Hypogonadism and Testosterone Replacement Therapy

Testosterone Replacement Therapy Hypogonadism and Testosterone Replacement Therapy a report by Adrian S Dobs, MD, MHS and Anjana Myneni, MD Professor of Medicine and Oncology, Department of Medicine, Johns Hopkins University School of Medicine, and Medical Resident, Department of Internal Medicine, Sinai Hospital, Johns Hopkins University Male hypogonadism affects an estimated four to five million men in the US. It is defined as failure of the testes to produce an adequate amount of testosterone and/or conduct normal spermatogenesis. The production of adequate amounts of testosterone is necessary for development of external genitalia and development of secondary sexual characteristics in children and adolescents. In adults, androgen production is necessary for maintenance of lean body mass (LBM), bone mass, libido, sexual function, and spermatogenesis. Differential Diagnosis Signs and symptoms of male hypogonadism can be obvious in a pre-pubertal man (e.g. infantile genitalia) and subtle in a post-pubertal man, who may complain of fatigue, sexual dysfunction, or decreased energy. By typical classification, hypogonadism can be primary (testicular failure) or secondary (hypothalamic or pituitary disorders). 1 Primary hypogonadism (hypergonadotropic hypogonadism) results in low serum testosterone and elevated gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone (FSH). Genetic disorders such as Klinefelter s syndrome or any testicular trauma (surgery, radiation, chemotherapy) are examples of hypergonadotropic hypogonadism. In secondary hypogonadism (hypogonadotropic hypogonadism), LH and FSH are low or inappropriately normal in the presence of low testosterone levels. Involvement of the hypothalamus or the pituitary gland (tumor, infiltrative diseases, trauma, radiation) results in hypogonadotropic hypogonadism. Another approach might be to think in terms of congenital causes (e.g. Klinefelter s or Kallman s syndromes, pseudohermaphroditism, sickle cell disease) versus acquired causes (e.g. pituitary tumors, injury or disease of the testes, stress, obesity, aging, and systemic diseases such as infections). Other causes of male hypogonadism include hyperprolactinemia, hypercortisolism, and hemochromatosis, an extremely common genetic disorder that is under-diagnosed. Screening for all of these should be part of an initial evaluation of hypogonadal young men. In addition to pathological hypogonadism, another clinical entity gaining recognition is what is called andropause, i.e. age-related decline in testosterone levels. Approximately 20% of men over the age of 65 have low serum testosterone levels. This type of hypogonadism is multifactorial and is due to a combination of primary testicular failure and pituitary insufficiency. Testosterone s effects are clearly more pronounced during puberty, but its influences are present throughout all phases of a man s life (see Figure 1). Laboratory Evaluation When hypogonadism is clinically suspected, it is essential to accurately measure serum testosterone levels.tests should be conducted in the morning, when levels of circulating testosterone are normally highest. 2 At least two abnormal test results are necessary before committing an individual to potentially lifelong testosterone therapy. A level of <200ng/dl would be considered hypogonadal, while levels between 200 and 400 would require more specific laboratory evaluation. Accuracy of laboratory test results depends to a large extent on the choice of testing methodology. Two per cent of circulating testosterone is free, and the remaining 98% is either tightly bound to sex-hormone binding globulin (SHBG) (approximately 40%) or more weakly bound to albumin (approximately 58%). Both albumin-bound and free testosterone are thought to be biologically active. 3 Total testosterone concentrations do Adrian S Dobs, MD, MHS, is Professor of Medicine and Oncology in the Department of Medicine at Johns Hopkins University School of Medicine, Baltimore, where she is also an active teacher in both endocrinology and general medicine. She is an active investigator in the field of sex hormone disorders, and is a dedicated clinical investigator who has published extensively in HIV-related endocrinopathies and risks and benefits of testosterone replacement therapies. Anjana Myneni, MD is a third year medical resident in the Department of Internal Medicine at Sinai Hospital/John Hopkins University. She is also a member of the American Medical Association (AMA) and an associate member of the Endocrine Society. Dr Myneni has submitted multiple abstracts to peer-reviewed journals and has been conducting an independent study evaluating bone mineral density and the risk of osteoporosis in grand multiparous Ashkenazi Jews. She also serves on the resident and faculty advisory committee board at Sinai Hospital in the Department of Medicine. 