Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes:

An Endocrine Society Clinical Practice Guideline

T h e E n d o c r i n e S o c i e t y ’ s

CliniCal Guidelines

Authors: Shalender Bhasin, Glenn R. Cunningham, Frances J. Hayes, Alvin M. Matsumoto, Peter J. Snyder, Ronald S. Swerdloff, and Victor M. Montori

Affiliations: Boston University School of Medicine (S.B.), Boston, Massachusetts; Baylor College of Medicine/Veterans Affairs Medical Center (G.R.C.), Houston, Texas; St. Vincent’s University Hospital (F.J.H.), Dublin, Ireland; University of Washington/Veterans Affairs Puget Sound Health Care System (A.M.M.), Seattle, Wash-ington; University of Pennsylvania School of Medicine (P.J.S.), Philadelphia, Pennsylvania; Harbor University of California, Los Angeles Medical Center (R.S.S.), Torrance, California; and Mayo Clinic (V.M.M.), Rochester, Minnesota.

Disclaimer: Clinical Practice Guidelines are developed to be of assistance to endocrinologists and other health care professionals by providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the inde-pendent judgment of health care providers and each patient’s individual circumstances.

The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The Society shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein.

First published in Journal of Clinical Endocrinology & Metabolism, June 2010, Vol. 95(6):2536–2559.

This revised guideline replaces the previous version published in 2006: Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori, VM 2006 Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline (J Clin Endocrinol Metab 91:1995–2101l doi: 10.1210/jc.2005–2847)

This guideline is also available with CME. Go to http://www.endo-society.org/guidelines/Current-Clinical-Practice-Guidelines.cfm for more details.

© The Endocrine Society, 2010

Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes:

An Endocrine Society Clinical Practice Guideline

T h e E n d o c r i n e S o c i e t y ’ s

CLInICAL GUIDELInES

Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes:

An Endocrine Society Clinical Practice Guideline

T h e E n d o c r i n e S o c i e t y ’ s

CliniCal Guidelines

Table of Contents

abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

summaryofRecommendations.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Methodofdevelopmentofevidence-BasedClinicalPracticeGuidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

diagnosisofHypogonadism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

TreatmentofandrogendeficiencyWithTestosterone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

OrderForm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32

Reprintinformation,Questions&Correspondences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . insideBackCover

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Abstract

Objective:Toupdate theguidelines for theevalua-tionandtreatmentofandrogendeficiencysyndromesinadultmenpublishedpreviouslyin2006.

Participants:TheandrogensinMenGuidelineTaskForcewascomposedofachair,selectedbytheClin-ical Guidelines subcommittee of The endocrinesociety,fiveadditionalexperts,amethodologist,andamedicalwriter.TheTaskForcereceivednocorpo-ratefundingorremuneration.

Evidence: Thisevidence-basedguidelinewasdevel-opedusingtheGradingofRecommendations,assess-ment, development, and evaluation (GRade)systemtodescribe the strengthof recommendationsandthequalityofevidence.

Consensus Process: Consensusofthisguidelinewasguidedbysystematicreviewsofevidenceanddiscus-sionsduringin-persongroupmeetings,severalconfer-ence calls, and e-mail communications. The draftspreparedbytheTaskForcewerereviewedsuccessivelyby The endocrine society’s Clinical Guidelinessubcommittee,ClinicalaffairsCoreCommittee,andapproved by Council. at each stage of review, theTaskForcereceivedwrittencommentsand incorpo-ratedneededchanges.TaskForcemembershadfinalresponsibilityforandcontrolovercontentpresentedinthisguideline.

Conclusions:Werecommendmakingadiagnosisofandrogen deficiency only in men with consistentsymptoms and signs and unequivocally low serumtestosterone levels. We suggest the measurement ofmorningtotaltestosteronelevelbyareliableassayastheinitialdiagnostictest.Werecommendconfirma-tionofthediagnosisbyrepeatingthemeasurementofmorningtotaltestosteroneandinsomemeninwhomtotaltestosteroneisnearthelowerlimitofnormalorin whom sex hormone binding globulin (sHBG)abnormality is suspected by measurement of free orbioavailabletestosteronelevel,usingvalidatedassays.We recommend testosterone therapy for men withsymptomaticandrogendeficiencytoinduceandmain-tain secondary sex characteristics and to improvetheirsexualfunction,senseofwell-being,musclemassand strength, andbonemineral density.We recom-mendagainststartingtestosteronetherapyinpatientswith breast or prostate cancer, a palpable prostatenodule or induration or prostate-specific antigengreaterthan4ng/mlorgreaterthan3ng/mlinmenathighriskforprostatecancersuchasafricanameri-cansormenwithfirst-degree relativeswithprostatecancerwithoutfurtherurologicalevaluation,hemato-crit>50%,untreatedsevereobstructivesleepapnea,severe lower urinary tract symptoms with interna-tional Prostate symptom score (iPss) > 19, oruncontrolledorpoorlycontrolledheartfailure.Whentestosteronetherapyisinstituted,wesuggestaimingatachievingtestosteronelevelsduringtreatmentinthemid-normalrangewithanyoftheapprovedformula-tions,chosenonthebasisofthepatient’spreference,considerationofpharmacokinetics,treatmentburden,andcost.Menreceivingtestosteronetherapyshouldbemonitoredusingastandardizedplan.

J Clin Endocrinol Metab, June 2010, 95(6):2536–2559

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SUMMARY OF RECOMMENDATIONS

1.1. DIAGNOSIS AND EVALUATION OF PATIENTS WITH SUSPECTED ANDROGEN DEFICIENCY

We recommend making a diagnosis of androgendeficiencyonlyinmenwithconsistentsymptomsandsignsandunequivocallylowserumtestosteronelevels.(1| )

Wesuggestthatcliniciansmeasureserumtestos-terone level in patients with clinical manifestationsshown in Table 1a. We suggest that clinicians alsoconsider measuring serum testosterone level whenpatients report the less specific symptoms and signslistedinTable1B.(2| )

We suggest the measurement of morning totaltestosteronelevelbyareliableassayastheinitialdiag-nostictest.(2| )

We recommend confirmation of the diagnosis byrepeatingmeasurementoftotaltestosterone.(1| )

We suggestmeasurementof freeorbioavailabletestosterone level, using an accurate and reliableassay, in some men in whom total testosteroneconcentrationsarenearthelowerlimitofthenormalrangeandinwhomalterationsofsHBGaresuspected.(2| )

Wesuggestthatanevaluationofandrogendefi-ciencyshouldnotbemadeduringanacuteorsubacuteillness.(2| )

1.1.1. Further evaluation of men deemed androgen deficient

WerecommendmeasurementofserumlHandFsHlevelstodistinguishbetweenprimary(testicular)andsecondary (pituitary-hypothalamic) hypogonadism.(1| )

inmenwithsecondaryhypogonadism,wesuggestfurtherevaluationtoidentifytheetiologyofhypotha-lamic and/or pituitary dysfunction. This evaluationmay include measurements of serum prolactin andiron saturation, pituitary function testing, andmagnetic resonance imaging of the sella turcica.(2| )

inmenwithprimarytesticularfailureofunknownetiology,wesuggestobtainingakaryotypetoexcludeKlinefeltersyndrome,especiallyinthosewithtestic-ularvolumelessthan6ml.(2| )

Wesuggestmeasurementofbonemineraldensityby using dual-energy x-ray absorptiometry (dXa)scanninginmenwithsevereandrogendeficiencyorlowtraumafracture.(2| )

1.2. SCREENING FOR ANDROGEN DEFICIENCY (GENERAL POPULATION)

We recommend against screening for androgendeficiencyinthegeneralpopulation.(1| )

1.2.2. Case finding of androgen deficiency

We suggest that clinicians not use the availablecase-finding instruments for detection of androgendeficiencyinmenreceivinghealthcareforunrelatedreasons.(2| )

We suggest that clinicians consider case detec-tion by measurement of total testosterone levels inmenwithcertainclinicaldisorders,listedinTable3,inwhichtheprevalenceoflowtestosteronelevelsishigh or for whom testosterone therapy is suggested/recommendedinsection2.0.(2| )

2.0. TREATMENT OF ANDROGEN DEFICIENCY WITH TESTOSTERONE

Werecommendtestosteronetherapyforsymptomaticmen with classical androgen deficiency syndromesaimed at inducing and maintaining secondary sexcharacteristicsandatimprovingtheirsexualfunction,sense of well-being, and bone mineral density.(1| )

We recommend against testosterone therapy inpatientswithbreast (1| )orprostate cancer.(1| )

We recommend against testosterone therapywithoutfurtherurologicalevaluationinpatientswithpalpable prostate nodule or induration or prostate-specific antigen (Psa)4ng/mlorPsa 3ng/ml inmenathighriskofprostatecancer, suchasafricanamericans or men with first-degree relatives withprostatecancer.(1| )

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We recommend against testosterone therapy inpatientswithhematocritabove50%,untreatedsevereobstructive sleep apnea, severe lower urinary tractsymptoms[americanurologicalassociation(aua)/internationalProstatesymptomscore(iPss)19],oruncontrolled or poorly controlled heart failure, or inthosedesiringfertility.(1| )

We suggest initiating testosterone therapy withanyofthefollowingregimens,chosenonthebasisofthepatient’spreference,considerationofpharmacoki-netics,treatmentburden,andcost.(2| )• 75–100 mg of testosterone enanthate or cypio-

nate administered intramuscularly (iM) weekly,or150–200mgadministeredevery2weeks.

