MJA PracticeMJA Essentials Practice Essentials EndocrinologyEndocrinology 11: Androgen deficiency and replacement therapy in men David J Handelsman and Jeffrey D Zajac While androgen replacement therapy is essential and effective in overt deficiency, it is no anti-ageing elixir WHILE ANDROGEN DEFICIENCY may not shorten life ABSTRACT expectancy, its pervasive effects on the development and maintenance of masculine sexual characteristics and ana- The Medical Journal of Australia ISSN: 0025-729X 17 May ■ Androgen deficiency is a clinical diagnosis confirmed by bolic status of somatic tissues can impoverish quality of life. 2004 180 10 529-535 hormone assays. Yet most of these effects are easily correctible by simple and ©The Medical Journal of1 Australia 2004 www.mja.com.au ■ Among younger men, androgen deficiency is usually due cost-effectiveMJA Practice treatment. Essentials — AppropriateEndocrinology management of androgen replacement therapy is rewarding for doctor and to underlying hypothalamopituitary or testicular disorders. patient, whereas confused management can lead to mutual ■ Androgen replacement therapy should be started after frustration. proof of androgen deficiency and should continue lifelong with monitoring. Aetiology ■ Men presenting with erectile dysfunction should be evaluated for androgen deficiency, but it is an uncommon Common causes of androgen deficiency are shown in Box 1. cause; if overt androgen deficiency is confirmed, an Classical androgen deficiency is caused by testicular disor- underlying disorder needs further specialist investigation. ders that reduce testosterone production and by hypotha- lamic–pituitary disorders that reduce pituitary secretion of ■ In the absence of characteristic underlying testicular or gonadotropins, the tropic drive to testosterone secretion. pituitary disorders, new diagnosis of androgen deficiency Common testicular causes are Klinefelter’s syndrome, in older men is difficult because of the non-specific which is associated with a 47,XXY karyotype, and develop- symptoms and the decline in blood testosterone levels mental and toxic damage to the testes. seen in healthy ageing and chronic medical disorders. Pituitary tumours and their treatment are the most com- ■ There remains no convincing evidence that androgen mon cause of gonadotropin deficiency as part of hypopitui- therapy is either effective treatment or safe for older men tarism, while Kallmann’s syndrome is the most frequent unless they have frank androgen deficiency. form of isolated gonadotropin deficiency. An increasing number of genetic causes of this syndrome have been MJA 2004; 180: 529–535 recognised, including inactivating mutations in the KAL1 gene (which encodes a cell-adhesion protein) and the FGFR1 (fibroblast growth factor receptor 1) gene. These Epidemiology interfere with the development or function of the gonadotro- The prevalence of classical androgen deficiency is about 1 in pin-releasing hormone neurones. Kallmann’s syndrome 200 adult men. However, as recent evidence suggests that often includes other abnormalities, such as anosmia and only 10%–30% of men with Klinefelter’s syndrome are midline cranial defects, colour blindness, deafness and diagnosed clinically during their lifetimes,2,3 and as other synkinesis. Inactivating mutations in genes such as the causes of androgen deficiency have less distinctive clinical DAX-1 (adrenal hypoplasia congenita), GnRH (gonadotro- features, it is likely that they are underdiagnosed. However, pin-releasing hormone) receptor and GPR54 (G protein- age-related androgen deficiency is frequently overdiagnosed. coupled receptor) genes cause isolated hypogonadotropic hypogonadism without the above clinical features. Partial or transient androgen deficiency with mixed cen- Clinical features tral and peripheral components may occur in chronic illness, The clinical features of androgen deficiency depend on the severe acute illness, drug use, ageing and constitutional 1 delay of puberty. epoch of life affected. Leydig cells in the testes secrete testosterone at adult male blood levels during fetal sexual Series Editors: Donald J Chisholm and Jeffrey D Zajac differentiation, the perinatal androgen surge, and from puberty onwards. ANZAC Research Institute, Concord Hospital, Sydney, NSW. David J Handelsman, FRACP, PhD, Director. During fetal life, androgen deficiency disrupts male sexual Department of Medicine, University of Melbourne, differentiation and somatic development. The effects are Austin Hospital, Melbourne, VIC. usually not correctible by postnatal hormone administra- Jeffrey D Zajac, PhD, FRACP, Head. tion. Reprints will not be available from the authors. Correspondence: Professor David J Handelsman, ANZAC Research Institute, Concord