Mirjam Christ-Crain Endokrinologie

TESTOSTERON

MirjamChrist-CrainEndokrinologie

EntwicklungderTestosteronsubs>tu>on

Laytonetal.JCEM2014

Laytonetal.JCEM2014

Therapieo@bei“normalen”Werten

Mittwoch, 29. März 2017

«Testosteronetherapyispopular,butstudiesaremixed»NewYork8mes,29.März2017

¨  67-jährigerPa>ent,BMI26¨  Anamnese:AbnahmederLibido,Müdigkeit,wenigerEnergie

¨  PersönlicheAnamnese:arterielleHypertonieKHKmitSt.n.Myokardinfarktvor3Jahren

¨  TotalesTestosteron8.9nmol/L(Referenz12-29)¨  LH2.9(1.7-8.6),FSH3.7(1.5-12.4)U/L

KlinischerFall

WaswürdenSietun?

EdiVoteStart EdiVoteStop

030 000

Standard

1.  BehandlungmitTestosteron

2.  KeineBehandlungmitTestosteron

50%

50%

Übersicht

¨  PhysiologievonTestosteron¨  Wenabklären?¨  Wasundwannmessen?¨  PrimärerundsekundärerHypogonadismus¨  Par>alandrogendeficiencyoftheagingmale(PADAM)

¨  Testosterontherapie

Spermien

Hypothalamus

GnRH

Hypophyse

FSHLHTestosteron

Tes>s

TestosteronWirkungauf:

Haare,Haut,KnochenMuskulatur,Femgewebe

VerhaltenSexualfunk>on

PhysiologievonTestosteron

80% 15-20%

2%

SHBGgebundenesTAlbumingebundenesT

FreiesT

BioverfügbaresT

TestosteronimPlasma

4

5

6

7

8

4 8 12 16 20 24

JungeMänner(mean25J.)

ÄltereMänner(mean70J.)

Tageszeit

Testosteron(nmol/l)

Bremneretal,JClinEndocrinolMetab1983;56:1278

12

16

20

24

28

ZirkadianeRhythmikvonTestosteron

Sugges>veSymptome:•  Libidomangel,verminderteSpontanerek8onen•  Gynäkomas8e•  ReduzierteKörperbehaarung&Rasurhäufigkeit•  Hodenvolumen<5ml,Infer>lität•  Osteopenie/Osteoporose,FrakturenWeiterewenigerspezifischeSymptome•  AbnahmevonEnergie,Mo8va8on,Ini8a8ve•  DepressiveS>mmung,Konzentra8onsstörungen•  Schlafstörungen,Müdigkeit•  MildeAnämie•  AbnahmevonMuskelmasse-undKra@,ZunahmederFe\masse

Wenabklären?Symptome

Christ-Crain et al. Swiss Med Wkly 04

Wasundwannmessen?Screening: TotalesTestosteron,morgens,2x

ReferenzbereichejenachLabor

FreiesTestosteron:Wannnö>g:WennSHBG↓↑(v.a.Adipositas)Wie:-Goldstandard:EquilibriumDialyse-DirekteMessunginRou>nelabors:→unzuverlässigundnichtempfohlen

-FreiesTestosteronberechnen:MessenvontotalemTestosteron,Albumin,SHBG;FormelnachVermeulen:

zB.www.labor-limbach.de

TotalesTestosteron2xmorgens↓

LH

Prim.Hypogonadismus

LH↑

SekundärerHypogonadismus

LH⇔-↓

AbklärungHypogonadismus

DD

• Klinefelter(XXY):eunychoider&gynoiderHabitus,Tes>s<8ml,infer>l,Pubertastarda

• Hodenschädigung:DDorchi>s,trauma,Radiotherapie,Chemotherapy,Kryptorchismus

PrimärerHypogonadismus

DD

• Prolak>nom

• HypophysenmakroadenommitHypopituitarismus

SekundärerHypogonadismus

LH

Prim.Hypogonadismus

KlinefelterSyndrom,Hodenschädigung

LH↑

Prolak>nom,Hypophysen-makroadenom

Sek.Hypogonadismus

LH⇔-↓

TestosteronSubs>tu>on

Hypogonadismus(T2xmorgens↓)

Hypogonadismus

Hypogonadismus(T↓)

LH

Prim.Hypogonadismus

LH↑

Sek.Hypogonadismus

LH⇔-↓

PADAM(par>alandrogendeficiencyoftheagingmale)

?

Hypogonadismus

Alter Alter

Frauen Männer

Menopausevs.“Andropause

Muskelmasse↓

Fem↑

Konzentra>on,S>mmung↓

Libido↓ErektDysfunk>on

Knochendichte↓

Yesterday,allthosetroublesseemedsofaraway…..

Gynäkomas>e

TESTOSTERON UNTERSTÜTZT LANGFRISTIG DEN ABBAU DER FETTMASSE

Srinivas-Shankaretal.,JCEM2010

BenefitseinerTestosteronbehandlung:MuskelmasseundMuskelkra@

SnyderPetal.JAMAintmed2017

BenefitseinerTestosteronbehandlung:Knochendichte

n engl j med 374;7 nejm.org February 18, 2016616

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

to report that their energy was better at the end of the trial (P<0.001) (Fig. S4 in the Supplemen-tary Appendix).

All TrialsSensitivity analyses of the primary outcomes did not suggest that missing values affected any conclusions appreciably (Table S3 in the Supple-mentary Appendix). We found no significant interactions of treatment with age (P values ranged from 0.45 to 0.78 in the three trials), body-mass index (P values ranged from 0.35 to 0.85), or race (P values ranged from 0.49 to 0.72).

Adverse EventsAlthough more men assigned to testosterone than those assigned to placebo had an incre-ment in the PSA level of 1.0 ng per milliliter or more during the treatment period (23 vs. 8), only 1 man (in the testosterone group) received a di-agnosis of prostate cancer during that time. Two men in the testosterone group and 1 in the pla-cebo group received a diagnosis during the sub-sequent year (Table 4, and Table S4 in the Sup-plementary Appendix). The change in the IPSS did not differ significantly between the two groups. A hemoglobin level of 17.5 g per deciliter or more was observed in 7 men in the testoster-one group and none in the placebo group.

Seven men in each study group were adjudi-cated to have had major cardiovascular events (myocardial infarction, stroke, or death from car-diovascular causes) during the treatment period and two men in the testosterone group and nine men in the placebo group were adjudicated to have had major cardiovascular events during the subsequent year (Table 4, and Table S4 in the Supplementary Appendix). There was no pattern

Figure 1. Primary Outcomes in the Three Main Trials of the Testosterone Trials.