• Oneortwo5-mgnongenital,testosteronepatchesappliednightlyovertheskinoftheback,thigh,orupperarm,awayfrompressureareas.

• 5–10gofa1%testosteronegelapplieddailyoveracoveredareaofnongenitalskin(patientsshouldwashhandsafterapplication).

• 30mgofabioadhesivebuccaltestosteronetabletappliedtobuccalmucosaevery12hours.

• Testosteronepelletsimplantedsubcutaneouslyatintervalsof3to6months;thedoseandregimenvarywiththeformulationused.

• Oraltestosteroneundecanoate,injectabletestos-terone undecanoate, testosterone-in-adhesivematrix patch, and testosterone pellets whereavailable.

Monitoring strategies and schedule

Werecommendevaluatingthepatient3to6monthsaftertreatmentinitiationandthenannuallytoassesswhethersymptomshaverespondedtotreatmentandwhether the patient is suffering any adverse effects,andtocheckcompliance.(1| )

Wesuggestmonitoringtestosteronelevels3to6months after initiation of testosterone therapy. Wesuggestaimingatachievingserumtestosteronelevelsduring treatment in the mid-normal range. in menreceiving testosterone enanthate or cypionate, wesuggest aiming for testosterone levels between 400and 700 ng/dl one week after the injection.(2| )

Werecommenddetermininghematocritatbase-line,at3to6months,andthenannually.ifhemato-critis>54%,stoptherapyuntilhematocritdecreases

toa safe level,evaluate thepatient forhypoxiaandsleepapnea,andreinitiatetherapyatareduceddose.(1| )

Wesuggestrepeatingbonemineraldensityofthelumbarspine,femoralneck,andhipafter1to2yearsof testosterone therapy in hypogonadal men withosteoporosisorlowtraumafracture.(2| )

inmen40yearsofageorolderwhohaveabase-linePsa>0.6ng/ml,werecommenddigitalexami-nationoftheprostateandPsameasurementbeforeinitiating treatment, at 3 to 6 months, and then inaccordance with evidence-based guidelines for pros-tatecancerscreening,dependingontheageandraceofthepatient.(1| )

Werecommendthatcliniciansobtainurologicalconsultationifthereis:(1| )• anincreaseinserumorplasmaPsaconcentra-

tiongreaterthan1.4ng/mlwithinany12-monthperiodoftestosteronetreatment.

• aPsavelocityofmorethan0.4ng/ml·yrusingthe Psa level after 6 months of testosteroneadministration as the reference. Psa velocityshouldbeusedonlyiftherearelongitudinalPsadataformorethan2years.

• detection of a prostatic abnormality on digitalrectalexamination.

• aua/iPssscore>19.

We recommend evaluation for symptoms and signsof formulation-specific adverse events at each visit:(1| )• injectable testosterone esters: inquire about

fluctuations in mood or libido, and cough afterinjection, and evaluate hematocrit to detectexcessive erythrocytosis, especially in olderpatients.

• Testosteronepatch:look for signsof skin reac-tionattheapplicationsite.

• Testosterone gels: advise patients to cover theapplicationsitewithclothingandwashtheskinbeforehaving skin-to-skincontact,becausegelsleave a residue of testosterone on the skin thatcanbetransferredtoawomanorchildwhocomesinclosecontact.

• Buccaltestosteronetablets:inquireaboutaltera-tionsintasteandexaminegumsandoralmucosaforirritation.

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METHOD OF DEVELOPMENT OF EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES

The Clinical Guidelines subcommittee of Theendocrine society deemed testosterone therapy inandrogen-deficient men a priority area in need ofpractice guidelines and appointed a Task Force toformulate evidence-based recommendations. TheTaskForceelectedtousetheapproachrecommendedby the Grading of Recommendations, assessment,development,andevaluation(GRade)workgroup,aninternationalgroupwithexpertiseindevelopmentandimplementationofevidence-basedguidelines(1).

The Task Force used systematic reviews of availableevidence and two commissioned systematic reviews(2–4) to inform its key recommendations andconsis-tent language. The Task Force also used consistentlanguageandgraphicaldescriptionsofboththestrengthofarecommendationandthequalityofevidence.Thestrength of a recommendation is indicated by thenumber1(strongrecommendation,associatedwiththephrase“werecommend”)or2(weakrecommendation,associatedwiththephrase“wesuggest”).Thequalityoftheevidenceisindicatedbycross-filledcircles,suchthat

denotes very low quality evidence; ,low quality; , moderate quality; and ,highquality.TheTaskForcehasconfidencethatpersonswhoreceivecareaccordingtothestrongrecommenda-tions will derive, on average, more good than harm.Weakrecommendationsrequiremorecarefulconsider-ationoftheperson’scircumstances,values,andprefer-encestodeterminethebestcourseofaction.

linkedtoeachrecommendationisadescriptionoftheevidence, values that panelists considered in makingtherecommendation,andinsomeinstancesremarks,a section in which panelists offer technical sugges-tions for dosing and monitoring. These technicalcommentsreflectthebestavailableevidenceappliedtoatypicalpatient.Often,thisevidencecomesfromthe unsystematic observations of the panelists andtheirvaluesandpreferences;therefore,theseremarksshouldbeconsideredsuggestions.

2.2. TESTOSTERONE THERAPY IN MEN WITH SEXUAL DYSFUNCTION

Wesuggestthatcliniciansoffertestosteronetherapytomenwithlowtestosteronelevelsandlowlibidotoimprovelibido(2| )andtomenwitherectiledysfunction (ed) who have low testosterone levelsafter evaluation of underlying causes of ed andconsideration of established therapies for ed.(2| )

2.3. OLDER MEN WITH LOW SERUM TESTOSTERONE CONCENTRATION

We recommend against a general policy of offeringtestosteronetherapytoalloldermenwithlowtestos-teronelevels.(1| )

We suggest that clinicians consider offeringtestosterone therapy on an individualized basis tooldermenwithlowtestosteronelevelsonmorethanone occasion and clinically significant symptoms ofandrogen deficiency, after explicit discussion of theuncertainty about the risks and benefits of testos-teronetherapy.(2| )

2.4. PATIENTS WITH CHRONIC ILLNESS AND LOW TESTOSTERONE LEVELS

Wesuggestthatcliniciansconsidershort-termtestos-terone therapy as an adjunctive therapy in HiV-infectedmenwithlowtestosteronelevelsandweightlosstopromoteweightmaintenanceandgainsinleanbodymass(lBM)andmusclestrength.(2| )

2.4.2. Glucocorticoid-treated men

Wesuggestthatcliniciansoffertestosteronetherapyto men receiving high doses of glucocorticoids whohavelowtestosteronelevelstopromotepreservationoflBMandbonemineraldensity.(2| )

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The age-related decline in testosterone levels,confirmedinseveralcross-sectionalandlongitudinalstudies (7–9), results from defects in both testicularand hypothalamic-pituitary function. The averagedeclineinserumtestosteronelevelswithaginginmenis1–2%peryear(7,8).asignificantfractionofoldermenhavelevelsbelowthelowerlimitofthenormalrangeforhealthy,youngmen(8,9).

1.1. DIAGNOSIS AND EVALUATION OF PATIENTS WITH SUSPECTED ANDROGEN DEFICIENCY

1.1.A. Recommendations

We recommend making a diagnosis of androgen defi-ciency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. (1| )

We suggest that clinicians measure serum testosterone level in patients with clinical manifestations shown in Table 1. We suggest that clinicians also consider measuring serum testosterone level when patients report the less specific symptoms and signs listed in Table 1. (2| )

We suggest the measurement of morning total testos-terone level by a reliable assay as the initial diagnostic test. (2| )

We recommend confirmation of the diagnosis by repeating measurement of total testosterone. (1| )

We suggest measurement of free or bioavailable testos-terone level, using an accurate and reliable assay, in some men in whom total testosterone concentrations are near the lower limit of the normal range and in whom alterations of SHBG are suspected. (2| )

We suggest that an evaluation of androgen deficiency should not be made during an acute or subacute illness. (2| )

1.1.B. Evidence

The clinical presentation of hypogonadism in mendependson theageofonsetofandrogendeficiency.Onset in adulthood leads to a clinical syndrome

1.0. DIAGNOSIS OF HYPOGONADISM

Definition of hypogonadism.Hypogonadisminmenisaclinicalsyndromethatresultsfromfailureofthetestis to produce physiological levels of testosterone(androgendeficiency)andanormalnumberofsper-matozoaduetodisruptionofoneormorelevelsofthehypothalamic-pituitary-testicular(HPT)axis.

Classification of hypogonadism. abnormalities ofthe HPT axis at the testicular level cause primarytesticular failure, whereas central defects of thehypothalamusorpituitarycause secondary testicularfailure. Hypogonadism also can reflect dual defectsthataffectboththetestisandthepituitary.

• Primary testicular failure results in low testos-terone levels, impairment of spermatogenesis,andelevatedgonadotropinlevels.

• secondarytesticularfailureresultsinlowtestos-terone levels, impairment of spermatogenesis,andloworlow-normalgonadotropinlevels.

