Treat Endocrinol 2005; 4 (5): 293-309 REVIEW ARTICLE 1175-6349/05/0005-0293/$34.95/0

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Male An Update on Diagnosis and Treatment

Emily Darby and Bradley D. Anawalt Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington, USA

Contents

Abstract ...... 293 1. Hypothalamic-Pituitary-Testicular Axis ...... 294 2. Etiologies ...... 294 3. Diagnosis ...... 295 3.1 History and Physical Examination ...... 295 3.2 Screening Questionnaires ...... 295 3.3 Laboratory Testing ...... 295 3.4 Further Work-Up ...... 296 4. Physiologic Effects of Replacement Therapy ...... 296 4.1 Physiologic Benefits versus Risks of Androgen Replacement Therapy ...... 296 4.2 Sexual Function ...... 297 4.3 Lean Body Mass, Strength, and Fat Mass ...... 297 4.4 and Fractures ...... 297 4.5 Mood ...... 298 4.6 Bladder Outlet Obstruction ...... 298 4.7 ...... 298 4.7.1 and ...... 298 4.7.2 () and Prostate Cancer ...... 299 4.8 Cardiovascular Disease ...... 299 5. Treatment Options ...... 299 5.1 Oral ...... 299 5.1.1 Alkylated Oral Testosterones ...... 299 5.1.2 ...... 299 5.1.3 Buccal Testosterone ...... 301 5.1.4 Other Oral Preparations ...... 301 5.2 Injectable Androgens ...... 301 5.2.1 Testosterone ...... 301 5.2.2 Testosterone Undecanoate Injections ...... 301 5.2.3 (Bucyclate) ...... 302 5.2.4 Microencapsulated Testosterone ...... 302 5.3 Implantable Androgens ...... 302 5.4 Testosterone ...... 302 5.4.1 Scrotal Testosterone Patch ...... 302 5.4.2 Non-Scrotal Testosterone Patch ...... 302 5.4.3 Testosterone ...... 303 5.5 Dihydrotestosterone Gel ...... 303 5.6 Selective Modulators/7-α-Methyl-19 Nortestosterone ...... 304 5.7 Treatment to Achieve ...... 304 6. Monitoring Recommendations ...... 304 7. Conclusions ...... 305

Abstract Male hypogonadism is one of the most common endocrinologic syndromes. The diagnosis is based on clinical plus laboratory confirmation via the measurement of low morning testosterone levels on 294 Darby & Anawalt

two different occasions. Serum luteinizing and follicle-stimulating hormone levels distinguish between primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism. Hypogonadism associated with aging (andropause) may present a mixed picture, with low testosterone levels and low to low-normal gonado- tropin levels. Androgen replacement therapy in hypogonadal men has many potential benefits: improved sexual function, an enhanced sense of well-being, increased lean body mass, decreased body fat, and increased bone density. However, it also carries potential risks, including the possibility of stimulating the growth of an occult prostate cancer. The benefits of androgen therapy outweigh the risks in men with classic hypogonadism. However, for men with mild hypogonadism or andropause, the balance between benefits and risks is not always clear. Unfortunately, studies to date have included too small a number of patients and have been too short in duration to provide meaningful data on the long-term risks versus the benefits of androgen replacement therapy in these populations. Several products are currently marketed for the treatment of male hypogonadism. Weekly-to-biweekly injections of (cipionate) or (enantate) are widely used, as they are economical and generally well tolerated. However, once-daily transdermal therapies have become increasingly popular and now include both patch and gel systems. Intramuscular of testosterone undecanoate is an attractive new therapy that can be administered quarterly. To confirm an adequate replacement dosage, assessment of clinical responses and measurement of serum testosterone levels generally suffice. For selected men, serial measurement of bone mineral density during androgen therapy might be helpful to confirm end-organ effects. For men aged >50 years, we advocate measurement of for detection of and a digital rectal examination with a serum prostate-specific antigen level measurement for prostate cancer screening during the first few months of androgen therapy. Subsequently, a hematocrit should be obtained yearly or after changes in therapy, and annual prostate cancer screening can be offered to the patient after a discussion of its risks and benefits.

Many physicians remain under-educated about hypogonadism levels (hypergonadotropic hypogonadism). Secon- despite the fact that it is one of the most common endocrinologic dary and tertiary hypogonadism, caused by pituitary under-secre- disorders in men. alone occurs in 1 in 500 tion of LH and FSH and hypothalamic under-secretion of GnRH, [1] men. In addition, the prevalence of men with low testosterone respectively, are usually grouped together and termed secondary levels increases dramatically with age. While 12% of men aged hypogonadism or hypogonadotropic hypogonadism. Aging-relat- <50 years have serum total testosterone levels in the hypogonadal ed is frequently due to a combination of range, almost 50% of men in their 80s have low serum total testicular and hypothalamic dysfunction. testosterone levels.[2] The estimated prevalence of clinical hypogo- nadism (low serum testosterone levels plus symptoms) is lower but still significant: 4.1% for men aged 40–49 years and 9.4% for 2. Etiologies men aged 60–70 years, respectively.[3] The purpose of this review is to discuss key issues in the diagnosis, sequelae, and treatment of The causes of male hypogonadism are diverse and include this common condition, with particular emphasis on the variety of genetic disorders, pituitary tumors, endocrinopathies such as therapies currently available for androgen replacement. hyperprolactinemia and Cushing syndrome, systemic diseases,

1. Hypothalamic-Pituitary-Testicular Axis Table I. Classification of hypogonadism Gonadotropin-releasing hormone (GnRH) is secreted in a pul- Classification Location of Testosterone FSH and LH satile fashion from the and stimulates the release of pathology (LH) and follicle-stimulating hormone (FSH) Primary Testes Low to low- High from the . LH, in turn, promotes secretion of testos- hypogonadism normal terone from the Leydig cells in the testes, while FSH stimulates Secondary Pituitary Low Low or low- and inhibin B production from the Sertoli cells. hypogonadism normal Testosterone and its metabolites act to inhibit LH and FSH secre- Tertiary Hypothalamus Low Low or low- tion via negative feedback on the hypothalamus and pituitary. hypogonadism normal Interruption of this axis at any level results in low serum testoster- Aging-related Testes and Low to low- Normal or slightly one levels (table I). Primary hypogonadism occurs due to testicular hypogonadism hypothalamus normal elevated failure and is characterized by low testosterone levels and high FSH = follicle-stimulating hormone; LH = luteinizing hormone.

