APPROACH TO THE PATIENT: Androgen Deficiency
Hypogonadism is often characterized by decreased sex drive, reduced frequency of sexual activity, inability to maintain erections, reduced beard growth, loss of muscle mass, decreased testicular size, and gynecomastia. Erectile dysfunction and androgen deficiency are two distinct clinical disorders that can coexist in middle-aged and older men. Less than 10% of patients with erectile dysfunction have testosterone deficiency. Thus, it is useful to evaluate men presenting with erectile dysfunction for androgen deficiency. Except when extreme, these clinical features of androgen deficiency may be difficult to distinguish from changes that occur with normal aging.
Moreover, androgen deficiency may develop gradually. Several epidemiologic studies, such as the Framingham Heart Study, the Massachusetts Male Aging Study, the Baltimore Longitudinal Study of Aging, and the Study of Osteoporotic Fractures in Men, have reported a high prevalence of low testosterone levels in middle-aged and older men. The age-related decline in testosterone should be distinguished from classical hypogonadism due to diseases of the testes, the pituitary, and the hypothalamus.
When symptoms or clinical features suggest possible androgen deficiency, the laboratory evaluation is initiated by the measurement of total testosterone, preferably in the morning using a reliable assay, such as LC-MS/MS that has been calibrated to an international testosterone standard (Fig. 11-6). A consistently low total testosterone level <300 ng/dL measured by a reliable assay, in association with symptoms, is evidence of testosterone deficiency. An early-morning testosterone level >400 ng/dL makes the diagnosis of androgen deficiency unlikely. In men with testosterone levels between 200 and 400 ng/dL, the total testosterone level should be repeated and a free testosterone level should be measured. In older men and in patients with other clinical states that are associated with alterations in SHBG levels, a direct measurement of free testosterone level by equilibrium dialysis can be useful in unmasking testosterone deficiency.
When androgen deficiency has been confirmed by the consistently low testosterone concentrations, LH should be measured to classify the patient as having primary (high LH) or secondary (low or inappropriately normal LH) hypogonadism. An elevated LH level indicates that the defect is at the testicular level. Common causes of primary testicular failure include Klinefelter’s syndrome, HIV infection, uncorrected cryptorchidism, cancer chemotherapeutic agents, radiation, surgical orchiectomy, or prior infectious orchitis. Unless causes of primary testicular failure are known, a karyotype should be performed in men with low testosterone and elevated LH to exclude Klinefelter’s syndrome. Men who have low testosterone levels but “inappropriately normal” or low LH levels have secondary hypogonadism; their defect resides at the hypothalamic-pituitary level. Common causes of acquired secondary hypogonadism include space-occupying lesions of the sella, hyperprolactinemia, chronic illness, hemochromatosis, excessive exercise, and the use of anabolic-androgenic steroids, opiates, marijuana, glucocorticoids, and alcohol. Measurement of PRL and MRI scan of the hypothalamic-pituitary region can help exclude the presence of a space-occupying lesion. Patients in whom known causes of hypogonadotropic hypogonadism have been excluded are classified as having IHH. It is not unusual for congenital causes of hypogonadotropic hypogonadism, such as Kallmann’s syndrome, to be diagnosed in young adults.
TREATMENT Androgen Deficiency GONADOTROPINS
Gonadotropin therapy is used to establish or restore fertility in patients with gonadotropin deficiency of any cause. Several gonadotropin preparations are available. Human menopausal gonadotropin (hMG; purified from the urine of postmenopausal women) contains 75 IU FSH and 75 IU LH per vial. hCG (purified from the urine of pregnant women) has little FSH activity and resembles LH in its ability to stimulate testosterone production by Leydig cells. Recombinant LH is now available. Because of the expense of hMG, treatment is usually begun with hCG alone, and hMG is added later to promote the FSH-dependent stages of spermatid development. Recombinant human FSH (hFSH) is now available and is indistinguishable from purified urinary hFSH in its biologic activity and pharmacokinetics in vitro and in vivo, although the mature β subunit of recombinant hFSH has seven fewer amino acids. Recombinant hFSH is available in ampoules containing 75 IU (~7.5 μg FSH), which accounts for >99% of protein content. Once spermatogenesis is restored using combined FSH and LH therapy, hCG alone is often sufficient to maintain spermatogenesis.