• Combined primary and secondary testicularfailureresults in lowtestosterone levels, impair-ment of spermatogenesis, and variable gonado-tropin levels, dependingonwhetherprimaryorsecondarytesticularfailurepredominates.

Thisclassificationhastherapeuticimplicationsbecausefertility can be restored with appropriate hormonalstimulationinpatientswithsecondaryhypogonadism,butnotinmostpatientswithprimaryhypogonadism.Fertilityoptionsformenwithprimarytesticularfailurearelimitedtotheuseofdonorsperm,adoption,or,insomepatients,assistedreproductivetechnologies,suchas intracytoplasmic sperm injection. also, furtherevaluation of secondary hypogonadism may uncoverapituitarytumororsystemicillness.

Combined primary and secondary hypogonadismoccurs with hemochromatosis, sickle cell disease,thalassemia, glucocorticoid treatment, alcoholism,anddaX-1mutations,andinoldermen(5,6).

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in population-based surveys of community-dwellingmiddle-agedandoldermen, low libido,edandhotflushes,aswellaslessspecificsymptomssuchasfatigueor loss of vigor, irritability or depressed mood, poorconcentration,reducedphysicalperformance,orsleepdisturbance, were associated with low testosteronelevels(10–12).inthesesurveys,thecrudeprevalenceofsymptomaticandrogendeficiencywas~6%inthepopulationofmiddle-agedtooldermenandincreasedwithage,waistcircumference,andpoorself-reportedhealthstatus,butwasunrelatedtoraceandethnicity(12). in other population-based studies, the preva-lence of low testosterone irrespective of symptomswasassociatedwithage,obesity,diabetes,andcomor-bidities or health status (9, 12, 13). The overallprevalenceoflowtestosteronewasfoundtobehigherinaprimarycarepractice–basedpopulationofpatientsthan that reported in populations of community-dwellingmen(14).

Thethresholdtestosteronelevelbelowwhichsymp-toms of androgen deficiency and adverse healthoutcomes occur and testosterone administrationimprovesoutcomes in the general population isnotknown.However,inhealthymenaswellasinreferralpatient populations, the threshold of testosteronelevelsvaried forvarious symptomsofandrogendefi-ciency and target organs, and among individuals(11,12,15).Formostsymptoms,theaveragetestos-terone threshold corresponded to the lower limit ofthe normal range for young men, i.e., ~300 ng/dl(10.4 nmol/l) with a greater likelihood of havingsymptomsbelowthisthresholdthanaboveit(11,15).

serumtestosteronelevelsvarysignificantlyasaresultofcircadianandcircannual rhythms,episodic secre-tion, and measurement variations (16–19). Testos-teroneconcentrationsmaybeaffectedbyillnessandcertain medications (e.g., opiates and glucocorti-coids). Total testosterone concentrations are alsoinfluencedbyalterationsinsHBGconcentrations.

serum testosterone levels exhibit a circadian varia-tionwithpeakvaluesinthemorning;thiscircadianrhythm is blunted with aging (16). Because of thiscircadianvariationintestosteronelevelsandthefactthatnormalrangesforserumtestosteroneareusuallyestablishedusingmorningbloodsamples,testosterone

TABLE 1. Symptoms and signs suggestive of androgen deficiency in men

A.Morespecificsymptomsandsigns

• Incompleteordelayedsexualdevelopment,eunuchoidism

• Reducedsexualdesire(libido)andactivity

• Decreasedspontaneouserections

• Breastdiscomfort,gynecomastia

• Lossofbody(axillaryandpubic)hair,reducedshaving

• Verysmall(especially<5ml)orshrinkingtestes

• Inabilitytofatherchildren,loworzerospermcount• Heightloss,lowtraumafracture,lowbone

mineraldensity• Hotflushes,sweats

B.Otherlessspecificsymptomsandsigns

• Decreasedenergy,motivation,initiative,andself-confidence

• Feelingsadorblue,depressedmood,dysthymia

• Poorconcentrationandmemory

• Sleepdisturbance,increasedsleepiness• Mildanemia(normochromic,normocytic,inthe

femalerange)• Reducedmusclebulkandstrength

• Increasedbodyfat,bodymassindex

• Diminishedphysicalorworkperformance

substantiallydifferentfromthatresultingfromonsetinthefetalorprepubertalperiod.incontrasttomenwhose hypogonadism is of postpubertal onset, menwhosehypogonadismisofprepubertalonsetandwhowere not adequately treated will exhibit eunuchoidproportions, delayed development of secondary sexcharacteristics,andhighpitchedvoice.

diagnosisofandrogendeficiencyinmenposesseveralchallenges.symptomsand signsarenonspecificandmodifiedbyage,comorbidillness,severityanddura-tion of androgen deficiency, variation in androgensensitivity, and previous testosterone therapy. ThesignsandsymptomslistedinTable1arebasedonthepanelists’ experience in clinic-based populations ofandrogen-deficientmenwhoarelikelytohavemoresevereandrogendeficiency;population-basedsurveysofsymptomsandsignsinmenwithclassicalandrogendeficiencyhavenotbeenconducted.

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TABLE 2. Conditions associated with alterations in SHBG concentrations

ConditionsassociatedwithdecreasedSHBGconcentrations• Moderateobesity*

• Nephroticsyndrome*

• Hypothyroidism• Useofglucocorticoids,progestins,andandrogenic

steroids*• Acromegaly

• Diabetesmellitus*

ConditionsassociatedwithincreasedSHBGconcentrations• Aging*

• Hepaticcirrhosisandhepatitis*

• Hyperthyroidism

• Useofanticonvulsants*

• Useofestrogens

• HIVdisease

* ParticularlycommonconditionsassociatedwithalterationsinSHBGconcentrations

gonadal men (18, 19). Total testosterone levels areaffectedbyalterationsinsHBGthatoccurinobesity,oldage,diabetesmellitus,hyper-andhypothyroidism,andacromegaly,and inmentakingcertainmedica-tions(Table2).accurateandreliableassaysforfreeorbioavailabletestosteronemeasurementsusuallyarenot available in local laboratories, and these testsshould be performed in a reliable reference labora-tory. Free testosterone measurements by analogmethods are frequently available in local laborato-ries, but these measurements are affected by altera-tionsinsHBGandareinaccurate(19).Theiruseisnot recommended. Free testosterone level can bemeasuredaccuratelybyequilibriumdialysisorcalcu-lated from total testosterone, sHBG, and albumin(20).ThecalculatedfreetestosteroneconcentrationsaredependentonthequalityoftotaltestosteroneandsHBG assays. The calculated free testosteroneconcentrations differ systematically from thosemeasured by equilibrium dialysis and vary with thealgorithmusedforcalculatingfreetestosterone(21).Bioavailabletestosteroneismeasuredbyammoniumsulfateprecipitationor calculated from total testos-teroneandsHBG.

measurementforthediagnosisofandrogendeficiencyshould be performed in the morning. it has beenargued that morning testosterone measurements arenot needed in older men in whom the circadianrhythmisblunted.However,asubstantialfractionofoldermen,65to80yearsofage,haslowserumtestos-teronelevelsintheafternoonwillhavenormaltestos-teroneconcentrationsinthemorning(17).

itisimportanttoconfirmlowtestosteroneconcentra-tionsinmenwithaninitialtestosteronelevelinthemildlyhypogonadalrange,because30%ofsuchmenmay have a normal testosterone level on repeatmeasurement(17).also,15%ofhealthyyoungmenmayhaveatestosteronelevelbelowthenormalrangein a 24-hour period. in a community-based, multi-ethniccohortofmiddle-agedtooldermen,day-to-dayvariationsinserumtestosteroneconcentrationswerefoundtobesufficientlylargethatsingletestosteronemeasurements were inadequate to characterize anindividual’s levels, and at least two testosteronemeasurementswereneededtodiagnoseandrogendefi-ciencywithgreaterconfidence(17).

serumtotaltestosteroneconcentrationrepresentsthesum of unbound and protein-bound testosterone incirculation. Most of the circulating testosterone isboundtosHBGandtoalbumin(18,19);only0.5–3%ofcirculatingtestosteroneisunboundor“free.”Theterm “bioavailable testosterone” refers to unboundtestosterone plus testosterone bound loosely toalbumin;thistermreflectsthehypothesisthatinaddi-tion to the unbound testosterone, albumin-boundtestosterone is readily dissociable and thus bioavail-able.Freeorbioavailabletestosteroneconcentrationsshouldbemeasuredwhentotaltestosteroneconcen-trations are close to the lower limit of the normalrange and when altered sHBG levels are suspectede.g., inoldermenandinmenwithobesity,diabetesmellitus, chronic illness, or thyroid disease (condi-tionslistedinTable2).