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Table II. Etiologies of primary and secondary hypogonadism 3.2 Screening Questionnaires Primary (hypergonadotropic) Secondary (hypogonadotropic) Two screening questionnaires are potentially useful in identify- hypogonadism hypogonadism ing older men who may be at risk for hypogonadism: the Andro- Klinefelter syndrome Hyperprolactinemia gen Deficiency in the Aging Male questionnaire based on symp- Dysgenetic testes Pituitary lesions (tumor, granuloma, toms;[4] and the Massachussetts Male Aging Study questionnaire abscess) derived from risk factors.[5] These screening instruments have a Myotonic dystrophy fair sensitivity but relatively poor specificity and have not been Sertoli cell-only syndrome widely adopted in clinical practice. Vanishing testes syndrome Cryptorchidism Cushing syndrome 3.3 Laboratory Testing Orchiectomy Severe or chronic illnessa In a patient presenting with symptoms or signs of androgen Testicular trauma Drug use (opiates, glucocorticoids) deficiency, the diagnosis of hypogonadism should be confirmed Autoimmune orchitis abuse by the presence of low serum testosterone levels. However, the orchitis Pituitary irradiation, trauma, or assay of choice has been a matter of some controversy. The surgery majority of serum testosterone is protein bound, with about 40% Radiation or chemotherapy tightly bound to -binding globulin (SHBG) and about Environmental toxins 58% weakly bound to albumin. The remaining 2% is considered to Alcohol abuse Idiopathic hypogonadotropic be ‘free’. Because testosterone can rapidly dissociate from albu- hypogonadism min, all non-SHBG-bound testosterone is considered bioavailable. Other genetic mutations Total testosterone levels include both protein-bound and free Prader-Willi syndrome testosterone. a Common etiologies include wasting syndromes (e.g. cancer, AIDS, Total testosterone is traditionally measured via radioim- and starvation), end-stage renal and disease, and morbid munoassay. In general, this method is reliable, inexpensive, and . rapid. However, some automated assays may over- or under- congenital anatomic abnormalities, trauma or surgery, tox- Table III. Signs and symptoms of pre- and post-pubertal hypogonadism ins, and infection (table II). Pre-pubertal hypogonadism Post-pubertal hypogonadism Eunuchoidal stature Normal stature 3. Diagnosis Small testes (usually <6 cm3) Testes volume normal to slightly low (>10 cm3); soft Small penis (<5cm) Penis normal size 3.1 History and Physical Examination Lack of normal scrotal rugae and Normal scrotal rugae and pigmentation pigmentation Hypogonadism is a syndrome, with the patient history and Small prostate Normal prostate physical examination as the keys to making a diagnosis. The Scant facial, axillary, and pubic Thinning of facial, axillary, and timing of the onset of hypogonadism affects the symptoms and hair pubic hair signs of this syndrome (table III). Pre-pubertal hypogonadism is High pitched voice Lack of male pattern baldness characterized by eunuchoidal body habitus, , small Gynecomastia Normal voice testes, and a lack of secondary sexual characteristics, which can Gynecomastia usually be detected by a thorough physical examination. However, Lack of Infertility post-pubertal androgen deficiency may present with a constella- Low bone mineral density Loss of libido tion of symptoms such as weakness, decreased libido, depressed Low muscle mass, high Low bone mineral density mood, or malaise; these symptoms are often overlooked or attrib- percentage of body fat uted to other conditions. The history should include a review of Mild anemia Low muscle mass, high (including any over-the-counter, herbal, or illicit percentage of body fat drugs), toxin or radiation exposures, and family history. Further- Mild anemia more, the clinician should examine the patient for visual field Hot flashes deficits or focal neurologic signs that might indicate pituitary or CNS disease. Decreased sense of well-being

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estimate testosterone levels in the lower ranges,[6] and it is impor- secretion than serum FSH levels, but LH levels fluctuate signifi- tant that the reference range is established in the individual labora- cantly throughout the day. Reproducibly elevated LH levels con- tory.[6,7] Importantly, SHBG is decreased in patients with obesity, firm primary hypogonadism even when serum testosterone levels hypothyroidism, and type 2 diabetes mellitus and is increased in are low-normal, and elevated FSH levels are useful to verify aging men and men taking anticonvulsants. Therefore, total testos- primary hypogonadism. terone levels can be misleading in these disorders. Furthermore, Morley et al.[8] found that measurement of total testosterone to 3.4 Further Work-Up establish hypogonadism misclassified 42% of normal healthy men compared with classification using a measurement of bioavailable If a patient is found to have primary hypogonadism, no further testosterone. work-up is necessary. Some clinicians advocate karyotyping if Klinefelter syndrome is suspected, but this test is costly and Thus, free or bioavailable testosterone levels are often a better Klinefelter syndrome may be reasonably diagnosed in men with measure of testosterone production than total testosterone levels. small, hard testes and elevated . In patients with The gold standard for measurement of free testosterone is equilib- secondary hypogonadism, the history and physical examination rium dialysis, and bioavailable testosterone is measured via am- should focus on probable causes with a directed work-up as monium sulfate precipitation of SHBG-bound testosterone; how- indicated. In addition, serum transferrin saturation and ever, both methods are time consuming and expensive. More levels should be measured to screen for hemochromatosis and recently, free and non-SHBG-bound (also known as weakly hyperprolactinemia, respectively. Finally, men aged <60 years bound) testosterone levels have been calculated based on total without a probable cause for hypogonadism, men aged >60 years testosterone, albumin, and SHBG levels. Calculated free testoster- with very low testosterone levels (total testosterone <200 ng/dL), one levels have been shown to correlate well with free testosterone and those with visual changes, headache, hyperprolactinemia, or levels obtained by equilibrium analysis.[8,9] Direct estimation of secondary hypothyroidism (low serum thyroxine with a low or free testosterone by analog radioimmunoassay is notorious- normal thyroid-stimulating hormone) should have a pituitary ly inaccurate and should not be used.[7,9,10] Many commercial imaging study performed to exclude a large pituitary mass. laboratories can quickly perform an inexpensive panel that in- cludes serum total testosterone and SHBG levels plus calculated 4. Physiologic Effects of Androgen free and weakly bound testosterone levels. Currently, calculated Replacement Therapy free and weakly bound testosterone levels are the preferred test for reliable assessment of hypogonadism. Clinicians without easy access to a laboratory that can perform accurate free and weakly 4.1 Physiologic Benefits versus Risks of Androgen bound testosterone levels may use total testosterone levels. How- Replacement Therapy ever, they should consider the measurement of free testosterone After the diagnosis of hypogonadism is established, the practi- levels when assessing a patient who is likely to have abnormal tioner and patient must decide if the benefits of androgen therapy SHBG levels. justify the risks and cost. For younger men and older men with Because of the circadian variation in serum testosterone, with classic hypogonadism without contraindications to androgen ther- [11] levels peaking in the early morning, testosterone should ideally apy (table IV), the benefits of therapy outweigh the risks. be measured using a blood sample drawn before 10.00am. Older However, for many older men with mild, aging-related hypogo- [12] men tend to lose this circadian rhythm, so the timing of the nadism, the choice is not as clear. Testosterone levels clearly phlebotomy for testosterone measurement may be less important decline with aging, and this is even more notable when free or in the elderly. However, healthy older men may retain the circadi- bioavailable testosterone levels are measured.[2] However, serum [13] an variation of testosterone levels into their 70s. Thus, in all testosterone levels (total, free, and bioavailable) may not correlate men, it is best to confirm a low testosterone level from an after- noon blood draw using a value obtained from an early morning Table IV. Contraindications to testosterone therapy blood sample. In addition, because of the week-to-week variability Prostate cancer in testosterone levels,[8,14] low serum testosterone levels should be confirmed at least once before making the diagnosis of hypogona- Untreated hyperprolactinemiaa dism. Severe bladder outlet obstructiona LH and FSH levels should also be measured in men with low Sleep apneaa serum testosterone levels because gonadotropin levels differenti- a ate between primary and secondary hypogonadism (table Polycythemia I). Serum LH levels provide a better marker for low testosterone a Relative contraindications.