The primary outcome of the Sexual Function Trial (Panel A) was the change from baseline in the score for sexual activity (question 4) on the Psychosexual Daily Questionnaire (PDQ-Q4; range, 0 to 12, with higher scores indicating more activity). The primary outcome of the Physical Function Trial (Panel B) was the percentage of men who had an increase of at least 50 m in the distance walked during the 6-minute walk test. The primary outcome of the Vitality Trial (Panel C) was the percentage of men who had an increase of at least 4 points in the score on the Functional Assess-ment of Chronic Illness Therapy (FACIT)–Fatigue scale (range, 0 to 52, with higher scores indicating less fatigue). P values were calculated with the use of a linear random-effects model for sexual activity and logistic random-effects models for walking ability and vitality. The I bars represent standard deviations.

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The New England Journal of Medicine Downloaded from nejm.org on April 2, 2017. For personal use only. No other uses without permission.

Copyright © 2016 Massachusetts Medical Society. All rights reserved.

Snjderetal.,NEnglJMed2016Cunninghametal.,JCEM2016

culating total T, free T, and estradiol levels. We were notable to demonstrate T threshold levels for the sexual func-tion outcomes.

These data are consistent with those from a recentlyreported trial of men with low sexual desire (85% of men)or decreased energy and low T levels, which reported sig-nificantly greater improvements in self-reported sex drive,erectile function, and sexual activity with T administra-tion than with placebo; unlike the TTrials, this trial in-cluded much younger men who had a mean age of 55.3years (13). Similar instruments were used in both trials toassess erectile function and sexual activity, and outcomeswere similar. In both trials, T treatment improved sexualdesire, erectile function, and sexual activity at 3 months,

and in our trial it was sustained forthe 12 months of treatment (21). TheTestosterone Effects on Atheroscle-rosis in Aging Men Trial did not finda significant difference in the changein erectile function, sexual desire, orpartner intimacy in men with a meanage of 66.9 ! 5.0 years and low nor-mal T levels, who were not selectedon the basis of sexual symptoms(12). Taken together, these data sug-gest that T therapy improves sexualdesire, erectile function, and overallsexual activity in younger and oldermen with low libido and low T levels.

The consistency of the effects of Ton multiple domains of sexual func-tion—sexual desire, erectile function,andoverallsexualactivity—assessedus-ing a number of self-reported instru-ments, is noteworthy. Additionally,the consistent improvements ob-served with T treatment on 10 of 12measures of sexual activity is impor-tant and is supportive of the benefi-cial effects of T on sexual function inolder men with low T levels.

The clinical significance of thesefindings is supported by the treat-ment effects and effect sizes on sex-ual outcomes and the change in dailysexual activities. We previously re-ported that sexual activity, theprimary outcome of the Sexual Func-tion Trial as measured by summa-tion of 12 components of PDQ-Q4,showed a treatment effect of 0.58(95% CI 0.38, 0.78; P " .001) andan effect size of 0.45 (95% CI 0.30,

0.60) (21). T treatment had a treatment effect of 2.93(95% CI 2.13, 3.74; P " .001) and an effect size of 0.44(95% CI 0.32, 0.56) on sexual desire and a treatmenteffect of 2.64 (95% CI 1.68, 3.61; P " .001) and an effectsize of 0.32 (95% CI 0.20,0.44) on erectile function (21).Effect sizes of 0.5 are generally considered to indicate amoderate effect, whereas an effect of 0.2 is consideredsmall. Although significant, the effect on erectile functionis more modest than the 5.7 point increase in EFD scoresobserved when men 60 and older were treated with silde-nafil (34). The global impression of change in sexual desirealso was significantly improved (P " .001). Figure 2B doc-uments that men in the T group had increases in 10 of 12measurements of daily sexual activities.

A

BFigure 2. A, Forest plots showing the effect of treatment on each item of the PDQ-Q4. B,Average daily frequency of each item of the PDQ-Q4 by treatment group.

doi: 10.1210/jc.2016-1645 press.endocrine.org/journal/jcem 3101

BenefitseinerTestosteronbehandlung:Sexualfunk>on

BenefiteinerTestosteronbehandlung:Vitalität,Müdigkeit?

n engl j med 374;7 nejm.org February 18, 2016616

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

to report that their energy was better at the end of the trial (P<0.001) (Fig. S4 in the Supplemen-tary Appendix).

All TrialsSensitivity analyses of the primary outcomes did not suggest that missing values affected any conclusions appreciably (Table S3 in the Supple-mentary Appendix). We found no significant interactions of treatment with age (P values ranged from 0.45 to 0.78 in the three trials), body-mass index (P values ranged from 0.35 to 0.85), or race (P values ranged from 0.49 to 0.72).

Adverse EventsAlthough more men assigned to testosterone than those assigned to placebo had an incre-ment in the PSA level of 1.0 ng per milliliter or more during the treatment period (23 vs. 8), only 1 man (in the testosterone group) received a di-agnosis of prostate cancer during that time. Two men in the testosterone group and 1 in the pla-cebo group received a diagnosis during the sub-sequent year (Table 4, and Table S4 in the Sup-plementary Appendix). The change in the IPSS did not differ significantly between the two groups. A hemoglobin level of 17.5 g per deciliter or more was observed in 7 men in the testoster-one group and none in the placebo group.

Seven men in each study group were adjudi-cated to have had major cardiovascular events (myocardial infarction, stroke, or death from car-diovascular causes) during the treatment period and two men in the testosterone group and nine men in the placebo group were adjudicated to have had major cardiovascular events during the subsequent year (Table 4, and Table S4 in the Supplementary Appendix). There was no pattern

Figure 1. Primary Outcomes in the Three Main Trials of the Testosterone Trials.

The primary outcome of the Sexual Function Trial (Panel A) was the change from baseline in the score for sexual activity (question 4) on the Psychosexual Daily Questionnaire (PDQ-Q4; range, 0 to 12, with higher scores indicating more activity). The primary outcome of the Physical Function Trial (Panel B) was the percentage of men who had an increase of at least 50 m in the distance walked during the 6-minute walk test. The primary outcome of the Vitality Trial (Panel C) was the percentage of men who had an increase of at least 4 points in the score on the Functional Assess-ment of Chronic Illness Therapy (FACIT)–Fatigue scale (range, 0 to 52, with higher scores indicating less fatigue). P values were calculated with the use of a linear random-effects model for sexual activity and logistic random-effects models for walking ability and vitality. The I bars represent standard deviations.

