Benefits and Health Implications of Testosterone Therapy ... 2017... · erectile dysfunction, and increased incidence of mortality (for Received August 17, 2017. ... Adverse Effects

Benefits and Health Implications of Testosterone Therapy in Men WithTestosterone Deficiency

Abdulmaged M. Traish, PhD, MBA

ABSTRACT

Received Au

DepartmentUSA

Copyright ªElsevier Inchttps://doi.o

Sex Med R

Introduction: Testosterone (T) deficiency (TD; hypogonadism) has deleterious effects on men’s health; nega-tively affects glycometabolic and cardiometabolic functions, body composition, and bone mineral density;contributes to anemia and sexual dysfunction; and lowers quality of life. T therapy (TTh) has been used for thepast 8 decades to treat TD, with positive effects on signs and symptoms of TD.

Aim: To summarize the health benefits of TTh in men with TD.

Methods: A comprehensive literature search was carried out using PubMed, articles relevant to TTh wereaccessed and evaluated, and a comprehensive summary was synthesized.

Main Outcome Measures: Improvements in signs and symptoms of TD reported in observational studies,registries, clinical trials, and meta-analyses were reviewed and summarized.

Results: A large body of evidence provides significant valuable information pertaining to the therapeutic value ofTTh in men with TD. TTh in men with TD provides real health benefits for bone mineral density, anemia,sexual function, glycometabolic and cardiometabolic function, and improvements in body composition,anthropometric parameters, and quality of life.

Conclusion: TTh in the physiologic range for men with TD is a safe and effective therapeutic modality andimparts great benefits on men’s health and quality of life. Traish AM. Benefits and Health Implications ofTestosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev 2017;X:XXXeXXX.

Copyright � 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Key Words: Testosterone; Testosterone Deficiency; Testosterone Therapy; Sexual Function; MetabolicSyndrome; Diabetes; Bone Mineral Density

INTRODUCTION

Testosterone Is a Metabolic Hormone and Plays aVital Role in Human PhysiologyTestosterone (T) and its metabolite, 5a-dihydrotestosterone,

regulate energy metabolism, nitrogen retention, muscle growthand maintenance, inhibit adipogenesis, and modulate malereproductive and sexual function.1e14 T exerts an importantmetabolic and functional role in many tissues and organs(Figure 1). Among the well-documented physiologic roles of T isits regulation of muscle growth and function and inhibition ofadipogenesis.15e24 The role of T in the regulation of bonemetabolism, erythropoiesis, endothelial and liver functions, andhair growth is well established.25e55 The wide distribution ofandrogen receptors in various tissues, including the central

gust 17, 2017. Accepted October 6, 2017.

of Urology, Boston University School of Medicine, Boson, MA,

2017, International Society for Sexual Medicine. Published by. All rights reserved.rg/10.1016/j.sxmr.2017.10.001

ev 2017;-:1e20

nervous system, strongly supports the premise that T plays a keyphysiologic role in regulating human physiology and that T is anintegral hormone in maintaining human health.1e14

Hypogonadism (Testosterone Deficiency)In an effort to use terminology that promotes accuracy and

clarity of T deficiency (TD) and T therapy (TTh), this reviewhas adopted the language recommended by an internationalexpert consensus panel.7 Testosterone deficiency is used insteadof the older term hypogonadism. Also, testosterone therapy isused instead of testosterone replacement therapy.7 TD is chara-cterized by low levels of circulating plasma T concomitantwith a host of clinical signs and symptoms attributed todecreased physiologic T levels and function.7,8,56e62 TD is awell-established significant medical condition, which has beenrecognized since 1940.6,7,63,64 TD negatively affects men’shealth and is associated with increased body weight, adiposity,waist circumference (WC), insulin resistance (IR), type 2diabetes mellitus (T2DM), hypertension, inflammation,atherosclerosis and cardiovascular disease (CVD), infertility,erectile dysfunction, and increased incidence of mortality (for

1

https://doi.org/10.1016/j.sxmr.2017.10.001

Figure 1. Testosterone, directly or through conversion to 5a-dihydrotestosterone or estradiol, modulates multipotent stem cellmetabolism and function to promote differentiation to progenitor cells for muscle, endothelium, bone, and red blood cells. DHT ¼ 5a-dihydrotestosterone; E2 ¼ estradiol; T ¼ testosterone. From Carruthers M, Trinick TR, Jankowska E, et al. Are the adverse effects ofglitazones linked to induced testosterone deficiency? Originally published and reprinted from BioMed Central from Carruthers M,Trinick TR,Jankowska E,Traish AM. Are the adverse effects of glitazones linked to induced testosterone deficiency? Cardiovasc Diabetol 2008;7:30.333

2 Traish

review see 7e9,65e67). Clinically, TD is divided into primary(testicular dysfunction), secondary (pituitary or hypothalamicfailure), or mixed hypogonadism (a combination of testicularfailure and pituitary hypothalamic failure).60 Signs andsymptoms associated with TD include sexual dysfunction,depressed mood, decreased motivation, fatigue, and dimin-ished quality of life.6,26

Signs and Symptoms of TDThe signs and symptoms of TD encompass several domains

(sexual, physical, psychological, and cognitive). Sexual dysfunc-tions such as decreased or lost sexual desire, diminishednocturnal and morning erections, and erectile dysfunction areoften among the most recognized symptoms of TD.57 Otherrecognized symptoms of TD are diminished physical vigor, sar-copenia, energy, and motivation, fatigue, depressive mood, andsleep disturbances. In addition, visceral obesity is often observed,and muscle mass and bone mineral density (BMD) are oftenreduced. Other signs are the presence of smaller testicles,decreased body hair, and gynecomastia. It must be noted thatowing to interindividual variability, not all these manifestationsmust be present simultaneously to determine the signs andsymptoms of TD.57 Several comorbidities are associated withTD. These include metabolic syndrome (MetS), obesity, dia-betes, hypertension, and hyperlipidemia.68 Thus, it is not sur-prising that there is an association among obesity, MetS, andTD.69e72 It is reasonable to suggest that obese men exhibitincreased risk of TD and have similar signs and symptomsof TD.

Adverse Effects of TD on Men’s HealthTD is associated with decreased lean body mass (LBM),

increased fat mass (FM), increased state of inflammation, MetS,dyslipidemia, IR, adiposity, T2DM, bone loss, and anemia.73e92

TD and T2DM are often diagnosed together in the same patient;TD might be more prevalent in men with T2DM, higher bodymass index (BMI), or excessive obesity (BMI > 40 kg/m2); andmen with TD are at a greater risk of developingT2DM.72,74,75,88e100 Acute T withdrawal markedly decreasesinsulin sensitivity in young healthy men with idiopathic hypo-gonadotropic hypogonadism in the absence of changes in BMI ordetectable changes in body composition.101,102 TD has beenindependently associated with IR in older men withoutdiabetes.5,103

An inverse relation between T and IR also has been postulatedand higher physiologic T levels appear to be protective againstthe development of T2DM.80,87,88,90,104e108 Decreased T levelspredict IR and incident T2DM in older adults and increased riskof MetS and T2DM even in initially non-obesemen.71,80,83,85e88,90,93,104e112 TD increases insulin levels andthe homeostatic model assessment for IR (HOMA-IR).107 Menwith T2DM are often obese, with significantly lower T levels andhigher fasting insulin levels compared with non-obese men.97e99

An inverse relation between circulating T levels and inflam-matory cytokines has been reported and TTh in men with TDhas been shown to rebalance the relation between T and in-flammatory cytokines.70,73e77,79,113 Men with MetS haveincreased fasting insulin levels and decreased total T comparedwith men without MetS.72 TD is a stronger risk factor in the

Sex Med Rev 2017;-:1e20

Wai

st C

ircum

fere

nce

(cm

)

1 Year 2 Years 3 Years 4 Years 5 Years 6 Years 7 Years 8 Years

Treated 360 356 341 310 255 224 199 160

Control 295 295 295 285 280 246 164 55

−12

−10

−8

−6

−4

−2

0

2

Wai

st C

ircum

fere

nce

(cm

)

Treated Control Adjusted Difference(Treated − Control)

Figure 2. Changes in waist circumference in testosterone-treatedand untreated (control) groups. Changes (yellow bars) wereadjusted for baseline differences between testosterone-treated(green bars) and untreated control (red bars) groups. From TraishAM, Haider A, Haider KS, et al. Long-term testosterone therapyimproves cardiometabolic function and reduces risk of cardiovas-cular disease in men with hypogonadism: a real-life observationalregistry study setting comparing treated and untreated (control)groups. J Cardiovasc Pharmacol Ther 2017;22:414e433.155

Reprinted with permission.

Testosterone Therapy in Men With Deficiency 3

development of increased insulin and glucose levels comparedwith overweight or obesity.100 TD is associated with adverseplasma levels of triglycerides, insulin, and high-density lipopro-tein cholesterol in young men.114,115 Low T levels are associatedan unfavorable lipid profile.114e121

TD is associated with increased cardiometabolicrisk.101,122e124 Total T levels are inversely associated with risk ofCV events, and this association remains significant even afteradjustment for traditional CV risk factors.125 Patients with cor-onary artery disease exhibit significantly lower mean T levels thanhealthy subjects.126 Men with coronary artery disease havesignificantly lower levels of free T and free androgen index thancontrols, even after adjusting for age and BMI.127e130 Thesefindings suggest that men with TD could be at greater risk forcoronary atherosclerosis.131 Men with an unfavorable lipid profilehave significantly lower levels of total T.114e119 Men with TDexhibit greater intima-media thickness compared with controlsand carotid intima-media thickness correlates inversely with Tlevels after adjustment for age, total cholesterol, BMI, bloodpressure, and smoking.91,92,110,122,123,132e137 TD contributes toendothelium damage and dysfunction and androgen therapyenhances endothelial repair and function and increases synthesisand release of endothelial nitric oxide in thevasculature.1,2,44,45,47,138e147 T levels are inversely associatedwith systolic blood pressure and increased arterialstiffness.80,148e150 TTh is associated with a significant decrease inblood pressure.151e156 Shores et al84 reported increased mortalityin men with decreased T levels compared with men with normalT levels. Men with total T levels in the lowest quartile are 40%more likely to die than those with higher T levels, independent ofage, adiposity, and lifestyle.62,79,110,157e162

The relation between TD and sexual function has beenrecognized for decades and a large number of basic science andclinical studies have documented that androgens are critical forthe development of male sexual organs and maintenance ofsexual function in men.138,163e178

HEALTH BENEFITS OF TTH IN MEN WITH TD

TTh Increases LBM, Decreases FM, and ImprovesBody CompositionClinical trials, meta-analyses, and observational studies suggest

that TTh improves anthropometric parameters. TTh in menwith medically induced TD results in a dose-dependent increasein muscle mass and a decrease in FM.15,19 It is widelyacknowledged that TTh in men with TD increases LBM anddecreases FM. Without exception, interventional and observa-tional studies have clearly demonstrated that TTh in men withTD increases LBM, decreases FM, and improves bodycomposition.6,7,9e11,16e18,22,23,27,31,78,154e156,179e207 Largeobservational registry studies of long-term TTh in men with TDhave reported consistent and sustained weight loss and decreasedWC and BMI.155,156,196 In a study of 411 obese men with TD,


long-term TTh resulted in progressive and sustained weight lossand decreased WC and BMI in all classes of obesity.196 Thegreater the weight, BMI, and WC at baseline, the more profoundthe decreases in these parameters were in response to TTh. Thesefindings were further corroborated by a recent study in whichlong-term TTh was compared in T-treated and non-treatedgroups.155 The decreases in WC (Figure 2), body weight, andBMI were accompanied by decreases in fasting blood glucose,glycated hemoglobin (HbA1c; Figure 3), blood pressure, totalcholesterol, low-density lipoprotein cholesterol, and triglycerides(Figure 4) with a concomitant increase in high-density lipopro-tein.155 These findings corroborate those reported previously byothers.116,121,154e156,196

TTh in men with TD has been shown to ameliorate frailtyand physical decline, such as sarcopenia, muscle strength, andphysical function (reviewed in 16e18,179e183,198,201,208,209). Inseveral meta-analyses, Corona et al210e212 reported that TTh wasassociated with a significant decrease in BMI and FM in un-controlled and placebo-controlled trials. Although TTh consis-tently increased muscle mass in all reported studies, there wereinconsistencies with regard to improvement in muscle strengthand physical function.213e217

TTh Ameliorates Components of MetS, IncreasesInsulin Sensitivity, and Lowers Risk of T2DM

Considerable evidence exists from a large number of studiessuggesting that TTh ameliorates components of MetS,improves lipid profiles, lowers blood glucose and HbA1c,improves insulin sensitivity, attentuates inflammation,decreases systolic and diastolic blood pressures, and improvescardiometabolic functions.154,155,184,185,196,218 Meta-analyses

Glu

cose

(mm

ol/L

)


Treated 360 356 341 310 255 224 199 160Control 295 295 295 285 280 246 164 55

−0.5

−0.4

−0.3

−0.2

−0.1

0

Glu

cose

(mm

ol/L

)


HbA

1c (%

)


Treated 241 241 225 197 147 119 97 85

Control 288 294 295 281 280 246 164 55

−2

−1.5

−1

−0.5

0

0.5

HbA

1c (%

)


A B

Figure 3. Changes in fasting blood glucose and HbA1c in testosterone-treated and untreated (control) groups. Panel A shows changes inglucose levels (yellow bars) adjusted for baseline differences between testosterone-treated (green bars) and untreated control (red bars)groups. Panel B shows changes in HbA1c (yellow bars) adjusted for baseline differences between testosterone-treated (green bars) anduntreated control (red bars) groups. HbA1c ¼ glycated hemoglobin. From Traish AM, Haider A, Haider KS, et al. Long-term testosteronetherapy improves cardiometabolic function and reduces risk of cardiovascular disease in men with hypogonadism: a real-life observationalregistry study setting comparing treated and untreated (control) groups. J Cardiovasc Pharmacol Ther 2017;22:414e433.155 Reprinted withpermission.