Hospital, In adolescence, androgen deficiency manifests as late or Hospital Road, Concord, NSW 2139. [email protected] incomplete sexual and somatic maturation. The most valua- MJA Vol 180 17 May 2004 529 Endocrinology MJA Practice Essentials The effect of androgen on sexual function manifests 1: Common causes of androgen deficiency primarily through effects on libido. However, the threshold Classical androgen deficiency is low, with libido maintained by low circulating testosterone Testicular disorders levels.4,5 Sexual function is impaired only by severe andro- Klinefelter’s syndrome and variants (mosaic) gen deficiency, and then characteristically through reduced Cryptorchidism and defects of testis development libido, with the resulting reduced sexual activity rarely Orchitis troubling the affected man. In men presenting with erectile Orchidectomy (advanced prostate cancer, bilateral testicular dysfunction, the preserved libido indicates a low a priori cancer) likelihood of androgen deficiency. In such cases, empirical Toxin exposure (cancer chemotherapy or radiotherapy, androgen therapy is inappropriate, as it may enhance libido environmental, occupational and domestic toxins) but not erectile capacity. Hypothalamic–pituitary dysregulation Idiopathic hypogonadotropic hypogonadism and variants: ■ Kallmann’s syndrome (associated with anosmia and midline Diagnosis cranial defects; caused by mutations in the KAL1 or FGRF1 [fibroblast growth factor receptor 1] genes) Androgen deficiency is a clinical diagnosis confirmed by 1,6 ■ Other genetic causes (including inactivating mutations in the hormonal assays. Neither the clinical features, which are DAX-1 [adrenal hypoplasia congenita], GnRH-receptor or GPR54 mostly non-specific, nor the hormonal findings, unless [G protein-coupled receptor] genes) severe (ie, persistently castrate levels), are sufficient alone Pituitary tumour and treatment (surgery, irradiation) for diagnosis. Circulating testosterone level can be lowered Haemochromatosis by intercurrent medical conditions. Craniopharyngioma Clinical diagnosis depends on recognising clinical features Partial or transient androgen deficiency in characteristic settings. Lifelong androgen replacement Constitutional delay of puberty should not be recommended without a full history and Acute critical illness, burns, major trauma or surgery careful physical examination, coupled with reliable hormo- Drug use (eg, opiates, glucocorticoids, anabolic steroids) nal assays. Chronic disease and its treatment The history should include: Ageing (“late-onset” androgen deficiency) ■ childhood (cryptorchidism, hernia and hypospadias) and GnRH = gonadotropin-releasing hormone. pubertal development (voice change, shaving onset and growth spurt relative to peers); ■ fertility history (paternity relative to opportunity); ■ known testicular abnormalities; ble clinical assessment is testicular examination, not only as ■ toxin exposure, medication and occupation; and testis growth is the first objective physical sign of puberty, ■ recent changes in sexual function and patterns of body but as serial observation of testis volume is the most reliable hair. gauge of progression of normal puberty (see Box 2). For Physical examination must include: example, puberty has commenced when testis volume ■ palpation of the testes for volume and consistency (atrophy); exceeds 4 mL (even before somatic manifestations are evi- dent), and physical and mental virilisation are imminent when volume exceeds 8 mL. The other characteristic physi- cal features of pubertal virilisation include growth of the 2: Measurement of testicular volume larynx (voice change), height (bone growth spurt, epiphy- seal fusion), musculature, genitals (enlarged phallus and scrotum with thickened, rugose, pigmented skin) and body hair (facial and truncal body hair, onset of shaving, subse- quent temporal recession and balding). In adult (post-pubertal) life, androgen deficiency causes regression of some features of virilisation. Symptoms are characteristically non-specific, notably reduced sense of well-being and energy levels (lethargy, easy fatigue, lack of stamina or endurance), reduced libido, mood changes (irri- tability, “short-fuse”, non-coping behaviour) and loss of physical, social and sexual drive. Flushing similar to the vascular instability in postmenopausal women occurs in some men with castrate testosterone levels, but is rare in less severe deficiency. Objective effects of androgen deficiency An orchidometer is the standard instrument for measuring the testes. The beads are marked with the corresponding volume (mL). include mild to moderate (but not severe) reduction in (Photograph courtesy of Danielle Edwards, Austin Health, haemoglobin level, weight gain and reduction