1. Plymate S R, Hypogonadism in men: an overview, in: Bagatell C J, Bremner W J (eds), Androgens in Health and Disease Humana Press, New Jersey (2003): pp. 23 44. 2. Plymate S R,Tenover J S, Bremner W J, Circadian variation in testosterone, sex hormone-binding globulin bound testosterone in healthy young and elderly men, J. Androl. (1989);10: pp. 366 371. 3. Dunn J F, Nisula B C, Rodbard D, Transport of steroid hormones:binding of 21 endogenous steroid to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma, J. Clin. Endocrinol. Metab. (1981);53: pp. 58 68. 75

Testosterone Replacement Therapy Figure 1: Plasma Testosterone Levels During the Life-cycle in Men 7 Table 1: Conditions or Compounds that may Alter SHBG Production Decreased SHBG Levels Moderate obesity Low protein state (e.g. nephrotic syndrome) Hypothyroidism Glucocorticoids Progestins Androgens, anabolic steroids Increased SHBG Levels Aging Hepatic cirrhosis Hyperthyroidism Anticonvulsants Estrogens not accurately reflect gonadal status when there are substantial alterations in SHBG concentrations. Alterations in SHBG levels are caused by an array of medical conditions (see Table 1). 4 For the reasons given above, testosterone assays that are not affected by changes in SHBG are generally preferred, including free or bioavailable testosterone calculated from total testosterone, SHBG (+/- albumin); free testosterone measured by equilibrium dialysis, and bioavailable testosterone measured by ammonium sulfate precipitation. Free testosterone measured by direct analog assays is not considered to be reliable and should not be used in clinical practice. 5,6 When consistently low testosterone levels are confirmed with accurate methodology, it is necessary to distinguish hypogonadism due to a primary testicular disorder (hypergonadotropic hypogonadism) from that caused by pituitary dysfunction (hypogonadotropic hypogonadism). As a more sensitive serum marker of testicular disease, gonadotropin levels are extremely useful in identifying mild to moderate degrees of primary hypogonadism caused by conditions such as Klinefelter s syndrome, chemotherapy-induced destruction, orchitis, and irradiation. In patients with secondary hypogonadism, other laboratory tests, including measurement of prolactin levels or iron saturation, should be performed to identify specific causes of secondary hypogonadism, such as hemochromatosis, hyperprolactinemia, hypopituitarism, and others. 4 Chronic diseases, such as cancer, hepatic, or renal disease, are commonly associated with declines in serum testosterone levels and inappropriately normal serum gonadotropins. Radiographic imaging of the sella with magnetic resonance imaging (MRI) should be conducted in younger men with hypogonadotropic hypogonadism and in older patients with extremely low testosterone (<150mg/dl) and low LH and FSH concentrations to rule out structural pituitary/hypothalamic lesions. Potential Benefits of Testosterone Replacement Therapy Pre-pubertal males will virilize with testosterone treatment. Post-pubertal males commonly have improvements in several end-organs. This includes improvement in sexual function (both libido and erectile function) and psychosocial measures, and increased bone density and lean muscle. The longterm benefits of the latter on frailty is unknown. Testosterone Replacement Therapy The primary therapeutic goal of testosterone replacement therapy is to obtain physiological levels of testosterone. Target levels in the middle of physiological ranges for a particular age are appropriate (for example, mid- to high-normal levels in younger men and low- to mid-normal levels in older men).this strategy helps avoid excess dosages as suggested by suppressed serum gonadotropin concentrations. It is important to minimize the patient s exposure to supraphysiological levels of testosterone in order to avoid adverse effects such as erythrocytosis. Table 2 lists the testosterone delivery formulations that are currently approved in the US. 76 4. Matsumoto A M, The testis, in: Felig P, Frohman L A (eds), Endocrinology and Metabolism 4th ed. New York: McGraw- Hill (2001): pp. 635 705. 5. Winters S J, Kelley D E, Goodpaster B, The analog free testosterone assay: are the results in men clinically useful?, Clin. Chem. (1998);44: pp. 2,178 2,182. 6. Vermeulen A,Verdonck L, Kaufman J M, A critical evaluation of simple methods for the estimation of free testosterone in serum, J. Clin. Endocrinol. Metab. (1999);84: pp. 3,666 3,672. 7. Ewing L L et al., Int. Rev. Physiology (1980);22: pp. 41 115.