4 Traish

have shown that TTh decreases total cholesterol, low-density li-poprotein cholesterol, and triglycerides and improves high-densitylipoprotein and systolic and diastolic blood pressures.210e212

Higher T levels have been shown to produce a 42% lower riskof T2DM82 and T2DM has been associated with lower total Tlevels.210,211 In 2 meta-analyses, Corona et al184,185 showed thatTTh significantly ameliorates hyperglycemia, HbA1c, andHOMA-IR index.

TTh Improves BMDSeveral clinical trials and observational studies have demon-

strated that TTh improves BMD.30,186,187,219e226 A significantincrease in structural and mechanical properties of trabecularbone in response to TTh has been recently reported.219 Theincrease in structural and mechanical properties is concomitantwith a parallel decrease in bone resorption markers and increasesin osteoblastic activity markers are concomitant with a significantincrease in BMD.220e222 Normalizing serum T in men with TDproduced significant improvement of T scores after 6 years ofTTh in men with osteoporosis to such an extent that 40 of 45men (89%) no longer fulfilled criteria for osteoporosis at the lastmeasurement.227 Furthermore, in a recent study with a follow-upof 8 years, mean T scores of vertebral and femoral BMDincreased significantly.228 These findings confirmed that BMD issignificantly improved with TTh in men with TD. In severalmeta-analyses, Corona et al210e212 showed a positive effect ofTTh on improving lumbar BMD.

TTh Improves Sexual FunctionThe link between TD and erectile dysfunction,

diminished libido, and lower sexual activity in men with TDis well-established.176,229 Experimental animal studies have

unequivocally demonstrated a critical role for androgens inregulating sexual function.230,231 Clinical trials, observationalstudies, registry studies, and meta-analyses have demonstratedthat TTh produces significant improvements in sexual functionin men with TD. In placebo-controlled randomized clinical trialsand observational studies, significant improvement in sexualfunction in men with TD has been reported in response to TTh(Figure 5).165,177,197,232e237 These findings strongly support thepremise that T is an important physiologic hormone in sexualfunction. An 8-year study showed that TTh resulted inimprovement in mean 5-item (P < .05) and 15-item (P < .05)International Index of Erectile Function (IIEF) scores (Figure 6).All subscale scores of the 5 erectile function domains, includingorgasmic function, sexual desire, intercourse satisfaction, andoverall satisfaction, significantly improved after TTh(P < .05).228 Findings from recent controlled randomized clin-ical studies have strongly suggested that TTh significantly im-proves all domains of sexual function.177,232 Because sexualhealth is an integral element of overall health, and sexualdysfunction is often associated with increased onset of depres-sion, lower mood, and loss of self-esteem, TTh could be animportant novel therapeutic approach to improve men’s overallhealth and quality of life.

TTh Attenuates Lower Urinary Tract SymptomsPreclinical studies have shown that androgen deprivation de-

creases bladder capacity and alters tissue histologic architecture,with a decrease in the ratio of smooth muscle to connectivetissue. T treatment has been found to improve bladder capacityand restore the ratio of smooth muscle to connective tissue.238 Ttreatment also has been shown to protect the lower urinary tractfrom MetS-induced alterations,239,240 and low T has been shown


Tota

l Cho

lest

erol

(mm

ol/L

)


Treated 360 356 341 310 255 224 199 160

Control 295 295 295 285 280 246 164 55

−3

−2.5

−2

−1.5

−1

−0.5

0

0.5To

tal C

hole

ster

ol (m

mol

/L)


LDL

(mm

ol/L

)


Treated 360 356 341 310 255 224 199 160Control 295 295 295 285 280 246 164 55

−2

−1.5

−1

−0.5

0

0.5

LDL

(mm

ol/L

)


HD

L (m

mol

/L)


Treated 360 356 341 310 255 224 199 160

Control 295 295 295 285 280 246 164 55

0

0.2

0.4

0.6

0.8

HD

L (m

mol

/L)


Trig

lyce

rides

(mm

ol/L

)


Treated 360 356 341 310 255 224 199 160Control 295 295 295 285 280 246 164 55

−1.2

−1

−0.8

−0.6

−0.4

−0.2

0

0.2

Trig

lyce

rides

(mm

ol/L

)


A

C D

B

Figure 4. Changes (yellow bars) in lipid profile in testosterone-treated (green bars) and untreated control (red bars) groups. Panel Ashows changes in total cholesterol adjusted for baseline differences between testosterone-treated and untreated control groups. Panel Bshows changes in LDL cholesterol adjusted for baseline differences between testosterone-treated and untreated control groups. Panel Cshows changes in HDL cholesterol adjusted for baseline differences between testosterone-treated and untreated control groups. Panel Dshows changes in triglycerides adjusted for baseline differences between testosterone-treated and untreated control groups. HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein. From Traish AM, Haider A, Haider KS, et al. Long-term testosterone therapy improvescardiometabolic function and reduces risk of cardiovascular disease in men with hypogonadism: a real-life observational registry studysetting comparing treated and untreated (control) groups. J Cardiovasc Pharmacol Ther 2017;22:414e433.155 Reprinted with permission.


to correlate negatively with detrusor pressure at maximal flowand ureteral closure and could promote detrusor obstruction,suggesting that androgens ameliorate lower urinary tract symp-toms (LUTS). Clinical studies have demonstrated that obesemen with LUTS exhibit lower T levels.241 Chang et al242 re-ported that TD might contribute to the pathophysiologicmechanism of LUTS and that endogenous T levels correlatenegatively with severity of LUTS. A registry study of 999 menwith clinically diagnosed TD showed modest positive effects ofTTh on LUTS243 with no significant changes in prostate vol-ume. Several studies have reported that TTh attenuatesLUTS.244e249 Patients with moderate LUTS who were treatedwith T for 1 year exhibited improvement in storage and voidingsymptoms without clinical progression of benign prostatic hy-perplasia or prostate-specific antigen.249 An 8-year study of TThshowed that mean IPSS decreased significantly from 8.54 ± 6.6at baseline to 6.78 ± 5.44 (P < .05) at the end of the 8-yearstudy period.228 In meta-analyses, Corona et al210e212 reportedthat significant improvement in the IPSS was noted in response


to TTh. These findings support a role of TTh in amelioratingLUTS in men with TD.

TTh Ameliorates Conditions of AnemiaAnemia is a frequent symptom of TD and could contribute to

the observed loss of energy and vitality observed in men withTD.250 Approximately 30% of all anemia cases in older patientsare of unknown etiology. The prevalence of anemia in older menis significantly higher than in younger men.251e254 Althoughmen with TD are not always diagnosed with anemia, the relationbetween TD and low hemoglobin is significant, suggesting thatlow T is one of the causal factors of anemia. Given that anemiahas a negative functional outcome in elderly patients,253e256

TTh in men with TD could improve functional recovery inolder patients, because it is well established that TTh in menwith TD increases their hemoglobin levels.28

A recent randomized placebo-controlled clinical trial foundthat TTh ameliorated anemia in men who were anemic with or

Figure 5. The primary outcome of the Sexual Function Trial wasthe change from baseline in the score for sexual activity on thePDQ-Q4 (range ¼ 0e12, with higher scores indicating more ac-tivity). PDQ-Q4 ¼ question 4 of the Psychosexual Daily Ques-tionnaire. From Snyder PJ, Bhasin S, Cunningham GR, et al. Effectsof testosterone treatment in older men. N Engl J Med2016;374;611e624.232 Reprinted with permission.

6 Traish

without a known cause. Furthermore, TTh in men with anemiasignificantly increased hemoglobin concentration above baselinecompared with the placebo group. One key observation was thatin men with unexplained anemia, 58.3% who received TTh wereno longer anemic at month 12 compared with only 22.2% in theplacebo group.257 These findings were consistent with anobservational study that found a decrease in the prevalence ofanemia from 29.6% to 10.0% after TTh for 54 weeks.258

IIEF−

EF

Treated Controls

1015

2025

Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8

Treated 82 82 79 75 72 61 59 57 49Control 82 82 82 81 78 77 68 46 14

NS

#

##

## # # #

# − Signifficant at p<0.0001

Figure 6. Effects of testosterone therapy on erectile function.Changes in IIEF-EF score in testeosterone-treated and untreatedpropensity-matched groups during 8-year follow-up period. IIEF-EF ¼ International Index of Erectile Function erectile functiondomain. From Haider KS, Haider A, Doros G, et al. Long-termtestosterone therapy improves urinary and sexual function andquality of life in men with hypogonadism: results from apropensity-matched subgroup of a controlled registry study. J Urolhttps://doi.org/10.1016/j.juro 2017.07.039.178 Reprinted withpermission.

Benefits of TTh in Decreasing All-Cause andVascular Mortality7 observational studies reported that TTh was associated with

decreased risk for overall mortality or myocardial infarction(MI).259e264 The Veterans Administration clinical databasestudy showed a 39% lower risk for mortality in men with TDwho received TTh compared with men with TD who remaineduntreated.260 An increased mortality risk (hazard ratio ¼ 2.02,95% CI ¼ 1.2e3.4) was reported in men with T2DM and TDwho did not receive TTh compared with men who receivedTTh.259 The relation between TD and increased risk ofCV-related mortality was illustrated by a meta-analysis of which16,184 community-dwelling men with mean follow-up ofapproximately 10 years.62 A significant increase in mortality isassociated with TD. However, no studies have unequivocallyestablished a direct relation between low T and mortality, buthigher T levels have been correlated with lower mortality and thelowest T levels have been associated with increased mortality.265

All the evidence available to date suggests that low T, free T, andbioavailable T are associated with increased risk of CV-relatedand all-cause mortality.

TTh Improves Mood and Depressive Symptoms,Energy, and Quality of LifeTD adversely affects mood and depressive

symptoms.29,232,266e277 Wang et al29 reported significantimprovement in positive mood and decrease in negative moodwith TTh over a period of 36 months. In a multicenter12-month observational registry study (N ¼ 849) of men withTD treated with 1% T gel, Patient Health Questionnaire(PHQ-9) scores improved significantly (P < .01) after 3 monthsof TTh and by 12 months PHQ-9 scores demonstrated clinicallymeaningful improvement, and the number of patients withmoderately severe to severe symptoms decreased from 17.3% to2.1%, respectively.268 A modest improvement in global cogni-tion with TTh also was reported.272 Observational studies of 799men on TTh showed a 22% decrease in fatigue scores over 6months.267 In a meta-analysis of 16 randomized trials, Ama-natkar et al266 examined data from 994 subjects and found thatTTh had a significant effect on mood in men with TD.

It is well recognized that TD significantly impairs quality oflife. TTh promotes improvement of depression, BMD, energy,libido, erectile function, muscle mass, IR, and LUTS.268 Nianet al278 reported that TTh improved patients’ health-relatedquality of life as assessed by decreased Aging Males’ Symptoms(AMS) total score and psychological, somatic, and sexual subscalescores.

DISCUSSION

This review presents findings of the contemporary literatureon TTh in men with TD and its positive benefits on men’shealth. A large body of evidence is accumulating from


https://doi.org/10.1016/j.juro%202017.07.039


randomized clinical trials, observational and registry studies, andmeta-analyses supporting a therapeutic role for T in men withTD. The most recent data from several randomized placebo-controlled clinical trials have demonstrated that TTh in menwith TD provides real health benefits for BMD, anemia, andsexual function.177,219,232

The findings reported in these recent trials showed that TThproduces significant improvement in sexual activity, sexualdesire, and erectile function. Furthermore, men receiving TThreported slightly better mood and lower severity of depressivesymptoms.177,232 TTh is effective in correcting sexual dysfunc-tion as demonstrated by improvements in erectile function andlibido.177,232 Meta-analyses of pooled studies have demonstrateda strong and favorable response of TTh on sexual function.176,212

Animal studies have defined the critical importance of androgensin maintaining the biochemical and physiologic mechanisms oferectile function.230,231 In addition to improvement in sexualfunction, TTh has been shown to decrease LUTS and improvebladder functions by increasing bladder capacity and complianceand decreasing detrusor pressure at maximal flow in men withTD.247 These findings are congruent with data reported from alarge number of observational and registry studies demonstratingbenefits of TTh on sexual function.

One of the important benefits of TTh on men’s health is theimprovement in metabolic and glycemic control. TTh in menwith TD showed improved metabolic profiles with increasedinsulin sensitivity, lower blood glucose levels, and lower HbA1c

levels.111,112 Data of meta-analyses strongly suggested that TThlowered HbA1c in placebo-controlled and uncontrolled trials andshowed a favorable glycometabolic profile as demonstrated by thesignificant effect of active treatment on glycemia and insulinsensitivity as detected by HOMA-IR index.210e212 In addition,data from long-term observational studies and meta-analysesdemonstrated a positive effect of TTh on LBM and FM withparallel decreases in BMI, WC, and body weight and improve-ment in overall body composition.112,184e187,191,208,212,279 TThattenuates components of MetS.154,184,185,211,212 This is ofcritical importance, because MetS is a risk factor for CVD.