Total testosterone concentrations are measured byradioimmunoassay (Ria), immunometric assays, orliquid chromatography tandem mass spectrometry.automatedassaysfortotaltestosteroneareavailablein most hospital laboratories and usually are suffi-cientlyaccuratetodistinguisheugonadalfromhypo-

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1.1.1. FURTHER EVALUATION OF MEN DEEMED ANDROGEN DEFICIENT (FIG. 1)

1.1.1.A. Recommendations

We recommend measurement of serum LH and FSH levels to distinguish between primary (testicular) and secondary (pituitary-hypothalamic) hypogonadism. (1| )

In men with secondary hypogonadism, we suggest further evaluation to identify the etiology of hypothalamic and/or pituitary dysfunction. This evaluation may include measurements of serum prolactin and iron saturation, pituitary function testing, and magnetic resonance imaging of the sella turcica. (2| )

In men with primary testicular failure of unknown etiology, we suggest obtaining a karyotype to exclude Klinefelter syndrome, especially in those with testicular volume less than 6 ml. (2| )

In men being evaluated for infertility, we recommend obtaining at least two seminal fluid analyses. (1| )

We suggest measurement of bone mineral density by using dual-energy x-ray absorptiometry (DXA) scanning in men with severe androgen deficiency or low trauma fracture. (2| )

1.1.1.B. Evidence

Measurement of lH and FsH concentrations canhelp distinguish between primary and secondaryhypogonadism. Men with primary hypogonadismhave low testosterone levels in association withelevated lH and FsH levels, while men withsecondaryhypogonadismhavelowtestosteronelevelsinassociationwithloworinappropriatelynormallHlevels.BecauselHissecretedinapulsatilemannerbythepituitary,serumlHlevelsinmenwithsecondaryhypogonadismmaybebelowthenormalrangeorinlow-normalrangebutclearlyinappropriateinrelationtothelowtestosteroneconcentrations.inindividualswithcompleteidiopathichypogonadotropichypogo-nadism(e.g.,Kallmannsyndrome)andseveregonad-aotropinsuppressionordeficiency,lHpulsatilitymaybe absent or markedly suppressed and these men

Thenormativerangesfortotalandfreetestosteronelevelsinhealthyyoungmenvaryamonglaboratoriesandassays(18).insomelaboratories,thelowerlimitof the normal range for total testosterone level inhealthyyoungmenis280-300ng/dl(9.8-10.4nmol/l).similarly, in some reference laboratories, the lowerlimitofthenormalrangeforserumfreetestosteronelevel,measuredbytheequilibriumdialysismethod,is5–9pg/ml(0.17-0.31nmol/l).Thecliniciansshouldusethelowerlimitofnormalrangeforhealthyyoungmenestablishedintheirlaboratory.

Theassessmentofmenforandrogendeficiencyshouldincludeageneralhealthevaluationtoexcludesystemicillness, use of certain medications (e.g., opiates orhigh-dose glucocorticoid therapy) and recreationaldrugs that affect testosterone production or metabo-lism,eatingdisorders,andexcessiveexercisebecausethese conditions can lower testosterone levels tran-siently(5).long-actingopioidanalgesicssuppressthehypothalamic-pituitary-gonadal (HPG) axis in men,produce symptomatic androgen deficiency, and areassociatedwithincreasedriskofosteoporosis(22,23).Thesuppressionoftestosteroneisparticularlyprofoundinmenonmethadonemaintenancetherapybecauseofits longdurationofaction;buprenorphinesuppressesplasmatestosteronetoalesserextentthanmethadone(24). androgen deprivation therapy using gonado-tropin-releasing hormone (GnRH) analogs in menwith prostate cancer has emerged as an importantcauseof therapeutically inducedandrogendeficiencythatisassociatedwithincreasedriskofsexualdysfunc-tion, fatigue, fractures, cardiovascular disease, anddiabetes (25). The diagnosis of androgen deficiencyshouldnotbemadeduringanacuteillness.

1.1.C. Values

Our proposed diagnostic strategy reflects our prefer-ence to avoid labeling men with low testosteronelevelsduetosHBGabnormalities,naturalvariationsin testosterone levels, or transient disorders asrequiring testosterone therapy. Our strategy alsoreflects our preference to avoid treatment in menwithout unequivocally low testosterone levels andsymptoms in whom the benefits and risks of testos-teronetherapyremainunclear.

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obstructivesleepapnea,andgeneticdisordersassoci-atedwithgonadotropindeficiency.Themeasurementofserumprolactinandironsaturationcanhelpdeter-minethepresenceofhyperprolactinemiaandhemo-chromatosis, respectively. assessment of anteriorpituitary function, if clinically indicated or in thepresence of severe secondary hypogonadism (testos-terone level<150ng/dl [<5.2nmol/l]),canuncoverotherpituitaryhormonedeficiencies.adiagnosisof

usuallyhaveverylowtestosteroneandlHlevels.inmost clinical laboratories, lH levels are measuredusingnonradioactiveimmunometricassaysthathavesufficient sensitivity to distinguish between normalandlowlevels.

in men deemed to have secondary hypogonadism,additional diagnostic evaluation may be needed toexclude pituitary neoplasia, hyperprolactinemia,hemochromatosis and other infiltrative diseases,

FIG. 1. An approach for the diagnostic evaluation of adult men suspected of having androgen deficiency. FSH = follicle- stimulating hormone; LH = luteinizing hormone; MRI=magnetic resonance imaging; SFA,=seminal fluid analysis; SHBG = sex hormone-binding globulin; T = testosterone

# Insomelaboratories,thelowerlimitofthenormaltestosteronerangeinhealthyyoungmenisapproximately280–300ng/dl(9.8–10.4nmol/l);however,thisrangemayvaryindifferentlaboratories.Usethelowerlimitoftherangeestablishedinyourreferencelaboratory.

@ Insomereferencelaboratories,thelowerlimitofthenormalfreetestosteronerangeinhealthyyoungmenisapproximately5–9ng/dL(0.17–0.31nmol/liter)usingequilibriumdialysisorcalculatedfromtotaltestosteroneandSHBG;however,thisrangemayvaryindifferentlaboratories,dependingonthespecificequilibriumdialysisorcalculatedfromtotaltestosteroneandSHBGassaysandthereferencepopulationused.Usethelowerlimitoftherangeestablishedinyourreferencelaboratory.

^ ConditionsinwhichSHBGlevelsmaybealteredarelistedinTable2.

* PerformpituitaryimagingMRItoexcludepituitaryand/orhypothalamictumororinfiltrativedisease,ifseveresecondaryhypogonadism(serumT<150ng/dl),panhypopituitarism,persistenthyperprolactinemia,orsymptomsorsignsoftumormasseffect,suchasheadache,visualimpairment,orvisualfielddefect,arepresent.

History and physical (symptoms and signs)

Morning Total T

Low T #

Normal T

Exclude reversible illness, drugs, nutritional deficiencyRepeat T [use free or bioavailable T, if suspect altered SHBG^]

LH+FSHSFA [If fertility issue]

Follow up

Confirmed low T [Low total T#; or free or bioavailable T@)]

Low T, low or normal LH+FSH(secondary hypogonadism)

Low T, high LH+FSH(primary hypogonadism)

Prolactin, iron, other pituitary hormones, MRI

[under certain circumstances*]

Karyotype[Klinefelter syndrome]

Normal T, LH+FSH

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separated by an interval of several weeks should beperformedonsemensamplescollectedwithin1hourofejaculationafteratleast48hoursofabstinence.

The cost-effectiveness of these diagnostic strategieshasnotbeenevaluatedinclinicaltrials.

1.1.1.C. Values

Our recommended diagnostic strategy places a rela-tively higher value in detecting conditions (e.g.,pituitaryneoplasiaorother treatablepituitarydisor-ders) for which effective treatment or counseling isavailable. This strategy places a relatively lowervalue in avoiding the burden and cost of tests withunknownyield.

1.2. SCREENING FOR ANDROGEN DEFICIENCY

1.2.1. Screening in the general population

1.2.1.A. Recommendation

We recommend against screening for androgen deficiency in the general population. (1| )

1.2.1.B. Evidence

Becauseofthelackofconsensusonacasedefinitionand the extent towhich androgendeficiency is animportanthealthproblem,aswellasthelackofdataon the performance characteristics of candidatescreening tools, the usefulness of populationscreeningcannotbeevaluatedatpresent.Thelong-termhealthconsequencesoflowtestosteronelevelsareunknowninthetwolargestsubsetsofmenwithlow testosterone levels—older men and men withchronic illness. The impact of untreated androgendeficiencyonmortalityisunclear,althoughseveral,butnotall,epidemiologic studieshave reportedanassociationoflowtestosteronelevelswithhigherall-causemortality,particularlymortalityduetocardio-vascular disease (31–34). The benefits and adverseconsequences of long-term testosterone therapy onpatient-important outcomes in asymptomatic menwith presumed hypogonadism remain unclear (35,36). Therefore, screening for androgen deficiencydoesnotfulfillanyofthenecessarycriteriatojustify

idiopathic hypogonadotropic hypogonadism is madeafter excluding other causes of hypogonadotropichypogonadism. Patients with hypogonadotropichypogonadism should be examined for dysmorphicfeatures—suchasextremeobesity(e.g.,Prader-Willisyndrome), polydactyly, anosmia (e.g., Kallmannsyndrome),shortstature(e.g.,contiguousgenedele-tions of chromosome X), or kidney abnormalities(e.g.,Kallmannsyndrome)—tofacilitaterecognitionofspecificsyndromesbypatternrecognition.

in the evaluation of men with secondary hypogo-nadism, the cost-effectiveness of pituitary imagingMRitoexcludepituitaryand/orhypothalamictumorisunknown.surveysofmenwithsecondaryhypogo-nadism and sexual dysfunction have revealed a lowprevalence of hypothalamic-pituitary abnormalities(26,27).Thediagnosticyieldofpituitaryimagingtoexcludepituitaryand/orhypothalamictumorcanbeimprovedbyperformingthisprocedure inmenwithserumtestosteronebelow150ng/dl(26),panhypopi-tuitarism,persistenthyperprolactinemia,orsymptomsoftumormasseffect(headache,visualimpairment,orvisualfielddefect).

