In epidemiologic surveys, low total and bioavailable testosterone concentrations have been associated with decreased appendicular skeletal muscle mass and strength, decreased self-reported physical function, higher visceral fat mass, insulin resistance, and increased risk of coronary artery disease and mortality. An analysis of signs and symptoms in older men in the European Male Aging Study revealed a syndromic association of sexual and physical symptoms with testosterone levels <320 ng/dL in community-dwelling older men. In systematic reviews of randomized controlled trials, testosterone therapy in healthy older men with low or low-normal testosterone levels was associated with greater increments in lean body mass, grip strength, and self-reported physical function than was the case with placebo. Testosterone therapy also induced greater improvement in vertebral but not femoral bone mineral density. Testosterone therapy in older men with sexual dysfunction and unequivocally low testosterone levels improves libido, but testosterone effects on erectile function and response to selective phosphodiesterase inhibitors have been inconsistent. Testosterone therapy has not been shown to improve depression scores, fracture risk, cognitive function, or clinical outcomes in older men. Furthermore, neither the long-term risks nor the clinical benefits of testosterone therapy in older men have been demonstrated in adequately powered trials. Although there is no evidence that testosterone causes prostate cancer, there is concern that testosterone therapy might induce the growth of subclinical prostate cancers or exacerbate cardiovascular disease. One randomized testosterone trial in older men with mobility limitation and a high burden of chronic conditions such as diabetes, heart disease, hypertension, and hyperlipidemia reported a greater number of cardiovascular events in men randomized to the testosterone arm of the study than in those randomized to the placebo arm. Population screening of all older men for low testosterone levels is not recommended, and testing should be restricted to men who have symptoms or physical features attributable to androgen deficiency. Testosterone therapy is not recommended for all older men with low testosterone levels. In older men with significant symptoms of androgen deficiency who have testosterone levels <200 ng/dL, testosterone therapy may be considered on an individualized basis and should be instituted after careful discussion of the risks and benefits (see "Testosterone Replacement," below).
Approach to the Patient: Androgen Deficiency
Hypogonadism often is characterized by decreased sex drive, reduced frequency of sexual intercourse or inability to maintain erections, reduced beard growth, loss of muscle mass, decreased testicular size, and gynecomastia. Less than 10% of patients with erectile dysfunction alone have testosterone deficiency. Thus, it is useful to look for a constellation of symptoms and signs suggestive of androgen deficiency. Except when extreme, these clinical features may be difficult to distinguish from changes that occur with normal aging. Moreover, androgen deficiency may develop gradually. Although population studies such as the Massachusetts Male Aging Study and the Baltimore Longitudinal Study of Aging 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 classic hypogonadism due to diseases of the testes, the pituitary, or 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 (Fig. 346-6). A consistently low total testosterone level <300 ng/dL measured by a reliable assay in association with symptoms provides evidence of testosterone deficiency. An early-morning testosterone level >350 ng/dL makes the diagnosis of androgen deficiency unlikely. In men with testosterone levels between 200 and 350 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.
Evaluation of hypogonadism. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; T, testosterone.
When androgen deficiency has been confirmed by 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, and 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 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 substance abuse. Measurement of PRL and an 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.
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 usually is 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 ampules 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, 1500–2000 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 hours 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 the FSH dose is empirical. A common practice is to start with the addition of 75 IU FSH three times a 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 usually can 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.
Androgen therapy is indicated to restore testosterone levels to normal to correct features of androgen deficiency. Testosterone replacement improves libido and overall sexual activity and increases energy, lean muscle mass, and bone density. The benefits of testosterone replacement therapy have been proved only in men who have documented androgen deficiency, as demonstrated by testosterone levels that are well below the lower limit of normal (<250 ng/dL).
Testosterone is available in a variety of formulations with distinct pharmacokinetics (Table 346-3). Testosterone serves as a prohormone and is converted to 17β-estradiol by aromatase and to 5α-dihydrotestosterone by 5α-reductase. Therefore, in 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.