Although a variety of treatment regimens are used, 1000–2000 IU of hCG or recombinant human LH (rhLH) administered intramuscularly three times weekly is a reasonable starting dose. Testosterone levels should be measured 6–8 weeks later and 48–72 h after the hCG or rhLH injection; the hCG/rhLH dose should be adjusted to achieve testosterone levels in the mid-normal range. Sperm counts should be monitored on a monthly basis. It may take several months for spermatogenesis to be restored; therefore, it is important to forewarn patients about the potential length and expense of the treatment and to provide conservative estimates of success rates. If testosterone levels are in the mid-normal range but the sperm concentrations are low after 6 months of therapy with hCG alone, FSH should be added. This can be done by using hMG, highly purified urinary hFSH, or recombinant hFSH. The selection of FSH dose is empirical. A common practice is to start with the addition of 75 IU FSH three times each week in conjunction with the hCG/rhLH injections. If sperm densities are still low after 3 months of combined treatment, the FSH dose should be increased to 150 IU. Occasionally, it may take ≥18–24 months for spermatogenesis to be restored.
The two best predictors of success using gonadotropin therapy in hypogonadotropic men are testicular volume at presentation and time of onset. In general, men with testicular volumes >8 mL have better response rates than those who have testicular volumes >4 mL. Patients who became hypogonadotropic after puberty experience higher success rates than those who have never undergone pubertal changes. Spermatogenesis can usually be reinitiated by hCG alone, with high rates of success for men with postpubertal onset of hypogonadotropism. The presence of a primary testicular abnormality, such as cryptorchidism, will attenuate testicular response to gonadotropin therapy. Prior androgen therapy does not preclude subsequent response to gonadotropin therapy, although some studies suggest that it may attenuate response to subsequent gonadotropin therapy. TESTOSTERONE REPLACEMENT
Androgen therapy is indicated to restore testosterone levels to normal to correct features of androgen deficiency. Testosterone replacement improves libido and overall sexual activity; increases energy, lean muscle mass, and bone density; and decreases fat mass. The benefits of testosterone replacement therapy have only been proven in men who have documented androgen deficiency, as demonstrated by testosterone levels that are well below the lower limit of normal.
Testosterone is available in a variety of formulations with distinct pharmacokinetics (Table 11-3). Testosterone serves as a prohormone and is converted to 17β-estradiol by aromatase and to 5α-dihydrotestosterone by steroid 5α-reductase. Therefore, when evaluating testosterone formulations, it is important to consider whether the formulation being used can achieve physiologic estradiol and DHT concentrations, in addition to normal testosterone concentrations. Although testosterone concentrations at the lower end of the normal male range can restore sexual function, it is not clear whether low-normal testosterone levels can maintain bone mineral density and muscle mass. The current recommendation is to restore testosterone levels to the mid-normal range. Oral Derivatives of Testosterone
Testosterone is well-absorbed after oral administration but is quickly degraded during the first pass through the liver. Therefore, it is difficult to achieve sustained blood levels of testosterone after oral administration of crystalline testosterone. 17α-Alkylated derivatives of testosterone (e.g., 17α-methyl testosterone, oxandrolone, fluoxymesterone) are relatively resistant to hepatic degradation and can be administered orally; however, because of the potential for hepatotoxicity, including cholestatic jaundice, peliosis, and hepatoma, these formulations should not be used for testosterone replacement. Hereditary angioedema due to C1 esterase deficiency is the only exception to this general recommendation; in this condition, oral 17α-alkylated androgens are useful because they stimulate hepatic synthesis of the C1 esterase inhibitor. Injectable Forms of Testosterone