...with the fastest growing testosterone replacement therapy available. * Adverse Events Adverse events reported at a level greater than 1% that were possibly or definitely related to the use of Testim in controlled clinical trials (N=304) across all dose groups were application site reaction (4%) and increase in hematocrit/hemoglobin (2%) Contraindications and Warnings Contraindications: Androgens are contraindicated in men with cancer known or suspected of the breast or prostate. Testim is not indicated for use in women, has not been evaluated for use in women, and must not be used in women. Warning: Geriatric patients treated with androgens may be at greater risk of prostatic hyperplasia and prostatic carcinoma. Auxilium Pharmaceuticals, Inc. * Data on file, Auxilium Pharmaceuticals, Inc. 0805-014.a

Brief Summary: Before prescribing Testim, please see full prescribing information. INDICATIONS AND USAGE: Testim is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: 1. Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome, orchiectomy, Klinefelter s syndrome, chemotherapy or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and gonadotropin (FSH, LH) above the normal range. 2. Hypogonadotrophic hypogonadism (congenital or acquired): idiopathic gonadotropin or luteinizing hormone releasing hormone (LHRH) deficiency or pituitary hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum levels but have gonadotropins in normal or low range. Testim has not been clinically evaluated in males under 18 years of age. CONTRAINDICATIONS: Androgens are contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate. Testim is not indicated for use in women, has not been evaluated for use in women, and must not be used in women. Pregnant and nursing women should avoid skin contact with Testim application sites on men. Testosterone may cause fetal harm. Testosterone exposure during pregnancy has been reported to be associated with fetal abnormalities. In the event that unwashed or unclothed skin to which Testim has been applied comes in direct contact with the skin of a pregnant or nursing woman, the general area of contact on the woman should be immediately washed with soap and water. Testim should not be used in patients with known hypersensitivity to any of its ingredients, including testosterone USP that is chemically synthesized from soy. WARNINGS: 1.Testim should not be applied to the abdomen. 2. Prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatitis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatitis can be a life-threatening or fatal complication. Long-term therapy with testosterone enanthate, which elevates blood levels for prolonged periods has produced multiple hepatic adenomas. Transdermal testosterone is not known to produce these adverse effects. 3. Geriatric patients treated with androgens may be at an increased risk for the development of prostatic hyperplasia and prostatic carcinoma. 4. Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility and Laboratory Tests). 5. Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required. 6. Gynecomastia occasionally develops and occasionally persists in patients being treated for hypogonadism. 7. The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases. PRECAUTIONS: Transfer of testosterone to another person can occur when vigorous skin-to-skin contact is made with the application site. (See Clinical Studies) The following precautions are recommended to minimize potential transfer of testosterone from Testim treated skin to another person: Patients should wash their hands thoroughly and immediately with soap and water after application of Testim. Studies of handwashing show that Testim is effectively removed from the skin surface by thorough washing with soap and water. Patients should cover the application site(s) with clothing after the gel has dried (e.g. a shirt). Prior to any situation in which direct skin-to-skin contact is anticipated, patients should wash the application sites thoroughly with soap and water so as to remove drug residue. In the event that unwashed or unclothed skin to which Testim has been applied does come in direct contact with the skin of another person, the general area of contact on the other person should be washed thoroughly with soap and water as soon as possible. Changes in body hair distribution, significant increase in acne, or other signs of virilization of the female partner should be brought to the attention of a physician. General: The physician should instruct patients to report any of the following: Too frequent or persistent erections of the penis, any changes in skin color, ankle swelling or unexplained nausea and vomiting, breathing disturbances, including those associated with sleep. Information for Patients: Advise patients to carefully read the information brochure that accompanies each carton of 30 Testim single-use tubes. Advise patients of the following: Testim should not be applied to the scrotum, penis, or abdomen. Testim should be applied once daily at approximately the same time each day to clean dry skin of the shoulders and/or upper arms. Washing or swimming may lessen testosterone levels; however, when washing occurs two or more hours post drug application, serum testosterone levels remain within the normal range. Testim may be transferred to another person by vigorous contact with the application site. Potential for transfer may be avoided by washing hands thoroughly with soap and water prior to any direct skin-to-skin contact. Laboratory Tests: 1. Hemoglobin and hematocrit levels should be checked periodically (to detect polycythemia) in patients on long-term androgen therapy. 