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well with the symptoms and signs of hypogonadism in aging body mass increases up to 1–5kg in men with baseline low to low- men,[15] making accurate diagnosis challenging. In addition, the normal testosterone levels.[28,37,39,41,42,49-58] However, a few trials phenotype of aging may have significant overlap with the signs or have demonstrated no effect or only a trend towards increased lean symptoms of hypogonadism. This clinical scenario, termed ‘an- body mass during androgen replacement therapy.[54,59,60] In several dropause’ or ‘partial androgen deficiency in the aging male’, has studies of men with low or low-normal testosterone levels, andro- recently been the subject of a multitude of excellent reviews,[16-22] gen therapy increased strength in at least one muscle but there is no current agreement that this population will benefit group,[28,37,52,53,55,58-62] but the finding was not univer- from routine androgen therapy. For older men with mild hypogo- sal.[42,49,54,56,57,63] These investigations suffer from small sample nadism or partial androgen deficiency, most experts agree that an size and short duration of therapy. It is also unclear whether all in-depth discussion of the effects of androgen supplementation on men studied were hypogonadal, as some trials included men with sexual function, muscle, bone, prostate, and cardiovascular func- low-normal testosterone levels[53,55,56,60,62,63] and only two studies tion is warranted so that the patient may make an informed included symptoms of hypogonadism as entry criteria.[39,57] An- decision. drogen therapy appears to decrease fat mass in hypogonadal men, although the results of clinical trials have been inconsistent, with 4.2 Sexual Function some studies showing decreased body fat[37,39,41,42,50,51,53,55,57,58,60] and others finding no significant change.[28,49,52,54,56,59] is common in men with hypogonadism. In Although self-image may improve from increased lean body studies using a wide variety of formulations, androgen replace- mass and decreased body fat, the benefits of potential changes in ment therapy has been shown to improve sexual desire/libido, body composition and strength on the overall level of function are sexual activity/satisfaction, spontaneous erections, erection dura- unclear from studies to date. One large cohort study demonstrated [23-42] tion, and sexual performance. In older, sexually active men, that hypogonadal older men have decreased balance and an in- exogenous testosterone appears to cause a significant, dose-depen- creased risk for falls,[64] but it remains unclear whether treatment dent increase in sexual function, but younger men have no further will reduce falls and their sequelae. Only a handful of prospective increase in sexual function with dosages of testosterone greater investigations have included a functional test of leg strength and than those that restore testosterone levels to just below the lower balance (e.g. a timed test of walking or stair climbing),[53,56,58,60] [43,44] limit of normal. The formulation of testosterone and the route with two showing some benefit.[56,58] of administration may affect the success of therapy. Conway et al.[24] performed a three-way, cross-over trial of oral testosterone 4.4 Bone Density and Fractures undecanoate versus testosterone esters versus testosterone pellets and found parenteral administration to be more effective for the Testosterone and its metabolites have major effects on bone improvement of libido and than oral testosterone undeca- formation and resorption, and hypogonadism is a major risk factor noate. However, the differences could have been due to the higher for . Cross-sectional studies show that hypogonadal testosterone levels achieved with the parenteral formulations. Two men have a low baseline bone mineral density (BMD).[51,65-70] As a studies of testosterone demonstrated higher serum testoster- result of decreased BMD, older hypogonadal men may be at an one levels and a greater improvement in sexual function in men increased risk for hip fracture. A case-control study of older men treated with a gel than those using a testosterone patch.[37,39] found that 71% of men presenting with hip fractures over a Treatment with dihydrotestosterone (androstanolone) has also 10-month period had low serum testosterone levels compared with [71] been shown to improve libido and the number and quality of 32% of control individuals. erections in hypogonadal men.[45,46] Improvement in sexual func- Most recent trials have demonstrated that testosterone replace- tion with 7-α-methyl-19 nortestosterone implants is similar to that ment increases BMD for men with low baseline testosterone seen with testosterone replacement in hypogonadal men.[47,48] Cul- levels.[42,51,54,65-67,69,72-79] In the last decade, five randomized, pla- tural or racial differences may play a role in improvements in cebo-controlled trials of androgen replacement for ≥6 months in sexual function with androgen replacement therapy, as Chinese hypogonadal men have included BMD as an end- men were less likely to report an improvement in sexual function point.[28,42,54,77,79,80] Three showed significant gains in spinal when administered testosterone or 7-α-methyl-19 nortestosterone BMD.[42,54,77,79] It is likely that the amount of BMD increase is than Scottish men receiving testosterone.[47] affected by the duration and degree of testosterone deficiency, the mode of testosterone delivery, and the average testosterone levels [28] 4.3 Lean Body Mass, Strength, and Fat Mass achieved during therapy. Wang et al. failed to show any signifi- cant increase in BMD in the hip or spine in younger men after 6 Androgens are known to have important effects on muscle and months of sublingual testosterone, but this formulation of testos- fat. Most recent studies of androgen replacement show that lean terone therapy does not uniformly provide robust serum testoster-

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one levels. In a 1-year trial of transdermal testosterone in older standardized questionnaires for the assessment of depression men, Kenny et al.[80] reported no change in BMD of the spine and a found that testosterone supplementation may be helpful as adju- modest 0.3% increase over baseline for BMD of the hip (a 1.6% vant therapy for men with antidepressant-refractory depression increase over placebo). Two longer-term studies of transdermal and low to low-normal testosterone levels.[88] testosterone therapy in older men did not demonstrate a significant [76,80] effect of treatment on BMD; but subset analysis of the largest 4.6 Bladder Outlet Obstruction study of transdermal testosterone showed that men with serum total testosterone levels <300 ng/dL and <200 ng/dL had increases The potential effects of testosterone therapy on the prostate in spinal BMD of 3.4% and 5.9%, respectively, during therapy.[76] have been thoroughly discussed in numerous recent reviews.[89-93] Amory et al.[79] showed a very significant increase in BMD at the Testosterone therapy does not appear to increase the incidence of spine (9.3–10.2%) and hip (2.2–2.7%) in older hypogonadal men symptomatic bladder outlet obstruction in older men, but men with treated with intramuscular testosterone. The authors postulated pre-treatment symptomatic bladder outlet obstruction or prostatic that the lower pre-treatment testosterone levels of study individu- disease were excluded in virtually all androgen replacement trials. als and the higher average treatment testosterone levels achieved Most studies have demonstrated an increase in prostate size to with intramuscular testosterone were responsible for the disparity volumes within the normal range for age and no significant between their findings and the results of other trials. It is also changes in voiding parameters. likely that the effects of androgens on BMD would be more remarkable in men who have never been treated with androgens or 4.7 Prostate Cancer who have not received androgens for many years. Of the random- ized, placebo-controlled, clinical trials studying the effects of 4.7.1 Testosterone and Prostate Cancer androgens on BMD in hypogonadal men, only one exclusively The association between serum testosterone levels and the enrolled androgen therapy-naive men.[54] Unfortunately, all ran- development of prostate cancer is unclear. Comprehensive re- domized controlled trials of androgen therapy have been under- views have yielded conflicting results. Shaneyfelt et al.[94] per- powered to investigate the occurrence of fracture as an endpoint. formed a systematic meta-analysis of previous studies and deter- , a metabolite of testosterone, plays a key role in bone mined that men in the top quartile for testosterone levels had twice homeostasis. Profound osteoporosis and poor bone development the risk of developing prostate cancer. However, another compre- were described in a 28-year-old man with an hensive review of prospective studies found no association be- gene mutation and a 24-year-old man unable to convert testoster- tween mean testosterone levels and prostate cancer risk.[95] one to estrogen due to an deficiency.[81,82] As hypothe- Morgentaler et al.[96] demonstrated an unexpectedly high rate of sized, estrogen therapy dramatically increased the BMD of the prostate cancer in men with low testosterone levels, despite these man with estrogen deficiency due to aromatase dysfunction.[83] men having normal prostate-specific antigen (PSA) levels and The effect of relative estrogen deficiency on bone in digital rectal examinations. Furthermore, two recent nested case- men is still unclear. Dihydrotestosterone therapy has been suggest- control studies determined that patients with total testosterone ed as a treatment for androgen deficiency, but dihydrotestosterone levels in the highest versus lowest quartile or quintile had a is not aromatizable and may not stimulate and maintain normal reduced risk of prostate cancer.[97,98] bone metabolism. Normal serum levels of dihydrotestosterone do Although testosterone may not play a role in the causation of not appear to be critical for the maintenance of normal bone de novo prostate cancer, it can promote the growth of an existing density.[79,84] cancer. Indeed, a cornerstone of therapy for metastatic prostate 4.5 Mood cancer is androgen suppression. Because of the potential risk of a prostate cancer stimulus, some experts recommend limiting the The majority of trials show that androgen replacement im- use of longer-acting androgen preparations in older men.[18] How- proves mood and the sense of well-being in hypogonadal ever, a review by Morales and Tenover[89] noted that 61% of trials men.[25,30,35,37,41,42,47,85,86] However, a few authors have reported no performed in middle-aged and older men demonstrated no change change in mood compared with baseline.[46,56,59,87] Mood tends to in PSA levels with testosterone therapy. Any increase in PSA improve very early in the course of therapy and then stabilize. levels with treatment is generally small (0.3–0.6 ng/mL),[89,90] and There has been a great deal of interest about the possible therapeu- longer-term studies have shown stabilization after 3–6 months.[42] tic role of testosterone therapy for depression, but most studies of In testosterone-treated men, the rate of increase in PSA is also androgen replacement therapy in hypogonadal men have excluded comparable to established norms.[89,99] Most trials of androgen men with clinical depression and have used non-standardized replacement have excluded individuals with any pre-existing pros- questionnaires to assess mood. One randomized trial that utilized tate disease and screened men closely at entry (in some cases via