The esterification of testosterone at the 17β-hydroxy position makes the molecule hydrophobic and extends its duration of action. The slow release of testosterone ester from an oily depot in the muscle accounts for its extended duration of action. The longer the side chain, the greater is the hydrophobicity of the ester and the longer is the duration of action. Thus, testosterone enanthate, cypionate, and undecanoate with longer side chains have longer duration of action than testosterone propionate. Within 24 h after intramuscular administration of 200 mg testosterone enanthate or cypionate, testosterone levels rise into the high-normal or supraphysiologic range and then gradually decline into the hypogonadal range over the next 2 weeks. A bimonthly regimen of testosterone enanthate or cypionate therefore results in peaks and troughs in testosterone levels that are accompanied by changes in a patient’s mood, sexual desire, and energy level. The kinetics of testosterone enanthate and cypionate are similar. Estradiol and DHT levels are normal if testosterone replacement is physiologic. Transdermal Testosterone Patch
The nongenital testosterone patch, when applied in an appropriate dose, can normalize testosterone, DHT, and estradiol levels 4–12 h after application. Sexual function and well-being are restored in androgen-deficient men treated with the nongenital patch. One 5-mg patch may not be sufficient to increase testosterone into the mid-normal male range in all hypogonadal men; some patients may need two 5-mg patches daily to achieve the targeted testosterone concentrations. The use of testosterone patches may be associated with skin irritation in some individuals. Testosterone Gel
Several transdermal testosterone gels (e.g., Androgel, Testim, Fortesta, and Axiron), when applied topically to the skin in appropriate doses (Table 11-3), can maintain total and free testosterone concentrations in the normal range in hypogonadal men. The current recommendations are to begin with an initial U.S. Food and Drug Administration–approved dose and adjust the dose based on testosterone levels. The advantages of the testosterone gel include the ease of application and its flexibility of dosing. A major concern is the potential for inadvertent transfer of the gel to a sexual partner or to children who may come in close contact with the patient. The ratio of DHT to testosterone concentrations is higher in men treated with the testosterone gel than in healthy men. Also, there is considerable intra- and interindividual variation in serum testosterone levels in men treated with the transdermal gel due to variations in transdermal absorption and plasma clearance of testosterone. Therefore, monitoring of serum testosterone levels and multiple dose adjustments may be required to achieve and maintain testosterone levels in the target range. Buccal Adhesive Testosterone
A buccal testosterone tablet, which adheres to the buccal mucosa and releases testosterone as it is slowly dissolved, has been approved. After twice-daily application of 30-mg tablets, serum testosterone levels are maintained within the normal male range in a majority of treated hypogonadal men. The adverse effects include buccal ulceration and gum problems in a few subjects. The effects of food and brushing on absorption have not been studied in detail.
Implants of crystalline testosterone can be inserted in the subcutaneous tissue by means of a trocar through a small skin incision. Testosterone is released by surface erosion of the implant and absorbed into the systemic circulation. Two to six 200-mg implants can maintain testosterone in the mid- to high-normal range for up to 6 months. Potential drawbacks include incising the skin for insertion and removal and spontaneous extrusions and fibrosis at the site of the implant. Testosterone Formulations Not Available in the United States
Testo-sterone undecanoate, when administered orally in oleic acid, is absorbed preferentially through the lymphatics into the systemic circulation and is spared the first-pass degradation in the liver. Doses of 40–80 mg orally, two or three times daily, are typically used. However, the clinical responses are variable and suboptimal. DHT-to-testosterone ratios are higher in hypogonadal men treated with oral testosterone undecanoate, as compared to eugonadal men.
After initial priming, long-acting testosterone undecanoate in oil, when administered intramuscularly every 12 weeks, maintains serum testosterone, estradiol, and DHT in the normal male range and corrects symptoms of androgen deficiency in a majority of treated men. However, large injection volume (4 mL) is its relative drawback. Novel Androgen Formulations
A number of androgen formulations with better pharmacokinetics or more selective activity profiles are under development. A long-acting ester, testosterone undecanoate, when injected intramuscularly, can maintain circulating testosterone concentrations in the male range for 7–12 weeks. Initial clinical trials have demonstrated the feasibility of administering testosterone by the sublingual or buccal routes. 7α-Methyl-19-nortestosterone is an androgen that cannot be 5α-reduced; therefore, compared to testosterone, it has relatively greater agonist activity in muscle and gonadotropin suppression but lesser activity on the prostate.
