CLINICAL Assessment and management of male androgen disorders: Irene Chan Mark Ng Tang Fui an update Jeffrey D Zajac Mathis Grossmann

which is easily diagnosed by testicular Background examination, is not uncommon.3 Organic Male hypogonadism, caused by intrinsic pathology of the hypothalamic–pituitary– hypogonadism needs to be distinguished testicular (HPT) axis, is an under-diagnosed condition not to be missed. By from the less well-defined entity called contrast, late onset hypogonadism (LOH), due to functional suppression of the HPT late onset hypogonadism (LOH), which axis from age-related comorbidities, may be less common than previously believed. is caused by functional (and hence Objective potentially reversible) suppression of the This article outlines the aetiology, clinical features, investigation and management HPT axis due to accumulation of age- of male hypogonadism and discusses the more controversial area of LOH. related comorbidities, especially obesity. Discussion Recent data suggest that LOH is less Pathologically based hypogonadism is, after a thorough diagnostic work-up, common than previously believed and has treated with testosterone replacement therapy, unless fertility is desired. LOH with a prevalence of about 2%.4 modest reductions in testosterone levels should primarily be managed by attention to lifestyle measures, especially weight loss, and optimisation of comorbidities. In contrast to women who experience a sudden Clear treatment goals should be identified, and efficacy and safety should be drop in oestradiol levels around the time monitored according to published clinical practice guidelines. that menses ceases, the age-related drop in Keywords testosterone in men is more gradual at 0.5–2.0% men’s health; endocrine system diseases; obesity; diabetes mellitus per year from early adulthood onwards. As levels of sex hormone binding globulin (SHBG) rise with age by 1–2% per year, the decline in free testosterone level is greater and is 2–3% per Male hypogonadism is a clinical year. Most older men have testosterone levels syndrome that results from failure within the reference range and there is recent to produce physiological levels of evidence from Australia that healthy ageing alone testosterone (androgen deficiency) and may not be associated with marked decreases in a normal number of spermatozoa due testosterone levels.5 However, the age-dependent to organic pathology that disrupts one decrease in testosterone levels is accelerated or more levels of the hypothalamic– by accumulation of comorbidities, especially pituitary–testicular (HPT) axis.1 It obesity.6 Indeed, a normal testosterone level can therefore includes androgen deficiency be considered to be a sensitive biomarker of good and infertility, although both components health. can be present in isolation. The prevalence of organic hypogonadism Diagnosis of hypogonadism in Australia is about 1 in 500 men2 and The diagnosis of androgen deficiency should be general practitioners (GPs) will see made only in men with consistent symptoms several such men in their practice. There and signs, and unequivocally and repeatedly is evidence that male hypogonadism low serum testosterone levels.1 In practice this is under-diagnosed and late diagnosis diagnosis is often difficult, especially in older of, for example, Klinefelter’s syndrome, obese men with chronic disease, as symptoms

REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 43, NO. 5, MAY 2014 277 CLINICAL Assessment and management of male androgen disorders: an update and signs are often non-specific and because related to other medical conditions. In men aged symptoms and signs. Patients should be well or there is no evidence-based, universally agreed over 50 years, digital rectal examination must be medically stable, without acute decompensation pathological testosterone cut-off level.1,7 performed to exclude palpable prostate pathology of any underlying comorbidity. As testosterone before commencing testosterone replacement release is diurnal, with the highest levels in Clinical diagnosis therapy. In addition, although controversial the early morning, blood samples should be Given that hypogonadism is primarily a clinical in the general population, regular testing for taken close to 8 am. Food intake can reduce diagnosis supported by consistent biochemical prostate-specific antigen (PSA) is recommended total testosterone acutely by as much as findings, a thorough history and examination during testosterone therapy and a baseline PSA 25%, explaining the importance of a fasting are essential. Clinical assessment should be of >4 ng/ml without urological evaluation is a blood sample. There is marked variability in focused on eliciting symptoms and signs of contraindication to testosterone treatment.1 testosterone levels not only between individuals androgen deficiency and on identifying clues to but also within an individual. Therefore, repeated Biochemical diagnosis the underlying aetiology (Table 18). Signs and measurements are necessary to confirm a symptoms include incomplete or delayed sexual Of the total circulating testosterone, 60% is low testosterone