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EMAS position statement: Testosterone replacement therapy in the aging male‏

      Highlights

      • Late-onset hypogonadism (LOH) represents a common clinical entity among aging males.
      • Typical sexual symptoms suggestive of androgen deficiency comprise loss of libido, decreased spontaneous erections and erectile dysfunction.
      • Testosterone replacement therapy (TRT) should be offered to these individuals, only if a combination of testosterone deficiency symptoms and low testosterone is present.
      • Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk—benefit assessment.
      • Evidence from large randomized prospective trials regarding beneficial effects and cardiovascular safety of testosterone replacement therapy is needed.

      Abstract

      Introduction

      Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate.

      Aims

      The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks.

      Materials and methods

      Literature review and consensus of expert opinion.

      Results and conclusions

      Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.

      Keywords

      1. Introduction

      Aging or the process of becoming older represents the accumulation of physical, psychological, and social changes in a human being over time, ultimately resulting in death. Late-onset hypogonadism (LOH) is characterized by decreasing circulating testosterone concentrations, in combination with a spectrum of clinical symptoms and signs, during normal aging [
      • Lamberts S.W.
      • van den Beld A.W.
      • van der Lely A.J.
      The endocrinology of aging.
      ].
      Recently, new testosterone formulations, in combination with increased marketing efforts and wider recognition of LOH, have contributed to broad testosterone testing and supplementation, in many countries [
      • Layton J.B.
      • Li D.
      • Meier C.R.
      • Sharpless J.L.
      • Stürmer T.
      • Jick S.S.
      • et al.
      Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011.
      ]. However, testosterone preparations seem to be increasingly prescribed and consumed even without documented testosterone deficiency, especially in the USA. Part of the currently discussed testosterone adverse effects might be attributed to this improper prescribing [
      • Nieschlag E.
      Current topics in testosterone replacement of hypogonadal men.
      ].
      Figure thumbnail fx1
      The aim of this position statement is to provide and critically appraise evidence on testosterone replacement therapy (TRT) in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks.