It should be noted that TTh produces improvements in obeseand non-obese men with TD. 3 long-term observational studiesof TTh in obese men with a follow-up duration of 5 to 8 yearsdemonstrated significant benefits of TTh.156,196,228 In a study inwhich 255 men with TD treated with TTh were followed for upto 5 years, marked, sustained, and significant weight loss andmarked decreases in WC and BMI were observed. A follow-upstudy with a pooled analysis of 411 men with various classes ofobesity and TD found that long-term TTh produced significantand sustained weight loss and marked decreases in WC andBMI.196

Most importantly, TTh improved erectile function as assessedby the IIEF erectile function domain and improvement in qualityof life as assessed by the AMS scale. Significant improvementswere noted in blood pressure, markers of inflammation, and liver


function test enzyme activities, and significant improvement inglycemic control was found as assessed by blood glucose andHbA1c. In addition, improvements in lipid profile were marked.In another long-term study, Permpongkosol et al228 followedpatients on TTh for 8 years. They found that TTh in obese mensignificantly decreased WC, body fat, HbA1c, cholesterol, low-density lipoprotein cholesterol, and International ProstateSymptom Score (IPSS) and improved IIEF score and vertebraland femoral BMD. They lamented that some obesity parametersshowed no improvements. It is becoming clear that benefits ofTTh in men with TD are noted in non-obese and obese men andin men with diabetes or MetS. The benefits observed in menwith various comorbidities suggest that TTh is of benefit torestore physiologic homeostasis in many tissues and organs.

It is well established that men with TD are at higher risk ofosteopenia, osteoporosis, and bone fracture.280 TTh in thephysiologic range to improve and maintain bone density in menwith TD is a rational and logical approach.25,26,187,222 Severalstudies have demonstrated that TTh increases spinal bone den-sity in men with TD and that bone density is maintained abovethe fracture threshold.25,281 Most importantly, TTh producesimprovement in trabecular and cortical BMD of the spine in-dependent of age and type of hypogonadism.282 The pooledresults of a meta-analysis also support a beneficial effect of TThon lumbar spine bone density. In a recent clinical trial, TTh inmen with TD demonstrated significant improvements in volu-metric BMD and estimated bone strength.219 These findingssupport TTh in men with TD to prevent bone loss and maintainBMD and decrease fracture and frailty.

In a recent clinical trial, TTh of men with TD producedimprovements in men with anemia of known cause and in menwith anemia of unknown cause.257 Most importantly, TTh inmen with unexplained anemia resulted in a marked decrease inanemia at 12 months; 58.3% were no longer anemic comparedwith only 22.2% in the placebo group. The improvement inhemoglobin levels in men with known causes of anemia byrestoration of T levels to the physiologic range suggests that TDcontributes to anemia. The finding that TTh in men with TDand unexplained anemia increased hemoglobin concentration is avery relevant observation because no other treatment has beenreported to correct unexplained anemia in older men.

Several studies have suggested that TD has a negative effect onmood and depressive symptoms.29,232,266e272,283 Men with TDare often bothered with loss of libido or diminished libido,dysphoria, fatigue, and irritability.29,283e285 These symptoms areoften diagnosed with those of major depression. TTh in menwith TD is associated with improved mood and well-being anddecreased fatigue and irritability.209,283,286 In a meta-analysis of16 randomized trials, Amanatkar et al266 reported that TTh hada significant effect on mood in men with TD. TTh improvesdepression, energy, libido, and erectile function.268 TTh im-proves patients’ health-related quality of life in terms of lowerAMS total score and psychological, somatic, and sexual subscale

8 Traish

scores.278,287,288 In 2 studies, TTh improved PHQ-9 scoressignificantly (P < .01) after 3 months and by 12 months PHQ-9scores demonstrated clinically meaningful improvement.268,269

Wang et al29 demonstrated significant improvement in positivemood and decrease in negative mood with TTh over a period of36 months. Observational studies of 799 men on TTh showed a22% decrease in fatigue scores over 6 months.267 TTh in oldermen resulted in some benefit in mood and depressive symptomsbut no benefit in vitality.177,232

Prostate Cancer Risk With TThOne of the most serious concerns among physicians regarding

TTh is the risk of prostate cancer (PCa).289 Since the landmarkstudy in men with metastatic PCa suggesting that T activatesPCa,290,291 it was believed that T would cause PCa and wouldpromote its rapid growth. However, this was not demonstratedin a large prospective longitudinal study involving 3,886 menwith PCa and 6,448 age-matched controls pooled from multipleindividual studies that showed no significant relation betweenserum androgens and PCa risk.292 In addition, data from theplacebo arm of the Reduction by Dutasteride of Prostate CancerEvents (REDUCE) trial, in which 3,255 men underwent pros-tate biopsy at years 2 and 4 as part of the study protocol, andserum concentrations of T and 5a-dihydrotestosterone obtainedat baseline showed no association with PCa risk.293 Similarfindings were reported in the placebo arm of the Prostate CancerPrevention Trial (PCPT).294 Specifically, men with the highestserum concentrations of T and 5a-dihydrotestosterone had nogreater risk of developing PCa than men with the lowest con-centrations. A plethora of clinical data has emerged contradictingthe basic premise that T causes prostate cancer.295e301 In a meta-analysis of 22 randomized controlled trials involving 2,351 men,those who received TTh were at no greater risk of developingPCa than men who received placebo.302 Recently, Baillargeonet al303 investigated the SEER database for high-grade PCa andprior exposure to TTh. Of 52,579 men with PCa, those withexposure to TTh were at no greater risk for having developedhigh-grade PCa than untreated men. These findings were sup-ported by other long-term registry studies.243,304 An observa-tional study by Wallis et al305 investigated a large Canadiandatabase of 10,311 men treated with TTh and 28,029 controls.The 5-year cumulative incidences of PCa diagnosis were 3.2%(95% CI ¼ 2.9e3.4) in the control group and 2.8% (95% CI ¼2.4e3.1; P ¼ .04) in the group exposed to TTh. Interestingly,men with the longest duration of treatment had the lowest rate ofPCa.305 To date, a moderate number of case series studies havedemonstrated minimal risk of PCa recurrence or progressionwith TTh.306e309

CVD Risk With TThThe Testosterone in Older Men with Sarcopenia (TOM)

study reported more CV events in men who received T gel thanplacebo and the study was terminated.310 This was a 6-month

study (N ¼ 209) in men at least 65 years old with limitedmobility owing to frailty. The T-treated group experienced 23CV events and the placebo group experienced 5 events. It shouldbe noted that this study included events such as palpitations,syncope, pedal edema, and non-specific electrocardiographicchanges, none of which were defined or captured systematicallyand were included whether they were noted by the study in-vestigators, self-reported, or appeared in outside medical records.Basaria et al310 concluded that “The lack of a consistent patternin these events and the small number of overall events suggest thepossibility that the differences detected between the twotrial groups may have been due to chance alone.” Interestingly,a similar UK study of frail men with limited mobility,Srinivas-Shankar et al191 reported only 2 major adverse cardiacevents (MACEs), which were in the placebo arm.

Vigen et al311 published a retrospective study of 8,709 men inthe Veterans Administration health care system who underwentcoronary angiography and had T levels lower than 300 ng/dL. Atbaseline (date of angiography) none were treated with T. 2groups were identified: one was composed of men who eventu-ally received a prescription for TTh and the other was composedof men who did not receive a prescription. The initial publica-tion reported that “the absolute rate of adverse events [cumula-tive for stroke, myocardial infarction (MI), and death] was25.7% in the T-treated group and 19.9% in the untreatedgroup.”However, after publication it was recognized these resultswere incorrect, and in fact the T-treated group had demonstrateda lower absolute rate of events, by half!312e316 The actual valuesfor absolute rates of events were 10.1% for the T-treated groupand 21.2% for the untreated group.312e316 The investigatorspublished a correction and “absolute rate of events” was changedto “estimated cumulative probability of events” based on com-plex and non-validated statistical methods at the time. Monthslater, they published a second correction reporting a nearly 10%contamination rate of the all-male population by women.

A retrospective analysis from a large insurance database waspublished by Finkle et al317 suggesting an increase in non-fatal MIby 36% in the 90 days after a T prescription compared with the12 months before the prescription. Because no control group wasincluded, it remains impossible to determine whether the menwith TD who did not receive a prescription would have had agreater, lower, or identical rate of MI. Studies based on flawedmethodology yet claiming increased CVD risk must be viewedwith extreme caution. Furthermore, their conclusions should becounterweighed against a considerable body of evidence suggest-ing that higher levels of serum T and TTh are associated with CVbenefits.13,155 As reviewed by Morgentaler et al6,7 and Hackett,318

low T levels represent a risk factor for CVD and mortality,whereas higher T values could offer a protective effect.

A host of real-life observational studies have demonstrated thatmortality is decreased by half in men who received TThcompared with untreated men with TD.84,259,260,318e321 In astudy of 83,010 men with recorded low T levels,262 all-cause



mortality, MI, and stroke were significantly decreased in menwho achieved adequate normalization of T levels compared withmen who did not receive TTh or men who did not achieveadequate normalization of T levels. Interestingly, the risk ofstroke and MI in men with inadequate TTh was similar to thatof untreated men. Wallis et al305 compared the effects of TTh in10,311 men with a median follow-up of 5.3 years and comparedthe CV events recorded with those of 28,029 untreated men(controls). TTh produced a marked decrease in overall mortality(hazard ratio ¼ 0.88, 95% CI ¼ 0.84e0.93) comparedwith untreated men. Several other studies reported no increasedCVD risk or protective effects of T on the vascular system,including a decrease in atrial fibrillation, against a major CVDevent.261e264,305,322e327 Thus, conclusions on CVD risk shouldbe viewed with extreme caution when based on contaminateddata or use of non-validated statistical methods311 or meta-analyses that include studies that do not meet the inclusioncriteria328 or studies that were not designed to investigate CVDrisk as primary end point310 or comparing 2 groups that havenothing in common.317 The T Trials have provided the strongestpieces of evidence that TTh does not appear to be a risk forCVD.177,219,232,257,329,330 This multicenter, large prospectivecontrolled T trial involving 790 men assigned to T or placebo gelfor 1 year, with a second year of monitoring off treatment trial(sponsored by the National Institutes of Health), in men at least65 years old demonstrated significant benefits for sexual desire,activity, and function and physical activity and mood. With re-gard to CV events, there were identical numbers (n ¼ 7) ofMACEs in the 2 arms. In the second year, there were only 2events in the T arm and 9 in the placebo arm. Hospitalizationsalso were fewer in the T arm. Although this study did not pro-vide a definitive statement regarding CV risk, one must recognizethat no signal whatsoever of increased CV risk was reported inthis large study of a relatively at-risk population (men > 65 yearsold). The number of MACEs over the 2-year study period was16 for placebo compared with 9 for the T arm. Although onemust remain cautious in drawing conclusions from smallnumbers of men, it is instructive to recall the powerful negativeattention given to the TOM study310 in which there were 4MACEs in the T arm and none in the placebo arm.

A number of studies have suggested a potential association ofTTh with CV events.310,311,317,328 However, an emerging bodyof evidence suggests that the conclusion of such studies is marredby methodologic and interpretational flaws and the CV risk isexaggerated (for review see 6,7,13,14). Several recent observationalstudies,155 clinical trials,232 and meta-analysis331 have notdemonstrated an association between TTh and CVD. A recentreview by Onasanya et al332 found that 6 systematic reviews andmeta-analyses showed no significant association between exoge-nous T and CV events. However, 2 of these 6 meta-analysesshowed increased risk in subgroup analyses of oral T and menat least 65 years old during their first treatment year. As pointedout by Traish,13,14 only 1 of 9 meta-analyses reviewed showed anassociation between TTh and CV risk. Cheetham et al264


described a retrospective cohort study in which 8,808 menwere prescribed T and 35,527 men never received a T pre-scription (median follow ¼ 3.2 years). The rates of the compositeCV end point were 23.9 per 1,000 person-years in the noneT-treated group vs 16.9 per 1,000 person-years in the T-treatedgroup. It was concluded that men with TD who received TThhad a lower risk of CV outcomes over a median follow-up of 3.4years. These findings support the suggestion that TTh is safe andeffective and might be protective.305 Thus, the purported risks ofTTh with regard to CVD are not supported by scientific orclinical evidence. Even the most recent reported T trial by Budoffet al,329 which showed some differences in plaque calcificationbetween T-treated and untreated groups, did not report CVevents. To this end, TTh seems to be safe and effective for themanagement of men with TD.

In summary, TTh in the physiologic range in men with TDimparts great benefits to men’s health as demonstrated by theimprovement in glycometabolic and cardiometabolic function,improved sexual function, body composition, and BMD,amelioration of anemia, and improvement in overall quality of life.

Corresponding Author: Abdulmaged M. Traish, PhD, MBA,Professor of Urology, Department of Urology, Boston UniversitySchool of Medicine, Boson, MA 02118, USA; E-mail: [email protected]

Conflicts of Interest: The author reports no conflicts of interest.

