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Home , Androgen deficiency, Hypogonadism

Male : Quick Reference for Residents

Soe Naing, MD, MRCP(UK), FACE Endocrinologist Associate Clinical Professor of Medicine Director of Division of Medical Director of Community Diabetes Care Center UCSF-Fresno Medical Education Program

Version: SN/8-21-2017

Male hypogonadism

From Harrison's Principles of Internal Medicine, 19e and Up-To-Date accessed on 8-21-2017

Testosterone is FDA-approved as replacement therapy only for men who have low levels due to disorders of the , , or brain that cause hypogonadism. Examples of these disorders include primary hypogonadism because of genetic problems, or damage from chemotherapy or (mump orchitis). However, FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging.

Some studies reported an increased risk of heart attack, , or death associated with testosterone treatment, while others did not.

FDA cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by a medical condition. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm

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Hypothalamic-pituitary-testicular axis

Schematic representation of the hypothalamic-pituitary- testicular axis. GnRH from the stimulates the gonadotroph cells of the pituitary to secrete LH and FSH. LH stimulates the Leydig cells of the testes to secrete testosterone. The high concentration of testosterone within the testes is essential for within the seminiferous tubules. FSH stimulates the Sertoli cells within the seminiferous tubules to make inhibin B, which also stimulates spermatogenesis. Testosterone inhibits GnRH secretion, and inhibin B inhibits FSH secretion.

GnRH: -releasing ; FSH: follicle-stimulating hormone; LH: .

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Causes of male hypogonadism. From Current Medical Diagnosis & Treatment 2016 > Endocrine Disorders

Hypogonadotropic (Low or Normal LH) Hypergonadotropic (High LH) Aging Aging Alcohol Antitumor chemotherapy Chronic illness Bilateral anorchia Congenital syndromes Idiopathic Constitutional delay Cushing syndrome Leprosy Lymphoma  Male climacteric  GnRH agonist (leuprolide) Myotonic dystrophy  Ketoconazole  Marijuana Orchitis  Prior Radiation therapy  Sertoli cell-only syndrome Hemochromatosis Testicular trauma Tuberculosis Hypothyroidism Uremia Idiopathic 17-Ketosteroid reductase deficiency Major medical or surgical illnesses Malnourishment (BMI > 30) Prader-Willi syndrome

BMI, body mass index; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

Clinical features and diagnosis of male hypogonadism

Hypogonadism in a male refers to a decrease in one or both of the two major functions of the testes: sperm production or testosterone production. These abnormalities can result from of the testes (primary hypogonadism) or disease of the hypothalamus or pituitary (secondary hypogonadism). The distinction between these disorders, which will be described below, is made by measurement of the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH): ● The patient has primary hypogonadism if the serum testosterone concentration and/or the sperm count are below normal and the serum LH and/or FSH concentrations are above normal. ● The patient has secondary hypogonadism if the serum testosterone concentration and/or the sperm count are below normal and the serum LH and/or FSH concentrations are normal or low.

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In primary hypogonadism, spermatogenesis tends to be impaired to a greater degree than Leydig cell function, at least in its early stages. In contrast, both functions are impaired to the same degree with secondary hypogonadism. Spermatogenesis cannot be increased in men with primary hypogonadism because of damage to the seminiferous tubules. However, successful pregnancies have now been reported with men with primary hypogonadism, including men with Klinefelter syndrome, using sperm extracted from the testes with subsequent in vitro fertilization by intracytoplasmic sperm . In contrast, men with secondary hypogonadism can often have spermatogenesis restored with gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH) therapy (if pituitary function is normal and the patient has access to a center that provides this therapy). CLINICAL FEATURES — The clinical features of male hypogonadism depend upon the age of onset, severity of testosterone deficiency, and whether there is a decrease in one or both of the two major functions of the testes: sperm production and testosterone production. There are several possible clinical manifestations of testosterone deficiency, which are determined by its time of onset during reproductive development. There are two main clinical manifestations of impaired spermatogenesis: and decreased testicular size.

Signs and symptoms of adult male hypogonadism

Prepubertal onset Postpubertal onset

Primary Secondary Primary Secondary

Symptoms

Low energy + + + +

Low libido + + + +

Physical findings

Small testes + + + ±

Small phallus + + – –

Decreased body/facial hair + + ± ±

Decreased muscle mass + + ± ±

Eunuchoid proportions + + – –

Gynecomastia + ± + –

Symptoms and physical findings in adults who have untreated hypogonadism grouped by whether the hypogonadism is of prepubertal or postpubertal onset and whether it is primary or secondary.