Table 346-3 Clinical Pharmacology of Some Testosterone Formulations |Favorite Table|Download (.pdf)
Table 346-3 Clinical Pharmacology of Some Testosterone Formulations
|Formulation||Regimen||Pharmacokinetic profile||DHT and E2||Advantages||Disadvantages|
|Testosterone enanthate or cypionate||150–200 mg IM q 2 weeks or 75-100 mg/week||After a single IM injection, serum T levels rise into the supraphysiologic range, then decline gradually into the hypogonadal range by the end of the dosing interval||DHT and E2 levels rise in proportion to the increase in T levels; T:DHT and T:E2 ratios do not change||Corrects symptoms of androgen deficiency; relatively inexpensive if self-administered; flexibility of dosing||Requires IM injection; peaks and valleys in serum T levels|
|1% Testosterone gel|
Available in sachets, tubes, and pumps
5–10 g T gel containing 50–100 mg T qid
|Restores serum T and E2 levels to physiologic male range||Serum DHT levels are higher and T:DHT ratios are lower in hypogonadal men treated with the T gel than in healthy eugonadal men||Corrects symptoms of androgen deficiency; provides flexibility of dosing, ease of application; good skin tolerability||Potential of transfer to a female partner or child by direct skin-to-skin contact; skin irritation in a small proportion of treated men; moderately high DHT levels|
|Transdermal testosterone patch||1 or 2 patches, designed to nominally deliver 5–10 mg T over 24 h applied qid on nonpressure areas||Restores serum T, DHT, and E2 levels to physiologic male range||T:DHT and T:E2 levels are in physiologic male range||Ease of application; corrects symptoms of androgen deficiency||Serum T levels in some androgen-deficient men may be in the low-normal range; these men may need application of 2 patches daily; skin irritation at the application site occurs frequently in many patients|
|Buccal, bioadhesive, T tablets||30-mg controlled-release, bioadhesive tablets bid||Absorbed from buccal mucosa||Normalizes serum T and DHT levels in hypogonadal men||Corrects symptoms of androgen deficiency in healthy, hypogonadal men||Gum-related adverse events in 16% of treated men.|
|Testosterone pellets||3–6 pellets implanted SC; dose and regimen vary with formulation||Serum T peaks at 1 month and then is sustained in normal range for 3–6 months, depending on formulation||T:DHT and T:E2 ratios do not change||Corrects symptoms of androgen deficiency||Requires surgical incision for insertions; pellets may extrude spontaneously|
|17-α-methyl testosterone||This 17-α-alkylated compound should not be used because of potential for liver toxicity.||Orally active||Clinical responses are variable; potential for liver toxicity; should not be used for treatment of androgen deficiency|
|Oral testosterone undecanoate*||40–80 mg PO bid or tid with meals||When administered in oleic acid, T undecanoate is absorbed through lymphatics, bypassing portal system; considerable variability in the same individual on different days and among individuals||High DHT to T ratio||Convenience of oral administration||Not approved in the United States; variable clinical responses, variable serum T levels, high DHT:T ratio|
|Injectable long-acting testosterone undecanoate in oil*||European regimen 1000 mg IM, followed by 1000 mg at 6 weeks and 1000 mg q 10–14 weeks||When administered at a dose of 750–1000 mg IM, serum T levels are maintained in the normal range in a majority of treated men||DHT and E2 levels rise in proportion to increase in T levels; T:DHT and T:E2 ratios do not change||Corrects symptoms of androgen deficiency; requires infrequent administration.||Requires IM injection of a large volume (4 mL); cough reported immediately after injection in a very small number of men|
|Testosterone-inadhesive matrix patch*||2 × 60 cm2 patches delivering approximately 4.8 mg of T/d||Restores serum T, DHT, and E2 to physiologic range||T:DHT and T:E2 are in physiologic range.||Lasts 2 d||Some skin irritation|
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 the hydrophobicity of the ester, and the longer the duration of action. Thus, testosterone enanthate, cypionate, and undecanoate with longer side chains have longer durations of action than does testosterone propionate. Within 24 hours 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
Nongenital testosterone patches, when applied in an appropriate dose, can normalize testosterone, DHT, and estradiol levels 4–12 hours 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.
Two testosterone gels, Androgel and Testim, when applied topically to the skin in 5-, 7.5-, and 10-g doses, can maintain total and free testosterone concentrations in the mid- to high-normal range in hypogonadal men. The current recommendations are to begin with a 50-mg dose and adjust the dose on the basis of testosterone levels. The advantages of the testosterone gel include ease of application and 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.
Buccal Adhesive Testosterone
A buccal testosterone tablet that 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
Testosterone undecanoate, when administered orally in oleic acid, is absorbed preferentially through the lymphatics into the systemic circulation and is spared 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. Ratios of DHT to testosterone are higher in hypogonadal men treated with oral testosterone undecanoate compared with 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, the large injection volume (4 mL) is a relative drawback.
