be offered again.

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REFERENCES

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25. Gerstenbluth, RE, Maniam, PN, Corty, EW, Seftel, AD. Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement. J Androl 2002; 23:922.
26. Meikle, AW, Arver, S, Dobs, AS, et al. Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 1997; 49:191.
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28. Behre, HM, Bohmeyer, J, Nieschlag, E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994; 40:341.
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35. Catalona, WJ, Hudson, MA, Scardino, PT, et al. Selection of optimal prostate specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristics. J Urol 1994; 152:3037.
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GRAPHICS

Structure of the different testosterone preparations
algorithm
Structure of the testosterone preparations available for the treatment of men with hypogonadism.

Serum testosterone concentrations during the course of chronic administration of three different testosterone preparations to hypogonadal men
graph
A) During 14 days following the injection of 200 mg of testosterone enanthate. B) During the 24 hours after application of one or two testosterone patches that deliver approximately 5 mg of testosterone each. C) During the 24 hours after application of a testosterone gel containing 50 or 100 mg of testosterone. Data from: Snyder, PJ, Lawrence, DA. J Clin Endocrinol Metab 1999; 51:1335. Dobs, AS, Meikle, AW, Arver, S, et al. J Clin Endocrinol Metab 1999; 84:3469. Swerdloff, RS, Wang, C, Cunningham, G, Dobs, A. J Clin Endocrinol Metab 2000; 85:4500.
 

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