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DIAGNOSIS — The diagnosis is based upon the presence of signs and symptoms of male hypogonadism and unequivocally low serum total testosterone concentrations between 8 and 10 AM on at least two occasions. Candidates for testing — Population screening for male hypogonadism has not been shown to be cost- effective and is not recommended. Instead, we suggest case detection by measuring serum testosterone in situations in which the prevalence of hypogonadism is high, as suggested by the Endocrine Society guidelines. ● of the sellar region ● Medications that affect testosterone production, such as high-dose glucocorticoids for a prolonged period and sustained-release ● Human immunodeficiency virus (HIV)-associated weight loss ● End-stage renal disease and maintenance hemodialysis ● Moderate-to-severe chronic obstructive lung disease ● Infertility ● or low-trauma fracture, especially in a young man ● Type 2 diabetes mellitus Men with acute or subacute illness should not be assessed for hypogonadism, as they will have a transient functional secondary hypogonadism.

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Initial evaluation — The evaluation and diagnosis of male hypogonadism are usually straightforward. The clinician obtains clues to the possible presence of hypogonadism from the history and physical examination and confirms the diagnosis by appropriate laboratory testing. Initial laboratory testing is based upon measuring the products of the testes (testosterone and sperm) and the pituitary that control their production (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]). Testosterone is produced by the Leydig cells of the testes under stimulation of LH. Sperm are produced in the seminiferous tubules under stimulation principally by the high concentration of testosterone in the testes but also by FSH. Testosterone, in turn, inhibits both LH and FSH secretion, the latter via conversion to . FSH is also inhibited by inhibin, a product of the Sertoli cells of the seminiferous tubules. Evaluation of the male with possible hypogonadism (From Up-To-Date accessed on 2-12-2016)

T: testosterone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; PRL: ; T4: thyroxine; Fe: iron; MRI: magnetic resonance imaging. * This algorithm applies to the evaluation of outpatients. Men with acute or subacute illness should not be assessed for hypogonadism, as they will have a transient functional secondary hypogonadism. ¶ Iron and transferrin are measured to assess the possibility that hemochromatosis is the cause of secondary hypogonadism. When an MRI should be performed depends upon several factors. One is the patient's serum T relative to his age. A male <40 years with a serum T <250 ng/dL warrants an MRI but in a male >60 years, a value of <150 ng/dL would be necessary to warrant it. An MRI should also be performed if other pituitary hormones are abnormal, eg, if serum prolactin is elevated or if serum T4 and/or early morning cortisol are below normal.

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Evaluation of hypogonadism.

(From Harrison's Principles of Internal Medicine, 19e > Disorders of the Testes and Male Reproductive System)

GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; T, testosterone.

SUMMARY AND RECOMMENDATIONS FOR DIAGNOSIS: ● Hypogonadism in a male refers to a decrease in either or both of the two major functions of the testes: sperm production and testosterone production. These abnormalities may result from disease of the testes (primary hypogonadism) or disease of the pituitary or hypothalamus (secondary hypogonadism). ● Failure to undergo or complete indicates deficient testosterone secretion. ● Symptoms that could indicate hypogonadism in an adult male are decreases in energy, libido, muscle mass, and body hair, as well as hot flashes, , and infertility. ● Population screening for male hypogonadism has not been shown to be cost-effective and is not recommended. Instead, we suggest case detection by measuring serum testosterone when hypogonadism is suspected, such as in those with sexual symptoms, osteoporosis-associated 8

fractures, human immunodeficiency virus (HIV)-associated weight loss, those taking sustained- release opioids or high-dose glucocorticoids for prolonged periods, and those who are incompletely virilized or have small testes on examination. Men with acute or subacute illness should not be assessed for hypogonadism, as they will have a transient functional secondary hypogonadism. ● To make the diagnosis of hypogonadism, we suggest measuring a morning serum total testosterone concentration between 8 and 10 AM. If a man is suspected of having an abnormality in testosterone binding to -binding globulin (SHBG), measurement of free testosterone by equilibrium dialysis should be performed. The two most common situations of abnormal testosterone binding are obesity, which decreases SHBG concentrations, and aging, which increases SHBG. ● If the testosterone is subnormal, it should be repeated, and a serum luteinizing hormone (LH) concentration should be measured to distinguish primary from secondary hypogonadism. ● A semen analysis is also part of the evaluation of hypogonadism if the patient is pursuing or has been diagnosed with infertility. If subnormal, a serum follicle-stimulating hormone (FSH) concentration is measured to distinguish primary from secondary hypogonadism. ● The patient has primary hypogonadism if the serum testosterone concentration and/or the sperm count are below normal and the serum LH and/or FSH concentrations are above normal. ● The patient has secondary hypogonadism if the serum testosterone concentration and/or the sperm count are subnormal and the serum LH and/or FSH concentrations are normal or reduced.