2. Liver function, prostate specific antigen (PSA), cholesterol, and high-density lipoprotein (HDL) should be checked periodically. 3. To ensure proper dosing, serum testosterone concentrations should be measured (See Dosage and Administration). Drug Interactions: Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone. Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirements. Propranolol: In a published pharmacokinetic study of an injectable testosterone product, administration of testosterone cypionate led to an increased clearance of propranolol in the majority of men tested. It is unknown if this would apply to Testim. Corticosteroids: The concurrent administration of testosterone with ACTH or corticosteroids may enhance edema formation; thus these drugs should be administered cautiously, particularly in patients with cardiac or hepatic disease. Drug/Laboratory Test Interactions: Androgens may decrease levels of thyroxin-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction. Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal Data: Testosterone has been tested by subcutaneous injection and implantation in mice and rats. In mice, the implant induced cervical-uterine tumors, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats. Human Data: There are rare reports of hepatocellular carcinoma in patients receiving longterm oral therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In men receiving testosterone replacement therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men. Pregnancy Category X (see Contraindications) Teratogenic Effects: Testim is not indicated for women and must not be used in women. Testosterone may cause fetal harm. Nursing Mothers: Testim is not indicated for women and must not be used in nursing mothers. Pediatric Use: Safety and efficacy of Testim in patients <18 years old has not been established. ADVERSE REACTIONS: In a controlled clinical study, 304 patients were treated with Testim 50 mg or 100 mg or placebo for up to 90 days. Two hundred-five (205) patients received Testim 50 mg or 100 mg daily and 99 patients received placebo. Patients with adverse events that were possibly or probably related to study drug and reported by 1% of the Testim patients and greater than placebo are: application site reactions, benign prostatic hypertrophy, blood pressure (diastolic) decreased, blood pressure increased, gynecomastia, headache, hematocrit/hemoglobin increased, hot flushes, insomnia, lacrimation increased, mood swings, smell disorder, spontaneous penile erection and taste disorder. The following adverse events possibly or probably related to Testim occurred in fewer than 1% of patients but were greater in Testim groups compared to the placebo group: activated partial thromboplastin time prolonged, blood creatinine increased, hemoglobin abnormal, prothrombin time prolonged, appetite increased, sensitive nipples, and acne. In this clinical trial of Testim, six patients had adverse events that led to their discontinuation. These events included: vertigo, coronary artery disease, depression with suicidal ideation, urinary tract infection/pneumonia (none of which were considered related to Testim administration), mood swings and hypertension. No Testim patients discontinued due to skin reaction. In one foreign Phase 3 trial, one subject discontinued due to a skin-related adverse event. In the pivotal US and European Phase 3 trials combined, at the 50 mg dosage strength, the percentage of subjects reporting clinically notable increases in hemoglobin or hematocrit were similar to placebo. However, in the 100 mg dose group, 2.3% and 2.8% of patients had a clinically notable increase in hemoglobin ( 19 g/dl) or hematocrit ( 58%), respectively. In the combined ongoing US and European open label extension studies, approximately 140 patients received Testim for at least 6 months. The preliminary results from these studies are consistent with those reported for the US controlled clinical trial. DRUG ABUSE AND DEPENDENCE: Testim contains testosterone, a Schedule III controlled substance as defined by the Anabolic Steroids Control Act. Oral ingestion of Testim will not result in clinically significant serum testosterone concentrations due to extensive first-pass metabolism. OVER- DOSAGE: There were no reports of overdose in the Testim clinical trials. There is one report of acute overdosage by injection of testosterone enanthate: testosterone levels of up to 11,400 ng/dl were implicated in a cerebrovascular accident. DOSAGE AND ADMINISTRA- TION: The recommended starting dose of Testim is 5g of gel (one tube) containing 50 mg of testosterone applied once daily (preferably in the morning) to clean, dry intact skin of the shoulders and/or upper arms. Morning serum testosterone levels should then be measured approximately 14 days after initiation of therapy to ensure proper serum testosterone levels are achieved. If the serum testosterone concentration is below the normal range, or if the desired clinical response is not achieved, the daily Testim dose may be increased from 5g (one tube) to 10g (two tubes) as instructed by the physician. 