Androgen Deficiency in the Aging
Total Page：16
File Type：pdf, Size：1020Kb
CLINICAL Androgen deficiency Ranjan Arianayagam Mohan Arianayagam in the aging man 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. Discussion Androgen physiology 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 man constitutes a valid disorder.4 From Aetiology of late onset data available on diagnostic criteria of hypogonadism 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 effects anterior pituitary (and who should respond to treatment) remains 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 10 6 comorbidities. Decreased libido is the most repeat measurement. An abnormal result Decreased muscle mass and strength common symptom of LOH and findings of physical requires the morning blood sample to be examination are usually unremarkable.4 repeated to account for circadian variation. A Decreased bone mineral density and 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 –