Testosterone treatment of male hypogonadism

GENERAL PRINCIPLES — The following principles should guide testosterone therapy: ● Testosterone should be administered only to a man who is hypogonadal, as evidenced by clinical symptoms and signs consistent with deficiency and a distinctly subnormal serum testosterone concentration. In comparison, increasing the serum testosterone concentration in a man who has symptoms suggestive of hypogonadism but whose testosterone concentration is already normal will not relieve those symptoms. ● Symptoms and signs suggestive of include low libido, decreased morning erections, loss of body hair, low bone mineral density (BMD), gynecomastia, and small testes. Symptoms and signs such as , depression, anemia, reduced muscle strength, and increased fat mass are less specific. ● Testosterone can be replaced satisfactorily whether the testosterone deficiency is due to primary or secondary hypogonadism. ● The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range. It is not yet known if restoring the normal circadian rhythm of testosterone is important. ● The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs with increasing frequency in men above age 60 years, in the absence of identifiable pituitary or hypothalamic disease, is uncertain. ● Testosterone therapy is indicated only for testosterone deficiency, not for impaired spermatogenesis. Testosterone therapy impairs spermatogenesis further by suppressing pituitary gonadotropin secretion.

CLINICAL BENEFITS OF TESTOSTERONE THERAPY IN HYPOGONADAL MEN — The desirable effects of testosterone administration include the development or maintenance of secondary sexual 9

characteristics and increases in libido, muscle strength, fat-free mass, and bone density. Undesirable effects related directly to testosterone include , disorders (such as benign prostatic hyperplasia [BPH] symptoms), sleep apnea, and erythrocytosis.

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 Breast 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 African Americans or 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 American Urological Association/International Prostate Symptom Score >19 Uncontrolled or poorly controlled congestive heart failure , stroke, or acute coronary syndrome in the preceding 6 months

Abbreviation: PSA, prostate-specific antigen.

GENERAL APPROACH TO TREATMENT Appropriate candidates — Testosterone should be administered only to a man who is hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a subnormal morning (8 to 10 AM) serum testosterone concentration on three separate occasions. Ideally, samples should be drawn fasting; in one report, an oral glucose load suppressed serum testosterone concentrations acutely. Symptoms and signs suggestive of androgen deficiency include low libido, decreased morning erections, loss of body hair, low bone mineral density (BMD), gynecomastia, and small testes. Symptoms and signs such as fatigue, depression, anemia, reduced muscle strength, and increased fat mass are less specific. The beneficial effects of testosterone in these men are clear, and they should be treated with testosterone to raise their serum testosterone concentrations to normal. In men who have a low testosterone for no apparent reason other than age, the benefits of testosterone treatment have not been established. In these men, we suggest testosterone treatment only if the serum testosterone concentration is unequivocally low at 8 to 10 AM on three occasions, and only if the man has signs and/or symptoms of hypogonadism. Experts disagree as to what level should be considered unequivocally low in these men; some favor <300 ng/dL, but others <200 ng/dL. All agree, however, that whatever the cutoff, the result should be confirmed on multiple occasions early in the morning and accompanied by signs and symptoms of hypogonadism before considering treatment. The clinician should discuss with these men the uncertainty of the benefits of testosterone treatment and the possible risks, including erythrocytosis, exacerbation of prostate cancer, benign prostatic hyperplasia (BPH), and cardiovascular disease.

In men who have symptoms that could be the result of low testosterone (eg, fatigue) but who do not have repeatedly subnormal serum testosterone concentrations, we recommend strongly 10

against testosterone treatment because there is no reason to think these men would benefit from treatment, and therefore they are subject only to possible risk.