      2. Pathophysiology and characteristics of LOH

      A decline in testosterone concentrations starts at, approximately, 40 or even 30 years of age [
      • Feldman H.A.
      • Longcope C.
      • Derby C.A.
      • et al.
      Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal resultsfrom the Massachusetts male aging study.
      ,
      • Wylie K.
      • Rees M.
      • Hackett G.
      • et al.
      Androgens, health and sexuality in women and men.
      ]. It has been estimated that 7% of 40–60-year-old men present with serum total testosterone concentrations of less than 12 nmol/l (3.5 ng/ml), increasing to 21% in 60–80-year-old and 35% of men aged 80 years or more [
      • Vermeulen A.
      • Kaufman J.M.
      Ageing of the hypothalamo–pituitary–testicular axis in men.
      ]. Prospective data from the recent European Male Aging Study (EMAS), on 2599 men aged 40–79 years, have revealed a 2.1% prevalence of LOH, defined as three sexual symptoms, namely decreased libido, spontaneous erections and erectile dysfunction in the presence of low testosterone [
      • Tajar A.
      • Huhtaniemi I.T.
      • O'Neill T.W.
      • Finn J.D.
      • Pye S.R.
      • Lee D.M.
      • EMAS Group
      • et al.
      Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS).
      ].
      According to the most recent statement of the International Society for the Study of the Aging Male (ISSAM) [
      • Lunenfeld B.
      • Mskhalaya G.
      • Zitzmann M.
      • Arver S.
      • Kalinchenko S.
      • Tishova Y.
      • et al.
      Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men.
      ], LOH, defined as a series of symptoms in older adults related to testosterone deficiency [
      • Blumel J.E.
      • Chedraui P.
      • Gili S.A.
      • Navarro A.
      • Valenzuela K.
      • Vallejo S.
      Is the Androgen Deficiency of Aging Men (ADAM) questionnaire useful for the screening of partial androgenic deficiency of aging men.
      ], combines features of both testicular (primary) and hypothalamic-pituitary (secondary) hypogonadism [
      • Nieschlag E.
      • Behre H.M.
      • Bouchard P.
      • Corrales J.J.
      • Jones T.H.
      • Stalla G.K.
      • Webb S.M.
      • Wu F.C.
      Testosterone replacement therapy: current trends and future directions.
      ]. Recently, EMAS, by studying 3369 men between 40 and 79 years of age [
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • Pye S.R.
      • Silman A.J.
      • Finn J.D.
      • EMAS Group
      • et al.
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      ], defined LOH by the presence of at least three sexual symptoms, associated with total testosterone concentrations of less than 11 nmol/l (3.2 ng/ml) and free testosterone concentrations of less than 220 pmol/l (64 pg/ml). LOH might be attributed to a number of causes [e.g., decreased number of Leydig cells, reduced Leydig cell response to gonadotropins (LH, FSH), decreased testicular blood flow, hypothalamic-pituitary fatigue (changes in the pattern of LH release)], as well as external factors (e.g., systemic disorders, drugs, environmental, lifestyle) [
      • Nieschlag E.
      • Behre H.M.
      • Bouchard P.
      • Corrales J.J.
      • Jones T.H.
      • Stalla G.K.
      • Webb S.M.
      • Wu F.C.
      Testosterone replacement therapy: current trends and future directions.
      ]. Clinical tools, such as the Saint Louis University Androgen Deficiency in the Aging Male (ADAM) and the Aging Male Symptom (AMS) rating have been developed for the screening of LOH, with a sensitivity of 96% and a specificity of 30%, respectively [
      • Heinemann L.A.
      • Saad F.
      • Zimmermann T.
      • et al.
      The Aging Males’ Symptoms (AMS) scale: update and compilation of international versions.
      ]. However, their use has not been established due to low specificity [
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations.
      ].
      Signs and symptoms suggestive of androgen deficiency in older men can be more or less specific, comprising reduced libido and sexual activity, decreased spontaneous erections, gynecomastia, low trauma fracture and/or low bone mineral density, hot flushes/sweats, decreased energy and physical performance, dysthymia, poor concentration and memory, sleep disturbances, anemia, reduced muscle strength and increased body fat [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ]. There is a rough correlation between LOH symptoms and testosterone concentrations [