level and a diagnosis of development (if hypogonadism occurs before tightly bound to SHBG, 38% is loosely bound hypogonadism should never be based on a single or during puberty), reduced libido, decreased to albumin and only 2% is free. Bioavailable testosterone level. spontaneous erections, breast discomfort, loss of testosterone refers to albumin-bound and free There is no general agreement on the body hair, reduced shaving, very small (especially testosterone. Total testosterone is the mainstay of acceptable normal range of testosterone. <5 ml) or shrinking testes, infertility, height biochemical diagnosis of androgen deficiency. Reference intervals also vary between laboratories loss, low trauma fracture, low bone mineral The initial diagnostic test in suspected because of differences in assay methods and/ density, hot flushes. It should be kept in mind androgen deficiency is measurement of fasting or reference population of men. In practice, if the that clinical features can be non-specific and morning total testosterone in men with consistent total testosterone level is 12 nmol/L or above, the patient is usually eugonadal and further testing is generally not required. If the total testosterone Table 1. Causes of androgen deficiency8 level in a man with consistent symptoms Partial/transient Primary (elevated FSH/ Secondary (low/normal and signs is less than 12 nmol/L, a repeat LH) FSH/LH) measurement of fasting morning testosterone Acute illness ACQUIRED STRUCTURAL level is suggested. Levels of 8–12 nmol/L may Chronic disease Testicular damage Tumour be considered borderline and <8 nmol/L low. If • ESRF • Trauma Surgery a testosterone level is borderline, requesting • COPD • Orchitis Radiation measurement of free testosterone may be • HIV • CTX/RTX/toxins Trauma helpful because the levels of total testosterone • T2DM Drugs Infiltration can be affected by alterations in levels of SHBG Androgen • Spironolactone • Iron overload and albumin. Men with obesity and diabetes deprivation therapy • Ketoconazole • Sarcoid commonly have a low SHBG and here a normal (GnRH agonists) • Histiocytosis free testosterone can be reassuring that such Anabolic steroids men are not, in fact, hypogonadal. In general, a repeatedly low testosterone level CONGENITAL GENETIC is more indicative of hypogonadism in younger, Klinefelter syndrome Kallmann syndrome healthier and leaner men but more difficult to Cryptorchidism 'Idiopathic' HH interpret in older obese men with chronic disease Mutations in androgen LH/FSH beta subunit mutations 6,7 biosynthesis enzymes and non-specific symptoms. LH/FSH-receptor mutations FUNCTIONAL Aetiology of hypogonadism Myotonic dystrophy Hyperprolactinaemia Once the low testosterone value has been Morbid obesity confirmed on repeated morning measurements Cushing’s syndrome in patients with consistent symptoms and Alcohol excess* signs, luteinizing hormone (LH) and follicle COPD, chronic obstructive pulmonary disease; CTX, chemotherapy; ESRF, end stage stimulating hormone (FSH) values should be renal disease; RTX, radiotherapy; HH, hypogonadotropic hypogonadism; obtained to further distinguish between primary T2DM, type 2 diabetes mellitus or secondary hypogonadism (Table 1). Elevated *Alcohol excess typically causes mixed (combined primary and secondary) hypogonadism. LH and FSH values indicate primary (testicular)

278 REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 43, NO. 5, MAY 2014 Assessment and management of male androgen disorders: an update CLINICAL hypogonadism, whereas low or importantly even for example due to a microprolactinoma, the Haemochromatosis can be ruled out by measuring inappropriately ‘normal’ LH and FSH values may hypogonadism will respond to, and should be iron levels and determining the fasting transferrin indicate secondary (pituitary–hypothalamic) treated by, normalising the prolactin level rather saturation. Biochemical assessment of pituitary hypogonadism. Combined primary and secondary than by testosterone therapy. (dys-)function may be necessary, and pituitary hypogonadism have variable gonadotropin levels, In the work-up for secondary hypogonadism, imaging may need to be considered. Given that depending on whether primary or secondary it is very important not to miss pituitary functional hypogonadism due to comorbidities hypogonadism predominates. or hypothalamic pathology, which can presents with secondary hypogonadism, the yield damage gonadotroph production, resulting in of organic pathology is low in older obese men Primary hypogonadism hypogonadism. A careful clinical assessment with comorbidities and only modest reductions in It is important to ask the patient about the age of for a pituitary mass effect (headache, visual testosterone levels. onset of his problems, about congenital defects field defect, eye movement disturbance), as The practitioner needs to be aware that men such as cryptorchidism, pubertal development, well as for features of hypopituitarism or of with prior or current anabolic steroid use may fertility, previous testicular trauma or infection, a hormone producing pituitary tumour (eg. present with low testosterone and LH