Inappropriate use of testosterone in healthy middle-aged men — There has been a dramatic increase in inappropriate use of testosterone therapy in healthy middle-aged and older men. This is likely due, at least in part, to direct-to-consumer advertising encouraging use of testosterone products for nonspecific symptoms, such as decreased energy and sexual interest. It is important for clinicians to understand that the diagnosis of testosterone deficiency should be made only on the basis of clinical symptoms and signs consistent with androgen deficiency and consistently subnormal serum testosterone concentrations at 8 to 10 AM on three occasions. For men with vague symptoms that could be the result of low testosterone (eg, fatigue), and a single but not repeatedly subnormal serum testosterone concentration, we recommend strongly against testosterone use. The Endocrine Society’s guidelines and others also strongly advocate this approach. Treatment should not be prescribed on a “trial” basis, because the results are not interpretable and because once men have started treatment, they may find cessation difficult because of the prolonged period of hypogonadism during recovery of the pituitary-testicular axis. In addition, testosterone therapy eventually results in suppression of spermatogenesis and decreased testicular size.

Choice of testosterone regimen — Choosing among the different testosterone preparations requires an understanding of their pharmacokinetics. Native testosterone is absorbed well from the intestine, but it is metabolized so rapidly by the liver that it is virtually impossible to maintain a normal serum testosterone concentration in a hypogonadal man with oral testosterone. The solutions to this problem that have been developed over many years involve modifying the testosterone molecule, changing the method of testosterone delivery, or both. A number of testosterone preparations are currently available or are under development for treating testosterone deficiency (see table). We usually suggest testosterone gels because they typically result in normal and relatively stable serum testosterone concentrations, and most patients prefer them to other preparations. However, other factors affect choice of regimen, including patient preference, cost, convenience, and insurance coverage, which varies by plan and regimen. In general, the newest preparations (the gels) cost the most, the patch costs somewhat less, and injectable esters cost the least. Monitoring Serum testosterone concentration — Patients who are treated with testosterone should be monitored to determine that normal serum testosterone concentrations are being achieved. Monitoring should be done two to three months after initiation of treatment and after changing a dose. When the dose appears to be stable, monitoring over 6 to 12 months should suffice. They should also be monitored for both desirable and undesirable effects. The timing of serum testosterone measurements varies with the preparation that is used. ● Serum testosterone should be measured midway between injections in men who are receiving or cypionate, and the value should be mid-normal, eg, 500 to 600 ng/dL. The dose should be reduced if higher values are obtained.

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● The serum testosterone can be measured at any time in men who are using any of the preparations, with the recognition that the peak values occur six to eight hours after application of the patch. ● Serum testosterone concentrations vary substantially when a gel is used, but not in a predictable way. Therefore, we suggest two serum testosterone measurements before making dose adjustments. Patients can have the two samples obtained with as many days between as fits their schedules. Ideally, the two samples should be obtained before the outpatient visit, so the results are available at the time of the visit. Although it is ideal to measure testosterone twice before making dose adjustments, a single measurement represents an improvement over typical practice, as fifty percent of men prescribed testosterone have no biochemical monitoring for the first six months. If the patient has primary hypogonadism, normalization of the serum LH concentration should also be used to judge the adequacy of the testosterone dose, no matter which testosterone preparation is used. Suggested prostate monitoring — As a practical approach, we agree with the Endocrine Society’s 2010 Clinical Guidelines. ●Before initiating testosterone replacement, a digital rectal examination should be performed and serum prostate-specific antigen (PSA) should be measured. In men who have a prostate nodule or a serum PSA greater than 4.0ng/mL with no identifiable risk factors or 3.0 ng/mL at increased risk, such as African-Americans or men with a family history of prostate cancer, urologic evaluation should be performed before testosterone treated is initiated. ●Three months after initiating testosterone replacement, the digital rectal examination and PSA measurement should be repeated. If a nodule has developed or if the PSA has increased more than 1.4 ng/mL above baseline, confirmed by another measurement, urologic consultation should be sought. Thereafter, digital rectal examination and PSA measurement should be performed once a year, as in any man. An increase in PSA of more than 0.4 ng/mL per year, confirmed by repeat measurement, should also lead to urologic consultation.