Funding: Partial financial support was provided by ReprosTherapeutics Inc.

STATEMENT OF AUTHORSHIP

Category 1

(a) Conception and Design
Abdulmaged M. Traish
(b) Acquisition of Data
(c) Analysis and Interpretation of Data
Category 2

(a) Drafting the Article
(b) Revising It for Intellectual Content
Category 3

(a) Final Approval of the Completed Article
REFERENCES1. Kelly DM, Jones TH. Testosterone: a metabolic hormone in

health and disease. J Endocrinol 2013;217:R25-R45.

2. Kelly DM, Jones TH. Testosterone: a vascular hormone in

health and disease. J Endocrinol 2013;217:R47-R71.

mailto:[email protected]

mailto:[email protected]

http://refhub.elsevier.com/S2050-0521(17)30119-1/sref1




10 Traish

3. Kelly DM, Jones TH. Testosterone and cardiovascular risk inmen. Front Horm Res 2014;43:1-20.

4. Kelly DM, Jones TH. Testosterone and obesity. Obes Rev2015;16:581-606.

5. Rao PM, Kelly DM, Jones TH. Testosterone and insulinresistance in the metabolic syndrome and T2DM in men. NatRev Endocrinol 2013;9:479-493.

6. Morgentaler A, Miner MM, Caliber M, et al. Testosteronetherapy and cardiovascular risk: advances and controversies.Mayo Clin Proc 2015;90:224-251.

7. Morgentaler A, Zitzmann M, Traish A, et al. Internationalexpert consensus conference on testosterone deficiency andits treatment- resolutions and conclusions. Mayo Clin Proc2016;91:881-896.

8. Traish AM, Miner MM, Morgentaler A, et al. Testosteronedeficiency. Am J Med 2011;124:578-587.

9. Traish AM. Testosterone and weight loss: the evidence. CurrOpin Endocrinol Diabetes Obes 2014;21:313-322.

10. Traish AM. Adverse health effects of testosterone deficiency(TD) in men. Steroids 2014;88:106-116.

11. Traish AM. Outcomes of testosterone therapy in menwith testosterone deficiency (TD): part II. Steroids 2014;88:117-126.

12. Traish AM, Zitzmann M. The complex and multifactorialrelationship between testosterone deficiency (TD), obesityand vascular disease. Rev Endocr Metab Disord 2015;16:249-268.

13. Traish A. Testosterone therapy in men with testosteronedeficiency: are we beyond the point of no return? InvestigClin Urol 2016;57:384-400.

14. Traish AM. Testosterone therapy in men with testosteronedeficiency: are the benefits and cardiovascular risks real orimagined? Am J Physiol Regul Integr Comp Physiol 2016;311:R566-R573.

15. Bhasin S,Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J PhysiolEndocrinol Metab 2001;281:E1172-E1181.

16. Bhasin S. Regulation of body composition by androgens.J Endocrinol Invest 2003;26:814-822.

17. Bhasin S. Testosterone supplementation for aging-associated sarcopenia. J Gerontol A Biol Sci Med Sci2003;58:1002-1008.

18. Bhasin S, Taylor WE, Singh R, et al. The mechanisms ofandrogen effects on body composition: mesenchymalpluripotent cell as the target of androgen action. J GerontolA Biol Sci Med Sci 2003;58:M1103-M1110.

19. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are asresponsive as young men to the anabolic effects of gradeddoses of testosterone on the skeletal muscle. J Clin Endo-crinol Metab 2005;90:678-688.

20. Bhasin S, Parker RA, Sattler F, et al; AIDS Clinical TrialsGroup Protocol A5079 Study Team. AIDS Clinical TrialsGroup Protocol A5079 Study Team. Effects of testosteronesupplementation on whole body and regional fat mass anddistribution in human immunodeficiency viruseinfected men

with abdominal obesity. J Clin Endocrinol Metab 2007;92:1049-1057.

21. Bhasin S, Travison TG, Storer TW, et al. Effect of testos-terone supplementation with and without a dual 5a-reduc-tase inhibitor on fat-free mass in men with suppressedtestosterone production: a randomized controlled trial.JAMA 2012;307:931-939.

22. Singh R, Artaza JN, Taylor WE, et al. Androgens stimulatemyogenic differentiation and inhibit adipogenesis in C3H10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology 2003;144:5081-5508.

23. Singh R, Artaza JN, Taylor WE, et al. Testosterone inhibitsadipogenic differentiation in 3T3-L1 cells: nuclear trans-location of androgen receptor complex with beta-catenin andT-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology2006;147:141-154.

24. Chazenbalk G, Singh P, Irge D, et al. Androgens inhibit adi-pogenesis during human adipose stem cell commitment topreadipocyte formation. Steroids 2013;78:920-926.

25. Behre HM, Kliesch S, Leifke E, et al. Long-term effect oftestosterone therapy on bone mineral density in hypogonadalmen. J Clin Endocrinol Metab 1997;82:2386-2390.

26. Behre HM, Tammela TL, Arver S, et al; European Testogel®Study Team. A randomized, double-blind, placebo-controlledtrial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms ofandrogen deficiency over 6 months with 12 months open-label follow-up. Aging Male 2012;15:198-207.

27. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testos-terone treatment on bone mineral density in men over 65years of age. J Clin Endocrinol Metab 1999;84:1966-1972.

28. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testos-terone replacement in hypogonadal men. J Clin EndocrinolMetab 2000;85:2670-2677.

29. Wang C, Cunningham G, Dobs A, et al. Long-term testos-terone gel (AndroGel) treatment maintains beneficial effectson sexual function and mood, lean and fat mass, and bonemineral density in hypogonadal men. J Clin EndocrinolMetab 2004;89:2085-2098.

30. Isidori AM, Giannetta E, Greco EA, et al. Effects of testos-terone on body composition, bone metabolism and serumlipid profile in middle-aged men: a meta-analysis. ClinEndocrinol (Oxf) 2005;63:280-293.

31. Aversa A, Bruzziches R, Francomano D, et al. Effects of long-acting testosterone undecanoate on bone mineral density inmiddle-aged men with late-onset hypogonadism and meta-bolic syndrome: results from a 36 months controlled study.Aging Male 2012;15:96-102.

32. Borst SE, Yarrow JF. Injection of testosterone may be saferand more effective than transdermal administration forcombating loss of muscle and bone in older men. Am JPhysiol Endocrinol Metab 2015;308:E1035-E1042.

33. Shahidi NT. Androgens and erythropoiesis. N Engl J Med1973;289:72-80.



















































































































34. Coviello AD, Kaplan B, Lakshman KM, et al. Effects of gradeddoses of testosterone on erythropoiesis in healthy young andolder men. J Clin Endocrinol Metab 2008;93:914-919.

35. Gardner FH, Nathan DG. Androgens and erythropoiesis. 3.Further evaluation of testosterone treatment of myelofi-brosis. N Engl J Med 1966;274:420-426.

36. Naets JP, Wittek M. The mechanism of action of androgenson erythropoiesis. Ann N Y Acad Sci 1968;149:366-376.

37. Beggs LA, Yarrow JF, Conover CF, et al. Testosterone altersiron metabolism and stimulates red blood cell productionindependently of dihydrotestosterone. Am J Physiol Endo-crinol Metab 2014;307:E456-E461.

38. Sader MA, Griffiths KA, Skilton MR, et al. Physiologicaltestosterone replacement and arterial endothelial function inmen. Clin Endocrinol (Oxf) 2003;59:62-67.

39. Miller VM, Mulvagh SL. Sex steroids and endothelial func-tion: translating basic science to clinical practice. TrendsPharmacol Sci 2007;28:263-270.

40. Liao CH, Wu YN, Lin FY, et al. Testosterone replacementtherapy can increase circulating endothelial progenitor cellnumber in men with late onset hypogonadism. Andrology2013;1:563-569.

41. Sonmez A, Haymana C, Aydogdu A, et al. Endothelialdysfunction, insulin resistance and inflammation in congen-ital hypogonadism, and the effect of testosterone replace-ment. Endocrinol Jpn 2015;62:605-613.

42. Shoskes DA, Tucky B, Polackwich AS. Improvement ofendothelial function following initiation of testosteronereplacement therapy. Transl Androl Urol 2016;5:819-823.

43. Hwang I, Lee HS, Yu HS, et al. Testosterone modulatesendothelial progenitor cells in rat corpus cavernosum. BJUInt 2016;117:976-981.

44. Akishita M, Hashimoto M, Ohike Y, et al. Low testosteronelevel is an independent determinant of endothelial dysfunc-tion in men. Hypertens Res 2007;30:1029-1034.

45. Akishita M, Hashimoto M, Ohike Y, et al. Low testosteronelevel as a predictor of cardiovascular events in Japanesemen with coronary risk factors. Atherosclerosis 2010;210:232-236.

46. Corotchi MC, Popa MA, Simionescu M. Testosterone stimu-lates proliferation and preserves stemness of human adultmesenchymal stem cells and endothelial progenitor cells.Rom J Morphol Embryol 2016;57:75-80.

47. Traish AM, Galoosian A. Androgens modulate endothelialfunction and endothelial progenitor cells in erectile physi-ology. Korean J Urol 2013;54:721-731.

48. Kelly DM, Akhtar S, Sellers DJ, et al. Testosterone differen-tially regulates targets of lipid and glucose metabolism inliver, muscle and adipose tissues of the testicular feminizedmouse. Endocrine 2016;54:504-515.

49. Shen M, Shi H. Sex hormones and their receptors regulateliver energy homeostasis. Int J Endocrinol 2015;2015:294278.


50. Zhang H, Liu Y, Wang L, et al. Differential effects of estro-gen/androgen on the prevention of nonalcoholic fatty liverdisease in the male rat. J Lipid Res 2013;54:345-357.

51. Kim S, Kwon H, Park JH, et al. A low level of serum totaltestosterone is independently associated with nonalcoholicfatty liver disease. BMC Gastroenterol 2012;12:69.

52. Mody A, White D, Kanwal F, et al. Relevance of low testos-terone to non-alcoholic fatty liver disease. CardiovascEndocrinol 2015;4:83-89.

53. Upreti R, Hughes KA, Livingstone DE, et al. 5a-Reductasetype 1 modulates insulin sensitivity in men. J Clin EndocrinolMetab 2014;99:E1397-E1406.

54. Randall VA, Hibberts NA, Thornton MJ, et al. Do androgensinfluence hair growth by altering the paracrine factorssecreted by dermal papilla cells? Eur J Dermatol 2001;11:315-320.

55. Randall VA. Androgens and hair growth. Dermatol Ther2008;21:314-328.

56. Buvat J, Maggi M, Gooren L, et al. Endocrine aspects of malesexual dysfunctions. J Sex Med 2010;7:1627-1656.

57. Buvat J, Maggi M, Guay A, et al. Testosterone deficiency inmen: systematic review and standard operating proceduresfor diagnosis and treatment. J Sex Med 2013;10:245-284.

58. Wang C, Nieschlag E, Swerdloff R, et al. Investigation,treatment and monitoring of late-onset hypogonadism inmales: ISA, ISSAM, EAU, EAA and ASA recommendations.Eur J Endocrinol 2008;159:507-514.

59. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosteronetherapy in men with androgen deficiency syndromes: anEndocrine Society clinical practice guideline. J Clin Endo-crinol Metab 2010;95:2536-2559.

60. Wu FC, Tajar A, Beynon JM, et al; EMAS Group. Identificationof late-onset hpogonadism in middle-aged and elderly men.N Engl J Med 2010;363:123-135.

61. Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence andincidence of androgen deficiency in middle-aged and oldermen: estimates from the Massachusetts Male Aging Study.J Clin Endocrinol Metab 2004;89:5920-5926.

62. Araujo AB, Dixon JM, Suarez EA, et al. Clinical review:Endogenous testosterone and mortality in men: a systematicreview and meta-analysis. J Clin Endocrinol Metab 2011;96:3007-3019.

63. Aub JC. The use of testosterone. N Engl J Med 1940;222:877-881.

64. Aub JC, Kety SS. Recent advances in testosterone therapy.N Engl J Med 1943;228:338-343.

65. Traish AM, Guay A, Feeley R, et al. The dark side of testos-terone deficiency: I. Metabolic syndrome and erectiledysfunction. J Androl 2009;30:10-22.

66. Traish AM, Saad F, Guay A. The dark side of testosteronedeficiency: II. Type 2 diabetes and insulin resistance. J Androl2009;30:23-32.

67. Traish AM, Saad F, Feeley RJ, et al. The dark side oftestosterone deficiency: III. Cardiovascular disease. J Androl2009;30:477-494.













































































































12 Traish

68. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypo-gonadism in males aged at least 45 years: the HIM study. IntJ Clin Pract 2006;60:762-769.

69. Antonio L, Wu FC, O’Neill TW, et al; EMAS Study Group.Associations between sex steroids and the development ofmetabolic syndrome: a longitudinal study in European men.J Clin Endocrinol Metab 2015;100:1396-1404.

70. Laaksonen DE, Niskanen L, Punnonen K, et al. Sex hor-mones, inflammation and the metabolic syndrome: apopulation-based study. Eur J Endocrinol 2003;149:601-608.

71. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosteroneand sex hormone-binding globulin predict the metabolicsyndrome and diabetes in middle-aged men. Diabetes Care2004;27:1036-1041.