      • Kelleher S.
      • Conway A.J.
      • Handelsman D.J.
      Blood testosterone threshold for androgen deficiency symptoms.
      ,
      • Zitzmann M.
      • Faber S.
      • Nieschlag E.
      Association of specific symptoms and metabolic risks with serum testosterone in older men.
      ]. Loss of libido represents the most specific symptom of male hypogonadism [
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • Pye S.R.
      • Silman A.J.
      • Finn J.D.
      • EMAS Group
      • et al.
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      ,
      • Gooren L.J.
      • Behre H.M.
      Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010.
      ], mostly occurring below 15 or 12 nmol/l (4.3–3.5 ng/ml), while other symptoms (e.g., weakness and/or loss of muscle mass) are associated with much lower circulating total testosterone concentration (<5.2–6.9 nmol/l or <1.5–2.0 ng/ml) [
      • Finkelstein J.S.
      • Lee H.
      • Burnett-Bowie S.A.
      • Pallais J.C.
      • Yu E.W.
      • Borges L.F.
      • et al.
      Gonadal steroids and body composition, strength, and sexual function in men.
      ].
      A number of recent studies suggest an association between low testosterone concentrations with poor sleep quality [
      • Wittert G.
      The relationship between sleep disorders and testosterone in men.
      ], insulin resistance, increased risk for diabetes mellitus, obesity, metabolic syndrome and an unfavorable cardiovascular risk profile in general [
      • Wu F.C.
      • Tajar A.
      • Beynon J.M.
      • Pye S.R.
      • Silman A.J.
      • Finn J.D.
      • EMAS Group
      • et al.
      Identification of late-onset hypogonadism in middle-aged and elderly men.
      ,
      • Wang C.
      • Jackson G.
      • Jones T.H.
      • et al.
      Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes.
      ,
      • Oskui P.M.
      • French W.J.
      • Herring M.J.
      • Mayeda G.S.
      • Burstein S.
      • Kloner R.A.
      Testosterone and the cardiovascular system: a comprehensive review of the clinical literature.
      ,
      • Grossmann M.
      Testosterone and glucose metabolism in men: current concepts and controversies.
      ]. Within the EMAS study population, both moderately [defined as total testosterone of 8 nmol/l (2.3 ng/ml) or greater and less than 11 nmol/l (3.2 ng/ml) and free testosterone less than 220 pmol/l (63 pg/ml)] and severely [defined as total testosterone less than 8 nmol/l (2.3 ng/ml) and free testosterone less than 220 pmol/l (63 ng/ml)] androgen deficient men showed lower hemoglobin, mid-upper arm circumference, estimated heel bone mineral density, physical function measured by SF-36 questionnaire, slower gait speed and poorer general health, while severe LOH was associated with larger waist circumference, insulin resistance and metabolic syndrome [
      • Tajar A.
      • Huhtaniemi I.T.
      • O'Neill T.W.
      • Finn J.D.
      • Pye S.R.
      • Lee D.M.
      • EMAS Group
      • et al.
      Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS).
      ]. Regarding mortality, severe LOH has been related to an overall 5.5-fold higher risk of all-cause mortality [2-fold higher in those with testosterone ≤8 nmol/l (2.3 ng/ml), irrespective of symptoms, and 3-fold higher in those with three sexual symptoms, irrespective of testosterone concentrations] [
      • Pye S.R.
      • Huhtaniemi I.T.
      • Finn J.D.
      • Lee D.M.
      • O'Neill T.W.
      • Tajar A.
      • EMAS Study Group
      • et al.
      Late-onset hypogonadism and mortality in aging men.
      ]. Additionally, several other epidemiologic studies and meta-analyses have demonstrated higher all-cause mortality and cardiovascular mortality in men with low testosterone concentrations [
      • Araujo A.B.
      • Dixon J.M.
      • Suarez E.A.
      • Murad M.H.
      • Guey L.T.
      • Wittert G.A.
      Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis.
      ,