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The New England Journal of Medicine Downloaded from nejm.org on April 2, 2017. For personal use only. No other uses without permission.

Copyright © 2016 Massachusetts Medical Society. All rights reserved.

Snjderetal.,NEnglJMed2016

KeinBenefiteinerTestosteronbehandlung:Vitalität,Müdigkeit

n engl j med 374;7 nejm.org February 18, 2016616

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

to report that their energy was better at the end of the trial (P<0.001) (Fig. S4 in the Supplemen-tary Appendix).

All TrialsSensitivity analyses of the primary outcomes did not suggest that missing values affected any conclusions appreciably (Table S3 in the Supple-mentary Appendix). We found no significant interactions of treatment with age (P values ranged from 0.45 to 0.78 in the three trials), body-mass index (P values ranged from 0.35 to 0.85), or race (P values ranged from 0.49 to 0.72).

Adverse EventsAlthough more men assigned to testosterone than those assigned to placebo had an incre-ment in the PSA level of 1.0 ng per milliliter or more during the treatment period (23 vs. 8), only 1 man (in the testosterone group) received a di-agnosis of prostate cancer during that time. Two men in the testosterone group and 1 in the pla-cebo group received a diagnosis during the sub-sequent year (Table 4, and Table S4 in the Sup-plementary Appendix). The change in the IPSS did not differ significantly between the two groups. A hemoglobin level of 17.5 g per deciliter or more was observed in 7 men in the testoster-one group and none in the placebo group.

Seven men in each study group were adjudi-cated to have had major cardiovascular events (myocardial infarction, stroke, or death from car-diovascular causes) during the treatment period and two men in the testosterone group and nine men in the placebo group were adjudicated to have had major cardiovascular events during the subsequent year (Table 4, and Table S4 in the Supplementary Appendix). There was no pattern

Figure 1. Primary Outcomes in the Three Main Trials of the Testosterone Trials.

The primary outcome of the Sexual Function Trial (Panel A) was the change from baseline in the score for sexual activity (question 4) on the Psychosexual Daily Questionnaire (PDQ-Q4; range, 0 to 12, with higher scores indicating more activity). The primary outcome of the Physical Function Trial (Panel B) was the percentage of men who had an increase of at least 50 m in the distance walked during the 6-minute walk test. The primary outcome of the Vitality Trial (Panel C) was the percentage of men who had an increase of at least 4 points in the score on the Functional Assess-ment of Chronic Illness Therapy (FACIT)–Fatigue scale (range, 0 to 52, with higher scores indicating less fatigue). P values were calculated with the use of a linear random-effects model for sexual activity and logistic random-effects models for walking ability and vitality. The I bars represent standard deviations.

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P=0.30

No. at RiskTestosteronePlacebo

236238

219207

217196

206188

203191

Testosterone

Placebo

The New England Journal of Medicine Downloaded from nejm.org on April 2, 2017. For personal use only. No other uses without permission.

Copyright © 2016 Massachusetts Medical Society. All rights reserved.

Snjderetal.,NEnglJMed2016

Copyright 2017 American Medical Association. All rights reserved.

Testosterone Treatment and Cognitive Function in Older MenWith Low Testosterone and Age-Associated Memory ImpairmentSusan M. Resnick, PhD; Alvin M. Matsumoto, MD; Alisa J. Stephens-Shields, PhD; Susan S. Ellenberg, PhD; Thomas M. Gill, MD;Sally A. Shumaker, PhD; Debbie D. Pleasants, MEd; Elizabeth Barrett-Connor, MD; Shalender Bhasin, MD; Jane A. Cauley, DrPH;David Cella, PhD; Jill P. Crandall, MD; Glenn R. Cunningham, MD; Kristine E. Ensrud, MD, MPH; John T. Farrar, MD, PhD;Cora E. Lewis, MD, MPH; Mark E. Molitch, MD; Marco Pahor, MD; Ronald S. Swerdloff, MD; Denise Cifelli, MS; Stephen Anton, PhD;Shehzad Basaria, MD; Susan J. Diem, MD, MPH; Christina Wang, MD; Xiaoling Hou, MS; Peter J. Snyder, MD

IMPORTANCE Most cognitive functions decline with age. Prior studies suggest thattestosterone treatment may improve these functions.

OBJECTIVE To determine if testosterone treatment compared with placebo is associated withimproved verbal memory and other cognitive functions in older men with low testosteroneand age-associated memory impairment (AAMI).

DESIGN, SETTING, AND PARTICIPANTS The Testosterone Trials (TTrials) were 7 trials to assessthe efficacy of testosterone treatment in older men with low testosterone levels. TheCognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 USacademic medical centers, 788 men who were 65 years or older with a serum testosteronelevel less than 275 ng/mL and impaired sexual function, physical function, or vitality wereallocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 menmet criteria for AAMI based on baseline subjective memory complaints and objectivememory performance. Enrollment in the TTrials began June 24, 2010; the final participantcompleted treatment and assessment in June 2014.

INTERVENTIONS Testosterone gel (adjusted to maintain the testosterone level within thenormal range for young men) or placebo gel for 1 year.

MAIN OUTCOMES AND MEASURES The primary outcome was the mean change from baselineto 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among menwith AAMI. Secondary outcomes were mean changes in visual memory (Benton VisualRetention Test; score range, 0 to −26), executive function (Trail-Making Test B minus A;range, −290 to 290), and spatial ability (Card Rotation Test; score range, −80 to 80) amongmen with AAMI. Tests were administered at baseline, 6 months, and 12 months.

RESULTS Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baselinetestosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 toreceive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebocompleted the memory study. There was no significant mean change from baseline to 6 and 12months in delayed paragraph recall score among men with AAMI in the testosterone and placebogroups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88). Mean scores fordelayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in thetestosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebogroup. Testosterone was also not associated with significant differences in visual memory (−0.28[95% CI, −0.76 to 0.19]; P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = .14), orspatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = .89).

CONCLUSIONS AND RELEVANCE Among older men with low testosterone and age-associatedmemory impairment, treatment with testosterone for 1 year compared with placebo was notassociated with improved memory or other cognitive functions.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00799617

JAMA. 2017;317(7):717-727. doi:10.1001/jama.2016.21044

Editorial page 699

Author Video Interview andJAMA Report Video

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Related articles atjamainternalmedicine.com

Author Affiliations: Authoraffiliations are listed at the end of thisarticle.