72. Laaksonen DE, Niskanen L, Punnonen K, et al. The metabolicsyndrome and smoking in relation to hypogonadism inmiddle-aged men: a prospective cohort study. J Clin Endo-crinol Metab 2005;90:712-719.

73. Kupelian V, Chiu GR, Araujo AB, et al. Association of sexhormones and C-reactive protein levels in men. Clin Endo-crinol 2010;72:527-533.

74. Kapoor D, Clarke S, Stanworth R, et al. The effect oftestosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.Eur J Endocrinol 2007;156:595-602.

75. Kapoor D, Aldred H, Clark S, et al. Clinical and biochemicalassessment of hypogonadism in men with type 2 diabetes.Diabetes Care 2007;30:911-917.

76. Bhatia V, Chauhuri A, Tomar R, et al. Low testosterone andhigh C-reactive protein concentrations predict low hematocritin type 2 diabetics. Diabetes Care 2006;29:2289-2294.

77. Guler N, Batyraliev T, Dulger H, et al. The effects of shortterm (3 weeks) testosterone treatment on serum inflam-matory markers in men undergoing coronary artery stenting.Int J Cardiol 2006;109:339-343.

78. Aversa A, Bruzziches R, Francomano D, et al. Effects oftestosterone undecanoate on cardiovascular risk factors andatherosclerosis in middle-aged men with late-onset hypo-gonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.J Sex Med 2010;7:3495-3503.

79. Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testos-terone replacement on endogenous inflammatory cytokinesand lipid profile in hypogonadal men. J Clin EndocrinolMetab 2004;89:3313-3318.

80. Simon D, Charles MA, Nahoul K, et al. Association betweenplasma total testosterone and cardiovascular risk factors inhealthy adult men: the Telecom Study. J Clin EndocrinolMetab 1997;82:682-685.

81. Tsai EC, Matsumoto AM, Fujimoto WY, et al. Association ofbioavailable, free, and total testosterone with insulin resis-tance: influence of sex hormone-binding globulin and bodyfat. Diabetes Care 2004;27:861-868.

82. Ding EL, Song Y, Malik VS, et al. Sex differences of endog-enous sex hormones and risk of type 2 diabetes: a

systematic review and meta-analysis. JAMA 2006;295:1288-1299.

83. Oh JY, Barrett-Connor E,Wedick NM, et al; Rancho BernardoStudy. Endogenous sex hormones and the development oftype 2 diabetes in older men and women; the Rancho Ber-nardo study. Diabetes Care 2002;25:55-60.

84. Shores MM, Matsumoto AM, Sloan KL, et al. Low serumtestosterone and mortality in male veterans. Arch InternMed 2006;166:1660-1665.

85. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetesin men. Diabetes Care 2007;30:234-238.

86. Stellato RK, Feldman HA, Hamdy O, et al. Testosterone, sexhormone-binding globulin, and the development of type 2diabetes in middle-aged men: prospective results from theMassachusetts Male Aging Study. Diabetes Care 2000;23:490-494.

87. Rhoden EL, Ribeiro EP, Riedner CE, et al. Glycosylated hae-moglobin levels and the severity of erectile function in dia-betic men. BJU Int 2005;95:615-617.

88. Rhoden EL, Ribeiro DP, Teloken C, et al. Diabetes mellitus isassociated with subnormal serum levels of free testosteronein men. BJU Int 2005;96:867-870.

89. Haffner SM, Miettinen H, Karhapää P, et al. Leptin concen-trations, sex hormones, and cortisol in nondiabetic men.J Clin Endocrinol Metab 1997;82:1807-1809.

90. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Lowtestosterone levels are common and associated with insulinresistance in men with diabetes. J Clin Endocrinol Metab2008;93:1834-1840.

91. Fukui M, Kitagawa Y, Nakamura N, et al. Association be-tween serum testosterone concentration and carotidatherosclerosis in men with type 2 diabetes. Diabetes Care2003;26:1869-1873.

92. Fukui M, Kitagawa Y, Ose H, et al. Role of endogenousandrogen against insulin resistance and atherosclerosis inmen with type 2 diabetes. Curr Diabetes Rev 2007;3:25-31.

93. Kapoor D, Goodwin E, Channer KS, et al. Testosteronereplacement therapy improves insulin resistance, glycaemiccontrol, visceral adiposity and hypercholesterolaemia inhypogonadal men with type 2 diabetes. Eur J Endocrinol2006;154:899-906.

94. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrenceof hypogonadotropic hypogonadism in type 2 diabetes. J ClinEndocrinol Metab 2004;89:5462-5468.

95. Corona G, Mannucci E, Petrone L, et al. A comparison ofNCEP-ATPIII and IDF metabolic syndrome definitions withrelation to metabolic syndrome-associated sexual dysfunc-tion. J Sex Med 2007;4:789-796.

96. Corona G, Mannucci E, Petrone L, et al. NCEP-ATPIII-Definedmetabolic syndrome, type 2 diabetes mellitus, and preva-lence of hypogonadism in male patients with sexualdysfunction. J Sex Med 2007;4:1038-1045.

97. Pasquali R, Casimirri F, Cantobelli S, et al. Effect of obesityand body fat distribution on sex hormones and insulin inmen. Metabolism 1991;40:101-104.


















































































































98. Pasquali R, Macor C, Vicennati V, et al. Effects of acutehyperinsulinemia on testosterone serum concentrations inadult obese and normal-weight men. Metabolism 1997;46:526-529.

99. Muller M, Grobbee DE, den Tonkelaar I, et al. Endogenous sexhormones and metabolic syndrome in aging men. J ClinEndocrinol Metab 2005;90:2618-2623.

100. Pagotto U, Gambineri A, Pelusi C, et al. Testosteronereplacement therapy restores normal ghrelin in hypogonadalmen. J Clin Endocrinol Metab 2003;88:4139-4143.

101. Yialamas MA, Dwyer AA, Hanley E, et al. Acute sex steroidwithdrawal reduces insulin sensitivity in healthy men withidiopathic hypogonadotropic hypogonadism. J Clin Endo-crinol Metab 2007;92:4254-4259.

102. Rubinow KB, Tang C, Hoofnagle AN, et al. Acute sex steroidwithdrawal increases cholesterol efflux capacity and HDL-associated clusterin in men. Steroids 2012;77:454-460.

103. Yeap BB, Chubb SA, Hyde Z, et al. Lower serum testosteroneis independently associated with insulin resistance in non-diabetic older men: the Health in Men Study. Eur J Endo-crinol 2009;161:591-598.

104. Andersson B, Marin P, Lissner L, et al. Testosterone con-centrations in women and men with NIDDM. Diabetes Care1994;17:405-411.

105. Pitteloud N, Hardin M, Dwyer AA, et al. Increasing insulinresistance is associated with a decrease in Leydig celltestosterone secretion in men. J Clin Endocrinol Metab2005;90:2636-2641.

106. Pitteloud N, Mootha VK, Dwyer AA, et al. Relationship be-tween testosterone levels, insulin sensitivity, and mitochon-drial function in men. Diabetes Care 2005;28:1636-1642.

107. Osuna JA, Gomez-Perez R, Arata-Bellabarba G, et al. Rela-tionship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance inobese men. Arch Androl 2006;52:355-361.

108. Basaria S, Muller DC, Carducci MA, et al. Hyperglycemia andinsulin resistance in men with prostate carcinoma whoreceive androgen-deprivation therapy. Cancer 2006;106:581-588.

109. Colangelo LA, Ouyang P, Liu K, et al. Association ofendogenous sex hormones with diabetes and impairedfasting glucose in men. Diabetes Care 2009;32:1049-1051.

110. Vikan T, Johnsen SH, Schirmer H, et al. Endogenoustestosterone and the prospective association with carotidatherosclerosis in men: the Tromso study. Eur J Epidemiol2009;24:289-295.

111. Jones TH, Arver S, Behre HM, et al; TIMES2 Investigators.Testosterone replacement in hypogonadal men with type 2diabetes and/or metabolic syndrome (the TIMES2 Study).Diabetes Care 2011;34:828-837.

112. Heufelder AE, Saad F, Bunck MC, et al. Fifty-two-weektreatment with diet and exercise plus transdermal testos-terone reverses the metabolic syndrome and improves gly-cemic control in men with newly diagnosed type 2 diabetesand subnormal plasma testosterone. J Androl 2009;30:726-733.


113. Zhang Y, Gao Y, Tan A, et al. Endogenous sex hormones andC-reactive protein in healthy Chinese men. Clin Endocrinol2013;78:60-66.

114. Agledahl I, Hansen JB, Svartberg J. Impact of testosteronetreatment on postprandial triglyceride metabolism in elderlymen with subnormal testosterone levels. Scand J Clin LabInvest 2008;68:641-648.

115. Agledahl I, Skjaerpe PA, Hansen JB, et al. Low serumtestosterone in men is inversely associated with non-fastingserum triglycerides: the Tromsø study. Nutr Metab Car-diovasc Dis 2008;18:256-262.

116. Monroe AK, Dobs AS. The effect of androgens on lipids. CurrOpin Endocrinol Diabetes Obes 2013;20:132-139.

117. Jiann BP, Hsieh JT, Liu SP, et al. Associations of endogenoustestosterone and lipid profiles in middle-aged to olderTaiwanese men. Int J Impot Res 2011;23:62-69.

118. Firtser S, Juonala M, Magnussen CG, et al. Relation of totaland free testosterone and sex hormone-binding globulin withcardiovascular risk factors in men aged 24e45 years. TheCardiovascular Risk in Young Finns Study. Atherosclerosis2012;222:257-262.

119. Zmuda JM, Cauley JA, Kriska A, et al. Longitudinal relationbetween endogenous testosterone and cardiovascular dis-ease risk factors in middle-aged men. A 13-year follow-up offormer Multiple Risk Factor Intervention Trial participants.Am J Epidemiol 1997;146:609-617.

120. Van Pottelbergh I, Braeckman L, Bacquer DD, et al. Differ-ential contribution of testosterone and estradiol in thedetermination of cholesterol and lipoprotein profile in healthymiddle-aged men. Atherosclerosis 2003;166:95-102.

121. Stanworth RD, Kapoor D, Channer KS, et al. Dyslipidaemia isassociated with testosterone, oestradiol and androgen re-ceptor CAG repeat polymorphism in men with type 2 dia-betes. Clin Endocrinol 2011;74:624-630.

122. Hak AE, Witteman JCM, De Jong FH, et al. Low levels ofendogenous androgens increase the risk of atherosclerosis inelderly men: the Rotterdam Study. J Clin Endocrinol Metab2002;87:3623-3639.

123. Muller M, van den Beld AW, Bots ML, et al. Endogenous sexhormones and progression of carotid atherosclerosis inelderly men. Circulation 2004;109:2074-2079.

124. Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, et al.Plasma total testosterone and incident cardiovascular eventsin hypertensive patients. Am J Hypertens 2013;26:373-381.

125. Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serumtestosterone is associated with reduced risk of cardiovas-cular events in elderly men. The MrOS (Osteoporotic Frac-tures in Men) study in Sweden. J Am Coll Cardiol 2011;58:1674-1682.

126. Zhao SP, Li XP. The association of low plasma testosteronelevel with coronary artery disease in Chinese men. Int JCardiol 1998;63:161-164.

127. English KM, Mandour O, Steeds RP, et al. Men with coronaryartery disease have lower levels of androgens than menwith normal coronary angiograms. Eur Heart J 2000;21:890-894.


















































































































14 Traish

128. Dobrzycki S, Serwatka W, Nadlewski S, et al. An assessmentof correlations between endogenous sex hormone levels andthe extensiveness of coronary heart disease and the ejectionfraction of the left ventricle in males. J Med Invest 2003;50:162-169.

129. Rosano G, Sheiban I, Massaro R, et al. Low testosteronelevels are associated with coronary artery disease in malepatients with angina. Int J Impot Res 2007;19:176-182.

130. Hu X, Rui L, Zhu T, et al. Low testosterone level in middle-aged male patients with coronary artery disease. Eur JIntern Med 2011;22:133-136.

131. Phillips GB, Pinkernell BH, Jing TY. The association ofhypotestosteronemia with coronary artery disease in men.Arterioscler Thromb Vasc Biol 1994;14:701-706.

132. Makinen J, Jarvisalo M, Pollanen P, et al. Increased carotidatherosclerosis in andropausal middle-aged men. J Am CollCardiol 2005;45:1603-1608.

133. van den Beld AW, Bots ML, Janssen JAMLL, et al. Endog-enous hormones and carotid atherosclerosis in elderly men.Am J Epidemiol 2003;157:25-31.

134. De Pergola G, Pannacciulli N, Ciccone M, et al. Free testos-terone plasma levels are negatively associated with theintima-media thickness of the common carotid artery inoverweight and obese glucose-tolerant young adult men. IntJ Obes Relat Metab Disord 2003;27:803-807.

135. Fu L, Gao QP, Shen JX. Relationship between testosteroneand indexes indicating endothelial function in male coronaryheart disease patients. Asian J Androl 2008;10:214-218.

136. Svartberg J, Von Muhlen D, Mathiesen E, et al. Lowtestosterone levels are associated with carotid atheroscle-rosis in men. J Intern Med 2006;259:576-582.

137. Demirbag R, Yilmaz R, Ulucay A, et al. The inverse relation-ship between thoracic aortic intima media thickness andtestosterone level. Endocr Res 2005;31:335-344.