Selective AR modulators (SARMs) are a class of AR ligands that bind the AR and display tissue-selective actions. A number of nonsteroidal SARMs that act as full agonists on the muscle and bone and that spare the prostate to varying degrees have advanced to phase 3 human trials. Nonsteroidal SARMs do not serve as substrates for either the steroid 5α-reductase or the CYP19 aromatase. SARM binding to AR induces specific conformational changes in the AR protein, which then modulates protein-protein interactions between AR and its coregulators, resulting in tissue-specific regulation of gene expression. Pharmacologic Uses of Androgens
Androgens and SARMs are being evaluated as anabolic therapies for functional limitations associated with aging and chronic illness. Testosterone supplementation increases skeletal muscle mass, maximal voluntary strength, and muscle power in healthy men, hypogonadal men, older men with low testosterone levels, HIV-infected men with weight loss, and men receiving glucocorticoids. These anabolic effects of testosterone are related to testosterone dose and circulating concentrations. Systematic reviews have confirmed that testosterone therapy of HIV-infected men with weight loss promotes improvements in body weight, lean body mass, muscle strength, and depression indices, leading to the recommendation that testosterone be considered as an adjunctive therapy in HIV-infected men who are experiencing unexplained weight loss and who have low testosterone levels. Similarly, in glucocorticoid-treated men, testosterone therapy should be considered to maintain muscle mass and strength and vertebral bone mineral density. It is unknown whether testosterone therapy of older men with functional limitations is safe and effective in improving physical function, vitality, and health-related quality of life and reducing disability. Concerns about potential adverse effects of testosterone on prostate and cardiovascular event rates have encouraged the development of SARMs that are preferentially anabolic and spare the prostate.
Testosterone administration induces hypertrophy of both type 1 and 2 fibers and increases satellite cell (muscle progenitor cells) and myonuclear number. Androgens promote the differentiation of mesenchymal, multipotent progenitor cells into the myogenic lineage and inhibit their differentiation into the adipogenic lineage. Testosterone may have additional effects on satellite cell replication and muscle protein synthesis, which may contribute to an increase in skeletal muscle mass.
Other indications for androgen therapy are in selected patients with anemia due to bone marrow failure (an indication largely supplanted by erythropoietin) or for hereditary angioedema. Male Hormonal Contraception Based on Combined Administration of Testosterone and Gonadotropin Inhibitors
Supraphysiologic doses of testosterone (200 mg testosterone enanthate weekly) suppress LH and FSH secretion and induce azoospermia in 50% of Caucasian men and >95% of Chinese men. The WHO-supported multicenter efficacy trials have demonstrated that suppression of spermatogenesis to azoospermia or severe oligozoospermia (<3 million/mL) by administration of testosterone enanthate to men results in highly effective contraception. Because of concern about long-term adverse effects of supraphysiologic testosterone doses, regimens that combine other gonadotropin inhibitors, such as GnRH antagonists and progestins with replacement doses of testosterone, are being investigated. Oral etonogestrel daily in combination with intramuscular testosterone decanoate every 4–6 weeks induced azoospermia or severe oligozoospermia (sperm density <1 million/mL) in 99% of treated men over a 1-year period. This regimen was associated with weight gain, deceased testicular volume, and decreased plasma high-density lipoprotein (HDL) cholesterol, and its long-term safety has not been demonstrated. SARMs that are more potent inhibitors of gonadotropins than testosterone and spare the prostate hold promise for their contraceptive potential. Recommended Regimens for Androgen Replacement
Testosterone esters are administered typically at doses of 75–100 mg intramuscularly every week, or 150–200 mg every 2 weeks. One or two 5-mg nongenital testosterone patches can be applied daily over the skin of the back, thigh, or upper arm away from pressure areas. Testosterone gels are typically applied over a covered area of skin at initial doses that vary with the formulation; patients should wash their hands after gel application. Bioadhesive buccal testosterone tablets at a dose of 30 mg are typically applied twice daily on the buccal mucosa. Establishing Efficacy of Testosterone Replacement Therapy
Because a clinically useful marker of androgen action is not available, restoration of testosterone levels to the mid-normal range remains the goal of therapy. Measurements of LH and FSH are not useful in assessing the adequacy of testosterone replacement. Testosterone should be measured 3 months after initiating therapy to assess adequacy of therapy. There is substantial interindividual variability in serum testosterone levels, especially with transdermal gels, presumably due to genetic differences in testosterone clearance and transdermal absorption. In patients who are treated with testosterone enanthate or cypionate, testosterone levels should be 350–600 ng/dL 1 week after the injection. If testosterone levels are outside this range, adjustments should be made either in the dose or in the interval between injections. In men on transdermal patch, gel, or buccal testosterone therapy, testosterone levels should be in the mid-normal range (500–700 ng/dL) 4–12 h after application. If testosterone levels are outside this range, the dose should be adjusted. Multiple dose adjustments are often necessary to achieve testosterone levels in the desired therapeutic range.