Karyotype can be useful in excluding Klinefeltersyndrome ─ a common identifiable cause of primarytesticular failure ─ in men with primary testicularfailure,especiallyinthosewithtesticularvolumelessthan 6 ml, although men with mosaic Klinefeltersyndrome may have larger testicular volumes. Thekaryotype obtained from peripheral blood lympho-cytesmaybenormal(46,XY)inmenwithKlinefeltersyndrome who have mosaicism (46, XY/ 47, XXY).Men with Klinefelter syndrome can benefit fromgeneticcounselingandneedsurveillance forcertaindisordersforwhichtheyareatincreasedrisk(28).

Testosterone stimulatesbone formationand inhibitsbone resorption through multiple mechanisms thatinvolve both androgen and estrogen receptor-mediated processes (29,30). However, the cost-effectivenessofmeasuringbonemineraldensityandthe frequency at which it should be performed arestillbeingdebated.

if fertility is apressingclinical issue topatients andtheir partners, at least two seminal fluid analyses

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TABLE 3. Conditions in which there is a high prevalence of low testosterone levels and for which we suggest measurement of serum testosterone levels

• Sellarmass,radiationtothesellarregion,orotherdiseasesofthesellarregion

• Treatmentwithmedicationsthataffecttestosteroneproductionormetabolism,suchasglucocorticoidsandopioids

• HIV-associatedweightloss

• End-stagerenaldiseaseandmaintenancehemodialysis

• Moderatetoseverechronicobstructivelungdisease

• Infertility• Osteoporosisorlowtraumafracture,especiallyina

youngman• Type2diabetesmellitus

Inmenwithchronicdiseasessuchasdiabetesmellitus,end-stagerenaldisease,chronicobstructivelungdisease,measurementoftestosteronemaybeindicatedbysymptomssuchassexualdysfunction,unexplainedweightloss,weakness,ormobilitylimitation.Inmenwithsomeotherconditions,suchasapituitarymass,HIV-associatedweightloss,lowtraumafracture,ortreatmentwithmedicationsthataffecttestosteroneproduction,measure-mentoftestosteronemaybeindicatedregardlessofsymptoms.

testosterone therapy in these conditions is eitherlimitedornotavailable.

There is limited information about the performanceproperties of case-detection instruments that rely onself-report, namely, androgen deficiency in agingMales (adaM) (41), the aging Males’ symptoms(aMs)Ratingscale(42),andtheMassachusettsMaleagingstudyQuestionnaire(43).Therearenotrialsofcase-detectionstrategies inthesepatientpopulations,and the cost-effectiveness of the use of case-findinginstruments over measurement of serum testosteronelevelsisunknownandtheirspecificityispoor(44).

1.2.2.C. Values

Our recommendation in favor of case detection bymeasurementoftestosteronelevelsplacesarelativelyhighvalueonthepotentialbenefitsandarelativelylowvalueontheburdenoftestosteronetherapyanduncertaintyaboutitslong-termsafety.

it.noclinical trialshaveassessedtheeffectivenessofscreeningstrategies.

1.2.1.C. Values

The recommendation not to screen men in thegeneral population places a high value on avoidinglabelingandmedicalizationofotherwisehealthymenfor whom testing, treatment, and monitoring wouldrepresentaburdenwithunclearbenefit.Thisrecom-mendationalsoplacesahighvalueonavoidinginter-ventionswithunclearoutcomes.itplacesalowvalueonthepotentialbenefitsofearlydetectionandtreat-ment of androgen deficiency in men who have notsoughtmedicalattention.

1.2.2. Case Finding of Androgen Deficiency

1.2.2.A. Recommendations

We suggest that clinicians not use the available case-finding instruments for detection of androgen deficiency in men receiving health care for unrelated reasons. (2| )

We suggest that clinicians consider case detection by measurement of total testosterone levels in men with certain clinical disorders, listed in Table 3, in which the prevalence of low testosterone levels is high or for whom testosterone therapy is suggested/recommended in Section 2.0. (2| )

1.2.2.B. Evidence

ideally,casedetectionshouldidentifyfromtheclinicpopulationpatientswhopresentwithmedicalprob-lemsapparentlyunrelatedtoandrogendeficiency,butwho are likely to benefit from testosterone therapy.Candidategroupsinwhomthereishighprevalenceoflow testosterone levels and in whom we suggestmeasurementofserumtestosteronelevelarelistedinTable3;theseincludemenwithchronicillness,suchas those with HiV-associated weight loss, end-stage renal disease on dialysis, chronic obstructivepulmonary disease, osteoporosis or fracture afterlowtraumaatayoungage, type2diabetesmellitus,andmenreceivingchronicglucocorticoidandopioids(5, 6, 37–40). Most surveys of men with chronicillnessincludedrelativelysmall,conveniencesamples.The information about the benefits and risks of

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tate and PSA measurement before initiating treatment, at 3 to 6 months, and then in accordance with evidence-based guidelines for prostate cancer screening, depending on the age and race of the patient. (1| )

2.1.B. Evidence

2.1.1. Non–placebo-controlled studies.

loweringoftestosteroneconcentrationsinadultmenbysurgicalorchiectomyorbyGnRHagonistorantag-onist administration is associated with rapid andmarkedlossofbonemineraldensity(29),increaseinfatmass(45),andalossofmusclemassandstrength(45). lowering of testosterone concentrations alsoresultsinhotflushesandadecreaseinoverallsexualactivity,thoughts,andfantasies.

Testosterone therapy of young, hypogonadal men isassociated with improvements in overall sexualactivity scores, frequency of sexual thoughts andfantasies,anincreaseinattentivenesstoeroticstimuli,and an increase in the frequency and duration ofnighttime erections (46–53). Testosterone therapyincreases hair growth in several androgen-sensitiveareas. Testosterone therapy of healthy, hypogonadalmenalsoincreasesfat-freemass(47,48,54–57)andmusclestrength(47,54)anddecreasesfatmass(47,48, 57). although testosterone therapy of healthy,hypogonadal men increases bone mineral densitydepending on compliance (58–60), the effects oftestosteroneonfractureriskareunknown.

Testosteronetherapyimprovesthepositiveandreducesthenegativeaspectsofmood(60,61).uncontrolledstudies report improvements in energy and sense ofwell-beingaftertestosteronetherapy(62).inasmallopen-labeltrial,testosteronetherapyhasbeenreportedtoimprovesomequality-of-lifemeasuressuchassexualfunction,well-being,andmood inmenwithopioid-induced androgen deficiency (22). The effects oftestosterone on cognitive function are poorly under-stood;somestudiesreportsmalleffectsonvisuospatialcognitionandverbalmemoryandfluency(63,64).

data on the impact of testosterone replacement oninsulin sensitivity have yielded conflicting results.somestudieshavedemonstratedfavorableeffects in

2.0. TREATMENT OF ANDROGEN DEFICIENCY WITH TESTOSTERONE

2.1. TESTOSTERONE THERAPY IN ADULT MEN WITH CLASSICAL ANDROGEN DEFICIENCY

2.1.A. Recommendations

We recommend testosterone therapy for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteris-tics and at improving their sexual function, sense of well-being, and bone mineral density. (1| )

We recommend against testosterone therapy in patients with breast (1| ) or prostate cancer. (1| )

We recommend that clinicians assess prostate cancer risk in men being considered for testosterone therapy. We recommend against testosterone therapy without further urological evaluation in patients with palpable prostate nodule or induration or PSA > 4 ng/ml or PSA > 3 ng/ml in men at high risk of prostate cancer, such as African Americans or men with first-degree relatives with pros-tate cancer. (1| )

We recommend against testosterone therapy in patients with hematocrit >50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms (AUA/IPSS score > 19), or uncontrolled or poorly controlled heart failure, or in those desiring fertility. (1| )

We suggest that when clinicians prescribe testosterone therapy, the therapeutic target should be to raise serum testosterone levels into a range that is mid-normal for healthy, young men. (2| )

In men receiving testosterone enanthate or cypionate, serum testosterone levels vary during the dosing interval; we suggest aiming for testosterone levels between 400 and 700 ng/dl midway between injections. (2| )

In men 40 years of age or older who have a baseline PSA > 0.6 ng/ml, we recommend digital examination of the pros-

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shouldincludeconsiderationofadditionalriskfactors,suchasage,familyhistory(greaterriskinmenhavinga first-degree relative with prostate cancer), race(greater risk in african americans), prior biopsyhistory,comorbidities,andPsavelocityanddensity(75,76).We suggest estimatingprostatecancer riskusing the prostate cancer risk calculator (http://deb.uthscsa.edu/uRORiskCalc/Pages/calcs.jsp),which takes into consideration age, ethnicity, Psa,findingsofdigitalrectalexamination,familyhistory,theuseofa5-αreductaseinhibitor,andpriorbiopsyhistory. Men in the placebo arm of the ProstateCancer Prevention Trial were observed to haveincreased risk of an occult prostate cancer even iftheirPsawas<4.0ng/ml,andtheriskincreasedasthePsaincreasedabove0.5ng/ml(75).Theprostatecancerriskcalculatorprovidesameansforevaluatingprostate cancer risk in men who are consideringtestosteronetreatment(76),but itcanonlybeusedformen55to95yearsofage(76).inmendeemedtobe at high risk for prostate cancer, such as africanamericans and men with first-degree relatives withprostatecancer,aPsalevel>3ng/mlshouldprompta urological consultation before consideration oftestosteronetherapy.Furthermore,inmenwithhema-tocrit>50%,untreatedobstructivesleepapnea,severelower urinary tract symptoms, or severe congestiveheartfailure,testosteronemayworsenthesecondition(77).Testosteronetherapymaysuppressspermatogen-esisandisnotappropriateinmenwhodesirefertility.

