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