Restoration of sexual function, secondary sex characteristics, energy, and well-being and maintenance of muscle and bone health are important objectives of testosterone replacement therapy. The patient should be asked about sexual desire and activity, the presence of early morning erections, and the ability to achieve and maintain erections adequate for sexual intercourse. Some hypogonadal men continue to complain about sexual dysfunction even after testosterone replacement has been instituted; these patients may benefit from counseling. The hair growth in response to androgen replacement is variable and depends on ethnicity. Hypogonadal men with prepubertal onset of androgen deficiency who begin testosterone therapy in their late twenties or thirties may find it difficult to adjust to their newly found sexuality and may benefit from counseling. If the patient has a sexual partner, the partner should be included in counseling because of the dramatic physical and sexual changes that occur with androgen treatment. Contraindications for Androgen Administration
Testosterone administration is contraindicated in men with a history of prostate or breast cancer (Table 11-4). Testosterone therapy should not be administered without further urologic evaluation to men with a palpable prostate nodule or induration; to men with prostate-specific antigen levels >4 ng/mL or >3 ng/mL in men at high risk for prostate cancer such as African Americans or men with first-degree relatives with prostate cancer; or to men with severe lower urinary tract symptoms (American Urological Association lower urinary tract symptom score >19). Testosterone replacement should not be administered to men with baseline hematocrit ≥50%, severe untreated obstructive sleep apnea, uncontrolled or poorly controlled congestive heart failure, or myocardial infarction, stroke, or acute coronary syndrome in the preceding 6 months. Monitoring Potential Adverse Experiences
The clinical effectiveness and safety of testosterone replacement therapy should be assessed 3 to 6 months after initiating testosterone therapy and annually thereafter (Table 11-5). Potential adverse effects include acne, oiliness of skin, erythrocytosis, breast tenderness and enlargement, leg edema, induction and exacerbation of obstructive sleep apnea, and increased risk of detection of prostate events. In addition, there may be formulation-specific adverse effects such as skin irritation with transdermal patch, risk of gel transfer to a sexual partner with testosterone gels, buccal ulceration and gum problems with buccal testosterone, and pain and mood fluctuation with injectable testosterone esters. Older men with preexisting heart disease may be at increased risk of cardiovascular events after initiation of testosterone therapy. HEMOGLOBIN LEVELS
Administration of testosterone to androgen-deficient men is typically associated with a ~3% increase in hemoglobin levels, due to increased erythropoiesis, suppression of hepcidin, and increased iron availability for erythropoiesis. The magnitude of hemoglobin increase during testosterone therapy is greater in older men than younger men and in men who have sleep apnea, a significant smoking history, or chronic obstructive lung disease. The frequency of erythrocytosis is higher in hypogonadal men treated with injectable testosterone esters than in those treated with transdermal formulations, presumably due to the higher testosterone dose delivered by the typical regimens of testosterone esters. Erythrocytosis is the most frequent adverse event reported in testosterone trials in middle-aged and older men and is also the most frequent cause of treatment discontinuation in these trials. If hematocrit rises above 54%, testosterone therapy should be stopped until hematocrit has fallen to <50%. After evaluation of the patient for hypoxia and sleep apnea, testosterone therapy may be reinitiated at a lower dose. PROSTATE AND SERUM PROSTATE-SPECIFIC ANTIGEN LEVELS
Testosterone replacement therapy increases prostate volume to the size seen in age-matched controls but does not increase prostate volume beyond that expected for age. There is no evidence that testosterone therapy causes prostate cancer. However, androgen administration can exacerbate preexisting metastatic prostate cancer. Many older men harbor microscopic foci of cancer in their prostates. It is not known whether long-term testosterone administration will induce these microscopic foci to grow into clinically significant cancers.