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rectal ultrasound), perhaps excluding men at higher risk of this Eckardstein[104] found similar results in a survey of cross-sectional disease. studies; however, they noted that prospective studies failed to Changes in serum PSA levels represent a surrogate marker for show any association between the development of CAD and low prostate cancer, but trials of testosterone treatment have been too endogenous testosterone levels. small and too short to adequately answer the question of whether Testosterone has a mixed effect on risk factors for CAD. A testosterone therapy might lead to an increased risk of prostate meta-analysis of lipid changes during treatment with intramuscu- cancer. An estimated 6000 men would need to be randomized to lar testosterone esters confirmed a small but significant drop in testosterone therapy versus no treatment for up to 5 years for a trial high-density lipoprotein levels but also demonstrated clinically to be powered to detect a 30% difference in prostate cancer important decreases in total and low-density lipopro- incidence between groups.[100] Unfortunately, a trial designed to tein levels.[105] Hypogonadal men tend to have increased total and answer this and other questions regarding the risks and benefits of abdominal body fat and decreased muscle mass; these parameters androgen therapy in older men was delayed as more preliminary tend to improve with androgen therapy. Testosterone may also studies must be conducted first.[101] play a direct role in endothelial health and vasodilation.[104] Ran- domized placebo trials in both eugonadal and hypogonadal men 4.7.2 Dihydrotestosterone (Androstanolone) and Prostate Cancer with CAD and angina have shown a prolonged time to ST segment Dihydrotestosterone is a potent androgen that is thought to be a depression during the Bruce protocol in testosterone-treated men primary stimulus for prostatic growth, but serum dihydrotestoster- versus control individuals.[106,107] Unfortunately, to date, studies of one levels seem to have little correlation with the risk of prostate testosterone replacement therapy in hypogonadal men have been [94,95] cancer. Furthermore, short-term trials of dihydrotestosterone too small and too short in duration to detect changes in the therapy have not shown any significant effects on serum levels of occurrence of cardiovascular events such as acute coronary syn- [46,60] PSA. In fact, prostate size decreased in a significant propor- dromes. tion of men treated with dihydrotestosterone gel.[102] On the other hand, the Prostate Cancer Prevention Trial demonstrated that 5. Treatment Options a 5α-reductase inhibitor significantly lowered serum dihydrotes- tosterone levels and the risk of prostate cancer over a 7-year The goal of androgen replacement therapy is to alleviate the period; however, the group treated with a 5-α reductase inhibitor symptoms and signs of hypogonadism by restoring serum andro- had an increased rate of high-grade tumors compared with the gens and their effects to physiologic levels. Intramuscular and placebo group.[103] Co-treatment with testosterone and a 5-α- implantable testosterone has been used to treat hypogonadism reductase inhibitor in hypogonadal men has been shown to in- since the 1930s and 1940s. Oral, sublingual, buccal, transdermal, crease serum testosterone levels and decrease serum dihydrotes- and subcutaneous administration of testosterone have also been tosterone levels while producing a lesser increase in prostate investigated (table V). Other androgens and SARMs may have a volume at 36 months than treatment with testosterone alone.[79] role in therapy. However, the clinical role of 5-α-reductase inhibitor therapy for 5.1 Oral Androgens prostate cancer chemoprevention in both eugonadal and hy- pogonadal men remains uncertain. The current theory is that 5.1.1 Alkylated Oral Testosterones selective androgen receptor modulators (SARMs) that are resistant Although patients often prefer of medica- to 5-α-reductase may also reduce the risk of prostate cancer, tions, unmodified oral testosterone in normal doses is almost similar to the effects of selective estrogen receptor modulators on completely metabolized by first-pass metabolism in the liver. the risk of breast cancer in women. A study has demonstrated a Testosterone that is alkylated in the 17α-position (e.g. methyltes- decrease in prostate size and a reduction in PSA levels in hy- tosterone and ) escapes significant hepatic metab- pogonadal men treated with 7-α-methyl-19 nortestosterone, a olism, but carries a high risk of hepatic complications including SARM that is a non-reducible androgen.[48] cholestasis, hepatocellular adenomas, hepatoma, and peliosis hepatis.[108] 4.8 Cardiovascular Disease 5.1.2 Testosterone Undecanoate Male gender is an established risk factor for coronary artery Testosterone undecanoate is testosterone with an 11- disease (CAD), but an association between higher serum testoster- attached to the 17-β-. When testosterone un- one levels and CAD has not been borne out in cross-sectional and decanoate in an oily vehicle is taken orally, a small fraction is prospective population-based studies. Alexandersen and Chris- absorbed into intestinal lymphatics and avoids first-pass hepatic tiansen[22] noted that lower androgen levels were found in men metabolism. A typical daily dosage is 120–240mg divided into with CAD in 16 of 30 epidemiologic trials reviewed. Wu and von twice- or three times-daily doses. Peak serum levels are achieved

