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clinical Androgen deficiency in the aging man Ranjan Arianayagam Mohan Arianayagam Shaun McGrath Prem Rashid be the term used in this article. late onset Background hypogonadism may be defined as ‘a clinical and Androgen deficiency in the aging man is an area of considerable debate because a biochemical syndrome associated with advancing gradual decline in testosterone may simply be part of the normal aging process. However, age and characterised by typical symptoms there is an alternative view that androgen deficiency in the aging man may constitute a and a deficiency in serum testosterone levels’.6 valid and underdiagnosed disorder. throughout this article ‘total testosterone’ is Objective referred to as ‘testosterone’, any other forms (eg. To discuss the aetiology, clinical features, diagnosis and management of androgen free, bound) will be specified. deficiency in the aging man. Androgen physiology Discussion Late onset hypogonadism has clinical features that overlap with both normal aging and ninety-five percent of androgen production some pathological conditions. It can only be diagnosed on the basis of both suggestive occurs in the testes. testosterone is synthesised clinical features and clear biochemical evidence of testosterone deficiency. In this group and secreted by testicular leydig cells under of patients medication may play a role. the influence of pituitary luteinising hormone Keywords: aging; hypogonadism; androgens; testosterone (lh) and local paracrine factors.7 two percent of testosterone circulates freely, 44% is bound to sex hormone binding globulin (shbG) with high affinity, and 54% to albumin with lower affinity.7 it has multiple physiological effects including involvement in spermatogenesis, testicular The issue of androgen deficiency in function, hair growth, bone density, muscle mass the aging man continues to generate and distribution, libido and secondary sexual considerable discussion because a characteristics.7 testosterone is converted gradual decline in testosterone may be through 5-alpha reduction, mainly at the target only a part of the normal aging process organ level, to its biologically active form of and may not represent a true clinical dihydrotestosterone (Dht).7 the hypothalamic- entity.1–3 However, there is a possibility pituitary-gonadal axis is illustrated in Figure 1. that androgen deficiency in the aging Aetiology of late onset man constitutes a valid disorder.4 From hypogonadism data available on diagnostic criteria of symptoms and low testosterone levels, Androgen levels decrease by approximately the prevalence of symptomatic androgen 1% per year after the age of 408 and the deficiency may be up to 12% in males levels of shbG increase with age, resulting older than 40 years of age.5 in reduced bioavailable (free) testosterone.9 low testosterone levels in the aging male can Various interchangeable descriptions have been be associated with chronic conditions such as used in the literature. these include ‘testosterone obstructive sleep apnoea, depression, obesity, deficiency’, ‘andropause’ and ‘late onset chronic obstructive pulmonary disease, type hypogonadism’ (loh). the latter is in accordance 2 diabetes mellitus, rheumatoid arthritis, with the 2008 european guidelines6 and will haemochromatosis, and renal or liver disease.10–12 752 Reprinted from AustRAliAn FAmily PhysiciAn Vol. 39, no. 10, octobeR 2010 Androgen deficiency in the aging man clinical available assays to be helpful in clinical practice. Hypothalmic measurement of shbG is sometimes helpful in GnRH* determining who should be treated when the total testosterone is mildly reduced and the lh normal. however, correct identification of all men who are truly testosterone deficient Peripheral LH, FSH* from (and who should respond to treatment) remains effects anterior pituitary impossible without empirical validation of these Inhibin measures against independent biological markers of androgen action.19 bone density should be Testosterone Testicular Testicular measured when testosterone deficiency has been Leydig cells Sertoli cells confirmed.19 Rebate is available under medicare in the hypogonadal patient. Therapy risks and efficacy Figure 1. Testosterone production – the hypothalamic-pituitary-gonadal axis. Testosterone undergoes 5-alpha reduction into dihydrotestosterone in the peripheral tissues testosterone replacement has benefits in * GnRH: gonadotropin releasing hormone; FSH: follicle stimulating hormone patients with proven androgen deficiency – men with both suggestive clinical symptoms and Furthermore, several commonly used drugs (eg. for testosterone deficiency or the testing of biochemical testosterone deficiency.6 opiates, glucocorticoids, and gonadotropin- testosterone levels in asymptomatic individuals studies that have considered the risks and releasing hormone agonists such as finasteride, presenting with unrelated health complaints.10 efficacy of long term testosterone replacement oestrogen, spironolactone