011503.004 Auxilium Pharmaceuticals, Inc. 40 Valley Stream Parkway Malvern, PA 19355 www.auxilium.com

Hypogonadism and Testosterone Replacement Therapy Current Testosterone Delivery Systems Table 2: Currently Approved Testosterone Delivery Systems Intramuscular Injection As shown in the classic investigations over 20 years ago, injection of long-acting testosterone esters causes a rapid and often supraphysiological rise in serum concentrations that persists for one to three days following the injection. 8 Serum levels then fall during the dosing interval, often to the lower limit of the physiological range. The clinical compromise necessary to avoid sustained periods of supraphysiological testosterone has traditionally been to administer injections of 200mg testosterone every two weeks. 8 This strategy still results in significant variations in testosterone levels, often referred to as the rollercoaster effect. Transdermal Patches Transdermal administration of testosterone offers serum levels that more closely mimic the circadian ranges of healthy young men. Currently, one patch system, a nonscrotal transdermal system, is commercially available for replacement therapy in hypogonadal men. In clinical trials, the majority of patients were treated with 5mg of the patch system applied daily. The testosterone transdermal system produced average morning serum testosterone concentrations within normal range in 92% of patients who participated in these studies. 9 Gels Two formulations of testosterone gel are now available in a pump administration or 5mg or 10mg packets. Each provide fairly constant steady-state levels with little or no circadian variations. 10,11 For both gel products, the patient should apply the gel at approximately the same location (usually to the shoulders and upper arms) and time each day. Following application, the gel should be allowed to dry for about 10 to 15 minutes before putting a garment over the area of gel application. Serum total testosterone levels with the 5g formulation average about 550ng/dl and those with the 10g formulation about 750ng/dl. Buccal System The newest therapeutic option is a buccal system that provides testosterone through bioadhesive hydration Delivery System Standard Dosage for Clinical Considerations Androgen Deficency Intramuscular injections 200mg every two weeks Inexpensive Administered every two weeks Roller-coaster pharmacokinetics Requires injections Transdermal patch 5mg nightly Expensive Mimics circadian rhythm Daily administration Skin irritation Transdermal gel 5g gel daily Very expensive Testosterone levels wihtin physiological range Daily administration Possible transference to intimate contacts Buccal system 30mg twice-daily Expensive Testosterone levels wihtin physiological range Twice-daily dosing Possible oral irritation technology.a small tablet about the size and shape of a contact lens is placed above the teeth on the buccal mucosa. As the product absorbs water, testosterone is gradually released and absorbed across the buccal mucosa. When administered to hypogonadal men, the testosterone buccal system rapidly restores serum testosterone concentrations to within the normal range by seven days and maintains similar pharmacokinetics at the end of 12 weeks of buccal testosterone administration. The most frequent adverse event was gum or mouth irritation (9.2%).The majority of gumrelated adverse events were transient and resolved within one to 14 days. The recommended dosage for the buccal system is two applications daily, one in the morning and one 12 hours later. Investigational Therapies Several long-acting intramuscular (IM) testosterone compounds are currently under investigation for treatment of hypogonadism.testosterone undecanoate in a castor oil excipient is administered as a large bolus injection every 12 weeks, and it produces much more physiological testosterone levels than current injectable 8. Snyder P J, Lawrence D A, Treatment of male hypogonadism with testosterone enanthate, J. Clin. Endocrinol. Metab. (1980);51: pp. 1,335 1,339. 9. Androderm (testosterone transdermal system) prescribing information.watson Pharma Inc. 10. Swerdloff R S, Wang C, Cunningham G et al., Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men, J. Clin. Endocrinol. Metab. (2000);85: pp. 4,500 4,510. 11. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R, AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function, J. Clin. Endocrinol. Metab. (2003);88: pp. 2,673 2,681. 79