levels and radiotherapy, chemotherapy, use of medications Cushing’s syndrome) must be undertaken. use may be denied even with specific questioning. that inhibit androgen biosynthesis, and medical conditions that can cause both primary and secondary hypogonadism. A karyotype analysis Clinical suspicion of hypogonadism, clinically stable no should be obtained in men with primary testicular intercurrent illness failure to exclude Klinefelter’s syndrome (47XXY), which occurs in about 1 in 500 men.3 Secondary hypogonadism TT <8–12 nmol/L TT ≥ 8–12 nmol/L* Organic congenital causes of secondary hypogonadism are rare and include Kallmann Repeat, add free T Consider other causes for syndrome, GnRH receptor mutation and deficiency, clinical presentation eg. chronic or genetic mutations associated with other illness, psycho-social issues pituitary hormone deficiencies. These congenital T <8–12 nmol/L disorders are usually diagnosed in childhood Free T low or adolescence when patients present with Primary testicular failure: pubertal delay. Acquired causes of secondary consider karyotype for hypogonadism are summarised in Table 1. LH Klinefelter’s Androgen deprivation therapy given to men with prostate cancer is an increasingly important cause of severe androgen deficiency. Normal or low High Many chronic diseases are associated with low testosterone levels via suppression of gonadotropin production. Testosterone Hypogonadotrophic hypogonadism levels are commonly lowered in men with Check medications that may lower T metabolic syndrome, type 2 diabetes mellitus, • Anabolic steroids obesity, depression, obstructive sleep apnoea, • Opiates chronic kidney disease or anorexia nervosa.7 • Glucocorticoids In addition, certain medications, in particular Measure: glucocorticoids or opioids, reduce gonadotropins • Prolactin and testosterone levels. • Iron studies Hyperprolactinaemia can lead to secondary Consider pituitary imaging hypogonadism through suppression of the Review medical history pulsatile release of gonadotropin-releasing • Obesity, type 2 diabetes (very common) LH, luteinizing hormone hormone (GnRH) from the hypothalamus. Hence, • Severe chronic illness TT, testosterone trough measurement of prolactin levels is essential and, T, testosterone if elevated, its cause should be investigated. Figure 1. Work-up of androgen deficiency If there is pathological hyperprolactinaemia,

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Clues to androgen abuse are muscular build, a low men who have functional hypogonadism have times the upper limit of the eugonadal reference HDL level or a higher than expected haematocrit; profound androgen deficiency similar to men range for young men. However, the primary intent organic androgen deficiency is often associated with organic hypogonadism due to intrinsic of this PBS cut-off of 8 nmol/L was to restrict with mild anaemia due to the erythropoietic HPT axis pathology. The risk–benefit ratio of unproven overuse of testosterone therapy, and actions of testosterone. The diagnostic approach testosterone therapy in men with LOH is not well even in men with repeated total testosterone levels to hypogonadism is summarised in Figure 1. established because there are no large long-term of <8 nmol/L, treatment should be individualised. randomised controlled clinical trials (RCT) that It may be reasonable to consider a trial of Testosterone treatment provide information about benefits for patients testosterone therapy in selected men with LOH, It is very important to remember that an (eg. fracture reduction, improved functional in the absence of contraindications. As symptoms underlying aetiology should always be sought morbidity or mortality) or therapy-associated risks. of androgen deficiency should improve within 1–3 before testosterone therapy is considered. This In men with functional hypogonadism resulting months, a therapy trial of 3–6 months is usually is not only because hypogonadism can be due to from chronic illness, especially obesity, the of sufficient duration. It is important to inform the underlying pathologies such as a pituitary tumour focus of therapy should be on lifestyle measures patient that this approach is not backed by high- or haemochromatosis, important diagnoses not (especially weight loss) and optimisation of level evidence of efficacy and safety. In addition, to be missed, but also because gonadotropin comorbidities. Although difficult to achieve the patient should be informed at the outset that treatment of secondary hypogonadism may restore and sustain, moderate weight loss (<10%) can testosterone therapy will be stopped should there fertility. Importantly, if testosterone therapy is increase testosterone levels by 2–3 nmol/L. be no benefit, according to defined treatment commenced before the diagnosis is confirmed, the Substantially larger increases (up to >10 nmol/) goals agreed by the patient and practitioner. In diagnostic work-up can be obscured and fertility may be achieved in severely obese men who have such men, the therapeutic target should be to raise compromised. successful bariatric surgery.6,7 serum testosterone levels to the