and ketoconazole) will Accordingly, biochemical testing should only be therapy in loh have produced inconsistent reduce testosterone secretion and/or its effects.13 used if suggestive symptoms are present. Various results. A recent systematic review10 found there may also be variations in the sensitivity validated symptom scale questionnaires exist but inconsistent evidence of the benefits of of the testosterone receptor itself which may have limited clinical use.6,9,16 testosterone therapy on bone mineral density, explain why, at the same testosterone level, some Diagnostic difficulties also arise from sexual function, depression and cognition. men can be asymptomatic while others have uncertainty about the correct reference range however, it found that therapy did confer symptomatic loh.14 to apply to various age groups, and there are significant benefits through increased lean reliability issues with various testosterone body mass, reduction in fat mass and improved Diagnosis and presentation assays.15 the reference range generally used for grip strength. other research suggests an many features of aging parallel the features of the diagnosis of loh is the healthy young adult improvement in lower urinary tract symptoms hypogonadism in younger males.15 in addition, male range.17 the endocrine society of Australia (luts) in men with loh.20 evidence on improved among aging male patients, there is considerable defines hypogonadism as a morning testosterone physical function is inconsistent.10 overlap between the symptoms and clinical level of <8 nmol/l in the presence of any lh in terms of adverse events, therapy was examination findings of testosterone deficiency level, or a level of 8–15 nmol/l with a high associated with a significant increase in and the features of normal aging.13 common lh level, which indicates leydig cell failure.18 obstructive luts and increased haematocrit.10 features of loh, taken from international Prolactin should be measured if the total therefore, bladder outflow obstruction secondary guidelines, are summarised in Table 1. General testosterone is <5.2 nmol/l. Australian clinical to benign prostatic enlargement should be practitioners will notice that this list includes guidelines dictate that testosterone replacement treated before testosterone supplementation.17 clinical features that are also present in other for loh is only indicated when levels are below common conditions such as depression. the this range.18 timing of assays is important, as Table 1. Clinical features of LOH6 clinical picture varies according to factors that acute illness may result in a transient decrease include age, androgen sensitivity and medical in testosterone levels, which may necessitate Decreased libido comorbidities.10 Decreased libido is the most repeat measurement.6 An abnormal result Decreased muscle mass and strength common symptom of loh and findings of physical requires the morning blood sample to be Decreased bone mineral density and examination are usually unremarkable.4 repeated to account for circadian variation. A osteoporosis Diagnosis of loh requires two elements: the normal result does not need to be repeated. presence of at least one clinical symptom (Table luteinising hormone should also be Decreased vitality 1) and biochemical confirmation of low total measured to distinguish between primary and Depressed mood testosterone levels.6 the available evidence does secondary hypogonadism.6 measurement of free Increased body fat not support the use of population based screening testosterone is too inaccurate in commercially Reprinted from AustRAliAn FAmily PhysiciAn Vol. 39, no. 10, octobeR 2010 753 clinical Androgen deficiency in the aging man Table 2. Testosterone replacement in Australia (MIMS) Formulation Dosing Advantages Disadvantages Testosterone undecanoate – oral • 120–160 mg/day for 2–3 weeks, then • Oral administration • Testosterone levels (Andriol™, Andriol Testocaps™) 40–120 mg/day in 2 divided doses; vary needs to be taken with food as the testosterone is esterified to lipids and enters the circulation via the lymphatics Testosterone patch (Androderm™) • 5 mg patch/24 hours – titrate to • Easy to apply • Skin irritation serum testosterone, dose varies from • Diurnal variation 2.5–7.5 mg/24 hours Testosterone enanthate – depot • Intramuscular injection – 250 mg • Flexible dosing • Significant variation in (Testosterone enanthate injection™) every 2–3 weeks testosterone levels • Painful injection Testosterone propionate (30 mg) • Intramuscular injection – 100 mg • Flexible dosing • Significant variation in Testosterone phenylpropionate (60 mg) every 2 weeks, or 250 mg every testosterone levels Testosterone isocaproate (60 mg) 3 weeks • Painful injection Testosterone decanoate (100 mg) (Sustanon™) Testosterone gel • 50 mg/day – titrate to serum • Easy application • Potential for transfer to (Testogel™) testosterone others Testosterone pellets • Subcutaneous insertion – titrate 1–6 • Infrequent • Pellet extrusion pellets (each pellet 