 2005 Adis Data Information BV. All rights reserved. Treat Endocrinol 2005; 4 (5) 300 Darby & Anawalt Indicated for only mild hypogonadism irritation Caution in older men because of long half-life Increased dihydrotestosterone (androstanolone) levels Potential -skin transfer implantation cost Limited availability for 30 days ($US) = three times daily. tid (one dose or three to four divided doses) 200mg/2 weeks Increased risk of erythrocytosis = sublingual; SL = subdermal; SD = oral; PO others in the US (divided bid to tid) New Zealand, ,others 200mg/2 weeks availability = intramuscular; IM Summary of currently available androgen replacement therapies = twice a day; Table V. DrugTestosterone (PO) (PO and SL) US, , Australia,Fluoxymesterone (PO and SL) 10–50 mg/day Widely availableTestosterone undecanoate Market Widely available but not 75 5–20 mg/day 120–240mg Typical dosage 65–165 Risk of hepatic toxicity 60–80 Approximate retail cost Comments Risk of hepatic toxicity Wide fluctuation in serum testosterone levels bid Buccal testosteroneInjectable (IM) testosterone Testosterone cypionate (cipionate) US, UK US, Canada, othersTestosterone enanthate (enantate) US, Canada, UK, , 100mg/1 weekTestosterone undecanoate 100mg/1 week 30mg bid , limited European 60Implantable (SD) testosterone 70 Testosterone pellets 1000mg/8–12 weeks 180Transdermal androgens 60–80Testosterone patch US, UK, Australia Supra-physiologic testosterone levels Testosterone gel Excellent promise 150–450mg/3–6 months Application-site problems including gum Widely available 30 plus US, 5–10 mg/day (evening) 125–200 High rate of extrusion 5–10 g/day Application-site reactions 200 Well tolerated, adjustable

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2–6 hours after ingestion. Because of its short half-life, testoster- testosterone levels in a small group of healthy men whose endoge- one levels can fluctuate over the course of the day and may be nous testosterone production had been experimentally suppressed subnormal for a significant period of time.[26,78] A newer formula- with a GnRH antagonist.[116] tion is made with castor and propylene glycol instead of oleic acid, which results in a longer shelf life without changes in the 5.2 Injectable Androgens or .[109] Thus, while some men may find oral testosterone undecanoate preferable to injec- 5.2.1 Testosterone Esters tions and are reassured by its long-term safety record,[26] it is likely The mainstay of androgen therapy for many decades has been best used in men with mild hypogonadism. of testosterone esters. The two most com- monly used long-acting esters, testosterone cypionate (cipionate) 5.1.3 Buccal Testosterone and testosterone enanthate, have very similar pharmacokinet- More recently, pharmaceutical companies have been focusing ics.[117] A standard treatment dosage of these testosterone esters is on the development of testosterone for . A 100mg weekly or 200mg every 2 weeks. However, a lower starting small pilot study of a trans-buccal formulation demonstrated that dosage, such as 50–150mg every 2 weeks may be useful in older or peak serum testosterone levels were achieved within only 30 severely hypogonadal men.[118] Unfortunately, after an injection of minutes of administration and that levels returned to baseline over a typical dose of testosterone cypionate or testosterone enanthate, [29] 4–6 hours. A newer formulation of buccal testosterone was peak serum testosterone levels may exceed the normal range. If approved for use in the US in 2003. Initial trials have demonstrated injections are given at intervals longer than 2 weeks, serum that 85–93% of patients using the newer buccal formulation have testosterone levels may dip into the hypogonadal range.[117,119,120] mean serum testosterone levels that are within the therapeutic Some men may experience mood swings due to the large fluctua- [29,110,111] range over a 24-hour period. Dihydrotestosterone levels tions in testosterone levels during treatment with testosterone are increased over baseline, with 28.5% of serum sample levels cypionate or testosterone enanthate injections, and they may bene- [111] above normal at 12 weeks, while mean values remain within fit from smaller doses given more frequently (e.g. 100mg week- [29,110,111] the normal range. In a 3-month safety study by Wang ly).[119] Mixed long- and short-acting testosterone ester prepara- [111] et al. over 10% of patients withdrew within the first weeks of tions have been developed, but these have not produced a better treatment because of application problems or intolerance. Of the overall pharmacokinetic profile than intramuscular testosterone remaining 82 patients, 16.3% had either gum irritation or inflam- cypionate or testosterone enanthate.[113] One study showed that mation, and 3.1% withdrew because of mouth or gum adverse 70% of men tolerated weekly testosterone injections quite well; effects. Two patients developed significant erythrocytosis (hema- the most common adverse effects in the remaining men were ≥ tocrit 55%) that resolved after discontinuation of the . bleeding or pain at the injection site.[121] A retrospective study of The majority of patients found the form of treatment acceptable, older hypogonadal men treated with testosterone injections found and 45% said they preferred it to their previous method of andro- that ≈25% of these men developed polycythemia.[35] Polycythemia gen replacement (intramuscular or transdermal testosterone). due to intramuscular testosterone can be managed by a reduction of dosage, and lower initial doses are recommended in older men. 5.1.4 Other Oral Preparations Despite these adverse effects, injectable testosterone esters are Several other oral androgens have been studied, but they do not well tolerated by most men and are still widely used because of appear promising as treatments for hypogonadism. is their low cost. a relatively weak, non-aromatizable oral androgen with little cur- rent role in androgen replacement. It does not significantly affect 5.2.2 Testosterone Undecanoate Injections testosterone levels[78,112] or suppress gonadotropin levels,[113] but it Longer-acting androgens show great promise for the treatment does significantly raise levels of serum dihydrotestosterone in of male hypogonadism. An injectable form of testosterone undeca- hypogonadal men.[78,112] noate has been developed that has very favorable pharmacokinet- A formulation of sublingual testosterone with a cyclodextrin- ics. Intramuscular administration of 1000mg of testosterone un- drug complex increased serum testosterone levels when adminis- decanoate in tea tree oil normalized testosterone levels in hypogo- tered three times daily, but this formulation is no longer being nadal men within the first week after the injection, and levels developed.[27,28,114] An oral testosterone-triglyceride conjugate was declined to low-normal or hypogonadal levels after 7–8 recently tested in animals. It demonstrated significantly higher weeks.[31,122] Administration of 1000mg of intramuscular testoster- serum testosterone levels than oral testosterone undecanoate, but one undecanoate in also resulted in peak testosterone the half-life remained short.[115] Finally, a recent study showed that levels at day 7, but normal levels were maintained throughout testosterone and testosterone enanthate (enantate) dissolved in oil week 8.[122] Average dihydrotestosterone levels rose to within the and taken orally resulted in a dose-dependent increase in serum normal range; 2 of 14 individuals had supranormal measurements