Corresponding Author: Peter J.Snyder, MD, Division ofEndocrinology, Diabetes, andMetabolism, Perelman School ofMedicine, University of Pennsylvania,3400 Civic Center Blvd, Philadelphia,PA 19104 (pjs@mail.med.upenn.edu).

Research

JAMA | Original Investigation

(Reprinted) 717

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A ging is associated with declines in some cognitive func-tions, including verbal and visual memory, executivefunction, and spatial ability.1-3 Aging in men is also as-

sociated with a reduction in serum testosterone,4,5 raising thepossibility that reduced circulating testosterone concentra-tion may contribute to age-related cognitive decline. Supportfor this hypothesis comes from studies of clinical conditionsthat cause low testosterone levels,6,7 epidemiologicalinvestigations,8,9 and small randomized trials showing im-proved memory with testosterone supplementation.10 To-gether, these studies suggest that lower testosterone levels maybe associated with poorer cognitive functioning in older menand that testosterone treatment may improve cognitive func-tioning, especially memory.

An Institute of Medicine panel11 recommended investigat-ing the effects of testosterone treatment on conditions, includ-ing cognitive impairment, that might be caused by the decreasein testosterone. Men with age-associated memory impairment(AAMI) represent a clinically important group at risk for devel-oping more severe memory impairment (eg, mild cognitive im-pairment and dementia)12 for whom testosterone interventionmay be beneficial. AAMI is defined by subjective complaintsof memory decline and scores at least 1 SD below the mean foryoung adults on objective memory testing.13 A large percent-age of community-dwelling older adults meets these criteria.14

The Cognitive Function Trial determined the efficacy oftestosterone treatment on cognitive outcomes among oldermen enrolled in the Testosterone Trials (TTrials) with low tes-tosterone likely due to age.15 The primary hypothesis of theCognitive Function Trial was that testosterone treatment for1 year would improve or slow decline in verbal memory in thesubgroup of men 65 years or older with an average testoste-rone level of less than 275 ng/dL and AAMI. Secondary aimswere to determine if testosterone treatment affects other cog-nitive functions in these men with AAMI, and exploratory aimswere to determine the effect of testosterone treatment on cog-nitive function in all men in the TTrials.

MethodsStudy DesignThe TTrials are a coordinated set of 7 double-blind, placebo-controlled trials conducted at 12 US academic medical centers.15

To qualify for the TTrials, participants had to qualify forthe Sexual Function Trial, the Physical Function Trial, or theVitality Trial.16 Cognitive tests were administered to all par-ticipants, but the Cognitive Function Trial’s primary focus wasthe subgroup of men with AAMI.

The trial protocol (Supplement 1) and consent form were ap-proved by the institutional review boards of the University ofPennsylvania and all trial sites. All participants provided writ-ten, informed consent. An unblinded data and safety monitor-ing board monitored accumulating safety data every 3 months.

ParticipantsParticipants for the TTrials were recruited and screened asdescribed.16 Respondents were screened first by telephone

and then at 2 clinic visits. Inclusion criteria for the TTrialsoverall were 65 years or older and the mean of 2 morningserum testosterone concentrations less than 275 ng/dL(to convert to nmol/L, multiply by 0.0347). Additionally,inclusion in the Sexual Function Trial required self-reporteddecreased libido and sexual activity, inclusion in the Physi-cal Function Trial required self-reported difficulty walkingor climbing stairs and low gait speed, and inclusion in theVitality Trial required self-reported fatigue and reducedvitality.16 Exclusion criteria included a recent history or evi-dence of increased risk of conditions that testosteronemight exacerbate, cognitive impairment (Mini-Mental StateExamination score <24), and severe depression (PatientHealth Questionnaire-9 [PHQ-9] score ≥20) (eAppendix inSupplement 2).17

Men were classified as having AAMI if they had both sub-jective memory complaints and relative impairment onobjective tests of memory performance. Subjective memorycomplaints were indicated by a score of 4 or 5 on at least 1item of the Memory Assessment Clinics Questionnaire(MAC-Q).18 Objective memory impairment was defined by ascore more than 1 SD below the performance for young men(aged 20-24 years) but not greater than 2 SD below the scoresof age-matched men on tests of delayed paragraph recall orvisual memory. Men were “normal for age” if they did notmeet criteria for AAMI and had scores of 80 or more on theModified Mini-Mental State Examination (3MSE) measure ofglobal cognitive function. Demographic characteristicsincluding self-reported race (white, African American, orother) and ethnicity (Hispanic or non-Hispanic) were col-lected because there are race differences in genetic risk fac-tors for some conditions that affect cognitive function.

TreatmentIn the TTrials overall, participants were allocated to treat-ment by minimization, with participants assigned to theoptimally balanced treatment with 80% probability.19,20 Bal-ancing variables included participation in each of the 3 maintrials of the TTrials (Sexual Function Trial, Physical FunctionTrial, or Vitality Trial), trial site, screening testosteroneconcentration (≤200 ng/dL or >200 ng/dL), age (≤75 years or

Key PointsQuestion Is treatment with testosterone for 1 year associatedwith improved memory in older men with low testosterone andage-associated memory impairment?

Findings In this placebo-controlled study of 788 older men withsymptomatic hypogonadism, 493 had age-associated memoryimpairment, defined by subjective memory complaints andimpaired performance on tests of verbal and visual memory.Compared with placebo, 1 year of testosterone treatment was notsignificantly associated with improved memory or other cognitivefunctions in these men.

Meaning This study does not support the use of testosterone forthe treatment of age-associated memory decline in older men withsymptomatic hypogonadism.

Research Original Investigation Testosterone Treatment and Cognitive Function in Men With Memory Impairment

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A ging is associated with declines in some cognitive func-tions, including verbal and visual memory, executivefunction, and spatial ability.1-3 Aging in men is also as-

sociated with a reduction in serum testosterone,4,5 raising thepossibility that reduced circulating testosterone concentra-tion may contribute to age-related cognitive decline. Supportfor this hypothesis comes from studies of clinical conditionsthat cause low testosterone levels,6,7 epidemiologicalinvestigations,8,9 and small randomized trials showing im-proved memory with testosterone supplementation.10 To-gether, these studies suggest that lower testosterone levels maybe associated with poorer cognitive functioning in older menand that testosterone treatment may improve cognitive func-tioning, especially memory.