Novel Androgen Formulations
A number of androgen formulations with better pharmacokinetics or more selective activity profiles are under development. Two long-acting esters, testosterone buciclate and 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 route. 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 androgen receptor modulators (SARMs) are a class of androgen receptor ligands that bind the androgen receptor and display tissue-selective actions. A number of nonsteroidal SARMs that act as full agonists on the muscle and bone and spare the prostate to varying degrees have advanced to phase I and II 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 in 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 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 not known whether testosterone therapy in older men with functional limitations is safe and effective in improving physical function 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 selective androgen receptor modulators that are preferentially anabolic and spare the prostate.
Testosterone administration induces hypertrophy of both types 1 and 2 fibers and increases satellite cell (muscle progenitor cells) and myonuclear numbers. 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 that 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) and 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 white men and >95% of Asian men. The World Health Organization (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 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. Selective androgen receptor modulators 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 gel typically is applied over a covered area of skin at a dose of 5–10 g daily; patients should wash their hands after gel application. Bioadhesive buccal testosterone tablets at a dose of 30 mg typically are 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 into 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, presumably due to genetic differences in testosterone clearance. 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 or gel or buccal testosterone therapy, testosterone levels should be in the mid-normal range (500–700 ng/dL) 4–12 hours after application. If testosterone levels are outside this range, the dose should be adjusted.
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 346-4). Testosterone therapy should not be administered without further urologic evaluation to men with a palpable prostate nodule or induration or prostate-specific antigen >4 ng/mL or >3 ng/mL in men at high risk for prostate cancer such as blacks or men with first-degree relatives with prostate cancer or 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 recent myocardial infarction or unstable angina.
Table 346-4 Conditions in Which Testosterone Administration Is Associated with a Risk of Adverse Outcome |Favorite Table|Download (.pdf)
Table 346-4 Conditions in Which Testosterone Administration Is Associated with a Risk of Adverse Outcome
|Conditions in Which Testosterone Administration is Associated with Very High Risk of Serious Adverse Outcomes:|
|Metastatic prostate cancer|
|Conditions in Which Testosterone Administration is Associated with Moderate to High Risk of Adverse Outcomes:|
|Undiagnosed prostate nodule or induration|
|PSA >4 ng/mL (>3 ng/mL in individuals at high risk for prostate cancer, such as blacks and men with first-degree relatives who have prostate cancer)|
|Erythrocytosis (hematocrit >50%)|
|Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by the American Urological Association/International prostate symptom score >19|
|Uncontrolled or poorly controlled congestive heart failure|
Monitoring Potential Adverse Experiences
The clinical effectiveness and safety of testosterone replacement therapy should be assessed 3–6 months after initiating testosterone therapy and annually thereafter (Table 346-5). 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 disease. In addition, there may be formulation-specific adverse effects such as skin irritation with transdermal patches, 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.
Table 346-5 Monitoring Men Receiving Testosterone Therapy |Favorite Table|Download (.pdf)
Table 346-5 Monitoring Men Receiving Testosterone Therapy
|1. Evaluate patient 3–6 months after treatment initiation and then annually to assess whether symptoms have responded to treatment and whether patient is experiencing any adverse effects.|
2. Monitor testosterone level 3–6 months after initiation of testosterone therapy:
• Therapy should aim to raise serum testosterone level into mid-normal range.
• Injectable testosterone enanthate or cypionate: Measure serum testosterone level midway between injections. If testosterone is >700 ng/dL (24.5 nmol/L) or <400 ng/dL (14.1 nmol/L), adjust dose or frequency.
• Transdermal patches: Assess testosterone level 3–12 h after application of the patch; adjust dose to achieve testosterone level in mid-normal range.
• Buccal testosterone bioadhesive tablet: Assess level immediately before or after application of fresh system.
• Transdermal gels: Assess testosterone level any time after patient has been on treatment for at least 1 week; adjust dose to achieve serum testosterone level in the mid-normal range.
• Testosterone pellets: Measure testosterone levels at the end of dosing interval. Adjust number of pellets and/or dosing interval to achieve serum testosterone levels in normal range.
• Oral testosterone undecanoate*: Monitor serum testosterone level 3 to 5 h after ingestion.