      S. Bhasin, G. Huang, T.G. Travison, et al., Age-Related Changes in the Male Reproductive Axis, [Updated 2014 Feb 14]. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc., 2000. Available from: http://www.ncbi.nlm.nih.gov/%20books/NBK278998/.

      ].

      3. Indications for TRT in LOH

      Although the presence of LOH is well-established, there is ongoing debate and extensive discussion whether TRT should be given to these individuals or not [
      • Swerdloff R.
      • Anawalt B.D.
      Clinical decisions. Testosterone-replacement therapy.
      ]. High-quality data regarding benefit and risk of TRT in the aging male are rather limited so far.
      Testosterone replacement therapy may be considered in men over 50 years of age, if they have i) clinical manifestations indicative of androgen deficiency ii) low serum, bioavailable or free testosterone levels and iii) no contra-indications to treatment [
      • Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology
      Androgen deficiency in the aging male.
      ]. Studies of the effects of TRT have generated intense debate. A randomized controlled trial of TRT given for 6 months to older men with low-normal testosterone found that it did not affect bone mineral density, cognitive function, functional mobility, well-being or muscle strength; on the other hand, it had beneficial effects on waist and insulin resistance, but harmful effects on lipids and metabolic syndrome [
      • Emmelot-Vonk M.H.
      • Verhaar H.J.
      • Nakhai Pour H.R.
      • Aleman A.
      • Lock T.M.
      • Bosch J.L.
      • et al.
      Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial.
      ]. Regarding the cardiovascular system, low testosterone has been associated with increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as with impaired left ventricular function; however, TRT has not been proven so far to be beneficial with respect to cardiovascular disease; neither has it been definitely shown to have specific adverse cardiovascular effects [
      • Ruige J.B.
      • Ouwens D.M.
      • Kaufman J.M.
      Beneficial and adverse effects of testosterone on the cardiovascular system in men.
      ]. Additional data from recent studies suggest a beneficial effect of TRT in special populations, such as men with testosterone deficiency and type 2 diabetes mellitus as far as survival [
      • Muraleedharan V.
      • Marsh H.
      • Kapoor D.
      • Channer K.S.
      • Jones T.H.
      Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.
      ], glycemic control, cholesterol concentrations, body composition, libido and sexual function [
      • Jones T.H.
      • Arver S.
      • Behre H.M.
      • Buvat J.
      • Meuleman E.
      • Moncada I.
      • TIMES2 Investigators
      • et al.
      Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study).
      ], as well as patient-reported quality of life (QoL) [
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • Kennedy D.
      • Raju J.
      • Wilkinson P.
      Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes.
      ] are concerned. According to the BLAST-study [
      • Hackett G.
      • Cole N.
      • Bhartia M.
      • Kennedy D.
      • Raju J.
      • Wilkinson P.
      • Blast Study Group
      • et al.
      The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).
      ], achieving threshold serum concentrations seems to be of significant importance for the response to TRT.
      Current guidelines agree that a combination of symptoms of testosterone deficiency and low testosterone concentrations are required for diagnosis and treatment of LOH [
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations.
      ,
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ,
      • Dohle G.R.
      • Arvers S.
      • Bettocchi C.
      • et al.
      Guidelines on male hypogonadism.
      ]. Several recent epidemiological data from the USA [
      • Bhasin S.
      • Pencina M.
      • Jasuja G.K.
      • et al.
      Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham heart study and applied to three geographically distinct cohorts.
      ], Australia [
      • Sartorius G.
      • Spasevska S.
      • Idan A.
      • et al.
      Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study.
      ] and Europe [
      • Huhtaniemi I.T.
      • Tajar A.
      • Lee D.M.
      • EMAS Group
      • et al.
      Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men.
      ,
      • Frost M.
      • Wraae K.
      • Nielsen T.L.
      • et al.
      Similar reference intervals for total testosterone in healthy young and elderly men: results from the Odense androgen study.
      ] have set 12 nmol/l (3.5 ng/ml) as the lowest value for testosterone serum levels in healthy men.
      Measuring serum testosterone is justified only in aging men presenting with signs or symptoms suggestive of androgen deficiency [
      • Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology
      Androgen deficiency in the aging male.
      ]. According to the current clinical practice guidelines, a repeated measurement of serum testosterone concentrations should be performed in combination with sex hormone-binding globulin (SHBG) concentrations during the early morning hours [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ,
      • Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology
      Androgen deficiency in the aging male.
      ], in order to assess free testosterone concentrations as well. Mass spectrometric methods (LC–MS/MS) represent the gold standard for measuring testosterone [
      • Simoni M.
      • Fanelli F.
      • Roli L.
      • et al.
      Methodology for measuring testosterone, dihydrotestosterone and sex hormonebinding globulin in a clinical setting.
      ]. Medical conditions, such as moderate obesity, hypothyroidism, use of glucocorticoids, and diabetes mellitus are associated with decreased serum SHBG concentrations, while aging and hyperthyroidism induce increased serum SHBG concentrations [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ]. Therefore, further weight reduction efforts alone may be appropriate in obese patients with free testosterone concentrations within the normal range.