Testosterone Replacement Therapy testosterones. 12 A potent synthetic androgen known as 7 alpha-methyl-19-nortestosterone (MENT) is resistant to conversion by 5 alpha-reductase but is susceptible to aromatase, and it might provide androgen replacement with selective sparing of the prostate gland while supporting other androgendependant tissues. 13 MENT requires surgical implantation, and its target levels for testosterone replacement remain undefined. Potential Risks of Testosterone Therapy Testosterone replacement therapy can increase hormone levels to within physiological range and can improve many of the symptoms and findings associated with andropause. However, the benefits of treatment in androgen-deficient men must be weighed carefully against the risks it may pose to this population. One of the greatest concerns in prescribing testosterone replacement therapy is that it will stimulate growth of a previously undiagnosed prostate cancer. Data from three studies do suggest, however, that the incidence of prostate cancer in men receiving testosterone replacement is not significantly different from agematched control populations. 14 16 The concern about a possible relationship between testosterone therapy and an increased incidence of cardiovascular (CV) events stems from the observation that men have higher prevalence of age-adjusted cardiovascular disease (CVD) than women. There is no consistent data that testosterone affects many of the underlying factors that contribute to CVD, which include clotting, platelet function, endothelin level, lipid levels, vascular reactivity, and carotid intimal thickening. Guidelines for Monitoring A significantly elevated hematocrit (>52%) is an indication to stop therapy, reduce the dose of testosterone, and continue monitoring. Hematocrit should be measured at baseline, at three months, and then annually. Bone mineral density of the lumbar spine and/or femoral neck should also be measured at baseline, because many of the patients who are candidates for testosterone therapy will already have osteoporosis. Bone mineral density should be repeated annually or biannually. One must also monitor for potential adverse effects on the prostate. For BPH, the symptom score should be assessed and, if warranted by symptoms, the urine flowrate and post-void residual urine in the bladder by ultrasonography should be measured. For prostate cancer, digital rectal exam plus measurement of serum prostate-specific antigen (PSA) levels are indicated at baseline, at three months, at six months, and then annually in patients older than 50 years of age. Finally, precipitation or worsening of sleep apnea is a relatively rare concern but one that should certainly be considered when evaluating testosterone replacement therapy. Conclusions In summary, the diagnosis of male hypogonadism is a diagnostic and therapeutic challenge. The advent of reliable assays to measure testosterone not bound to SHBG has proven invaluable. The decision to treat with androgen replacement requires careful clinical assessment of the risk and benefits for the individual patient. Multiple options are now available for testosterone replacement therapy. They vary by delivery system, frequency of dosing, and pharmacokinetics, with each offering a different spectrum of advantages and disadvantages. Patients should be presented with these options and encouraged to select whichever one best meets personal preferences and circumstances. It is also helpful to point out that the decision is not a permanent one if one form of testosterone does not turn out to be appropriate for any number of reasons, it is often advantageous to switch to another delivery form.the guiding principle of androgen replacement therapy is to safely provide the benefits of androgens while exposing the patient to acceptably minimal risk of harm. Although there is significant uncertainty in the area of androgen therapy for men, there are now a number of diagnostic tools and therapeutic options that allow patients and clinicians to act as a team in making reasonable, effective, and safe choices. 80 12. Von Eckardstein S, Nieschlag E, Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study, J. Androl. (2002);23: pp. 419 425. 13. Anderson R A,Wallace A M, Sattar N, Kumar N, Sundaram K, Evidence for tissue selectivity of the synthetic androgen 7 alphamethyl-19-nortestosterone in hypogonadal men, J. Clin. Endocrinol. Metab. (2003);88: pp. 2,784 2,793. 14. Amory J K,Watts N B, Easley K A et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. (2004);89: pp. 503 510. 15. Schatzi G, Madersbacher S, Thurridl T et al., High-grade prostate cancer is associated with low serum testosterone levels, Prostate (2001);47: pp. 52 58. 16. Kenny A M, Prestwood K M, Gruman C A, Marcello K M, Raisz L G, Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, J. Gerontol. A. Bid. Sci. Med. Sci. (2001);56: pp. M266 M272.