An Institute of Medicine panel11 recommended investigat-ing the effects of testosterone treatment on conditions, includ-ing cognitive impairment, that might be caused by the decreasein testosterone. Men with age-associated memory impairment(AAMI) represent a clinically important group at risk for devel-oping more severe memory impairment (eg, mild cognitive im-pairment and dementia)12 for whom testosterone interventionmay be beneficial. AAMI is defined by subjective complaintsof memory decline and scores at least 1 SD below the mean foryoung adults on objective memory testing.13 A large percent-age of community-dwelling older adults meets these criteria.14

The Cognitive Function Trial determined the efficacy oftestosterone treatment on cognitive outcomes among oldermen enrolled in the Testosterone Trials (TTrials) with low tes-tosterone likely due to age.15 The primary hypothesis of theCognitive Function Trial was that testosterone treatment for1 year would improve or slow decline in verbal memory in thesubgroup of men 65 years or older with an average testoste-rone level of less than 275 ng/dL and AAMI. Secondary aimswere to determine if testosterone treatment affects other cog-nitive functions in these men with AAMI, and exploratory aimswere to determine the effect of testosterone treatment on cog-nitive function in all men in the TTrials.

MethodsStudy DesignThe TTrials are a coordinated set of 7 double-blind, placebo-controlled trials conducted at 12 US academic medical centers.15

To qualify for the TTrials, participants had to qualify forthe Sexual Function Trial, the Physical Function Trial, or theVitality Trial.16 Cognitive tests were administered to all par-ticipants, but the Cognitive Function Trial’s primary focus wasthe subgroup of men with AAMI.

The trial protocol (Supplement 1) and consent form were ap-proved by the institutional review boards of the University ofPennsylvania and all trial sites. All participants provided writ-ten, informed consent. An unblinded data and safety monitor-ing board monitored accumulating safety data every 3 months.

ParticipantsParticipants for the TTrials were recruited and screened asdescribed.16 Respondents were screened first by telephone

and then at 2 clinic visits. Inclusion criteria for the TTrialsoverall were 65 years or older and the mean of 2 morningserum testosterone concentrations less than 275 ng/dL(to convert to nmol/L, multiply by 0.0347). Additionally,inclusion in the Sexual Function Trial required self-reporteddecreased libido and sexual activity, inclusion in the Physi-cal Function Trial required self-reported difficulty walkingor climbing stairs and low gait speed, and inclusion in theVitality Trial required self-reported fatigue and reducedvitality.16 Exclusion criteria included a recent history or evi-dence of increased risk of conditions that testosteronemight exacerbate, cognitive impairment (Mini-Mental StateExamination score <24), and severe depression (PatientHealth Questionnaire-9 [PHQ-9] score ≥20) (eAppendix inSupplement 2).17

Men were classified as having AAMI if they had both sub-jective memory complaints and relative impairment onobjective tests of memory performance. Subjective memorycomplaints were indicated by a score of 4 or 5 on at least 1item of the Memory Assessment Clinics Questionnaire(MAC-Q).18 Objective memory impairment was defined by ascore more than 1 SD below the performance for young men(aged 20-24 years) but not greater than 2 SD below the scoresof age-matched men on tests of delayed paragraph recall orvisual memory. Men were “normal for age” if they did notmeet criteria for AAMI and had scores of 80 or more on theModified Mini-Mental State Examination (3MSE) measure ofglobal cognitive function. Demographic characteristicsincluding self-reported race (white, African American, orother) and ethnicity (Hispanic or non-Hispanic) were col-lected because there are race differences in genetic risk fac-tors for some conditions that affect cognitive function.

TreatmentIn the TTrials overall, participants were allocated to treat-ment by minimization, with participants assigned to theoptimally balanced treatment with 80% probability.19,20 Bal-ancing variables included participation in each of the 3 maintrials of the TTrials (Sexual Function Trial, Physical FunctionTrial, or Vitality Trial), trial site, screening testosteroneconcentration (≤200 ng/dL or >200 ng/dL), age (≤75 years or

Key PointsQuestion Is treatment with testosterone for 1 year associatedwith improved memory in older men with low testosterone andage-associated memory impairment?

Findings In this placebo-controlled study of 788 older men withsymptomatic hypogonadism, 493 had age-associated memoryimpairment, defined by subjective memory complaints andimpaired performance on tests of verbal and visual memory.Compared with placebo, 1 year of testosterone treatment was notsignificantly associated with improved memory or other cognitivefunctions in these men.

Meaning This study does not support the use of testosterone forthe treatment of age-associated memory decline in older men withsymptomatic hypogonadism.

Research Original Investigation Testosterone Treatment and Cognitive Function in Men With Memory Impairment

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Resnicketal.,JAMA2017

KeinBenefiteinerTestosteronbehandlung:Kogni>veFunk>on

Basariaetal.NEJM2010

Risiken?Testosteron&kardiovaskuläreEvents

Budoffetal,JAMA2017

Copyright 2017 American Medical Association. All rights reserved.

Testosterone Treatment and Coronary Artery Plaque Volumein Older Men With Low TestosteroneMatthew J. Budoff, MD; Susan S. Ellenberg, PhD; Cora E. Lewis, MD, MSPH; Emile R. Mohler III, MD; Nanette K. Wenger, MD;Shalender Bhasin, MD; Elizabeth Barrett-Connor, MD; Ronald S. Swerdloff, MD; Alisa Stephens-Shields, PhD; Jane A. Cauley, DrPH;Jill P. Crandall, MD; Glenn R. Cunningham, MD; Kristine E. Ensrud, MD, MPH; Thomas M. Gill, MD; Alvin M. Matsumoto, MD;Mark E. Molitch, MD; Rine Nakanishi, MD; Negin Nezarat, MD; Suguru Matsumoto, MD; Xiaoling Hou, MS; Shehzad Basaria, MD;Susan J. Diem, MD, MPH; Christina Wang, MD; Denise Cifelli, MS; Peter J. Snyder, MD

IMPORTANCE Recent studies have yielded conflicting results as to whether testosteronetreatment increases cardiovascular risk.

OBJECTIVE To test the hypothesis that testosterone treatment of older men with lowtestosterone slows progression of noncalcified coronary artery plaque volume.

DESIGN, SETTING, AND PARTICIPANTS Double-blinded, placebo-controlled trial at 9 academicmedical centers in the United States. The participants were 170 of 788 men aged 65 years orolder with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assignedto placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who wereenrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.