100 mg) application • Wound infection. Long acting testosterone • 1000 mg at week 1 and week 6 • Infrequent • Large volume to inject undecanoate injection then every 12 weeks application • Cannot be removed if (Reandron 1000™) complication occurs Note: Trade names in parentheses Although there is some doubt about its no evidence of the safety or efficacy of these is variable and checking a level after the impact on prostate cancer recurrence and treatments in loh. introduction of treatment (in the morning after progression,18 and its role in the progression the aim of testosterone replacement is to a testosterone patch placed at night or late of subclinical prostate cancer, the prevailing normalise testosterone levels. testosterone morning after testosterone gel application in the view is that testosterone replacement is replacement can be delivered in several ways morning) ensures adequate absorption in the contraindicated in patients with locally (Table 2) and must be tailored to the individual individual is documented. A trough testosterone advanced and metastatic prostate cancer,17,22 patient. concomitant lifestyle modifications may level after the fourth dose of long acting and is relatively contraindicated in men who are also be useful in improving overall wellbeing injectable testosterone undecanoate (Reandron at high risk of developing prostate cancer (eg. and may assist some symptoms (eg. mood and 1000tm) should be in the low-normal adult male strong family history).6 vitality) and can include weight loss, regular reference range (10–15 nmol/l) or interval there is also concern that testosterone exercise, moderating alcohol intake and adjustment is necessary. therapy may increase the risk of, or worsen, smoking cessation. An endocrinology opinion is An improvement in nonspecific symptoms is erythrocytosis, sleep apnoea, cardiovascular required before treatment when the diagnosis not an accurate marker. clinical improvement disease and thromboembolic events.13,17 in is uncertain, in all cases of hypogonadotrophic in libido, muscle function and body fat should particular, the potential to cause disordered hypogonadism (low testosterone and low lh), be evident within 3–6 months, although bone sleep and breathing, and polycythaemia, is hypopituitarism, and in cases when there are density may take longer to improve. Failure dose responsive.19 Accordingly, european relative contraindications to treatment. to improve in specific symptoms may require recommendations preclude treatment in patients cessation of treatment and further investigation Follow up with untreated sleep apnoea, significant into alternative pathologies.6 polycythaemia or severe heart failure.6,17 it is difficult to quantitatively monitor treatment there may be local reactions depending some patients with loh may be using effect as checking testosterone levels after on the testosterone delivery method. it is or have used alternative treatments such as short acting testosterone ester preparations also essential to monitor erythrocytosis and growth hormone, dehydroepiandrosterone and is not valuable in determining efficacy or testosterone dependent disease.6 in particular, testosterone cream or troches. there is currently safety. Absorption of transdermal preparations men must be monitored for prostate cancer. no 754 Reprinted from AustRAliAn FAmily PhysiciAn Vol. 39, no. 10, octobeR 2010 Androgen deficiency in the aging man clinical • The Andrology Australia website pro- aspects of sexual dysfunction in men. J sex med clear guidelines exist for men on testosterone vides useful information on loh: www. 2004;1:69–81. replacement with regard to prostate cancer 10. bhasin s, cunningham GR, hayes FJ, et al. andrologyaustralia.org/pagecontent. risk. it would be reasonable to follow current testosterone therapy in adult men with andro- asp?pagecode=loWtestosteRone gen deficiency syndromes: an endocrine society policies from the urological society of Australia • The European Association of Urology guide- clinical practice guideline. J clin endocrinol metab and new Zealand and screen men over the lines on loh: www.uroweb.org/guidelines/ 2006;91:1995–2010. age of 50 (or over 40 if they have a first degree online-guidelines. 11. Dhindsa s, Prabhakar s, sethi m, et al. Frequent occurrence of hypogonadotropic hypogonad- relative with prostate cancer) with annual serum Authors ism in type 2 diabetes. J clin endocrinol metab prostate specific antigen and digital rectal Ranjan Arianayagam bA, llb, mbbs(hons), is an 2004;89:5462–8. examination.23 intern, Royal north shore hospital, sydney, new 12. Zarrouf FA, Artz s, Griffith J, et al. testosterone and depression: systematic review and meta-analysis. J south Wales. [email protected] Psychiatr Pract 2009;15:289–305. Conclusion mohan Arianayagam bsc, mbbs, is urology 13. cunningham GR. testosterone replacement therapy While controversial, loh may be present in Fellow, Department of urology, Jackson memorial for late-onset hypogonadism. nat clin Pract urol 2006;3:260–7. hospital