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at least once in the first 2 weeks.[122] Injections of testosterone implantation is required in a minority of patients with multiple undecanoate in a castor oil preparation did not result in steady state extrusions.[134] Unfortunately, neither washing to remove surface kinetics when given at intervals of 6 weeks, but when the spacing particles nor antibiotic impregnation has been shown to decrease of injections was extended to 12 weeks, steady state kinetics were the rate of extrusion.[132,133] Despite the disadvantages of minor achieved.[30,38] Testosterone levels prior to the final injection were surgery and the risk of extrusion, satisfaction with testosterone at the very low end of normal.[38] A castor oil formulation of pellets at large treatment centers is generally excellent. A retro- testosterone undecanoate was marketed in Finland and spective study of 221 patients treated at one clinical center over 13 in 2004, with plans for introduction to other European countries in years showed an impressive 93% overall continuation rate.[131] In 2005.[123] The usual dosage is 1000mg injected intramuscularly one study of adolescent boys, all of the boys preferred the subcuta- every 8–12 weeks. neous testosterone pellets to intramuscular testosterone injec- tions.[135] However, availability of the testosterone implants is 5.2.3 Testosterone Buciclate (Bucyclate) limited to a few countries and a small number of treatment centers. Early studies sponsored by the WHO and the National Institute of Child Health and Development Center of Population Research 5.4 Transdermal Testosterone focused on testosterone buciclate (bucyclate) for the treatment of hypogonadism in men. Pharmacokinetic studies showed therapeu- 5.4.1 Scrotal Testosterone Patch tic testosterone levels for up to 12 weeks in both humans and Scrotal testosterone patches became available in the 1980s. animals.[124-126] However, drug development has stalled as this With a patch applied daily in the morning to shaved scrotal skin, drug has been superseded by injectable testosterone undecanoate. serum testosterone levels peaked in the first 2 hours and gradually 5.2.4 Microencapsulated Testosterone declined until the next application.[136] Several studies showed Microencapsulated testosterone is another long-acting prepara- sustained normal mean testosterone levels but high-normal to tion that has been investigated. An initial study demonstrated that supranormal levels of dihydrotestosterone.[136-139] The high testosterone levels could be increased for at least 11 weeks after dihydrotestosterone levels were attributed to conversion of the injection of testosterone microspheres, but the pharmacokinetics testosterone to dihydrotestosterone in the scrotal skin. The patch were not ideal, as there was a double peak and trough effect.[25] A was well tolerated, and men showed subjective improvement in newer formulation demonstrated more uniform testosterone levels the symptoms of hypogonadism.[136,137] However, some men did that did not decline for 11 weeks, but two deep intramuscular not like shaving their scrotal area, others had scrota that were too injections of 2.5mL were required.[127] More recently, the micro- small for the patch, and some had difficulty with adhesion. This spheres were reformulated for subcutaneous injection, and a small formulation is no longer available. study showed normal serum total testosterone levels for 10–11 5.4.2 Non-Scrotal Testosterone Patch weeks following subcutaneous injection. One to two large volume Similar to scrotal testosterone patches, non-scrotal testosterone injections were still required for the higher dose, but only 2 of 14 patch systems produce a normal circadian rhythm of peak serum individuals complained of moderate pain at the injection site.[128] testosterone levels in the morning with a gradual decline in testos- 5.3 Implantable Androgens terone levels into the evening; however, this formulation causes smaller increases in serum dihydrotestosterone levels. For all non- Implantable subdermal testosterone pellets have been used as a scrotal testosterone patch systems, the typical starting dose is 5mg means of androgen replacement since the 1930s, but have only applied to the flank, back (away from bony prominences), thigh, recently become widely used at some medical centers. Pellets are upper arm, or abdomen. The Androderm 1 patch, the first non- composed of crystalline testosterone melted into a cylindrical scrotal transdermal formulation, produces peak serum testosterone shape (3.2mm × 8–9mm). Each pellet contains 75mg of testoster- levels 6–8 hours after application with a decline to low-normal or one, and the dose can range from two to six pellets (150–450mg). slightly subnormal levels by 24 hours.[86,140] Based on these A minor surgery is required for implantation (with best results pharmacokinetic data, these patches should be replaced nightly at associated with implantation in the abdominal subdermis).[129] about 10.00pm. After patch removal, testosterone levels decline Stable, eugonadal-range testosterone levels can be maintained for rapidly to baseline.[140] Testoderm TTS is a non-scrotal patch nearly 6 months.[130] Adverse effects include local infections approved by the US FDA in 1997. Pharmacokinetic studies of this (0.6–5.4%)[130-132] and bleeding (2.3–8.8%).[131,132] Subdermal fi- preparation show peak serum testosterone levels 2–4 hours after brosis can also occur but is generally not clinically significant.[131] application and values in the low to mid-normal range 2–24 hours Implant extrusion arises in 8.5–12% of patients.[131-133] Earlier re- after application of a 5mg patch.[141,142] Thus, this patch should be

1 The use of trade names is for product identification purposes only and does not imply endorsement.

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replaced every morning. Some men will require 7.5mg or 10mg of patch. At 90 days, only 57% of patients treated with the 5mg patch testosterone to raise levels into the mid-normal range when using a versus 80% of patients treated with the 10g gel had serum total patch system.[143] testosterone levels above the lower limit of normal (10.4 nmol/L). The principal of patch systems is a fairly high Notably, 30 of 106 patients using the 10g dose of gel had maxi- rate of skin reactions, although Testoderm appears to have a mum serum total testosterone levels above normal at 30 days, but lower incidence of these than Androderm.[144] In a 1-year trial of only four men had mean serum testosterone levels above nor- Androderm, 56% of patients had local skin irritation and 18% mal.[41] As had been observed with AndroGel, Testim caused had blister reactions, attributed primarily to application of the an increase in serum dihydrotestosterone levels that was signifi- patch over bony areas/pressure points. Almost 9% of the patients cantly greater than levels seen with the transdermal patch sys- enrolled in the study withdrew as a result of skin reactions.[33] In a tem.[41] Over the course of the 90-day study, 3–6% of patients 3-month study in the UK, 60% of patients withdrew by week 8 using testosterone gel had at least one hematocrit value >55%.[41] because of skin reactions. Only 22% of men continued to use A third formulation of testosterone gel, CP601, has recently under- transdermal therapy after the study conclusion.[145] Patch-induced gone a preliminary study.[150] dermatitis is more common in older men, but the incidence can be The testosterone gel systems provide robust testosterone levels reduced with the application of 0.1% triamcinolone cream before and are well tolerated. Dosage adjustment is easily accomplished placing the patch.[146] Some hirsute men also complain that the with AndroGel (available in 2.5g and 5g doses), and there is now patch systems do not always adhere well. In general, the patch a pump system available that dispenses the gel in 1.25g increments systems work well and are preferred to injections by some men. to make dosage titration even more convenient. Testim is cur- The manufacturing and marketing of Testoderm TTS recently rently only available in 5g and 10g packets. It also has a musk-like ended, so supply of this product is limited. odor that some men find objectionable. The major adverse effect of the gel systems is erythrocytosis, an effect seen during exces- 5.4.3 Testosterone Gel sive androgen replacement with any form of therapy. Skin reac- Testosterone gel systems have become very popular for testos- tions are relatively uncommon with both currently marketed tes- terone replacement. About 10% of the gel is absorbed into the tosterone gel systems. Only about 5% of patients experienced mild stratum corneum of the skin, which acts as a controlled-release erythema with AndroGel.[37] There is a small potential risk of reservoir for systemic delivery. AndroGel was the first approved transfer of the gel to a partner or close contact, but there have been testosterone gel. Maximum serum testosterone levels are achieved no published reports of the effects of this vicarious exposure. The in 16–22 hours, and steady state is reached in 1–2 days.[14,147] likelihood of transfer is very low, and it is reduced by washing the Levels return to baseline 4 days after discontinuation.[147] In a application site after it has dried.[151] As very little testosterone is study comparing daily administration of AndroGel 5g and 10g absorbed after evaporation of the alcohol vehicle, bathing or (containing 50mg and 100mg of testosterone, respectively) with swimming after the gel has dried is unlikely to affect serum the application of an Androderm 5mg patch, it was seen that all testosterone levels. three regimens normalized mean serum total testosterone levels. However, serum total testosterone levels were 1.4 times higher 5.5 Dihydrotestosterone Gel with 10g of testosterone gel than with 5g of testosterone gel and 1.9 times higher with 10g of testosterone gel than with a testoster- Dihydrotestosterone gel was originally proposed as an alterna- one 5mg patch.[14] The gel formulation also caused significantly tive therapy for androgen replacement because, as a non-aromatiz- higher levels of dihydrotestosterone (4.8-fold increase over base- able androgen, it could provide the androgenic benefits of testos- line in the 10g group), whereas the patch system caused a minimal terone without the adverse effects of estrogen. An early study rise in dihydrotestosterone.[14] Serum dihydrotestosterone levels demonstrated elevated dihydrotestosterone levels between 2 and remained higher (at the upper limit of normal) in the 10g group 21 hours in healthy men,[152] and dihydrotestosterone gel was after 2 years of treatment.[42] In a study comparing buccal testoster- considered ‘most satisfactory’ compared with placebo by eight of one to testosterone gel (5g), testosterone gel increased mean serum nine hypogonadal men treated with 5g of 2.5% dihydrotestoster- dihydrotestosterone levels above the upper limit of normal.[148] one gel for 5 months.[45] Short-term application of dihydrotestos- Another testosterone gel, Testim, was first marketed in the US terone gel raised serum dihydrotestosterone levels while further in 2003. An initial pharmacokinetic study showed that treatment lowering serum testosterone and estrogen levels, and there were no with equivalent doses (5g of gel/50mg of testosterone) resulted in reports of skin irritation with short-term application in healthy higher serum testosterone and dihydrotestosterone levels using men.[153] Three months of therapy with dihydrotestosterone gel Testim than AndroGel.[149] In a study of Testim, the high-dose raised serum dihydrotestosterone levels and lowered serum testos- (10g) gel resulted in a significant increase in serum testosterone terone levels in men with baseline testosterone levels <15 nmol/L, levels over levels achieved with a 5mg transdermal testosterone but unexpectedly produced no change in levels. No