INTERVENTION Testosterone gel, with the dose adjusted to maintain the testosterone levelin the normal range for young men, or placebo gel for 12 months.

MAIN OUTCOMES AND MEASURES The primary outcome was noncalcified coronary arteryplaque volume, as determined by coronary computed tomographic angiography. Secondaryoutcomes included total coronary artery plaque volume and coronary artery calcium score(range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).

RESULTS Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65receiving placebo) completed the study and were available for the primary analysis. Amongthe 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline,70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units,reflecting severe atherosclerosis. For the primary outcome, testosterone treatmentcompared with placebo was associated with a significantly greater increase in noncalcifiedplaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3;P = .003). For the secondary outcomes, the median total plaque volume increased frombaseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3

to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3;P = .006), and the median coronary artery calcification score changed from 255 to 244Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group(estimated difference, −27 Agatston units; 95% CI, −80 to 26 Agatston units). No majoradverse cardiovascular events occurred in either group.

CONCLUSIONS AND RELEVANCE Among older men with symptomatic hypogonadism,treatment with testosterone gel for 1 year compared with placebo was associated with asignificantly greater increase in coronary artery noncalcified plaque volume, as measured bycoronary computed tomographic angiography. Larger studies are needed to understand theclinical implications of this finding.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00799617

JAMA. 2017;317(7):708-716. doi:10.1001/jama.2016.21043

Editorial page 699

Author Video Interview andJAMA Report Video

Related article page 717

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Related articles atjamainternalmedicine.com

Author Affiliations: Authoraffiliations are listed at the end of thisarticle.

Corresponding Author: Peter J.Snyder, MD, University ofPennsylvania, 3400 Civic CenterBlvd, Philadelphia, PA 19104(pjs@mail.med.upenn.edu).

Research

JAMA | Original Investigation

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A lthough testosterone replacement is increasinglybeing used clinically,1 the cardiovascular benefits andrisks of testosterone administration to older men with

age-related decline in testosterone levels remain uncertain.Several observational studies show an inverse associationbetween serum testosterone concentration and adverse car-diovascular outcomes, the metabolic syndrome, diabetes,and mortality,2-5 independent of traditional cardiovascularrisk factors.

Studies of the effects of testosterone on clinical cardio-vascular outcomes are conflicting.6 Meta-analyses of clinicaltrials have shown no association between testosterone treat-ment and cardiovascular adverse events, but none of the in-dividual trials included in the meta-analyses were designed toassess these events prospectively. A clinical trial in older menwith mobility limitation showed an excess of cardiovascularadverse events in men treated with testosterone compared withplacebo,7 but another trial in a similar population did not.8

These trials were also not designed to assess cardiovascular ad-verse events. Retrospective analyses of electronic medical rec-ords to evaluate the possible association of testosterone treat-ment with cardiovascular adverse events have also yieldedconflicting results.9-13

The Testosterone Trials (TTrials), a group of 7 placebo-controlled, coordinated trials, were designed to determine theefficacy of testosterone treatment of men aged 65 years or olderwith low testosterone concentrations for no apparent reasonother than age. The Cardiovascular Trial was designed to testthe hypothesis that testosterone treatment of older men withlow testosterone slows the progression of noncalcified coro-nary artery plaque volume, assessed by coronary computedtomographic angiography (CCTA), as an indicator of coronaryatherosclerosis.

MethodsStudy DesignThe overall study design of the TTrials14 as well as the designof the Cardiovascular Trial15 have been published. To qualifyfor the TTrials overall, a participant had to qualify for at least1 of the 3 main trials (Sexual Function Trial, Physical Func-tion Trial, and Vitality Trial). Those who qualified overall couldparticipate in any of the others for which they qualified. Par-ticipants were allocated to receive testosterone or placebo gelfor 1 year. This article describes the results of the Cardiovas-cular Trial.

The TTrials and the Cardiovascular Trial protocols were ap-proved by the institutional review boards of the participatingsites. The trial protocols for the TTrials and the Cardiovascu-lar Trial are available in Supplement 1. All participants pro-vided written informed consent. Participant safety and trialconduct were overseen by an independent data and safetymonitoring board.

ParticipantsParticipants were recruited primarily by mass mailings.16 Re-spondents were screened by telephone and then during 2 clinic

visits. The main overall inclusion criteria were men aged 65 yearsor older, serum testosterone levels that averaged lower than275 ng/dL (to convert to nanomoles per liter, multiply by 0.0347)on 2 morning samples, and subjective complaints and objec-tive evidence of sexual dysfunction, physical dysfunction,and/or reduced vitality. The main exclusion criterion was highrisk of prostate cancer.14 Men who had a history of myocardialinfarction or stroke within the previous 3 months and who hada systolic blood pressure higher than 160 mm Hg or diastolicblood pressure higher than 100 mm Hg were excluded.

Additional exclusion criteria for the Cardiovascular Trialwere related to CCTA: conditions that either increased the riskof performing the procedure (estimated glomerular filtrationrate <60 mL/min/1.73 m2 or known allergy to iodinated con-trast medium) or made the procedure technically impractical(weight >136 kg, inability to hold the breath for 10 seconds,a prior diagnosis of tachycardia or irregular heart rhythm[eg, atrial fibrillation], or history of coronary artery bypass graftsurgery). Self-report of race and ethnicity, by fixed categories,was collected as required by the National Institutes of Health.

Testosterone TreatmentParticipants were allocated to treatment by minimization, acomputerized allocation technique that calculates the assign-ment that provides the best balance across groups on speci-fied baseline characteristics. A random component wasincluded by assigning the optimally balancing treatment with80% probability.14 The balancing variables included partici-pation in the main trials, trial site, age younger than or olderthan 75 years, screening testosterone concentration lowerthan or higher than 200 ng/dL, and use of antidepressantsand phosphodiesterase type 5 (PDE5) inhibitors.14 There wasonly 1 treatment assignment that applied to all trials in whicha man participated.

Testosterone was administered as a 1% gel in a pumpbottle (AndroGel). Placebo gel was similar. The dose was ini-tially 5 g/d and was adjusted, if necessary, on the basis of tes-tosterone levels measured at a central laboratory (QuestClinical Trials) at months 1, 2, 3, 6, and 9, to try to keep theserum concentration within the normal range for young men(280-873 ng/dL). To maintain blinding when the dose wasadjusted in a man receiving testosterone treatment, the dosewas changed simultaneously in a man receiving placebo.