low-to-mid-normal Testosterone replacement is recommended Testosterone treatment in men with only range of healthy young men. The risk of iatrogenic for symptomatic classical androgen deficiency modest reductions in circulating testosterone suppression of the HPT axis with a short course syndromes after excluding contraindications levels should be considered only if such measures of testosterone therapy is low, but longer acting in the initial work up (Table 2). Men with fail, and is only recommended in the presence testosterone preparations should be avoided organic hypogonadism respond very well to of symptoms. Symptoms of hypogonadism are initially. In men suitable for long-term testosterone testosterone replacement therapy and show non-specific and may be consequent to underlying therapy, different options are available (Table a marked improvement in sexual function, comorbidities; men with symptomatic LOH are 3) and choice depends on patient and physician sense of well being and energy levels, and less likely to respond to testosterone therapy, preference. maintenance of secondary sexual characteristics. compared with younger men with organic Androgen deficiency and erectile dysfunction However, testosterone therapy does not improve hypogonadism in whom such comorbidities are are two overlapping conditions with distinct fertility; in fact, because of gonadotropin absent.7 pathophysiology. A randomised, placebo-controlled suppression, testosterone therapy may supress There are no restrictions regarding trial studied the effect of testosterone therapy spermatogenesis. Indeed, testosterone therapy is testosterone replacement in men with organic added to sildenafil in erectile dysfunction. The being evaluated in trials of male contraception. hypogonadism due to established pathology of results showed that sildenafil plus testosterone By contrast, in men with LOH, the distinction the HPT axis. By contrast, in men without classical was not superior to sildenafil plus placebo, between replacement and pharmacological androgen deficiency, testosterone therapy is although pre-treatment testosterone levels in such testosterone therapy becomes more difficult subsidised by the Pharmaceutical Benefit Scheme men were not unequivocally low.9 to define. Moreover, there is overlap between (PBS) only if the testosterone level is <8 nmol/L or Testosterone treatment: classical androgen deficiency and LOH. Certain 8–15 nmol/L with high LH levels, defined as >1.5 potential risks and monitoring for adverse events Table 2. Contraindications to testosterone therapy1 Young men with organic hypogonadism Breast or prostate cancer generally have a favourable risk–benefit ratio A palpable prostate nodule or induration without further urological evaluation with testosterone therapy, provided they are PSA >4 ng/mL (or >3 ng/mL in men at high risk of prostate cancer) without further monitored for side effects (Table 4) and men with urological evaluation contraindications (Table 2) have been excluded. Severe lower urinary tract symptoms (International prostate symptom score >19) By contrast, there may be increased risks in older, Haematocrit >50% obese men because of comorbidities, such as Untreated severe obstructive sleep apnoea prostate disease and undiagnosed obstructive Uncontrolled or poorly controlled heart failure sleep apnoea.1 RCTs in older men receiving When fertility is desired testosterone therapy and meta-analyses to date

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Table 3. Testosterone therapy: formulations1 Preparation/ Advantages Disadvantages Testosterone monitoring administration Testosterone gel Can be self-administered Chance for inadvertent transfer to close Morning, before application, 1%, daily Short half-life in case of side effects contacts (spouse, children, nurses) after use for 7 days Imprecise dose adjustment Marked variation in blood levels Skin irritation Testosterone Can be self-administered Skin irritation Morning after evening patch, daily Short half-life in case of side effects Limited scope for dose variation application Testosterone Can be self-administered Pump applicator required Monitor after 2 weeks, trough transdermal Short half-life in case of side-effects Must be administered in the axilla level taken 2–8 hours after solution, daily Low chance of inadvertent transfer Skin irritation application to others May not wash, shower or swim within 2 hours of application Testosterone Can be self-administered Frequent dosing required (2–3 times Monitor after 2 weeks undecanoate 40 Short half-life in case of side effects daily) mg capsule, 2–3 Marked variation in blood levels times per day Gastrointestinal intolerance Testosterone Convenience Injection site pain Morning, before fourth undecanoate 1 Compliance Contraindicated in men with injection. Aim for trough level g. IM injection Stable testosterone (T) levels coagulopathies 10–15 nmol/L. Allow a further 3-monthly Cannot be self-administered 2–3 injections after dose adjustment before rechecking Testosterone Convenience Invasive procedure required 6-monthly after a 600–800 mg implant 100 mg Compliance Extrusion, infection, bleeding dose 6 monthly Stable T levels