Prostate-specific antigen (PSA) levels are lower in testosterone-deficient men and are restored to normal after testosterone replacement. There is considerable test-retest variability in PSA measurements. Increments in PSA levels after testosterone supplementation in androgen-deficient men are generally <0.5 ng/mL, and increments >1.0 ng/mL over a 3- to 6-month period are unusual. The 90% confidence interval for the change in PSA values in men with benign prostatic hypertrophy, measured 3–6 months apart, is 1.4 ng/mL. Therefore, the Endocrine Society expert panel suggested that an increase in PSA >1.4 ng/mL in any 1 year after starting testosterone therapy, if confirmed, should lead to urologic evaluation. PSA velocity criterion can be used for patients who have sequential PSA measurements for >2 years; a change of >0.40 ng/mL per year merits closer urologic follow-up. CARDIOVASCULAR RISK
In epidemiologic studies, testosterone concentrations are negatively related to the risk of diabetes mellitus, heart disease, and all-cause and cardiovascular mortality. A recent testosterone trial in older men with mobility limitation was stopped early because of the higher rates of cardiovascular events in the testosterone arm than in the placebo arm of this trial. Meta-analyses of testosterone trials have found a significant increase in cardiovascular event rates in older men receiving testosterone therapy. Inferences about adverse events from previous trials included in these meta-analyses are limited by poor ascertainment, small numbers of events, heterogeneity of study populations, and small numbers of participants. Two retrospective analyses also found a higher frequency of cardiovascular events in association with testosterone therapy in older men with preexisting heart disease. Retrospective database analyses are limited by their inherent inability to verify the indication for treatment, diagnoses, or other relevant quantitative information and are susceptible to confounding by many other factors. Adequately powered prospective studies are needed to determine the effect on testosterone replacement on cardiovascular risk. Androgen Abuse by Athletes and Recreational Bodybuilders
The illicit use of androgenic-anabolic steroids (AAS) to enhance athletic performance first surfaced in the 1950s among power lifters and spread rapidly to other sports, professional as well as high school athletes, and recreational bodybuilders. In the early 1980s, the use of AAS spread beyond the athletic community into the general population, and now as many as 3 million Americans, most of them men, have likely used these compounds. Most AAS users are not athletes, but rather recreational weightlifters, who use these drugs to look lean and more muscular. The most commonly used AAS include testosterone esters, nandrolone, stanozolol, methandienone, and methenolol. AAS users generally use increasing doses of multiple steroids in a practice known as stacking.
The adverse effects of long-term AAS abuse remain poorly understood. Most of the information about the adverse effects of AAS has emerged from case reports, uncontrolled studies, or clinical trials that used replacement doses of testosterone. The adverse event data from clinical trials using physiologic replacement doses of testosterone have been extrapolated unjustifiably to AAS users who may administer 10–100 times the replacement doses of testosterone over many years and to support the claim that AAS use is safe. A substantial fraction of androgenic steroid users also use other drugs that are perceived to be muscle building or performance enhancing, such as GH; erythropoiesis-stimulating agents; insulin; and stimulants such as amphetamine, clenbuterol, cocaine, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as hCG, aromatase inhibitors, or estrogen antagonists. The men who abuse androgenic steroids are more likely to engage in other high-risk behaviors than nonusers. The adverse events associated with AAS use may be due to AAS themselves, concomitant use of other drugs, high-risk behaviors, and host characteristics that may render these individuals more susceptible to AAS use or to other high-risk behaviors.
The high rates of mortality and morbidities observed in AAS users are alarming. One Finnish study reported 4.6 times the risk of death among elite power lifters than in age-matched men from the general population. The causes of death among power lifters included suicides, myocardial infarction, hepatic coma, and non-Hodgkin’s lymphoma. A retrospective review of patient records in Sweden also reported higher standardized mortality ratios for AAS users than for nonusers. Thiblin and colleagues found that 32% of deaths among AAS users were suicidal, 26% homicidal, and 35% accidental. The median age of death among AAS users (24 years) is even lower than that for heroin or amphetamine users.
Numerous reports of cardiac death among young AAS users raise concerns about the adverse cardiovascular effects of AAS. High doses of AAS may induce proatherogenic dyslipidemia, increase thrombosis risk via effects on clotting factors and platelets, and induce vasospasm through their effects on vascular nitric oxide.