and the university of miami, Florida, up to 12.3% of the male population and there 14. harkonen K, huhtaniemi i, makinen J, et al. the united states of America may be benefits to identifying and treating this polymorphic androgen receptor gene cAG repeat, shaun mcGrath mbbs(hons), FRAcP, is pituitary-testicular function and andropausal symp- group of men. Population based screening is not consultant endocrinologist, Department of toms in ageing men. int J Androl 2003;26:187–94. indicated. in the general practice setting it is endocrinology, John hunter hospital, newcastle, 15. handelsman DJ, liu Py. Andropause: invention, useful to consider loh in men with suggestive new south Wales prevention, rejuvenation. trends endocrinol metab 2005;16:39–45. symptoms and investigate their androgen status. Prem Rashid mbbs, FRAcGP, FRAcs(urol), PhD, 16. martinez-Jabaloyas Jm, Queipo-Zaragoza A, et al. careful consideration and counselling is required is a urological surgeon and conjoint Associate Relationship between the saint louis university before commencing androgen replacement Professor, Department of urology, Port macquarie ADAm questionnaire and sexual hormonal levels in a male outpatient population over 50 years of age. base hospital and university of new south and, in particular, lower urinary tract symptoms eur urol 2007;52:1760–7. Wales Rural clinical school, new south Wales. and risk factors for prostate cancer need to be 17. Wang c, nieschlag e, swerdloff Rs, et al. isA, issAm, eAu, eAA and AsA recommendations: considered. conflict of interest: Prem Rashid has been a investigation, treatment and monitoring of visitor to the American medical systems (Ams) late-onset hypogonadism in males. Aging male Summary of key points us manufacturing facility undertaking a cadaveric 2009;12:5–12. 18. the endocrine society of Australia. use and misuse • Diagnosis of LOH requires both the dissection clinic and observed operative of androgens. Available at www.endocrinesociety. presence of at least one clinical symptom procedures by high volume implant urologists org.au/posstat2.htm. and biochemical confirmation of low total affiliated with Ams during that time. he also 19. liu Py, swerdloff Rs, Veldhuis JD. clinical review testosterone levels. has acted as a consultant for coloplast, Astra 171: the rationale, efficacy and safety of androgen therapy in older men: future research and current • Testosterone replacement confers benefits Zeneca, hospira and Abbott pharmaceuticals. no practice recommendations. J clin endocrinol metab through increased lean body mass, reduction commercial organisation initiated or contributed 2004;89:4789–96. in fat mass and improved grip strength. to the writing of the article. 20. Kalinchenko s, Vishnevskiy el, Koval An, et al. beneficial effects of testosterone administration • Treatment is precluded in patients with on symptoms of the lower urinary tract in men with References untreated sleep apnoea, significant late-onset hypogonadism: a pilot study. Aging male 1. handelsman DJ. testosterone: use, misuse and polycythaemia, severe heart failure, or 2008;11:57–61. abuse. med J Aust 2006;185:436–9. 21. ubm medica. mims. st leonards: ubm medica, significant lower urinary tract symptoms or 2. Finucane te. men, androgen deficiency, and issue 1, 2010. obstruction. pharmaceutical promotion. Arch intern med 22. morgentaler A. testosterone therapy in men with 2009;169:88–9. • Testosterone replacement is contraindicated prostate cancer: scientific and ethical considera- 3. Page st, matsumoto Am, bremner WJ. DheA tions. J urol 2009;181:972–9. in patients with prostate cancer, and is and testosterone in the elderly. n engl J med 23. urological society of Australia and new Zealand. relatively contraindicated in men who are at 2007;356:635–7. PsA testing guidelines, 2009. Available at www. 4. tostain Jl, blanc F. testosterone deficiency: a high risk of developing prostate cancer. usanz.org.au/usanz-2009-psa-testing-policy. common, unrecognized syndrome. nat clin Pract • An endocrinology opinion is required urol 2008;5:388–96. before treatment when the diagnosis is 5. Araujo Ab, esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J clin uncertain, in all cases of hypogonadotrophic endocrinol metab 2007;92:4241–7. hypogonadism, and in cases when there are 6. Wang c, nieschlag e, swerdloff R, et al. relative contraindications to treatment. investigation, treatment, and monitoring of late-onset hypogonadism in males: isA, issAm, Resources eAu, eAA, and AsA recommendations. eur urol 2009;55:121–30. • Additional information regarding the 7. nieschlag e. Andrology: male reproductive health urological society of Australia and new and dysfunction. berlin: springer, 2001. Zealand’s policy on PsA testing can be 8. Jones R. human Reproductive biology. 3rd edn. obtained at www.usanz.org.au/usanz- london: Academic press, 2006. 2009-psa-testing-policy 9. morales A, buvat J, Gooren lJ, et al. endocrine Reprinted from AustRAliAn FAmily PhysiciAn Vol. 39, no. 10, octobeR 2010 755