138. Traish AM, Goldstein I, Kim NN. Testosterone and erectilefunction: from basic research to a new clinical paradigm formanaging men with androgen insufficiency and erectiledysfunction. Eur Urol 2007;52:54-70.

139. Traish AM, Abu-Zahra H, Guay AT. The brain, the penis andsteroid hormones: clinical correlates with endothelialdysfunction. Curr Pharm Des 2008;14:3723-3736.

140. Lu YL, Kuang L, Zhu H, et al. Changes in aortic endotheliumultrastructure in male rats following castration, replacementwith testosterone and administration of 5alpha-reductaseinhibitor. Asian J Androl 2007;9:843-847.

141. Campelo AE, Cutini PH, Massheimer VL. Testosteronemodulates platelet aggregation and endothelial cell growththrough nitric oxide pathway. J Endocrinol 2012;213:77-87.

142. Goglia L, Tosi V, Sanchez AM, et al. Endothelial regulation ofeNOS, PAI-1 and t-PA by testosterone and dihy-drotestosterone in vitro and in vivo. Mol Hum Reprod 2010;16:761-769.

143. Yu J, Akishita M, Eto M, et al. Androgen receptor-dependentactivation of endothelial nitric oxide synthase in vascularendothelial cells: role of phosphatidylinositol 3-kinase/aktpathway. Endocrinology 2010;151:1822-1828.

144. Ong PJ, Patrizi G, Chong WC, et al. Testosterone enhancesflow-mediated brachial artery reactivity in men with coronaryartery disease. Am J Cardiol 2000;85:269-272.

145. Kang SM, Jang Y, Kim J, et al. Effect of oral administration oftestosterone on brachial arterial vasoreactivity in men withcoronary artery disease. Am J Cardiol 2002;89:862-864.

146. Empen K, Lorbeer R, Dörr M, et al. Association of testos-terone levels with endothelial function in men: results from apopulation-based study. Arterioscler Thromb Vasc Biol2011;32:481-486.

147. Perusquia M, Stallone JN. Do androgens play a beneficial rolein the regulation of vascular tone? Nongenomic vasculareffects of testosterone metabolites. Am J Physiol Heart CircPhysiol 2010;298:H1301-H1307.

148. Svartberg J, von Mühlen D, Schirmer H, et al. Association ofendogenous testosterone with blood pressure and left ven-tricular mass in men. The Tromsø Study. Eur J Endocrinol2004;150:65-71.

149. Smith MR, Bennett S, Evans L, et al. The effects of inducedhypogonadism on arterial stiffness, body composition, andmetabolic parameters in males with prostate cancer. J ClinEndocrinol Metab 2001;86:4261-4267.

150. Dockery F, Bulpitt CJ, Agarwal S, et al. Testosterone sup-pression in men with prostate cancer leads to an increase inarterial stiffness and hyperinsulinaemia. Clin Sci 2003;104:195-201.

151. Bhattacharya RK, Khera M, Blick G, et al. Effect of 12 monthsof testosterone replacement therapy on metabolic syndromecomponents in hypogonadal men: data from the TestimRegistry in the US (TRiUS). BMC Endocr Disord 2011;11:18-29.

152. Boyanov MA, Boneva Z, Christov VG. Testosterone supple-mentation in men with type 2 diabetes, visceral obesity andpartial androgen deficiency. Aging Male 2003;6:1-7.

153. Li JY, Zhu JC, Dou JT, et al. Effects of androgen supple-mentation therapy on partial androgen deficiency in the ag-ing male: a preliminary study. Aging Male 2002;5:47-451.

154. Traish AM, Haider A, Doros G, et al. Long-term testosteronetherapy in hypogonadal men ameliorates elements of themetabolic syndrome: an observational, long-term registrystudy. Int J Clin Pract 2014;68:314-329.

155. Traish AM, Haider A, Haider KS, et al. Long-term testos-terone therapy improves cardiometabolic function and re-duces risk of cardiovascular disease in men withhypogonadism: a real-life observational registry study settingcomparing treated and untreated (control) groups.J Cardiovasc Pharmacol Ther 2017;22:414-433.

156. Saad F, Haider A, Doros G, et al. Long-term treatment ofhypogonadal men with testosterone produces substantialand sustained weight loss. Obesity (Silver Spring) 2013;21:1975-1981.

157. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serumtestosterone and mortality in older men. J Clin EndocrinolMetab 2008;93:68-75.

















































































































158. Tivesten A, Vandenput L, Labrie F, et al. Low serumtestosterone and estradiol predict mortality in elderly men.J Clin Endocrinol Metab 2009;94:2482-2488.

159. Haring R, Volzke H, Steveling A, et al. Low serum testos-terone levels are associated with increased risk of mortalityin a population-based cohort of men aged 20e79. Eur HeartJ 2010;31:1494-1501.

160. Haring R, Baumeister SE, Volzke H, et al. Prospective inverseassociation of sex hormone concentrations in men withbiomarkers of inflammation and oxidative stress. J Androl2012;33:944-950.

161. Oskui PM, French WJ, Herring MJ, et al. Testosterone andthe cardiovascular system: a comprehensive review of theclinical literature. J Am Heart Assoc 2013;2:e000272.

162. Herring MJ, Oskui PM, Hale SL, et al. Testosterone and thecardiovascular system: a comprehensive review of the basicscience literature. J Am Heart Assoc 2013;2:e000271.

163. Hackett G, Cole N, Bhartia M, et al; BLAST Study Group.Testosterone replacement therapy improves metabolic pa-rameters in hypogonadal men with type 2 diabetes but not inmen with coexisting depression: the BLAST study. J SexMed 2014;11:840-856.

164. Hackett G, Cole N, Bhartia M, et al; Blast Study Group. Theresponse to testosterone undecanoate in men with type 2diabetes is dependent on achieving threshold serum levels(the BLAST study). Int J Clin Pract 2014;68:203-215.

165. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadalsteroids and body composition, strength, and sexual functionin men. N Engl J Med 2013;369:1011-1022.

166. Shi MD, Chao JK, Ma MC, et al. Factors associated with sexhormones and erectile dysfunction in male Taiwanese par-ticipants with obesity. J Sex Med 2014;11:230-239.

167. García-Cruz E, Leibar-Tamayo A, Romero J, et al. Metabolicsyndrome in men with low testosterone levels: relationshipwith cardiovascular risk factors and comorbidities and witherectile dysfunction. J Sex Med 2013;10:2529-2538.

168. Hamidi Madani A, Heidarzadeh A, Akbari Parsa N, et al.A survey on relative frequency of metabolic syndrome andtestosterone deficiency in men with erectile dysfunction. IntUrol Nephrol 2012;44:667-672.

169. Kang J II, Ham BK, Oh MM, et al. Correlation between serumtotal testosterone and the AMS and IIEF questionnaires inpatients with erectile dysfunction with testosterone defi-ciency syndrome. Korean J Urol 2011;52:416-420.

170. Jacob BC. Testosterone replacement therapy in males witherectile dysfunction. J Pharm Pract 2011;24:298-306.

171. Morales A. Androgens are fundamental in the maintenanceof male sexual health. Curr Urol Rep 2011;12:453-460.

172. Saad F, Grahl AS, Aversa A, et al. Effects of testosterone onerectile function: implications for the therapy of erectiledysfunction. BJU Int 2007;99:988-992.

173. Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use inmen with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo ClinProc 2007;82:20-28.


174. Mitkov MD, Aleksandrova IY, Orbetzova MM. Effect oftransdermal testosterone or alpha-lipoic acid on erectiledysfunction and quality of life in patients with type 2 dia-betes mellitus. Folia Med (Plovdiv) 2013;55:55-63.

175. Allan CA, Forbes EA, Strauss BJ, et al. Testosterone therapyincreases sexual desire in ageing men with low-normaltestosterone levels and symptoms of androgen deficiency.Int J Impot Res 2008;20:396-401.

176. Isidori AM, Buvat J, Corona G, et al. A critical analysis of therole of testosterone in erectile function: from pathophysi-ology to treatment—a systematic review. Eur Urol 2014;65:99-112.

177. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al.Testosterone treatment and sexual function in older menwith low testosterone levels. J Clin Endocrinol Metab 2016;101:3096-3104.

178. Haider KS, Haider A, Doros G, et al. Long-term testosteronetherapy improves urinary and sexual function and quality oflife in men with hypogonadism: tesults from a propensity-matched subgroup of a controlled registry study. J Urol.https://doi.org/10.1016/j.juro2017.07.039. E-pub ahead ofprint.

179. O’Connell MD, Roberts SA, Srinivas-Shankar U, et al. Do theeffects of testosterone on muscle strength, physical func-tion, body composition, and quality of life persist six monthsafter treatment in intermediate-frail and frail elderly men?J Clin Endocrinol Metab 2011;96:454-458.

180. O’Connell MD, Tajar A, Roberts SA, et al. Do androgens playany role in the physical frailty of ageing men? Int J Androl2011;34:195-211.

181. O’Connell MD, Ravindrarajah R, Tajar A, et al. Low testos-terone in ageing men: a modifiable risk factor for frailty?Trends Endocrinol Metab 2011;22:491-498.

182. O’Connell MD, Wu FC. Androgen effects on skeletal muscle:implications for the development and management of frailty.Asian J Androl 2014;16:203-212.

183. Albert SG, Morley JE. Testosterone therapy, association withage, initiation and mode of therapy with cardiovascularevents: a systematic review. Clin Endocrinol (Oxf) 2016;85:436-443.

184. Corona G, Giagulli VA, Maseroli E, et al. Testosterone sup-plementation and body composition: results from a meta-analysis study. Eur J Endocrinol 2016;174:R99-R116.

185. Corona G, Giagulli VA, Maseroli E, et al. Testosterone sup-plementation and body composition: results from a meta-analysis of observational studies. J Endocrinol Invest2016;39:967-981.

186. Page ST, Amory JK, Bowman FD, et al. Exogenous testos-terone (T) alone or with finasteride increases physicalperformance, grip strength, and lean body mass in older menwith low serum T. J Clin Endocrinol Metab 2005;90:1502-1510.

187. Svartberg J, Agledahl I, Figenschau Y, et al. Testosteronetreatment in elderly men with subnormal testosterone levelsimproves body composition and BMD in the hip. Int J ImpotRes 2008;20:378-387.










































































https://doi.org/10.1016/j.juro2017.07.039



































16 Traish

188. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Ef-fect of testosterone supplementation on functional mobility,cognition, and other parameters in older men: a randomizedcontrolled trial. JAMA 2008;299:39-52.

189. Kenny AM, Kleppinger A, Annis K, et al. Effects of trans-dermal testosterone on bone and muscle in older men withlow bioavailable testosterone levels, low bone mass, andphysical frailty. J Am Geriatr Soc 2010;58:1134-1143.

190. Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testos-terone administration to older men improves muscle func-tion: molecular and physiological mechanisms. Am J PhysiolEndocrinol Metab 2002;282:E601-E607.

191. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effectsof testosterone on muscle strength, physical function, bodycomposition, and quality of life in intermediate-frail and frailelderly men: a randomized, double-blind, placebo-controlledstudy. J Clin Endocrinol Metab 2010;95:639-650.

192. Travison TG, Basaria S, Storer TW, et al. Clinical meaning-fulness of the changes in muscle performance and physicalfunction associated with testosterone administration in oldermen with mobility limitation. J Gerontol A Biol Sci Med Sci2011;66:1090-1099.

193. Kvorning T, Christensen LL, Madsen K, et al. Mechanicalmuscle function and lean body mass during supervisedstrength training and testosterone therapy in aging men withlow-normal testosterone levels. J Am Geriatr Soc 2013;61:957-962.

194. Dos Santos MR, Sayegh AL, Bacurau AV, et al. Effect ofexercise training and testosterone replacement on skeletalmuscle wasting in patients with heart failure with testos-terone deficiency. Mayo Clin Proc 2016;91:575-586.

195. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-actingtestosterone treatment on functional exercise capacity,skeletal muscle performance, insulin resistance, and baror-eflex sensitivity in elderly patients with chronic heart failure adouble-blind, placebo-controlled, randomized study. J AmColl Cardiol 2009;54:919-927.

196. Saad F, Yassin A, Doros G, et al. Effects of long-term treat-ment with testosterone on weight and waist size in 411hypogonadal men with obesity classes IeIII: observationaldata from two registry studies. Int J Obes (Lond) 2016;40:162-170.

197. Saad F,Yassin A, Haider A, et al. Elderly men over 65 years ofage with late-onset hypogonadism benefit as much fromtestosterone treatment as do younger men. Korean J Urol2015;56:310-317.

198. Saad F, Röhrig G, von Haehling S, et al. Testosterone defi-ciency and testosterone treatment in older men. Geron-tology 2017;63:144-156.

199. Francomano D, Bruzziches R, Barbaro G, et al. Effects oftestosterone undecanoate replacement and withdrawal oncardio-metabolic, hormonal and body composition outcomesin severely obese hypogonadal men: a pilot study.J Endocrinol Invest 2014;37:401-411.

200. Francomano D, Lenzi A, Aversa A. Effects of five-yeartreatment with testosterone undecanoate on metabolic and

hormonal parameters in ageing men with metabolic syn-drome. Int J Endocrinol 2014;2014:527470.

201. Baumgartner RN, Waters DL, Morley JE, et al. Age-relatedchanges in sex hormones affect the sex difference in serumleptin independently of changes in body fat. Metabolism1999;48:378-384.