Monitoring Men Receiving Testosterone Therapy

1. Evaluate the patient 3–6 months after treatment initiation and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering from any adverse effects. 2. Monitor testosterone level 3–6 months after initiation of testosterone therapy: o Therapy should aim to raise serum testosterone level into the 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 the mid-normal range. . Buccal testosterone bioadhesive tablet: Assess level immediately before or after application of fresh system. . Transdermal gels and solution: Assess testosterone level 2–8 h after patient has been on treatment for at least 2 weeks; adjust dose to achieve serum testosterone level in the mid- normal range. 12

. Testosterone pellets: Measure testosterone levels at the end of the dosing interval. Adjust the number of pellets and/or the dosing interval to achieve serum testosterone levels in the normal range. . Oral testosterone undecanoatea: Monitor serum testosterone level 3–5 h after ingestion. . Injectable : Measure serum testosterone level just prior to each subsequent injection and adjust the 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 the 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 the age and race of the patient. 6. Obtain urologic consultation if there is: o An increase in serum PSA concentration >1.4 ng/mL within any 12-month period of testosterone treatment. o A PSA velocity of >0.4 ng/mL per year using the PSA level after 6 months of testosterone administration as the reference (only applicable if PSA data are available for a period exceeding 2 years). o Detection of a prostatic abnormality on digital rectal examination. o An AUA/IPSS prostate symptom score of >19. 7. Evaluate formulation-specific adverse effects at each visit: o Buccal testosterone tablets: Inquire about alterations in taste and examine the gums and oral mucosa for irritation. o Injectable testosterone esters (enanthate, cypionate, and undecanoate): Ask about fluctuations in mood or libido and, rarely, cough after injections. o Testosterone patches: Look for skin reaction at the application site. o Testosterone gels: Advise patients to cover the application sites with a shirt and to wash the skin with soap and water before having skin-to-skin contact, because testosterone gels leave a testosterone residue on the skin that can be transferred to a woman or child who might come in close contact. Serum testosterone levels are maintained when the application site is washed 4–6 h after application of the testosterone gel. o Testosterone pellets: Look for signs of infection, fibrosis, or pellet extrusion. aNot approved for clinical use in the United States.

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Abbreviations: AUA/IPSS, American Urological Association/International Prostate Symptom Score; PSA, prostate-specific antigen.

SUMMARY AND RECOMMENDATIONS FOR TESTOSTERONE TREATMENT— The following recommendations are consistent with the Endocrine Society Clinical Practice Guidelines. ● For men who are hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a subnormal morning (8 to 10 AM) serum testosterone concentration on three separate occasions, we suggest testosterone replacement therapy. For men who do not meet these criteria, we recommend against testosterone therapy ● The principal goal of testosterone therapy in hypogonadal men is to restore the serum testosterone concentration to the normal range. ● A number of testosterone preparations are available for androgen replacement. We suggest against the use of alkylated androgens. They are convenient because they are given orally, but they have been associated with adverse liver effects and there are more effective preparations available. ● We usually suggest transdermal testosterone to most hypogonadal men, especially a gel, because it usually produces normal serum testosterone concentrations and most patients find it the most convenient. Some men, however, prefer injections of long-acting testosterone esters because of the freedom from daily application, ● For some patients, cost may be an issue. In general, the newest preparations (the gels) cost the most, the patch costs somewhat less, and injectable esters cost the least. ● Men who begin using a transdermal preparation need to be seen two to three months after the initiation of therapy to measure the serum testosterone concentration and evaluate the possibility of undesirable effects. Men who use the transdermal patch or the recommended starting dose of a gel, but whose serum testosterone concentration is not high enough, can try wearing two patches or applying higher doses of a gel. ● For adult hypogonadal men starting testosterone enanthate, we suggest 100 to 200 mg every two weeks, which can be administered either by the patient himself or by someone in the patient's household. The patient should be seen approximately two to three months later and, if he is bothered by fluctuations in energy, mood, or libido, the regimen can be changed to 50 to 100 mg once a week or transdermal testosterone can be offered again. ● Serum testosterone concentrations should be monitored while a patient is being treated. The timing depends upon the preparation used. ● Men over age 50 years (or over age 40 years who have a family history or are African-American) should be screened for prostate cancer before starting therapy and during therapy, as outlined above. ● The hematocrit should be measured before initiating testosterone treatment, and if it is elevated, the cause should be sought before testosterone treatment is initiated. The hematocrit should be measured again after three to six months, and then yearly. If it increases above the upper limit of normal, a cause should be sought, and if none is found, the dose of testosterone should be decreased or stopped. The hematocrit should be re-evaluated two months after the decrease or discontinuation. If the hematocrit normalizes, a lower dose of testosterone should be continued or restarted. ● The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs with increasing age in men in the absence of identifiable pituitary, hypothalamic, or testicular disease is uncertain. We suggest that men who have symptoms or signs that could be caused by testosterone deficiency be considered for testosterone treatment only if they have an unequivocally low testosterone concentration more than once.