      4. How to treat—therapeutic agents

      TRT is indicated in patients with symptoms of androgen deficiency and serum testosterone concentrations below the normal range [
      • Nieschlag E.
      Current topics in testosterone replacement of hypogonadal men.
      ].
      Testosterone has already been in clinical use for almost eight decades [
      • Nieschlag E.
      • Nieschlag S.
      Testosterone deficiency: a historical perspective.
      ]. Today, different preparations and modes of application, such as intramuscular, subdermal, transdermal, oral and buccal agents are available (Table 1) [
      • Nieschlag E.
      Current topics in testosterone replacement of hypogonadal men.
      ]. Natural testosterone preparations should be preferred, resulting in circulating serum testosterone concentrations as close to physiology as possible and avoiding supra-physiologically high or low testosterone concentrations [
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations.
      ,
      ].
      Table 1Currently available preparations for TRT in aging males with LOH.
      Modified according to Bhasin et al., Endocrine Society Clinical Practice Guideline
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      .
      Route of applicationDosingInterval
      Transdermal
      Gel25–50 mgdaily
      Patches1.2–2.4 mgdaily
      Topical solution30–60 mgdaily
      Buccal
      Testosterone tablets30 mgtwice daily
      Intramuscular
      Testosterone enanthate250 mg2–3 weeks
      Testosterone undecanoate1000 mg12 weeks
      Oral
      Testosterone undecanoate3–4 × 40 mgdaily
      Subcutaneous
      Testosterone pellets4 × 200 mg4–6 months
      Transdermal testosterone preparations can be used as a first choice, since their pharmacokinetics is closest to optimal androgen substitution and they mimic physiological diurnal variations. Additionally, short-acting transdermal preparations offer the advantage of rapid testosterone discontinuation upon removal should an adverse event (e.g., elevated hematocrit or prostate carcinoma) [
      • Parsons J.K.
      • Carter H.B.
      • Platz E.A.
      • Wright E.J.
      • Landis P.
      • Metter E.J.
      Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy.
      ] occur. They should be, therefore, preferred over long-acting preparations, at least in the initial treatment of LOH [
      • Nieschlag E.
      Current topics in testosterone replacement of hypogonadal men.
      ,
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations.
      ].
      In a recent study regarding comparative safety of different preparations, testosterone injections were associated with a greater risk of cardiovascular events (e.g., myocardial infarction, unstable angina and stroke, hospitalizations and death) compared with transdermal gels, whereas patches and gels showed comparable risk profiles [
      • Layton J.B.
      • Meier C.R.
      • Sharpless J.L.
      • Stürmer T.
      • Jick S.S.
      • Brookhart M.A.
      Comparative safety of testosterone dosage forms.
      ]. This could be, in part, explained by varying pharmacokinetics, since injections cause spikes in testosterone concentrations, while transdermal patches and gels cause more subtle and sustained increases. TRT with intramuscular injections of testosterone esters (250 mg/2 weeks) can induce insulin resistance in healthy subjects [
      • Polderman K.H.
      • Gooren L.J.
      • Asscheman H.
      • Bakker A.
      • Heine R.J.
      Induction of insulin resistance by androgens and estrogens.
      ].
      Nonetheless, the selection of the optimal testosterone preparation should be a shared decision made by the patient and the treating physician [
      • Calof O.M.
      • Singh A.B.
      • Lee M.L.
      • et al.
      Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.
      ].

      5. Monitoring TRT in the aging male

      Testosterone replacement therapy should be initiated with a target serum testosterone into a range that is mid-normal for healthy, young men (suggested target serum testosterone concentration in men receiving testosterone enanthate 350–750 ng/dl, 1 week after injection); a 6-month time interval may be necessary to show a reduction in symptoms [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ,
      • Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology
      Androgen deficiency in the aging male.
      ]. No dose-effect correlation of TRT has been demonstrated so far; however, dose escalation in order to increase efficacy might increase adverse effects [
      • Liu P.Y.
      • Swerdloff R.S.
      • Veldhuis J.D.
      The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations.
      ].
      According to an Endocrine Society clinical practice guideline, men with LOH receiving TRT should have regularly scheduled testing for adverse events, optimally at 3, 6 and 12 months after initiation and, then, annually [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ]. Parameters for surveillance include well-being, libido and sexual activity, measurement of serum testosterone concentrations, haemoglobin and haematocrit, prostate-specific antigen (PSA) and digital rectal examination, and, biannually, bone mineral density [
      • Nieschlag E.
      Current topics in testosterone replacement of hypogonadal men.
      ]. A decision on whether to continue treatment can be made at 6 months.