202. von Haehling S, Morley JE, Anker SD. From muscle wastingto sarcopenia and myopenia: update 2012. J Cachexia Sar-copenia Muscle 2012;3:213-217.

203. Sinclair M, Grossmann M, Hoermann R, et al. Testosteronetherapy increases muscle mass in men with cirrhosis and lowtestosterone: a randomized controlled trial. J Hepatol 2016;65:906-913.

204. Ng Tang Fui M, Prendergast LA, Dupuis P, et al. Effects oftestosterone treatment on body fat and lean mass in obesemen on a hypocaloric diet: a randomised controlled trial.BMC Med 2016;14:153.

205. Ng Tang Fui M, Hoermann R, Prendergast LA, et al. Symp-tomatic response to testosterone treatment in dieting obesemen with low testosterone levels in a randomized, placebo-controlled clinical trial. Int J Obes 2017;41:420-426.

206. Magnussen LV, Glintborg D, Hermann P, et al. Effect oftestosterone on insulin sensitivity, oxidative metabolism andbody composition in aging men with type 2 diabetes onmetformin monotherapy. Diabetes Obes Metab 2016;18:980-989.

207. Bann D, Wu FC, Keevil B, et al. Changes in testosteronerelated to body composition in late midlife: findings from the1946 British birth cohort study. Obesity (Silver Spring)2015;23:1486-1492.

208. Morley JE, Perry HM III, Kaiser FE, et al. Effects of testos-terone replacement therapy in old hypogonadal males: apreliminary study. J Am Geriatr Soc 1993;41:149-152.

209. Morley JE. Androgens and aging. Maturitas 2001;38:61-71.

210. Corona G, Monami M, Rastrelli G, et al. Type 2 diabetesmellitus and testosterone: a meta-analysis study. Int JAndrol 2011;34:528-540.

211. Corona G, Monami M, Rastrelli G, et al. Testosterone andmetabolic syndrome: a meta-analysis study. J Sex Med2011;8:272-283.

212. Corona G, Isidori AM, Buvat J, et al. Testosterone supple-mentation and sexual function: a meta-analysis study. J SexMed 2014;11:1577-1592.

213. Carcaillon L, Blanco C, Alonso-Bouzón C, et al. Sex differ-ences in the association between serum levels of testos-terone and frailty in an elderly population: the Toledo Studyfor Healthy Aging. PLoS One 2012;7:e32401.

214. Eichholzer M, Barbir A, Basaria S, et al. Serum sex steroidhormones and frailty in older American men of the ThirdNational Health and Nutrition Examination Survey (NHANESIII). Aging Male 2012;15:208-215.

215. Mohr BA, Bhasin S, Kupelian V, et al. Testosterone, sexhormone-binding globulin, and frailty in older men. J AmGeriatr Soc 2007;55:548-555.


















































































































216. Hyde Z, Flicker L, Almeida OP, et al. Low free testosteronepredicts frailty in older men: the Health in Men Study. J ClinEndocrinol Metab 2010;95:3165-3172.

217. Tajar A, O’Connell MD, Mitnitski AB, et al; European MaleAging Study Group. Frailty in relation to variations in hor-mone levels of the hypothalamic-pituitary-testicular axis inolder men: results from the European Male Aging Study.J Am Geriatr Soc 2011;59:814-821.

218. Anaissie J, Roberts NH, Wang P, et al. Testosteronereplacement therapy and components of the metabolicsyndrome. Sex Med Rev 2017;5:200-210.

219. Snyder PJ, Kopperdahl DL, Stephen-Shields AJ, et al. Effectof testosterone treatment on volumetric bone density andstrength in older men with low testosterone. A controlledclinical trial. JAMA Int Med 2017;177:471-479.

220. Al Mukaddam M, Rajapakse CS, Bhagat YA, et al. Effects oftestosterone and growth hormone on the structural andmechanical properties of bone by micro-MRI in the distaltibia of men with hypopituitarism. J Clin Endocrinol Metab2014;99:1236-1244.

221. Wang C, Swerdloff RS, Iranmanesh A, et al. Effects oftransdermal testosterone gel on bone turnover markers andbone mineral density in hypogonadal men. Clin Endocrinol(Oxf) 2001;54:739-750.

222. Amory JK, Watts NB, Easley KA, et al. Exogenous testos-terone or testosterone with finasteride increases bone min-eral density in older men with low serum testosterone. J ClinEndocrinol Metab 2004;89:503-510.

223. Clarke BL, Khosla S. Androgens and bone. Steroids 2009;74:296-305.

224. Lee MJ, Ryu HK, An SY, et al. Testosterone replacement andbone mineral density in male pituitary tumor patients.Endocrinol Metab (Seoul) 2014;29:48-53.

225. Kacker R, Conners W, Zade J, et al. Bone mineral density andresponse to treatment in men younger than 50 years withtestosterone deficiency and sexual dysfunction or infertility.J Urol 2014;191:1072-1076.

226. Jo DG, Lee HS, Joo YM, et al. Effect of testosteronereplacement therapy on bone mineral density in patients withKlinefelter syndrome. Yonsei Med J 2013;54:1331-1335.

227. Haider A, Meergans U, Traish A, et al. Progressiveimprovement of t-scores in men with osteoporosis andsubnormal serum testosterone levels upon treatment withtestosterone over six years. Int J Endocrinol 2014;2014:496948.

228. Permpongkosol S, Khupulsup K, Leelaphiwat S, et al. Effectsof 8-year treatment of long-acting testosterone undeca-noate on metabolic parameters, urinary symptoms, bonemineral density, and sexual function in men with late-onsethypogonadism. J Sex Med 2016;13:1199-1211.

229. Traish AM, Guay AT. Are androgens critical for penile erec-tions in humans? Examining the clinical and preclinical evi-dence. J Sex Med 2006;3:382-404.

230. Traish AM, Park K, Dhir V, et al. Effects of castration andandrogen replacement on erectile function in a rabbit model.Endocrinology 1999;140:1861-1868.


231. Rogers RS, Graziottin TM, Lin CS, et al. Intracavernosalvascular endothelial growth factor (VEGF) injection andadeno-associated virus-mediated VEGF gene therapy pre-vents and reverse venogenic erectile dysfunction in rats. Int JImpot Res 2003;15:26-37.

232. Snyder PJ, Bhasin S, Cunningham GR, et al; TestosteroneTrials Investigators. Effects of testosterone treatment inolder men. N Engl J Med 2016;374:611-624.

233. Brock G, Heiselman D, Maggi M, et al. Effect of testosteronesolution 2% on testosterone concentration, sex drive andenergy in hypogonadal men: results of a placebo controlledstudy. J Urol 2016;195:699-705.

234. Brock G, Heiselman D, Knorr J, et al. 9-Month efficacy andsafety study of testosterone solution 2% for sex drive andenergy in hypogonadal men: results of a 6-month open-labelextension of a 3-month double-blind study. J Urol 2016;195:1509-1515.

235. Hackett G, Heald AH, Sinclair A, et al. Serum testosterone,testosterone replacement therapy and all-cause mortality inmen with type 2 diabetes: retrospective consideration of theimpact of PDE5 inhibitors and statins. Int J Clin Pract 2016;70:244-253.

236. Hackett G, Cole N, Saghir A, et al. Testosterone undecanoateimproves sexual function in men with type 2 diabetes andsevere hypogonadism: results from a 30-week randomizedplacebo-controlled study. BJU Int 2016;118:804-813.

237. Canguven O, Talib RA, El-Ansari W, et al. RigiScan data underlong-term testosterone therapy: improving long-term bloodcirculation of penile arteries, penile length and girth, erectilefunction, and nocturnal penile tumescence and duration.Aging Male 2016;19:215-220.

238. Tek M, Balli E, Cimen B, et al. The effect of testosteronereplacement therapy on bladder functions and histologyin orchiectomized mature male rats. Urology 2010;75:886-890.

239. Vignozzi L, Morelli A, Sarchielli E, et al. Testosterone protectsfrom metabolic syndrome-associated prostate inflammation:an experimental study in rabbit. J Endocrinol 2012;212:71-84.

240. Ko YH, Moon du G, Moon KH. Testosterone replacementalone for testosterone deficiency syndrome improves mod-erate lower urinary tract symptoms: one year follow-up.World J Mens Health 2013;31:47-52.

241. Kaplan SA, Lee JY, O’Neill EA, et al. Prevalence of lowtestosterone and its relationship to body mass index in oldermen with lower urinary tract symptoms associated withbenign prostatic hyperplasia. Aging Male 2013;16:169-172.

242. Chang IH, Oh SY, Kim SC. A possible relationship betweentestosterone and lower urinary tract symptoms in men.J Urol 2009;182:215-220.

243. Debruyne FM, Behre HM, Roehrborn CG, et al; RHYME In-vestigators. Testosterone treatment is not associated withincreased risk of prostate cancer or worsening of lowerurinary tract symptoms: prostate health outcomes in theRegistry of Hypogonadism in Men. BJU Int 2017;119:216-224.

















































































































18 Traish

244. Kalinchenko S, Vishnevskiy EL, Koval AN, et al. Beneficialeffects of testosterone administration on symptoms of thelower urinary tract in men with late-onset hypogonadism: apilot study. Aging Male 2008;11:57-61.

245. Shigehara K, Sugimoto K, Konaka H, et al. Androgenreplacement therapy contributes to improving lower urinarytract symptoms in patients with hypogonadism and benignprostate hypertrophy: a randomized controlled study. AgingMale 2011;14:53-58.

246. Amano T, Imao T, Takemae K, et al. Testosterone replace-ment therapy by testosterone ointment relieves lower urinarytract symptoms in late onset hypogonadism patients. AgingMale 2010;13:242-246.

247. Karazindiyano�glu S, Cayan S. The effect of testosteronetherapy on lower urinary tract symptoms/bladder and sexualfunctions in men with symptomatic late-onset hypogonad-ism. Aging Male 2008;11:146-149.

248. Koritsiadis G, Stravodimos K, Mitropoulos D, et al. Andro-gens and bladder outlet obstruction: a correlation withpressure-flow variables in a preliminary study. BJU Int2008;101:1542-1546.

249. Okada K, Miyake H, Ishida T, et al. Improved lower urinarytract symptoms associated with testosterone replacementtherapy in Japanese men with late-onset hypogonadism. AmJ Mens Health. pii:1557988316652843. E-pub ahead ofprint.

250. Ferrucci L, Maggio M, Bandinelli S, et al. Low testosteronelevels and the risk of anemia in older men and women. ArchIntern Med 2006;166:1380-1388.

251. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence ofanemia in persons 65 years and older in the United States:evidence for a high rate of unexplained anemia. Blood 2004;104:2263-2268.

252. Gaskell H, Derry S, Andrew Moore R, et al. Prevalence ofanaemia in older persons: systematic review. BMC Geriatr2008;8:1.

253. Röhrig G, Hörter M, Becker I, et al. Anemia prevalence andhematologic findings in German geriatric inpatients—resultsof the prospective cross-sectional multicenter study“GeriAnaemie2013”. Eur Geriatric Med 2016;7:328-332.

254. Röhrig G, Becker I, Schulz RJ, et al. Association betweenhematologic parameters and functional impairment amonggeriatric inpatients: data of a prospective cross-sectionalmulticenter study (“GeriPrävalenz2013”). Maturitas 2016;90:37-41.

255. Romero-Ruperto S, Pérez-Bocanegra MC, Duran-Taberna M,et al. Anemia in elderly patients admitted to an acute geri-atric ward. Rev Esp Geriatr Gerontol 2015;50:122-125.

256. Fukai S, Akishita M, Yamada S, et al. Association of plasmasex hormone levels with functional decline in elderly men andwomen. Geriatr Gerontol Int 2009;9:282-289.

257. Roy CN, Snyder PJ, Stephen-Shields AJ, et al. Association oftestosterone levels with anemia in older men. A controlledclinical trial. JAMA Int Med 2017;177:480-490.

258. Zhang LT, Shin YS, Kim JY, et al. Could testosteronereplacement therapy in hypogonadal men ameliorate anemia,

a cardiovascular risk factor? An observational, 54-week cu-mulative registry study. J Urol 2016;195:1057-1064.

259. Muraleedharan V, Marsh H, Kapoor D, et al. Testosteronedeficiency is associated with increased risk of mortality andtestosterone replacement improves survival in men with type2 diabetes. Eur J Endocrinol 2013;169:725-733.

260. Shores MM, Smith NL, Forsberg CW, et al. Testosteronetreatment and mortality in men with low testosterone levels.J Clin Endocrinol Metab 2012;97:2050-2058.

261. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardialinfarction in older men receiving testosterone therapy. AnnPharmacother 2014;48:1138-1144.

262. Sharma R, Oni OA, Gupta K, et al. Normalization of testos-terone level is associated with reduced incidence ofmyocardial infarction and mortality in men. Eur Heart J2015;36:2706-2715.

263. Anderson JL, May HT, Lappé DL, et al. Impact of testos-terone replacement therapy on myocardial infarction, stroke,and death in men with low testosterone concentrations in anintegrated health care system. Am J Cardiol 2016;117:794-799.

264. Cheetham TC, An J, Jacobsen SJ, et al. Association oftestosterone replacement with cardiovascular outcomesamong men with androgen deficiency. JAMA Intern Med2017;177:491-499.