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Testosterone deficiency in older men

As men age, their serum concentrations of testosterone and, to a greater extent, free testosterone, decrease. unlike , where complete estrogen deficiency with known clinical consequences occurs, the decline in testosterone in aging men is modest and the possible clinical consequences have not been well-established. Changes in body function occur in aging men that are similar to the manifestations of hypogonadism due to known disease, raising the possibility that the decline in testosterone production with aging may be a cause of these changes. The question of whether or not testosterone should be administered to older men is difficult to answer because it is not known whether testosterone treatment reverses the age- related decline in any function, nor is it known if testosterone treatment exacerbates any of the testosterone-dependent diseases, such as those of the prostate, to which older men are prone. SUGGESTED APPROACH Candidates for testosterone ● If a man has symptoms or conditions that suggest testosterone deficiency, such as decreased libido, energy, or mood, or osteoporosis or anemia, we suggest measuring the serum total testosterone concentration in the morning (eg, 8 to 10 AM). If it is less than 300 ng/dL, we suggest measuring it twice more, since testosterone concentrations fluctuate. ● Free testosterone should be measured (by equilibrium dialysis or calculated from total testosterone and sex hormone-binding concentration [SHBG]) only in men who are obese. ● If the total testosterone is less than 200 ng/dL, we recommend evaluation for known causes of hypogonadism. In the absence of documented pituitary or testicular disease, we recommend considering treatment with testosterone only if the testosterone concentration is consistently less than 200 ng/dL and only after discussion with the patient of the potential benefits and risks. This recommendation is the same as by some members of the Endocrine Societies Clinical Guidelines Committee, but more stringent than recommended by others. This recommendation, however, is less strict than that of the FDA, which does not recommend testosterone treatment except for low testosterone of known cause.

SUMMARY AND RECOMMENDATIONS FOR OLDER MEN ● Serum total testosterone concentrations fall with increasing age, and free testosterone concentrations fall even more. This fall might have adverse consequences on energy, sexual function, muscle mass and function, erythropoiesis, and bone. Some of the decline in testosterone is related to the development of obesity and other comorbidities such as diabetes mellitus; evaluation and management of these comorbidities is therefore essential. ● Older men with unequivocally low serum testosterone concentrations (less than 200 ng/dL should undergo the same diagnostic evaluation for hypogonadism as a young man with a low testosterone. ● It is unclear if increasing the serum testosterone concentrations of older men to those of young men will prevent or reverse these changes. While there might be clinical benefits of testosterone administration in selected older hypogonadal men, the increase in serum testosterone concentration could negatively impact one or more testosterone-dependent diseases to which older men are prone.

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● The Endocrine Society updated its evidence-based clinical guidelines for testosterone therapy in adult men with androgen deficiency in 2010. We generally agree with their approach in older men and suggest the following- • In the absence of known pituitary or testicular disease, we suggest testosterone therapy only for men with low serum testosterone concentrations on more than one occasion and symptoms of testosterone deficiency (such as decreased energy and libido). Clinicians should attempt to convey to their patients the uncertainty about the risks and benefits of testosterone therapy before prescribing testosterone treatment. • The target serum testosterone concentration in these men should be lower than that for younger men, for example, 300 to 400 ng/dL rather than 500 to 600 ng/dL to minimize the potential risk of testosterone-dependent diseases. • If treatment is undertaken, the man should be screened before treatment and monitored during treatment for evidence of testosterone-dependent diseases, such as prostate cancer. Testosterone treatment should not be initiated in a man with a prostate nodule by digital rectal examination or a prostate-specific antigen (PSA) greater than 4.0 ng/mL (or greater than 3.0 ng/mL if he has a family history of prostate cancer or is African American) without urologic consultation. After beginning treatment, a man should be monitored by digital rectal examination and by PSA at three months and then yearly. If a prostate nodule is detected at any time or the PSA increases by 1.4 ng/mL at three months or 0.4 ng/mL per year thereafter (confirmed by repeat measurement), urologic consultation should be obtained. . • If treatment is undertaken, the clinical outcomes for success should be well defined. If the symptoms or condition that led to measuring testosterone is not corrected in the expected period of time (eg, improvement in energy, libido, or hemoglobin in a few months or bone mineral density [BMD] in two years), discontinuation of the treatment should be considered. ● Data on the risk of cardiovascular complications with testosterone therapy have been conflicting, with some studies suggesting no increase in cardiovascular events in older men, while others suggest a possible increase in cardiovascular events in some men who take testosterone. This issue remains unclear.