      6. Treatment risks including contra-indications for TRT

      Testosterone replacement therapy may cause a number of potential adverse events including erythrocytosis, acne and oily skin, exacerbation of subclinical prostate cancer, growth of metastatic prostate cancer and reduced sperm production and fertility. Gynecomastia, male pattern balding, growth of breast cancer and/or induction or worsening of obstructive sleep apnea are less common and only weakly associated with TRT. Additionally, there are formulation-specific adverse effects [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ].
      TRT is associated with very high risk of certain serious adverse outcomes and therefore absolutely contra-indicated in men with metastatic prostate cancer or breast cancer. Medical conditions such as unevaluated prostate nodule or induration, PSA > 4 ng/ml, hematocrit > 50%, severe lower urinary tract symptoms associated with benign prostatic hypertrophy and/or uncontrolled or poorly controlled congestive heart failure are related to moderate to high risk of adverse outcomes with testosterone; hence, the Endocrine Society also refrains from using TRT in these individuals [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ]. Age per se is not a contra-indication to TRT [
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations.
      ].
      Recent studies have raised concern about the cardiovascular safety of TRT, especially in men with pre-existing heart disease and/or in men over the age of 65 [
      • Finkle W.D.
      • Greenland S.
      • Ridgeway G.K.
      • Adams J.L.
      • Frasco M.A.
      • Cook M.B.
      • et al.
      Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
      ,
      • Vigen R.
      • O'Donnell C.I.
      • Barón A.E.
      • Grunwald G.K.
      • Maddox T.M.
      • Bradley S.M.
      • et al.
      Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.
      ,
      • Basaria S.
      • Coviello A.D.
      • Travison T.G.
      • Storer T.W.
      • Farwell W.R.
      • Jette A.M.
      • et al.
      Adverse events associated with testosterone administration.
      ]. This has lead the Food and Drug Administration (FDA—US) requiring that manufacturers of testosterone products add information to the labeling about this possible increase in cardiovascular risk []. However, this risk was not confirmed by other reports [
      • Jones T.H.
      • Arver S.
      • Behre H.M.
      • Buvat J.
      • Meuleman E.
      • Moncada I.
      • TIMES2 Investigators
      • et al.
      Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study).
      ,
      • Shores M.M.
      • Smith N.L.
      • Forsberg C.W.
      • Anawalt B.D.
      • Matsumoto A.M.
      Testosterone treatment and mortality in men with low testosterone levels.
      ,
      • Page S.T.
      Testosterone, cardiovascular disease, and mortality in men: living in the dark.
      ]. The European Medicines Agency, American Association of Clinical Endocrinologists and American College of Endocrinology have agreed that there is no consistent evidence that testosterone therapy either increases or decreases cardiovascular risk [
      • Goodman N.
      • Guay A.
      • Dandona P.
      • Dhindsa S.
      • Faiman C.
      • Cunningham G.R.
      • AACE Reproductive Endocrinology Scientific Committee
      American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the association of testosterone and cardiovascular risk.
      , ]. Thus, the Endocrine Society suggested that large-scale, controlled studies are needed to resolve this controversy [], since even a small potential risk is unwarranted [
      • Polderman K.H.
      • Gooren L.J.
      • Asscheman H.
      • Bakker A.
      • Heine R.J.
      Induction of insulin resistance by androgens and estrogens.
      ], when balanced against a small potential benefit.
      There is also uncertainty about the potential effects of TRT on the risk of prostate cancer [
      • Wang C.
      • Nieschlag E.
      • Swerdloff R.
      • et al.
      Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations.
      ,
      • Tenover J.S.
      Experience with testosterone replacement in the elderly.
      ,

      Report of National Institute on Aging advisory panel on testosterone replacement in men, J. Clin. Endocrinol. Metabol. 86 (2001) 461–464.