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elevations in PSA levels or increases in prostate size were demon- Anderson et al.[48] noted similar effects on prostate size and a strated in the treatment group.[60] Kunelius et al.[46] reproduced significant reduction in PSA levels in hypogonadal men treated these results in a larger group of symptomatic men treated with with 7-α-methyl-19 nortestosterone for up to 24 weeks. The trial dihydrotestosterone gel for 6 months; however, they also demon- also demonstrated a disturbing decrease in spinal BMD. strated a significant decrease in serum estradiol levels in treated Newer non-steroidal SARMs that can be administered orally men. Although dihydrotestosterone gel may be useful in the treat- have undergone limited study in animals but appear to demon- ment of hypogonadism, there are still safety concerns about its strate some anabolic effects with less stimulatory effects on the potential effects on prostatic disease. However, one study of men prostate than testosterone.[159,160] treated with dihydrotestosterone gel for up to 5 years actually found that men who achieved higher dihydrotestosterone levels 5.7 Treatment to Achieve Fertility and greater estrogen suppression had a significant 15% reduction in prostate size.[102] Some experts speculate that since Androgen administration suppresses spermatogenesis in also play a role in prostatic hypertrophy, this effect could be due to healthy men. If hypogonadal men seek fertility, then specific estrogen suppression.[154] In addition, because dihydrotestosterone therapy beyond androgen administration is necessary. In men with is a non-aromatizable androgen that suppresses testosterone and primary hypogonadism, spermatogenic capacity is diminished if estrogen levels, there is some concern that it could cause unfavora- not extinguished, and the spermatogenic defect is unresponsive to ble effects on the brain, bone, and muscle.[154] therapy. Men with primary hypogonadism may occasionally be capable of some level of fertility with the use of assisted reproduc- 5.6 Selective Androgen Receptor Modulators/ tive technology, such as intracytoplasmic injection of harvested 7-α-Methyl-19 Nortestosterone sperm into the recipient ova. On the other hand, men with hypogo- nadotropic hypogonadism can frequently have spermatogenesis Aromatization of testosterone to estradiol appears to be vital for and fertility restored by treatment with gonadotropins or GnRH. the favorable effects of testosterone on bone and cognitive func- Complete discussion of infertility in hypogonadal men is beyond tion, while dihydrotestosterone plays a role in prostate hypertro- the scope of this review, but the topic has been thoroughly dis- phy with age. Thus, some investigators have begun developing cussed by others.[161,162] androgens that would retain the positive effects of testosterone and estradiol but not the effects on the prostate of dihydrotestosterone. 6. Monitoring Recommendations This category of drugs has been termed SARMs. One such compound that has undergone extensive investigation recently Recommendations for measuring testosterone vary by the mode is 7-α-methyl-19 nortestosterone. This substance has potent ef- of application. It is not necessary to check testosterone levels with fects on the androgen receptor but is resistant to conversion to the use of intramuscular testosterone esters, as improvement in a dihydrotestosterone-like compounds by 5α-reductase.[155] In stud- patient’s symptoms of hypogonadism usually suffices as an indi- ies in monkeys, 7-α-methyl-19 nortestosterone produced 10-fold cator of adequate testosterone replacement. Some experts advo- greater suppression of gonadotropins than testosterone but pro- cate adjusting the intramuscular dosage to target serum testoster- duced only twice the effect on prostate growth.[156] In healthy men, one levels in the mid-normal range at the midpoint between subcutaneous 7-α-methyl-19 nortestosterone implants caused a injections and in the low-normal range at the nadir immediately dose-dependent rise in serum 7-α-methyl-19 nortestosterone prior to the next injection. Patient symptoms, not serum testoster- levels (which remained relatively constant over a 4-week interval) one measurements, also generally guide the dosage of oral testos- and a decrease in the levels of testosterone, dihydrotestosterone, terone undecanoate and the timing of the implantation of testoster- and gonadotropins.[157,158] Treatment with 7-α-methyl-19 nortes- one pellets. As absorption of buccal and topical testosterone levels tosterone implants over 6 weeks in a small group of hypogonadal can be variable, it is important to check a morning serum testoster- men produced a significant rise in serum 7-α-methyl-19 nortestos- one level in a patient using a testosterone patch or buccal system, terone levels and a lowering of serum testosterone levels and or a random testosterone level in a patient using testosterone gel. produced similar improvements in mood and sexual function to For injectable testosterone undecanoate, serum testosterone levels intramuscular testosterone.[47] Implants inserted into the upper arm should be in the normal range within a week after the injection and were well tolerated except for a single insertion-site infection.[158] at the low end of normal prior to the next injection. Monitoring the A study of healthy young men who had four 7-α-methyl-19 adequacy of androgen replacement with the use of non-testoster- nortestosterone implants inserted at the same time suggested that one formulations (e.g. dihydrotestosterone gel or SARMs) will this mode of administration provides an effective dosage of 7-α- present a unique challenge. A convenient, inexpensive, and accu- methyl-19 nortestosterone for at least 12 months, and the treated rate marker of adequate androgen effect will be essential to titrat- men demonstrated a trend towards decreased prostatic size.[38] ing the dosage of dihydrotestosterone or SARMs.