Open-labelstudiesinyoung,hypogonadalmenhavefoundalowfrequencyofadverseeventswithreplace-ment doses of testosterone. Common drug-relatedadverseevents includeincrease inhematocrit,acne,oilinessofskin,andbreasttenderness(Table5).Thefrequency of breast enlargement, sleep apnea, andprostateeventsislowintrialsofyoung,hypogonadalmen.asystematicreviewoftestosteronetherapy inmen with low or low normal testosterone levelsincluded37randomizedcontrolledtestosteronetrialsin hypogonadal men, healthy older men, men withsexual dysfunction, HiV-infected men with weightloss, and in men with a variety of other conditions(2).Thismeta-analysisoflowqualityevidence,mostlybecause of large loss to follow-up and inconsistentresultsacrossstudies,foundthattestosteronetherapy

menwithobesity(65,66)ortype2diabetes(67),andinhealthyoldermen(68).incontrast,otherstudieshaveshownnochangesininsulinsensitivityfollowingandrogen administration to healthy young (69) andoldermen(70).

Testosterone therapy may be associated withincreasedriskofseriousadverseeffectsinmenwithsomedisorders(Table4).Metastaticprostatecancerand breast cancer are hormone-dependent cancersthatmaybe stimulated to growduring testosteronetreatment(71);testosteroneshouldnotbeadminis-tered to men with these cancers. although someclinicians have suggested that patients with organ-confinedprostatecancerwhohaveundergoneradicalprostatectomyandhavebeendisease-free2ormoreyearsafterradicalprostatectomyandwhohaveunde-tectable Psa levels may be considered for testos-terone replacement on an individualized basis(72–74),butthelackofdatafromrandomizedtrialsprecludesageneralrecommendation.

aprostatenoduleorindurationoraPsa>4.0ng/mlmayindicateapreviouslyunrecognizedprostatecancer.in addition to Psa and digital rectal examination(dRe)results,theassessmentofprostatecancerrisk

TABLE 4. Conditions in which testosterone administration is associated with a high risk of adverse outcome and for which we recommend against using testosterone

Veryhighriskofseriousadverseoutcomes

• Metastaticprostatecancer

• Breastcancer

Moderatetohighriskofadverseoutcomes• Unevaluatedprostatenoduleorinduration

• PSA>4ng/ml(>3ng/mlinindividualsathighriskforprostatecancer,suchasAfricanAmericansormenwithfirst-degreerelativeswhohaveprostatecancer)

• Hematocrit>50%

• SeverelowerurinarytractsymptomsassociatedwithbenignprostatichypertrophyasindicatedbyAUA/IPSSscore>19

• Uncontrolledorpoorlycontrolledcongestiveheartfailure

AUA/IPSS=AmericanUrologicalAssociation/InternationalProstateSymptomScore

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TABLE 5. Potential adverse effects of testosterone replacement

Adverseeventsforwhichthereisevidenceofassociationwithtestosteroneadministration• Erythrocytosis

• Acneandoilyskin

• Detectionofsubclinicalprostatecancer

• Growthofmetastaticprostatecancer

• Reducedspermproductionandfertility

Uncommonadverseeventsforwhichthereisweakevidenceofassociationwithtestosteroneadministration• Gynecomastia

• Malepatternbalding(familial)

• Growthofbreastcancer

• Inductionorworseningofobstructivesleepapnea

Formulation-specificadverseeffects• Intramuscularinjectionsoftestosteroneenanthate,

cypionateorundecanoate

– Fluctuationinmoodorlibido

– Painatinjectionsite

– Excessiveerythrocytosis(especiallyinolderpatients)

– Coughingepisodesimmediatelyaftertheintramuscularinjection*

• Transdermalpatches

– Frequentskinreactionsatapplicationsite

• Transdermalgel

– Potentialriskfortestosteronetransfertopartneroranotherpersonwhoisinclosecontact(needtoremindpatienttocoverapplicationsiteswithclothingandtowashskinandhandswithsoapbeforehavingskin-to-skincontactwithanotherperson)

– Skinirritation

• Buccaltestosteronetablets

– Alterationsintaste

– Irritationofgums

• Pelletimplants

– Infection,expulsionofpellet

• Oraltablets

– Effectsonliverandcholesterol(methyltestosterone)†

* Themechanismofcough,whichhasbeenreportedrarelyafterintramuscularinjectionsoftestosteroneundecanoateandevenmorerarelyaftertestosteroneenanthateandcypionate,isunknown,butithasbeenattributedtooilembolization.

† Livertoxicityhasbeenreportedmostlywithoral17-alphaalkylatedandrogens.Thefrequencyofskinreactionsishigherwiththetestosteronepatchthanwiththetransdermalgels.

wasassociatedwithgreaterincreasesinhemoglobin,hematocrit,andPsa,andagreaterdecreaseinhigh-density lipoprotein (Hdl) cholesterol level thanplacebo(2).Theseeffectsweremostmarkedinstudiesenrollingolderpatientswith low testosterone levelsusingintramusculartestosteronepreparations.Overallmortality,cardiovasculareventrates,prostatecancer,lowerurinarytractsymptomscores,andsystolicanddiastolicbloodpressuredidnotdiffer among testos-terone-andplacebo-treatedmen(2).

2.1.2. Placebo-controlled, randomized trials.

asystematic review foundno randomized, placebo-controlledtrialsoftheeffectoftestosteronetherapyondepression,cognition,fragilityfractures,qualityoflife, or cardiovascular outcomes in young, hypogo-nadal men (3). in trials that reported the effect oftestosteroneon libido(3,4,46,78–80)anderectilefunction (81–87) in hypogonadal men, testosteronetherapywasassociatedwithgreaterimprovementsinlibido (difference between testosterone and placebogroups1.2;95%confidenceinterval[Ci],0.3,2.2)butnosignificant improvements inself-reportederectilefunction (0.8; 95% Ci, –0.05, 1.6.) compared withplacebo (4). in a systematic review of testosteronetrials that were published before October 2004 andthat enrolled men with low testosterone levels (4),testosteronetherapywasassociatedwithamoderatenonsignificantandinconsistenteffectonsatisfactionwith erectile function (random effects pooled effectsize,0.80;95%Ci–0.10,1.60),alargeeffectonlibido(pooledeffectsize,1.31,95%Ci,0.40,2.25),andnosignificant effect on overall sexual satisfaction (4).Trialsthatenrolledpatientswithlowor low-normaltestosterone levels at baseline showeda small effecton satisfaction with erectile function (pooled effectsize,0.34;95%Ci,0.03,0.65),moderatenonsignifi-canteffectonlibido(pooledeffectsize,0.41;95%Ci,–0.01, 0.83), and no significant effect on overallsexualsatisfaction.Theinconsistencyacrosstrialsandimprecision of pooled estimates weaken these infer-ences (4). The trials of the effects of testosteronetherapyonerectileresponsetoselectivephosphodies-terase 5 (Pde-5) inhibitors have been inconclusive(87–93).

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Monitoring androgen-deficient men receiving testosterone therapy. androgen-deficient menreceivingtestosteronetherapywhoare>40yearsofage with a baseline Psa > 0.6 ng/ml should befollowed using a standardized, monitoring plan(Table 8) to facilitate early detection of adverseeventsandtopreventunnecessaryprostatebiopsiesthatmightleadtodetectionofsubclinicalprostatecancer(77,98).adifficultissueinthefollow-upofhypogonadal men receiving testosterone therapyrelates to thecriteria that shouldbeused toguidethe decision to perform prostate biopsy. Psameasurements have considerable test-retest vari-ability (99).TransientPsaelevationsmaybedueto other prostatic disorders. Psa levels may beincreased by prostatitis, benign prostatic hyper-plasia, prostate trauma, urinary tract infections,prostatecancer,andassayvariability.ifprostatitisissuspected, appropriate antibiotic treatment hasbeen reported to decrease Psa by approximately30% (100, 101). Therefore, we recommend thatPsaelevationsbeconfirmedbyrepeatingthetest.

The 90% confidence limit for the change in Psalevels between two tests performed 3 to 6 monthsapartinastudyofmenwithbenignprostatichyper-plasiawas1.4ng/ml(102).inasystematicreview,theaveragePsaincreaseafter initiationoftestosteronetherapy was 0.3 ng/ml in young, hypogonadal menand0.44ng/ml inoldermen(98).The increases inPsa levels after testosterone therapy in androgen-deficient men in excess of 1.4 ng/ml over a 3- to6-monthperiodareunusual.Theseconsiderationsledustosuggesturologicalconsultationforevaluationofconfirmed Psa increments > 1.4 ng/ml during any1-yearperiodafterinitiationoftestosteronetherapy.inmenforwhomsequentialPsameasurementsareavailable for more than 2 years, Carter (103) hasproposedtheuseofPsavelocitytoidentifymenathigher risk for prostate cancer. For periods of morethan 2 years, Psa velocity > 0.4 ng/ml·yr shouldwarrant a urological evaluation and more intensivefuturesurveillanceforprostatecancer(103).