Key PointsQuestion Is testosterone treatment of older men with lowtestosterone associated with a decrease in noncalcified coronaryartery plaque volume?

Findings In a controlled clinical trial, 1 year of testosteronetreatment of men aged 65 years or older with a low serumtestosterone level was associated with a significant increasein noncalcified coronary artery plaque volume of 41 mm3 morethan placebo.

Meaning Testosterone treatment of older men was associatedwith an increase in coronary artery plaque volume, but additionalstudies are needed to determine the clinical significance.

Testosterone Treatment and Coronary Artery Plaque Volume in Men With Low Testosterone Original Investigation Research

jama.com (Reprinted) JAMA February 21, 2017 Volume 317, Number 7 709

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Copyright 2017 American Medical Association. All rights reserved.

A lthough testosterone replacement is increasinglybeing used clinically,1 the cardiovascular benefits andrisks of testosterone administration to older men with

age-related decline in testosterone levels remain uncertain.Several observational studies show an inverse associationbetween serum testosterone concentration and adverse car-diovascular outcomes, the metabolic syndrome, diabetes,and mortality,2-5 independent of traditional cardiovascularrisk factors.

Studies of the effects of testosterone on clinical cardio-vascular outcomes are conflicting.6 Meta-analyses of clinicaltrials have shown no association between testosterone treat-ment and cardiovascular adverse events, but none of the in-dividual trials included in the meta-analyses were designed toassess these events prospectively. A clinical trial in older menwith mobility limitation showed an excess of cardiovascularadverse events in men treated with testosterone compared withplacebo,7 but another trial in a similar population did not.8

These trials were also not designed to assess cardiovascular ad-verse events. Retrospective analyses of electronic medical rec-ords to evaluate the possible association of testosterone treat-ment with cardiovascular adverse events have also yieldedconflicting results.9-13

The Testosterone Trials (TTrials), a group of 7 placebo-controlled, coordinated trials, were designed to determine theefficacy of testosterone treatment of men aged 65 years or olderwith low testosterone concentrations for no apparent reasonother than age. The Cardiovascular Trial was designed to testthe hypothesis that testosterone treatment of older men withlow testosterone slows the progression of noncalcified coro-nary artery plaque volume, assessed by coronary computedtomographic angiography (CCTA), as an indicator of coronaryatherosclerosis.

MethodsStudy DesignThe overall study design of the TTrials14 as well as the designof the Cardiovascular Trial15 have been published. To qualifyfor the TTrials overall, a participant had to qualify for at least1 of the 3 main trials (Sexual Function Trial, Physical Func-tion Trial, and Vitality Trial). Those who qualified overall couldparticipate in any of the others for which they qualified. Par-ticipants were allocated to receive testosterone or placebo gelfor 1 year. This article describes the results of the Cardiovas-cular Trial.

The TTrials and the Cardiovascular Trial protocols were ap-proved by the institutional review boards of the participatingsites. The trial protocols for the TTrials and the Cardiovascu-lar Trial are available in Supplement 1. All participants pro-vided written informed consent. Participant safety and trialconduct were overseen by an independent data and safetymonitoring board.

ParticipantsParticipants were recruited primarily by mass mailings.16 Re-spondents were screened by telephone and then during 2 clinic

visits. The main overall inclusion criteria were men aged 65 yearsor older, serum testosterone levels that averaged lower than275 ng/dL (to convert to nanomoles per liter, multiply by 0.0347)on 2 morning samples, and subjective complaints and objec-tive evidence of sexual dysfunction, physical dysfunction,and/or reduced vitality. The main exclusion criterion was highrisk of prostate cancer.14 Men who had a history of myocardialinfarction or stroke within the previous 3 months and who hada systolic blood pressure higher than 160 mm Hg or diastolicblood pressure higher than 100 mm Hg were excluded.

Additional exclusion criteria for the Cardiovascular Trialwere related to CCTA: conditions that either increased the riskof performing the procedure (estimated glomerular filtrationrate <60 mL/min/1.73 m2 or known allergy to iodinated con-trast medium) or made the procedure technically impractical(weight >136 kg, inability to hold the breath for 10 seconds,a prior diagnosis of tachycardia or irregular heart rhythm[eg, atrial fibrillation], or history of coronary artery bypass graftsurgery). Self-report of race and ethnicity, by fixed categories,was collected as required by the National Institutes of Health.

Testosterone TreatmentParticipants were allocated to treatment by minimization, acomputerized allocation technique that calculates the assign-ment that provides the best balance across groups on speci-fied baseline characteristics. A random component wasincluded by assigning the optimally balancing treatment with80% probability.14 The balancing variables included partici-pation in the main trials, trial site, age younger than or olderthan 75 years, screening testosterone concentration lowerthan or higher than 200 ng/dL, and use of antidepressantsand phosphodiesterase type 5 (PDE5) inhibitors.14 There wasonly 1 treatment assignment that applied to all trials in whicha man participated.

Testosterone was administered as a 1% gel in a pumpbottle (AndroGel). Placebo gel was similar. The dose was ini-tially 5 g/d and was adjusted, if necessary, on the basis of tes-tosterone levels measured at a central laboratory (QuestClinical Trials) at months 1, 2, 3, 6, and 9, to try to keep theserum concentration within the normal range for young men(280-873 ng/dL). To maintain blinding when the dose wasadjusted in a man receiving testosterone treatment, the dosewas changed simultaneously in a man receiving placebo.

Key PointsQuestion Is testosterone treatment of older men with lowtestosterone associated with a decrease in noncalcified coronaryartery plaque volume?

Findings In a controlled clinical trial, 1 year of testosteronetreatment of men aged 65 years or older with a low serumtestosterone level was associated with a significant increasein noncalcified coronary artery plaque volume of 41 mm3 morethan placebo.

Meaning Testosterone treatment of older men was associatedwith an increase in coronary artery plaque volume, but additionalstudies are needed to determine the clinical significance.

Testosterone Treatment and Coronary Artery Plaque Volume in Men With Low Testosterone Original Investigation Research

jama.com (Reprinted) JAMA February 21, 2017 Volume 317, Number 7 709

Copyright 2017 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/936056/ by a University of Basel User on 02/22/2017

Risiken?Testosteron&kardiovaskuläreEvents

Snjderetal,NEnglJMed2016

n engl j med 374;7 nejm.org February 18, 2016622

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

of a difference in risk with respect to the other cardiovascular adverse events (Table S4 in the Supplementary Appendix). No significant between-group differences were observed in cardiac ad-verse events defined according to Medical Diction-ary for Regulatory Activities classification (Tables S5 and S6 in the Supplementary Appendix).