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Testosterone replacement therapy preparations

Testosterone Preparation Disadvantages Dosage units supplied Typical dose range Application site formulation type (trade name in US) and toxicity

Long-acting Testosterone enanthate 200 mg/mL 100 to 200 mg Thighs for self Fluctuating injections (Delatestryl) every two weeks to injection, serum (intramuscular) 50 to 100 mg buttocks when testosterone weekly administered by levels, 21-gauge another person needles needed 100 mg/mL 100 to 200 mg for long-acting (Depo-Testosterone) 200 mg/mL every two weeks to esters 50 to 100 mg weekly

Mixture of testosterone 250 mg/mL 250 mg every three esters of propionate, weeks, or 100 to phenylpropionate, 200 mg every two isocaproate, and weeks, or 50 to 100 decanoate (Sustanon) not mg weekly available in United States

Extra-long-acting Testosterone undecanoate 1000 mg/4 mL 1000 mg initially, Gluteal medius Injection- injections (Nebido), not available in followed by 1000 only associated (intramuscular) United States mg at six weeks, pulmonary oil followed by 1000 microembolism mg Q10-14 weeks (POME), restricted access Testosterone undecanoate 250 mg/mL 750 mg initially, Gluteal medius in United States*, (Aveed), United States followed by 750 mg only trochar needed approved preparation after four weeks, for extra-long followed by 750 mg acting esters Q10 weeks

Transdermal Testosterone transdermal 2 mg/24-hour patch 2 to 6 mg/day Dry intact skin of Skin rash, poor patches 24-hour patch 4 mg/24-hour patch back, abdomen, adherence (Androderm) upper thighs, or arm

Testosterone transdermal 2.5 mg/24-hour patch 2.5 to 5 mg/day Dry intact skin of 24-hour patch 5 mg/24-hour patch upper arms, (Andropatch), not back, stomach, available in United States or thighs

Transdermal Testogel 1 percent gel 50 mg in 5 gram packet 50 to 100 mg/day Dry intact skin of Normal serum gels/pumps/solutions back, abdomen, testosterone Testim 1 percent gel 50 mg in 5 gram packet upper thighs, or levels not AndroGel 1 percent gel 25 mg in 2.5 gram arm achieved in all packet hypogonadal 50 mg in 5 gram packet males, potential for skin transfer AndroGel 1.62 percent gel 20.25 mg in 1.25 gram 20.25 to 81 mg/day packet

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40.5 mg in 2.5 gram packet Metered dose pump (20.25 mg per actuation)

Fortesta 2 percent gel Metered dose pump (10 10 to 70 mg/day Dry intact skin of mg per actuation) front and inner thighs

Axiron 2 percent solution Metered dose pump (30 30 to 120 mg/day Apply using mg per actuation) applicator to dry intact skin of axilla

Tostran 2 percent gel, not Metered dose pump (10 60 to 80 mg/day Dry intact skin of available in United States mg per actuation) abdomen and inner thighs

Oral testosterone Testosterone undecanoate 40 mg capsules 40 to 80 mg BID Oral medication Gastrointestinal (Andriol, Restandol), not after breakfast and side effects available in United States dinner

Testosterone Testosterone implant 75 mg pellets 150 to 450 mg Q3- Subcutaneous Incision required subcutaneous pellets 6 months implant under for insertion, implants (Testopel) clean skin in the pellet extrusion, (pellets) hips infection, fibrosis, no information available on optimal dosing

Buccal testosterone Buccal testosterone 30 mg per buccal system 30 mg BID Buccal Poor adherence, system application gum irritation (Striant)

* Subject to US Food and Administration (FDA)-required REMS (Risk Evaluation and Mitigation Strategy) program, which includes restricted distribution scheme and certification of healthcare providers and facilities.

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