      ] and sleep apnea [
      • Polderman K.H.
      • Gooren L.J.
      • Asscheman H.
      • Bakker A.
      • Heine R.J.
      Induction of insulin resistance by androgens and estrogens.
      ,
      • Matsumoto A.M.
      • Sandblom R.E.
      • Schoene R.B.
      • Lee K.A.
      • Giblin E.C.
      • Pierson D.J.
      • et al.
      Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep.
      ,
      • Hanafy H.M.
      Testosterone therapy and obstructive sleep apnea: is there a real connection?.
      ]. On the basis of limited data, TRT does not appear to increase the risk of prostate cancer [
      • Fernández-Balsells M.M.
      • Murad M.H.
      • Lane M.
      • Lampropulos J.F.
      • Albuquerque F.
      • Mullan R.J.
      • et al.
      Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.
      ]; however, it might increase serum PSA concentrations by 0.3 to 0.6 mg/dl [
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • Matsumoto A.M.
      • Snyder P.J.
      • Swerdloff R.S.
      • et al.
      Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
      ]. The same meta-analysis, including 51 studies with a follow-up ranging from 3 months to 3 years, revealed that TRT was associated with a significant increase in hemoglobin and hematocrit and a decrease in high-density lipoprotein (HDL) cholesterol, while there was no significant effect on mortality or cardiovascular outcomes [
      • Fernández-Balsells M.M.
      • Murad M.H.
      • Lane M.
      • Lampropulos J.F.
      • Albuquerque F.
      • Mullan R.J.
      • et al.
      Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.
      ].

      7. Conclusions

      LOH represents a common clinical entity among aging males; TRT should be offered to these individuals, only if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could have positive effects on obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis, but should undergo scheduled regular testing for adverse events. Potential effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit estimation [
      • Wylie K.
      • Rees M.
      • Hackett G.
      • et al.
      Androgens, health and sexuality in women and men.
      ].

      8. Recommendations

      • Testing for testosterone deficiency should be only performed in men with symptoms of androgen deficiency; universal testosterone testing in aging males is not recommended (1|+○○○).
      • Symptoms compatible with androgen deficiency involve loss of libido, erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, decreased vitality and depressed mood (1|++○○).
      • A general policy of offering TRT to all aging men with low testosterone concentrations is not recommended (1|+○○○).
      • Physicians should consider offering TRT, on an individual basis, to aging men with low testosterone concentrations on more than one occasion and clinically significant symptoms of androgen deficiency (2|+○○○).
      • Potential benefit of TRT should outweigh the cost, inconvenience and risks of therapy for aging males (1|+○○○).
      • It is always advisable to encourage aging males with LOH to undertake lifestyle modifications, including reduced caloric intake, increased daily physical activity, smoking cessation, reduced alcohol consumption and adoption of a healthy diet, before considering initiation of TRT (1|+○○○).
      • Currently available percutaneous, transdermal, subcutaneous and buccal testosterone preparations are considered to be safe and effective (2|++○○).
      • There is no consensus on the beneficial effects of TRT with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis (2|++○○).
      • Specific populations, such as older men with low testosterone concentrations and type 2 diabetes mellitus might benefit from TRT (1|+++○).
      • TRT is absolutely contra-indicated in cases of metastatic prostate (1|++○○), or breast cancer (1|+○○○), unevaluated prostate nodule or induration, PSA > 4 ng/ml (1|+++○), hematocrit >50%, severe lower urinary tract symptoms and/or uncontrolled congestive heart failure (1|+++○).
      • If TRT is prescribed, serum testosterone concentrations should be therapeutically raised into a range that is mid-normal for healthy, young men (2|+○○○).
      • Patients receiving TRT should undergo regular testing for adverse events; a critical risk-versus-benefit estimation on whether to continue TRT should be made 6 months after treatment initiation(1|++++).
      • Risks and benefits of TRT should be very carefully weighed up in testosterone deficient aging men with or without pre-existing heart disease, until evidence from large randomized prospective trials regarding cardiovascular safety of TRT becomes available(1|++○○).

      Conflict of interest

      None declared.

      Provenance and peer review

      EMAS position statement.

      Funding

      None.

      Contributors

      Christina Dimopoulou and Dimitrios Goulis prepared the initial draft, which was circulated to EMAS board members for comment and approval, production was coordinated by Dimitrios Goulis, Irene Lambrinoudaki and Margaret Rees.

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