265. Yeap BB, Alfonso H, Chubb SA, et al. In older men, anoptimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone withreduced ischemic heart disease mortality, while estradiollevels do not predict mortality. J Clin Endocrinol Metab2014;99:E9-E18.

266. Amanatkar HR, Chibnall JT, Seo BW, et al. Impact of exog-enous testosterone on mood: a systematic review and meta-analysis of randomized placebo-controlled trials. Ann ClinPsychiatry 2014;26:19-32.

267. Pexman-Fieth C, Behre HM, Morales A, et al. A 6-monthobservational study of energy, sexual desire, and body pro-portions in hypogonadal men treated with a testosterone 1%gel. Aging Male 2014;17:1-11.

268. Khera M. Male hormones and men’s quality of life. Curr OpinUrol 2016;26:152-157.

269. Kim C, Barrett-Connor E, Aroda VR, et al; Diabetes Pre-vention Program Research Group. Testosterone anddepressive symptoms among men in the Diabetes Preven-tion Program. Psychoneuroendocrinology 2016;72:63-71.

270. Ford AH, Yeap BB, Flicker L, et al. Prospective longitudinalstudy of testosterone and incident depression in older men:the Health in Men Study. Psychoneuroendocrinology 2016;64:57-65.

271. Westley CJ, Amdur RL, Irwig MS. High rates of depressionand depressive symptoms among men referred for border-line testosterone levels. J Sex Med 2015;12:1753-1760.

272. Wahjoepramono EJ, Asih PR, Aniwiyanti V, et al. The effectsof testosterone supplementation on cognitive functioningin older men. CNS Neurol Disord Drug Targets 2016;15:337-343.
















































































































273. Jockenhövel F, Minnemann T, Schubert M, et al. Comparisonof long-acting testosterone undecanoate formulation versustestosterone enanthate on sexual function and mood inhypogonadal men. Eur J Endocrinol 2009;160:815-819.

274. Zitzmann M, Mattern A, Hanisch J, et al. IPASS: a study onthe tolerability and effectiveness of injectable testosteroneundecanoate for the treatment of male hypogonadism in aworldwide sample of 1,438 men. J Sex Med 2013;10:579-588.

275. Shores MM, Sloan KL, Matsumoto AM, et al. Increasedincidence of diagnosed depressive illness in hypogonadalolder men. Arch Gen Psychiatry 2004;61:162-167.

276. Shores MM, Moceri VM, Sloan KL, et al. Low testosteronelevels predict incident depressive illness in older men: effectsof age and medical morbidity. J Clin Psychiatry 2005;66:7-14.

277. Seidman SN. The aging male: androgens, erectile dysfunc-tion, and depression. J Clin Psychiatry 2003;64(Suppl):31-37.

278. Nian Y, Ding M, Hu S, et al. Testosterone replacementtherapy improves health-related quality of life for patientswith late-onset hypogonadism: a meta-analysis of random-ized controlled trials. Andrologia. https://doi.org/10.1111/and.12630. E-pub ahead of print.

279. Morley JE, Kaiser FE, Sih R, et al. Testosterone and frailty.Clin Geriatr Med 1997;13:685-695.

280. Meier C, Nguyen TV, Handelsman DJ, et al. Endogenous sexhormones and incident fracture risk in older men: the DubboOsteoporosis Epidemiology Study. Arch Intern Med 2008;168:47-54.

281. De Rosa M, Paesano L, Nuzzo V, et al. Bone mineral densityand bone markers in hypogonadotropic and hyper-gonadotropic hypogonadal men after prolonged testosteronetreatment. J Endocrinol Invest 2001;24:246-252.

282. Leifke E, Körner HC, Link TM, et al. Effects of testosteronereplacement therapy on cortical and trabecular bone mineraldensity, vertebral body area and paraspinal muscle area inhypogonadal men. Eur J Endocrinol 1998;138:51-58.

283. Wang C, Alexander G, Berman N, et al. Testosteronereplacement therapy improves mood in hypogonadal men—aclinical research center study. J Clin Endocrinol Metab 1996;81:3578-3583.

284. McNicholas TA, Dean JD, Mulder H, et al. A novel testos-terone gel formulation normalizes androgen levels in hypo-gonadal men, with improvements in body composition andsexual function. BJU Int 2003;91:69-74.

285. Steidle C, Schwartz S, Jacoby K, et al; North AmericanAA2500 T Gel Study Group. AA2500 testosterone gelnormalizes androgen levels in aging males with improve-ments in body composition and sexual function. J ClinEndocrinol Metab 2003;88:2673-2681.

286. Lunenfeld B, Nieschlag E. Testosterone therapy in the agingmale. Aging Male 2007;10:139-153.

287. Cohen A, Lapin B, Wang CH, et al. Variation in testosteronelevels and health-related quality of life in men diagnosed with


prostate cancer on active surveillance. Urology 2016;94:180-187.

288. Brooke JC, Walter DJ, Kapoor D, et al. Testosterone defi-ciency and severity of erectile dysfunction are independentlyassociated with reduced quality of life in men with type 2diabetes. Andrology 2014;2:205-211.

289. Gooren LJ, Behre HM. Diagnosing and treating testosteronedeficiency in different parts of the world: changes between2006 and 2010. Aging Male 2012;15:22-27.

290. Huggins C, Hodges CV. Studies on prostatic cancer I. Theeffect of castration, of estrogen and of androgen injection onserum phosphatases in metastatic carcinoma of the pros-tate. Cancer Res 1941;1:293-297.

291. Huggins CB, Stevens RB, Hodges CV. The effects ofcastration on advanced carcinoma of the prostate gland.Arch Surg 1941;43:209.

292. Roddam AW, Allen NE, Appleby P, et al. Endogenous sexhormones and prostate cancer: a collaborative analysis of 18prospective studies. Endogenous Hormones and ProstateCancer Collaborative Group. J Natl Cancer Inst 2008;100:170-183.

293. Muller RL, Gerber L, Moreira DM, et al. Serum testosteroneand dihydrotestosterone and prostate cancer risk in theplacebo arm of the Reduction by Dutasteride of ProstateCancer Events trial. Eur Urol 2012;62:757-764.

294. Schenk JM, Till C, Hsing AW, et al. Serum androgens andprostate cancer risk: results from the placebo arm of theProstate Cancer Prevention Trial. Cancer Causes Control2016;27:175-182.

295. Morgentaler A, Traish AM. Shifting the paradigm of testos-terone and prostate cancer: the saturation model and thelimits of androgen-dependent growth. Eur Urol 2009;55:310-320.

296. Morgentaler A. Turning conventional wisdom upside-down:low serum testosterone and high-risk prostate cancer.Cancer 2011;117:3885-3888.

297. Khera M. Testosterone replacement in men with treated anduntreated prostate cancer. Sex Med Rev 2013;1:143-149.

298. Morgentaler A, Lipshultz LI, Bennett R, et al. Testosteronetherapy in men with untreated prostate cancer. J Urol 2011;185:1256-1260.

299. Morgentaler A. Goodbye androgen hypothesis, hello satura-tion model. Eur Urol 2012;62:765-767.

300. Morgentaler A. Testosterone therapy in men with prostatecancer: scientific and ethical considerations. J Urol 2013;189(Suppl):S26-S33.

301. Morgentaler A. Testosterone therapy can be given to menwith no concern that it will promote prostate cancer devel-opment or progression: pro. J Urol 2016;196:985-988.

302. Cui Y, Zong H, Yan H, et al. The effect of testosteronereplacement therapy on prostate cancer: a systematic reviewand meta-analysis. Prostate Cancer Prostat Dis 2014;17:132-143.




















https://doi.org/10.1111/and.12630

https://doi.org/10.1111/and.12630






















































































20 Traish

303. Baillargeon J, Kuo YF, Fang X, et al. Long-term exposure totestosterone therapy and the risk of high grade prostatecancer. J Urol 2015;194:1612-1616.

304. Haider A, Zitzmann M, Doros G, et al. Incidence of prostatecancer in hypogonadal men receiving testosterone therapy:observations from 5-year median followup of 3 registries.J Urol 2015;193:80-86.

305. Wallis CJ, Lo K, Lee Y, et al. Survival and cardiovascularevents in men treated with testosterone replacement ther-apy: an intention-to-treat observational cohort study. LancetDiabetes Endocrinol 2016;4:498-506.

306. Khera M, Crawford D, Morales A, et al. A new era oftestosterone and prostate cancer: from physiology to clinicalimplications. Eur Urol 2014;65:115-123.

307. Nguyen TM, Pastuszak AW. Testosterone therapy amongprostate cancer survivors. Sex Med Rev 2016;4:376-388.

308. Pastuszak AW, Khanna A, Badhiwala N, et al. Testosteronetherapy after radiation therapy for low, intermediate and highrisk prostate cancer. J Urol 2015;194:1271-1276.

309. Balbontin FG, Moreno SA, Bley E, et al. Long-actingtestosterone injections for treatment of testosterone defi-ciency after brachytherapy for prostate cancer. BJU Int 2014;114:125-130.

310. Basaria S, Coviello AD, Travison TG, et al. Adverse eventsassociated with testosterone administration. N Engl J Med2010;363:109-122.

311. Vigen R, O’Donnell CI, Barón AE, et al. Association oftestosterone therapy with mortality, myocardial infarction,and stroke in men with low testosterone levels. JAMA 2013;310:1829-1836 [erratum: JAMA 2014;311:967].

312. Traish AM, Guay AT, Morgentaler A. Death by testosterone?We think not! J Sex Med 2014;11:624-629.

313. Morgentaler A,Traish A, Kacker R. Deaths and cardiovascularevents in men receiving testosterone. JAMA 2014;311:961-962.

314. Morgentaler A. Testosterone, cardiovascular risk, and hor-monophobia. J Sex Med 2014;11:1362-1366.

315. Morgentaler A, Lunenfeld B. Testosterone and cardiovascularrisk: world’s experts take unprecedented action to correctmisinformation. Aging Male 2014;17:63-65.

316. Morgentaler A, Kacker R. Andrology: testosterone and car-diovascular risk—deciphering the statistics. Nat Rev Urol2014;11:131-132.

317. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk ofnon-fatal myocardial infarction following testosterone ther-apy prescription in men. PLoS One 2014;9:e85805.

318. Hackett G. The Graham Jackson Memorial Lecture ISSM2016—“The Man Who Knew Too Much”: time to recognizeerectile dysfunction and low testosterone as independentrisk factors for cardiovascular disease. Sex Med Rev 2017;5:256-265.

319. Shores MM, Matsumoto AM. Testosterone, aging and sur-vival: biomarker or deficiency. Curr Opin Endocrinol Dia-betes Obes 2014;21:209-216.

320. Shores MM, Biggs ML, Arnold AM, et al. Testosterone,dihydrotestosterone, and incident cardiovascular disease andmortality in the cardiovascular health study. J Clin Endo-crinol Metab 2014;99:2061-2068.

321. Muraleedharan V, Jones TH. Testosterone and mortality. ClinEndocrinol (Oxf) 2014;81:477-487.

322. Sharma R, Oni OA, Gupta K, et al. Normalization of testos-terone levels after testosterone replacement therapy isassociated with decreased incidence of atrial fibrillation.J Am Heart Assoc 2017;6:e004880.

323. Baillargeon J, Urban RJ, Morgentaler A, et al. Risk of venousthromboembolism in men receiving testosterone therapy.Mayo Clin Proc 2015;90:1038-1045.

324. Kloner RA. Testosterone and cardiovascular health: safety oftreatment of hypogonadism. Sex Med Rev 2015;3:56-62.

325. Tan RS, Cook KR, Reilly WG. Myocardial infarction and strokerisk in young healthy men treated with injectable testos-terone. Int J Endocrinol 2015;2015:970750.

326. Etminan M, Skeldon SC, Goldenberg SL, et al. Testosteronetherapy and risk of myocardial infarction: a pharmacoepide-miologic study. Pharmacotherapy 2015;35:72-78.

327. Hanske J,Von Landernberg N, Gild P, et al. Adverse effects oftestosterone replacement therapy for men, a matched cohortstudy. Eur Urol 2017;16(Suppl):e448.

328. Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy andcardiovascular events among men: a systematic review andmeta-analysis of placebo-controlled randomized trials. BMCMed 2013;11:108.

329. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosteronetreatment and coronary artery plaque volume in older menwith low testosterone. JAMA 2017;317:708-716.

330. Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al.Testosterone treatment and cognitive function in older menwith low testosterone and age-associated memory impair-ment. JAMA 2017;317:717-727.

331. Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular riskassociated with testosterone-boosting medications: a sys-tematic review and meta-analysis. Expert Opin Drug Saf2014;13:1327-1351.

332. Onasanya O, Iyer G, Lucas E, et al. Association betweenexogenous testosterone and cardiovascular events: anoverview of systematic reviews. Lancet Diabetes Endocrinol2016;4:943-956.

333. Carruthers M, Trinick TR, Jankowska E, Traish AM. Are theadverse effects of glitazones linked to induced testosteronedeficiency? Cardiovasc Diabetol 2008;7:30.





































































































http://refhub.elsevier.com/S2050-0521(17)30119-1/serf333



Documents

Benefits and Health Implications of Testosterone Therapy ... 2017... · erectile dysfunction, and increased incidence of mortality (for Received August 17, 2017. ... Adverse Effects