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There are several expert-panel guidelines for monitoring the dosages of androgen therapy. We do not recommend routine bone benefits and potential adverse effects of androgen replacement densitometry or serum lipid profile assessment before or during therapy, and the discrepancies among these guidelines reflect the androgen therapy, unless otherwise clinically indicated, because paucity of data upon which these guidelines are based. One of the the results of these tests will not alter the androgen replacement more popular guidelines from the American Association of dosage. When a clinician has a strong clinical suspicion that a Clinical is summarized in table VI.[162] The guide- patient is hypogonadal but laboratory testing is equivocal, a thera- lines developed at the Andropause Consensus 2000[163] recom- peutic trial of androgen therapy may be considered. When a mended even more frequent screening for prostate cancer during therapeutic trial of androgen therapy is used in these equivocal the first year of therapy. Most primary care guidelines do not cases, it is essential to use objective clinical endpoints of benefit support the practice of routine prostate cancer screening because (e.g. bone densitometry) and a careful assessment of risk in there is little evidence that it improves overall patient mortality. follow-up to determine whether to continue androgen therapy. It is Many primary care providers are concerned that the high inci- also important to document a thorough discussion with the patient dence of false positives during prostate cancer screening and the of the uncertainty of the diagnosis and the potential risks and discovery of clinically insignificant foci of prostate cancer may benefits of androgen therapy. result in procedures and therapies that could harm the patient. 7. Conclusions However, because there is a small theoretical risk that exogenous androgen therapy could stimulate the growth of an occult prostate Male hypogonadism is one of the most common endocrinologic cancer, it is reasonable for patients aged >50 years to undergo a syndromes. The diagnosis of this syndrome depends on clinical digital rectal examination plus a serum PSA level at baseline and suspicion, with confirmation via low serum morning calculated sometime during the third to sixth month of therapy. Although free and bioavailable testosterone levels on two different occa- expert guidelines suggest that prostate cancer screening should be sions. Serum FSH and LH levels help to differentiate primary and performed annually during androgen replacement therapy, it is secondary hypogonadism. Only men with secondary hypogonad- equally reasonable, based on current data for prostate screening, to ism require further work-up, including serum prolactin levels, discuss annual prostate cancer screening with older patients re- serum transferrin saturation, and, if indicated, pituitary imaging. ceiving androgen therapy. Individual patients may decide whether A wide array of products is currently available for the treatment to pursue screening after a thorough review of its risks and of hypogonadal men. Intramuscular injection of testosterone cy- benefits. pionate or testosterone enanthate every 7–14 days is inexpensive Because erythrocytosis is the most common clinically signifi- and well tolerated by most men. Many men are likely to choose the cant adverse effect of androgen therapy, a serum hemoglobin level new intramuscular formulation of testosterone undecanoate that or hematocrit should be performed at baseline, sometime during will soon be available in as it can be given every 8–12 the third to sixth month of therapy, and after any dosage change. If weeks. However, some men will continue to prefer the more erythrocytosis occurs, the dosage of testosterone should be re- expensive transdermal androgen therapies. Of the transdermal duced. Any cause of intermittent or persistent hypoxemia poten- formulations, the gels are the best tolerated, and they provide the tiates the risk of erythrocytosis with androgen therapy; clinicians most reliable mode of normalization of serum testosterone levels, should consider the possibility of occult causes of hypoxemia, with easy dose titration and once-daily administration. such as sleep apnea, in patients who become erythrocytotic on low Androgen replacement therapy is clearly beneficial to men with classic hypogonadism. However, for men with mild hypogonad- Table VI. 2002 American Association of Clinical Endocrinology guidelines ism and older men with low to low-normal serum testosterone for monitoring of testosterone therapy[158] levels, the benefits and risks are largely unknown because the Monitoring objective Recommendation clinical trials of androgen replacement have been too short in Clinical response Quarterly visits for 1 year duration and too small in size to answer questions about the effects of androgen replacement on clinically meaningful endpoints such Prostate Assess symptoms semi-annually to annually as fracture reduction, the ability to do daily tasks, and the risks of cardiovascular and prostate disease. Clinicians and patients are Annual prostate-specific antigen level becoming more aware of the widespread prevalence of low serum Polycythemia Hematocrit every 6 months for 18 months, testosterone levels in men. It is imperative that large, prospective then annually trials be conducted to better assess the risks and benefits of Lipids Baseline, in 6–12 months, then annually androgen therapy before market-driven forces become pre-emp- Bone density Baseline DEXA, repeat in 1–2 years tive as the arbiter of choice for clinicians. Surely, we have learned DEXA = dual energy x-ray absorptiometry. our lesson from the large clinical trials of estrogen replacement

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therapy in women, and we hope that we will soon have the data 22. Alexandersen P, Christiansen C. The aging male: testosterone deficiency and testosterone replacement: an update. Atherosclerosis 2004; 173 (2): 157-69 available to help clinicians and patients make rational decisions 23. Carey PO, Howards SS, Vance ML. Transdermal testosterone treatment of hy- about androgen therapy. pogonadal men. J Urol 1988; 140 (1): 76-9 24. Conway AJ, Boylan LM, Howe C, et al. Randomized of testosterone replacement therapy in hypogonadal men. Int J Androl 1988; 11 (4): 247-64 Acknowledgments 25. Burris AS, Ewing LL, Sherins RJ. Initial trial of slow-release testosterone micro- spheres in hypogonadal men. Fertil Steril 1988; 50 (3): 493-7 No sources of funding were used to assist in the preparation of this review. 26. Gooren LJ. A ten-year safety study of the oral androgen testosterone undecanoate. The authors would like to thank Anne Lee, PharmD, and Alice Moy for their J Androl 1994; 15 (3): 212-5 assistance in the preparation of table V. The authors are also grateful to 27. Salehian B, Wang C, Alexander G, et al. Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to Dr John Amory and Dr Alvin Matsumoto for their critical review of the testosterone enanthate. A clinical research center study. J Clin Endocrinol manuscript. Metab 1995; 80 (12): 3567-75 28. Wang C, Eyre DR, Clark R, et al. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone References formation markers in hypogonadal men: a clinical research center study. J Clin 1. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998; 158 (12): Endocrinol Metab 1996; 81 (10): 3654-62 1309-14 29. Dobs AS, Hoover DR, Chen MC, et al. Pharmacokinetic characteristics, efficacy, 2. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum and safety of buccal testosterone in hypogonadal males: a pilot study. J Clin total and free testosterone levels in healthy men: Baltimore Longitudinal Study Endocrinol Metab 1998; 83 (1): 33-9 of Aging. J Clin Endocrinol Metab 2001; 86 (2): 724-31 30. Nieschlag E, Buchter D, Von Eckardstein S, et al. Repeated intramuscular injec- 3. Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of tions of testosterone undecanoate for substitution therapy in hypogonadal men. androgen deficiency in middle-aged and older men: estimates from the Massa- Clin Endocrinol (Oxf) 1999; 51 (6): 757-63 chusetts Male Aging Study. J Clin Endocrinol Metab 2004; 89 (12): 5920-6 31. Zhang GY, Gu YQ, Wang XH, et al. A pharmacokinetic study of injectable 4. Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for testosterone undecanoate in hypogonadal men. J Androl 1998; 19 (6): 761-8 androgen deficiency in aging males. Metabolism 2000; 49 (9): 1239-42 32. Arver S, Dobs AS, Meikle AW, et al. Improvement of sexual function in testoster- 5. Smith KW, Feldman HA, McKinlay JB. Construction and field validation of a self- one deficient men treated for 1 year with a permeation enhanced testosterone administered screener for testosterone deficiency (hypogonadism) in ageing transdermal system. J Urol 1996; 155 (5): 1604-8 men. Clin Endocrinol (Oxf) 2000; 53 (6): 703-11 33. Arver S, Dobs AS, Meikle AW, et al. Long-term efficacy and safety of a 6. Wang C, Catlin DH, Demers LM, et al. Measurement of total serum testosterone in permeation-enhanced testosterone transdermal system in hypogonadal men. adult men: comparison of current laboratory methods versus liquid chromatog- Clin Endocrinol (Oxf) 1997; 47 (6): 727-37 raphy-tandem mass spectrometry. J Clin Endocrinol Metab 2004; 89 (2): 534- 34. Morales A, Johnston B, Heaton JP, et al. 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