Replacement doses of testosterone, when administered parenterally, are associated with only a small decrease in HDL cholesterol and little or no effect on total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. In contrast, supraphysiologic doses of testosterone and orally administered, 17α-alkylated, nonaromatizable AAS are associated with marked reductions in HDL cholesterol and increases in LDL cholesterol.
Recent studies of AAS users using tissue Doppler and strain imaging and MRI have reported diastolic and systolic dysfunction, including significantly lower early and late diastolic tissue velocities, reduced E/A ratio, and reduced peak systolic strain in AAS users than in nonusers. Power athletes using AAS often have short QT intervals but increased QT dispersion, which may predispose them to ventricular arrhythmias. Long-term AAS use may be associated with myocardial hypertrophy and fibrosis. Myocardial tissue of power lifters using AAS has been shown to be infiltrated with fibrous tissue and fat droplets. The finding of ARs on myocardial cells suggests that AAS might be directly toxic to myocardial cells.
Long-term AAS use suppresses LH and FSH secretion and inhibits endogenous testosterone production and spermatogenesis. Men who have used AAS for more than a few months experience marked suppression of the hypothalamic-pituitary-testicular (HPT) axis after stopping AAS that may be associated with sexual dysfunction, fatigue, infertility, and depression; in some AAS users, HPT suppression may last more than a year, and in a few individuals, complete recovery may never occur. The symptoms of androgen deficiency caused by androgen withdrawal may cause some men to revert back to using AAS, leading to continued use and AAS dependence. As many as 30% of AAS users develop a syndrome of AAS dependence, characterized by long-term AAS use despite adverse medical and psychiatric effects.
Supraphysiologic doses of testosterone may also impair insulin sensitivity. Orally administered androgens also have been associated with insulin resistance and diabetes.
Unsafe injection practices, high-risk behaviors, and increased rates of incarceration render AAS users at increased risk of HIV and hepatitis B and C. In one survey, nearly 1 in 10 gay men had injected AAS or other substances, and AAS users were more likely to report high-risk unprotected anal sex than other men.
Some AAS users develop hypomanic or manic symptoms during AAS exposure (irritability, aggressiveness, reckless behavior, and occasional psychotic symptoms, sometimes associated with violence) and major depression (sometimes associated with suicidality) during AAS withdrawal. Users may also develop other forms of illicit drug use, which may be potentiated or exacerbated by AAS.
Elevated liver enzymes, cholestatic jaundice, hepatic neoplasms, and peliosis hepatis have been reported with oral, 17α-alkylated AAS. AAS use may cause muscle hypertrophy without compensatory adaptations in tendons, ligaments, and joints, thus increasing the risk of tendon and joint injuries. AAS use is associated with acne, baldness, and increased body hair.
The suspicion of AAS use may be raised by the increased hemoglobin and hematocrit, suppressed LH and FSH and testosterone levels, low high-density lipoproteins cholesterol, and low testicular volume and sperm density in a person who looks highly muscular. Accredited laboratories use gas chromatography–mass spectrometry or liquid chromatography–mass spectrometry to detect anabolic steroid abuse. In recent years, the availability of high-resolution mass spectrometry and tandem mass spectrometry has further improved the sensitivity of detecting androgen abuse. Illicit testosterone use is detected generally by the application of the measurement of the urinary testosterone-to-epitestosterone ratio and further confirmed by the use of the 13C:12C ratio in testosterone by the use of isotope ratio combustion mass spectrometry. Exogenous testosterone administration increases urinary testosterone glucuronide excretion and consequently the testosterone-to-epitestosterone ratio. Ratios >4 suggest exogenous testosterone use but can also reflect genetic variation. Genetic variations in the uridine diphosphoglucuronyl transferase 2B17 (UGT2B17), the major enzyme for testosterone glucuronidation, affect the testosterone-to-epitestosterone ratio. Synthetic testosterone has a lower 13C:12C ratio than endogenously produced testosterone, and these differences in 13C:12C ratio can be detected by isotope ratio combustion mass spectrometry, which is used to confirm exogenous testosterone use in individuals with a high testosterone-to-epitestosterone ratio.