Discussion

Increasing the serum testosterone concentra-tions of men 65 years of age or older from mod-erately low to the mid-normal range for men 19 to 40 years of age had significant effects on all measures of sexual function and some measures of physical function, mood, and depressive symptoms — all to small-to-moderate degrees, consistent with the degree of testosterone defi-ciency.

Men who received testosterone reported bet-ter sexual function, including activity, desire, and erectile function, than those who received placebo. Although the effect sizes were low to moderate, men in the testosterone group were more likely than those in the placebo group to report that their sexual desire had improved, which suggests that this effect was of clinical relevance. The effect of testosterone on erectile function was less than that reported with phos-phodiesterase type 5 inhibitors.28

The percentage of men whose 6-minute walk-ing distance increased by at least 50 m did not differ significantly between the two study groups in the Physical Function Trial but did differ sig-nificantly when men in all three trials were in-cluded, although the effect sizes did not differ markedly (1.42 vs. 1.76). Furthermore, men who received testosterone were more likely than those who received placebo to report that their walking ability was better, which suggests that the effect, although small in magnitude, might be clinically relevant.

Testosterone had no significant benefit with respect to vitality, as assessed by the FACIT–Fatigue scale, except as a continuous outcome when men in all three trials were included. However, testosterone was associated with small but sig-nificant benefits with respect to mood and depressive symptoms. Men in the testosterone group were also more likely than those in the placebo group to report that their energy was better.

We observed four cases of prostate cancer, three of which were in men treated with testos-terone, and there was no significant difference in urinary symptoms (as assessed by means of the IPSS) between the study groups. The gener-alizability of these results is limited, however, because we excluded men with a high risk of prostate cancer and men with moderately severe urinary tract symptoms. Furthermore, the sam-ple size was inadequate to assess reliably the effect of testosterone on the risk of these con-ditions.

Some studies have suggested that testosterone treatment is associated with increased cardio-vascular risk,29-32 although others have not.6,33,34 We did not observe a pattern of increased risk, but this trial was too small to exclude other than a large increase.

Our three trials had certain strengths, includ-ing enrollment of men with an unequivocally

EventPlacebo (N = 394)

Testosterone (N = 394)

no. of participants

Prostate-related event

Increase in PSA level by ≥1.0 ng/ml 8 23

Prostate cancer 0 1

IPSS >19† 26 27

Hemoglobin ≥17.5 g/dl 0 7

Cardiovascular event‡

Myocardial infarction (definite or probable) 1 2

Stroke (definite or probable) 5 5

Death from cardiovascular causes 1 0

Myocardial infarction, stroke, or death from cardiovascular causes

7 7

Serious adverse events

Death 7 3

Hospitalization 78 68

Other§ 6 7

* PSA denotes prostate-specific antigen.† The International Prostate Symptom Score (IPSS) questionnaire is used to

identify symptoms of benign prostatic hyperplasia. Scores range from 0 to 35, with higher scores indicating more severe symptoms. A score of more than 19 indicates moderately severe lower urinary tract symptoms.

‡ Data on cardiovascular adverse events were collected with the use of a specific questionnaire administered at each visit and also identified from the adverse-event log and the form for reporting serious adverse events (see the protocol). Myocardial infarction, stroke, and death from cardiovascular causes were as-sessed by two adjudicators.

§ Other serious adverse events were defined as congenital anomaly, disability, a life-threatening event, or an event that may not be immediately life-threaten-ing but is clearly of major clinical significance.

Table 4. Adverse Events during the First Year (Treatment Period) of the Testosterone Trials.*

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Risiken?Prostata

KlareHypogonadismusSymptome

Testosteronmorgens2x<7-10nmol/L

ProbatorischeTherapieRisikovsBenefit

VorsichtbeikardiovaskulärenVorerkrankungen

PADAM:Wentherapieren?„personalisierteMedizin“

¨  67jährigerPa>ent,BMI26¨  Symptome:AbnahmederLibido,Müdigkeit,wenigerEnergie

¨  PersönlicheAnamnese:St.n.Myokardinfarktvor3Jahren

¨  TotalesTestosteron8.9nmol/L

KlinischerFall

• Andriol®40mgTbl2-3x/d

• TestosteronPflaster

• Testoviron®(125-250mgi.m.3-4weekly)

• Nebido®(1000mgi.m.3monatlich)

• Androgel®/Testogel®/Tostran®,(zBTestogel5gtäglich)

<<<<<<<

TestosteronTherapie

Bhasinetal.JCEM2010

MonitoringderTestosteronTherapieMonitoring

Symptome Evaluation 3 & 6 Monate nach Therapiebeginn, dann jährlich

Testosteronmessung 3 & 6 Monate nach Therapiebeginn, sollten im mittleren Normbereich liegen (Gel: „anytime“ (ideal 2-4h nach Applikation)) Nebido: vor nächster Injektion)

Hämatokrit 3 & 6 Monate nach Therapiebeginn, dann jährlich

Osteoporose Knochendichtemessung ca. 2 Jahre nach Therapiebeginn

Prostata Rektaluntersuchung und PSA: nach 3 & 6 Monaten, dann jährlich

Urologische Konsultation

Wenn PSA >1.4ng/ml ansteigt innerhalb der ersten 12 Monate Anschliessend: Wenn PSA pro Jahr >0.4ng/ml ansteigt Auffällige Rektalpalpation

¨  Wenabklären?MännermitklarenSymptomen,casedetec8onbeiKrankheitenmithoherPrävalenz(zBTyp2Diabetes)

¨  Wasundwannmessen?TotalesTestosteron,morgens,2xFreiesTestosteronfallsSHBGVeränderung,LH&FSH

¨  Wenbehandeln?Pa8entenmitprimäremundsekundäremHypogonadismusPADAM:beiWerten<7-10nmol/L

¨  Wiebehandeln:Testosteroni.m.oderGel

¨  Monitoring:nach3&6Monaten,dannjährlich.Symptome,Testosteron,Prostata,Hämatokrit,Knochen;Kardiovaskulär?

Zusammenfassung

Jonesetal.,Diabetescare2011

TIMES 2 Study: Multicenter RCT 220 Männer mit Hypogonadismus und metabolischem Syndrom

BenefiteinerTestosteronbehandlung:MetabolischeWirkung