Table 4. Adverse effects of testosterone therapy1 Key points • Organic androgen deficiency due to intrinsic More common HPT axis pathology can be missed, and there Erythrocytosis is indeed evidence that classical androgen Acne and oily skin deficiency is underdiagnosed. Such men usually Detection of subclinical prostate cancer benefit markedly from testosterone replacement Growth of metastatic prostate cancer (except fertility), with a generally low risk of Reduced sperm production and fertility adverse events. Uncommon • Testosterone therapy should not be started Gynaecomastia without a thorough work-up to delineate the Male pattern balding (familial) underlying aetiology and identify associated Growth of breast cancer pathologies. Induction or worsening of obstructive sleep apnoea • Older obese men with chronic comorbidities commonly present with non-specific symptoms have been underpowered to provide definitive pre-existing, clinically insignificant prostate and modestly low testosterone. In such men outcome data regarding cardiovascular and cancer. One recent RCT has shown an increase in emphasis should be on weight loss and prostate events. The main areas of concern relate cardiovascular events with testosterone treatment optimisation of comorbidities. The risk–benefit to prostate and cardiovascular events. While there in relatively frail older men,10 but numbers were ratio of testosterone therapy in such men is less is no evidence that testosterone causes prostate small and may have been due to chance. Another favourable than in men with organic androgen cancer, the main practical issue is that because of RCT in a similar population has not confirmed this deficiency. prostate monitoring during testosterone therapy, finding.11 Hence, monitoring patients according to • Testosterone therapy should include: there may be an increased risk of over-diagnosing a standardised monitoring plan is important.1 –– a discussion about the uncertainties

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regarding risks/benefits (especially in men Director, Department of Endocrinology, Austin 5. Sartorius G, Spasevska S, Idan A, et al. Serum Health, Melbourne, VIC testosterone, dihydrotestosterone and estradiol without organic androgen deficiency) concentrations in older men self-reporting very good Mathis Grossmann MD, PhD, FRACP, Principal –– patient-centred goals health: the healthy man study. Clin Endocrinol (Oxf) Research Fellow, Department of Medicine Austin 2012;77: 755–63. –– implementation of a standardised monitoring Health, University of Melbourne, and Head of 6. Ng Tan Fui M, Dupuis P, Grosssmann M. Lowered program Men’s Health, Department of Endocrinology, Testosterone in Male Obesity: Mechanisms, Morbidity –– ongoing evaluation for benefit/ adverse Austin Health, Melbourne, VIC and Management. Asian J Androl. In press. 7. Grossmann M. Low testosterone in men with type 2 events. Competing interests: None. diabetes: significance and treatment. J Clin Endocrinol –– Large, well-conducted clinical trials are Provenance and peer review: Not commissioned; Metab 2011;96: 2341–53. 8. Snyder P. Causes of secondary hypogonadism in externally peer reviewed. needed to provide more evidence to guide males. In: Matsumoto AM, Geffner M, editors. clinicians and patients regarding the UpToDate. Waltham: Wolters Kluwer 2014. benefits, and risks, of testosterone therapy. References 9. Spitzer M, Basaria S, Travison TG, et al. Effect of 1. Bhasin S, Cunningham GR, Hayes FJ, et al. testosterone replacement on response to sildenafil Testosterone therapy in men with androgen defi- citrate in men with erectile dysfunction: a parallel, Authors ciency syndromes: an Endocrine Society clinical randomized trial. Ann Intern Med 2012;157: 681–91. Irene Chan MBBS, BMedSc, Endocrinology practice guideline. J Clin Endocrinol Metab 2010;95: 10. Basaria S, Coviello AD, Travison TG, et al. Adverse Advanced Trainee, Department of Endocrinology, 2536–59. events associated with testosterone administration. Austin Health, Melbourne, VIC. KaIan.Chan@ 2. Handelsman DJ, Zajac JD. Androgen deficiency and N Engl J Med 2010;363:109–22. austin.org.au replacement therapy in men. Med J Aust 2014;180: 11. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. 529–35. Effects of testosterone on muscle strength, physi- Mark Ng Tang Fui MBBS, BMedSC, FRACP, 3. Herlihy AS, Halliday JL, Cock ML, McLachlan RI. cal function, body composition, and quality of life Consultant Endocrinologist, Department of The prevalence and diagnosis rates of Klinefelter in intermediate-frail and frail elderly men: a rand- Endocrinology, Austin Health, Melbourne, VIC syndrome: an Australian comparison. Med J Aust omized, double-blind, placebo-controlled study. J Clin 2011;194: 24–28. Endocrinol Metab 2010;95:639–50. Jeffrey D. Zajac MBBS, PhD, FRACP, Professor of 4. Wu FC, Tajar A, Beynon JM, et al. Identification of Medicine and Head of Department of Medicine, late-onset hypogonadism in middle-aged and elderly Austin Health, University of Melbourne, and men. N Engl J Med 2010;363:123–35.

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