Becausetheriskofprostatecancerisverylowinmenyounger than age 40, they may not need prostatemonitoring. The american urological association’s

Most studies of testosterone therapy in young,hypogonadalmenhavebeenopenlabelanddidnotinclude a placebo group. The observations fromtheseopen-labelstudiesareconsistentwiththesparsedatafromrandomizedtrialsandwiththeexperienceofthepanelists.(Quality of evidence: )

2.1.C . Values

Therecommendationtooffertestosteronetherapytohealthy,hypogonadalmenwithclassicandrogen-defi-ciencysyndromesplacesarelativelyhighervalueonalleviatinghypogonadalsymptomsandotherbenefitsoftestosteronetherapyandarelativelylowervalueonavoidingthepotentialburdenoflong-termtreatment,monitoring,cost,anditsunclearlong-termsafety.

2.1.D. Remarks

Table 6 summarizes the clinical pharmacology of theavailable testosterone formulations. When cliniciansrecommendtestosteronetherapy,wesuggestaimingatachieving testosterone levels in a range that ismidnormalforhealthy,youngmen.inmenreceivingtestosterone enanthate or cypionate, serum testos-teronelevelsvaryduringthedosinginterval;wesuggestaimingfortestosteronelevelsbetween350and750ng/dloneweekafter the injection.Testosteronetherapycanbeinitiatedwithanyofthesuggestedregimensinaccordwithconsiderationsofthepatient’spreference,pharmacokinetics of testosterone formulation, treat-mentburden,andcost(Table7).Outsidetheunitedstates,oral testosteroneundecanoate,amatrixtrans-dermaltestosteronepatch,andinjectabletestosteroneundecanoate are available for clinical use in manycountries;physiciansinthosecountrieswhowishtousethese formulations should follow the drug regimensapproved in those countries. see Tables 6 and 8 foradditionalsafetyandpharmacokineticsinformation.

Whenthegoaloftreatmentistoreplacetestosterone,treatment of men whose hypogonadism is of prepu-bertal onset is similar to that of men with hypogo-nadismofpostpubertalonset,asdescribedabove. incontrast, when the goal of treatment is to restorefertility,menwithhypogonadismofprepubertalonsetaremorelikelytorequirereplacementofFsHaswellaslH,whereasmenwithpostpubertalonsetaremorelikelytorequirereplacementoflHonly(94–97).

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TABLE 6. Clinical pharmacology of some testosterone formulations

Formulation Regimen Pharmacokinetic profile DHT and E2 Advantages Disadvantages

Tenanthateorcypionate

150–200mgIMq2wkor75–100mg/wk

AfterasingleIMinjection,serumTlevelsriseintothesupraphysi-ologicalrange,thendeclinegraduallyintothehypogonadalrangebytheendofthedosinginterval

DHTandE2levelsriseinproportiontotheincreaseinTlevels;T:DHTandT:E2ratiosdonotchange

Correctssymptomsofandrogendeficiency;relativelyinexpensive,ifself-administered;flexibilityofdosing

RequiresIMinjection;peaksandvalleysinserumTlevels

1%Testosteronegel

Availableinsachets,tubesandpumps5–10gTgelcontaining50–100mgTqd

RestoresserumTandE2levelstothephysiologicalmalerange

SerumDHTlevelsarehigherandT:DHTratiosarelowerinhypogonadalmentreatedwiththeTgelthaninhealthyeugonadalmen

Correctssymptomsofandrogendeficiency,providesflexibilityofdosing,easeofapplication,goodskintolerability

Potentialoftransfertoafemalepartnerorchildbydirectskin-to-skincontact;skinirritationinasmallproportionoftreatedmen;moderatelyhighDHTlevels

Transdermaltestosteronepatch

1or2patches,designedtonominallydeliver5–10mgTover24happliedqdonnonpressureareas

RestoresserumT,DHT,andE2levelstothephysiologicalmalerange

T:DHTandT:E2levelsareinthephysiologicalmalerange

Easeofapplication,correctssymptomsofandrogendeficiency

SerumTlevelsinsomeandrogen-deficientmenmaybeinthelow-normalrange;thesemenmayneedapplicationof2patchesdaily;skinirritationattheapplicationsiteoccursfrequentlyinmanypatients

Buccal,bioadhesive,Ttablets

30mgcontrolledrelease,bioadhesivetabletsbid

Absorbedfromthebuccalmucosa

NormalizesserumTandDHTlevelsinhypogonadalmen

Correctssymptomsofandrogendeficiencyinhealthy,hypogo-nadalmen

Gum-relatedadverseeventsin16%oftreatedmen

Tpellets 3-6pelletsimplantedsc;doseandregimenvarywithformulation

SerumTpeaksat1moandthenissustainedinnormalrangefor3–6mo,dependingonformulation

T:DHTandT:E2ratiosdonotchange

Correctssymptomsofandrogendeficiency

Requiressurgicalincisionforinsertions;pelletsmayextrudespontaneously

17-α methylT This17-α alkylatedcompoundshouldnotbeusedbecauseofpotentialforlivertoxicity.

Orallyactive Clinicalresponsesarevariable;potentialforlivertoxicity;shouldnotbeusedfortreatmentofandrogendeficiency

OralTundecanoate*

40to80mgpobidortidwithmeals

Whenadministeredinoleicacid,Tundecanoateisabsorbedthroughthelymphatics,bypassingtheportalsystem;considerablevariabilityinthesameindividualondifferentdaysandamongindividuals

HighDHTwithTratio Convenienceoforaladministration

NotapprovedintheUSA;variableclinicalresponses,variableserumTlevels,highDHT:Tratio

Injectablelong-actingTundecanoateinoil*

Europeanregimen1000mgIM,followedby1000mgat6wk,and1000mgq10–14wk

Whenadministeredatadoseof750to1000mgIM,serumTlevelsaremaintainedinthenormalrangeinamajorityoftreatedmen

DHTandE2levelsriseinproportiontotheincreaseinTlevels;T:DHTandT:E2ratiosdonotchange

Correctssymptomsofandrogendeficiency;requiresinfrequentadministration.

RequiresIMinjectionofalargevolume(4ml);coughreportedimmediatelyafterinjectioninaverysmallnumberofmen

Testosteronein-adhesivematrixpatch*

2X60cm2patchesdeliveringapproxi-mately4.8mgT/d

RestoresserumT,DHTandE2tothephysiologicalrange

T:DHTandT:E2areinthephysiologicalrange

Lasts2d Someskinirritation

DHT=dihydrotestosterone;E2=estradiol;T=testosterone

* TheseformulationsarenotapprovedforclinicaluseintheUSA,butareavailableoutsidetheUSAinmanycountries.Physiciansincountrieswheretheseformulationsareavailableshouldfollowtheapproveddrugregimens.

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before consideration of testosterone therapy. Menreceiving testosterone therapy should have hemato-critmeasuredatbaselineand3to6monthsafteriniti-ationoftestosteronetherapy.

2.2. TESTOSTERONE THERAPY IN MEN WITH SEXUAL DYSFUNCTION

2.2.A. Recommendation

We suggest that clinicians offer testosterone therapy to men with low testosterone levels and low libido to improve libido (2| ) and to men with ED who have low testosterone levels after evaluation of under-lying causes of ED and consideration of established ther-apies for ED. (2| )

2.2.B. Evidence

spontaneous and experimentally induced androgendeficiencyisassociatedwithadecreasedfrequencyofsexual thoughts and fantasies, nighttime erections.overall sexual activity, and attentiveness to eroticstimuli(4,46–53,59,78–83).androgendeficiencyisan important cause of hypoactive sexual desiredisorder. However, androgen deficiency and ed aretwoindependentlydistributedclinicaldisorderswithdistinct pathophysiology; the two disorders maycoexistinmiddle-agedandoldermen(53,84).

Libido. amongrandomizedtrialsthatenrolledpatientswithtotaltestosteronelevels<300ng/dl(10.4nmol/l),twoparalleltrials(48,82)andthreecrossovertrials(49,79, 83) reported effects on libido; the longest trialfollowedparticipantsfor6months(4,79).Theresultsof these trials were inconsistent but revealed a largeimprovementinlibido(1.3sdunits;95%Ci,0.4,2.2)(4).(Quality of evidence: )

among trials that enrolled men with total testos-terone levels > 300 ng/dl (10.4 nmol/l), a meta-analysisreportedfourtrialsthatevaluatedeffectsonlibido (4). not included in the meta-analysis is arecent placebo-controlled study of men > 55 yearsof age with total testosterone levels < 430 ng/dl(<15 nmol/l); in this trial, testosterone treatmentimproved sexualdesire (80).However, in themeta-analysis, the pooled effect of testosterone on libido

TABLE 7. Some recommended regimens* for testosterone replacement therapy

• 150to200mgadministeredevery2wk,or75–100mgoftestosteroneenanthateorcypionateadministeredIMweekly

• Oneortwo5-mgtestosteronepatchesappliednightlyovertheskinoftheback,thigh,orupperarm,awayfrompressureareas

• 5to10goftestosteronegelapplieddailyoveracoveredareaofskin

• 30mgofabioadhesive,buccaltestosteronetabletappliedtobuccalmucosatwicedaily

• Testosteronepellets(doseandregimenvarywiththeformulationused)

* FormulationsavailableinothercountriesbutnotintheUnitedStatesinclude:1)oraltestosteroneundecanoate(typicallyusedatadoseof40to80mgorallytwoorthreetimesdailywithmeals);2)twotestosteronematrixpatches30,45,or60cm2appliedevery2days;3);Injectabletestosteroneundecanoate1000mgfollowedbyasecond1000mginjection6weekslater,andthen1000mgevery10to14weeks.Physiciansinthosecountrieswheretheseformulationsareavailableshouldfollowtheapproveddrugregimens.SeeTables6and8foradditionalsafetyandpharmacokineticsinformation.