• Injectable testosterone undecanoate: Measure serum testosterone level just before each subsequent injection and adjust dosing interval to maintain serum testosterone in mid-normal range.
|3. Check hematocrit at baseline at 3–6 months and then annually. If hematocrit is >54%, stop therapy until hematocrit decreases to a safe level; evaluate patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose.|
|4. Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 years of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture, consistent with regional standard of care.|
|5. In men 40 years of age or older with baseline PSA >0.6 ng/mL, perform digital rectal examination and check PSA level before initiating treatment at 3–6 months and then in accordance with guidelines for prostate cancer screening depending on age and race of patient.|
6. Obtain urologic consultation if there is:
• An increase in serum PSA concentration >1.4 ng/mL within any 12-month period of testosterone treatment.
• A PSA velocity >0.4 ng/mL per year using PSA level after 6 months of testosterone administration as reference (applicable only if PSA data are available for a period exceeding 2 years).
• Detection of a prostatic abnormality on digital rectal examination.
• An AUA/IPSS prostate symptom score >19.
7. Evaluate formulation-specific adverse effects at each visit:
• Buccal testosterone tablets: Inquire about alterations in taste and examine gums and oral mucosa for irritation.
• Injectable testosterone esters (enanthate, cypionate, and undecanoate): Ask about fluctuations in mood or libido and, rarely, cough after injections.
• Testosterone patches: Look for skin reaction at application site.
• Testosterone gels: Advise patients to cover application sites with a shirt and wash skin with soap and water before having skin-to-skin contact because testosterone gels leave a testosterone residue on skin that can be transferred to a woman or child who comes in close contact. Serum testosterone levels are maintained when application site is washed 4–6 h after application of testosterone gel.
• Testosterone pellets: Look for signs of infection, fibrosis, or pellet extrusion.
Administration of testosterone to androgen-deficient men typically is associated with a 3–5% increase in hemoglobin levels due to 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 common adverse event reported in testosterone trials in middle-aged and older men and also the most common 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 PSA 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 ng/mL over a 3–6-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 suggests that an increase in PSA >1.4 ng/mL in any one 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.
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 the trial. Meta-analyses of testosterone trials have found no statistically significant increase in cardiovascular event rates in men receiving testosterone therapy, although nonsignificant increases have been noted. Inferences about adverse events from previous trials included in these meta-analyses were limited by poor ascertainment, small numbers of events, and small numbers of participants. Adequately powered prospective studies are needed to determine the effect of 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 2 million Americans, most of them men, probably have used these compounds. The most commonly used androgenic steroids include testosterone esters, nandrolone, stanozolol, methandienone, and methenolol. Athletes generally use increasing doses of multiple steroids in a practice known as stacking.
The adverse effects of long-term AAS abuse are 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 growth hormone; IGF-I; insulin; stimulants such as amphetamine, clenbuterol, cocaine, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as hCG, aromatase inhibitors, and estrogen antagonists. The men who abuse androgenic steroids are more likely to engage in other high-risk behaviors than are 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 other high-risk behaviors.
The high rates of mortality and morbidity observed in AAS users are alarming. One Finnish study reported 4.6 times the risk of death among elite power lifters than among 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.
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. The finding of androgen receptors on myocardial cells suggests that AAS may be directly toxic to myocardial cells.
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-alylated, nonaromatizable AAS are associated with marked reductions in HDL cholesterol and increases in LDL cholesterol.
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 suppression of the hypothalamic-pituitary- testicular (HPT) axis after stopping AAS that may be associated with sexual dysfunction, infertility, and depression; in some AAS users, gonadotropin suppression may last more than a year. The dysphoria caused by androgen withdrawal may cause some men to revert to using AAS, leading to continued use and AAS dependence. As many as 30% of AAS users develop a syndrome of AAS dependence that is characterized by long-term AAS use despite adverse medical and psychiatric effects.
Unsafe injection practices, high-risk behaviors, and increased rates of incarceration put 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 were other men.
Some AAS users develop manic symptoms during AAS exposure (sometimes associated with violence) and major depression (sometimes associated with suicidality) during AAS withdrawal. Users also may engage in 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 and baldness, as well as increased body hair.
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 improved the sensitivity of detecting androgen abuse. Illicit testosterone use generally is detected by the application of the measurement of the ratio of urinary testosterone to epitestosterone 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 ratio of testosterone to epitestosterone. Ratios above 4 suggest exogenous testosterone use but can also reflect genetic variation. Synthetic testosterone has a lower 13C:12C ratio than endogenously produced testosterone, and these differences in the 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 ratio of testosterone to epitestosterone.