Best Practice statement (2009) (104) recommendsobtainingabaselinePsaatage40,andthentodeter-minefuturescreeningintervalsbasedonthisvalue.

Menatleast40yearsofagewhohaveabaselinePsavalue above the median (0.6 ng/ml) and who arereceivingtestosteronetherapyshouldundergoprostatemonitoring by digital rectal examination and Psameasurement3to6monthsafterinitiatingtherapyandtheninaccordancewiththerecommendedguidelinestaking intoaccount theage, race, familyhistory,andother risk factors.The combined applicationofPsaanddigitalprostateexaminationimprovestheprostatecancerdetectionratewhencomparedwitheithertestalone(105–108).

Testosterone administration in hypogonadal men isassociatedwithadose-dependent increase inhemo-globinlevels(109–111);theincreaseinhemoglobinis greater in older men than in young hypogonadalmen(110–111).Baselinehematocrit>50%isarela-tivecontraindicationtotestosteronetherapybecausesomeof thesemenwilldevelopahematocrit>54%whentreatedwithtestosterone.Menwithhematocritlevel>50%shouldundergofurtherclinicalevaluation

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Erectile dysfunction. a meta-analysis by Jain et al.(85)evaluated theeffectsof testosterone therapy inmenwithed.among16publishedstudies(85),57%

wasnotsignificant(0.4sdunits;95%Ci,–0.01,0.8)(76).lackofprecisionaroundthisestimateweakensthisinference.(Quality of evidence: )

TABLE 8. Monitoring men receiving testosterone therapy

1.Evaluatethepatient3to6monthsaftertreatmentinitiationandthenannuallytoassesswhethersymptomshaverespondedtotreatmentandwhetherthepatientissufferingfromanyadverseeffects.

2.Monitortestosteronelevel3to6monthsafterinitiationoftestosteronetherapy:

• Therapyshouldaimtoraiseserumtestosteronelevelintothemid-normalrange.

• Injectabletestosteroneenanthateorcypionate:Measureserumtestosteronelevelmidwaybetweeninjections.Iftestosteroneis>700ng/dl(24.5nmol/l)or<400ng/dl(14.1nmol/l),adjustdoseorfrequency.

• Transdermalpatches:Assesstestosteronelevel3–12hafterapplicationofthepatch;adjustdosetoachievetestosteronelevelinthemidnormalrange.

• Buccaltestosteronebioadhesivetablet:Assesslevelimmediatelybeforeorafterapplicationoffreshsystem.• Transdermalgels:Assesstestosteronelevelanytimeafterpatienthasbeenontreatmentforatleast1wk;adjustdoseto

achieveserumtestosteronelevelinthemidnormalrange.

• Testosteronepellets:Measuretestosteronelevelsattheendofthedosinginterval.Adjustthenumberofpelletsand/orthedosingintervaltoachieveserumtestosteronelevelsinthenormalrange.

• Oraltestosteroneundecanoate*:Monitorserumtestosteronelevel3to5hafteringestion.• Injectabletestosteroneundecanoate*:Measureserumtestosteroneleveljustpriortoeachsubsequentinjectionandadjust

thedosingintervaltomaintainserumtestosteroneinmid-normalrange.

3.Checkhematocritatbaseline,at3to6months,andthenannually.Ifhematocritis>54%,stoptherapyuntilhematocritdecreasestoasafelevel;evaluatethepatientforhypoxiaandsleepapnea;reinitiatetherapywithareduceddose.

4.Measurebonemineraldensityoflumbarspineand/orfemoralneckafter1–2yroftestosteronetherapyinhypogonadalmenwithosteoporosisorlowtraumafracture,consistentwithregionalstandardofcare.

5.Inmen40yearsofageorolderwithbaselinePSAgreaterthan0.6ng/ml,performdigitalrectalexaminationandcheckPSAlevelbeforeinitiatingtreatment,at3to6months,andtheninaccordancewithguidelinesforprostatecancerscreeningdependingontheageandraceofthepatient.

6.Obtainurologicalconsultationifthereis:

• AnincreaseinserumPSAconcentration>1.4ng/mlwithinany12-monthperiodoftestosteronetreatment.• APSAvelocityof>0.4ng/ml·yrusingthePSAlevelafter6monthsoftestosteroneadministrationasthereference

(onlyapplicableifPSAdataareavailableforaperiodexceeding2yr).

• Detectionofaprostaticabnormalityondigitalrectalexamination.

• AnAUA/IPSSprostatesymptomscoreof>19.

7.Evaluateformulation-specificadverseeffectsateachvisit:

• Buccaltestosteronetablets:Inquireaboutalterationsintasteandexaminethegumsandoralmucosaforirritation.• Injectabletestosteroneesters(enanthate,cypionate,andundecanoate):Askaboutfluctuationsinmoodorlibido,and

rarelycoughafterinjections.• Testosteronepatches:Lookforskinreactionattheapplicationsite.

• Testosteronegels:Advisepatientstocovertheapplicationsiteswithashirtandtowashtheskinwithsoapandwaterbeforehavingskin-to-skincontact,becausetestosteronegelsleaveatestosteroneresidueontheskinthatcanbetransferredtoawomanorchildwhomightcomeinclosecontact.Serumtestosteronelevelsaremaintainedwhentheapplicationsiteiswashed4–6hafterapplicationofthetestosteronegel.

• Testosteronepellets:Lookforsignsofinfection,fibrosis,orpelletextrusion.

* NotapprovedforclinicaluseintheUnitedStates.

AUA/IPSS=AmericanUrologicalAssociationInternationalProstateSymptomScore;PSA=prostate-specificantigen

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2.2.D. Remarks

diagnostic and treatment recommendations are thesameasforpatientswithclassicalandrogendeficiency(Sections 1.1. and 2.1.).Menwithsexualdysfunctionshould be evaluated for the underlying causes,includinglowtestosteronelevels.

2.3. OLDER MEN WITH LOW SERUM TESTOSTERONE CONCENTRATION

2.3.A. Recommendation

We recommend against a general policy of offering testos-terone therapy to all older men with low testosterone levels. (1| )

We suggest that clinicians consider offering testosterone therapy on an individualized basis to older men with low testosterone levels on more than one occasion and clini-cally significant symptoms of androgen deficiency, after explicit discussion of the uncertainty about the risks and benefits of testosterone therapy. (2| )

Thepanelistsdisagreedonserumtestosterone levelsbelowwhichtestosteronetherapyshouldbeofferedtooldermenwithsymptoms.dependingontheseverityof clinical manifestations, some panelists favoredtreating symptomatic older men with a testosteronelevel below the lower limit of normal for healthyyoungmen(280–300ng/dl[9.7–10.4nmol/l]);othersfavored a level below 200 ng/dl (6.9 nmol/l). Thepanelists who favored treating men who had values<300ng/dlweremoreinfluencedbytheobservationthatmenwhohavevaluesbelowthatleveloftenhavesymptoms that might be attributable to low testos-terone.Thepanelistswhofavorednottreatingunlesstheserumtestosteronewasas lowas200ng/dlweremoreinfluencedbythelackoftestosteronetreatmenteffectsinrandomizedclinicaltrialswhensubjectshadpretreatment values of 300 ng/dl but suggestions ofbeneficialeffectswhenthepretreatmentvalueswerecloser to 200 ng/dl. The lack of definitive studiesprecludes an unequivocal recommendation andemphasizestheneedforadditionalresearch.

of subjects experienced an improvement in erectilefunction. ina later systematic reviewof randomizedplacebo-controlled trials that enrolled patients withtotaltestosterone<300ng/dl(10.4nmol/l)(4),twoparalleltrialsandtwocrossovertrialsreportedeffectson erectile function. The results were inconsistentacrosstrials,andthepooledestimatewasnotsignifi-cant(0.8sdunits;95%Ci,–0.1,1.6)(4).(Quality of evidence: )

among trials that enrolled men with total testos-terone>300ng/dl(10.4nmol/l),severalparalleltrialsenrolledmenwithedinwhomsildenafilhadfailed(87–93)andthreecrossovertrialsinmenwitheitherlow libido or ed (112, 113). These trials reportedinconsistent and nonsignificant effects on erectilefunction(0.3sdunits;95%Ci,–0.03,0.65)(4).Theinconsistencyacrosstrialsandtheimprecisionofthepooled estimate weaken our inferences. (Quality of evidence: )

Other sexual outcomes. severalstudieshaveevaluatedtheeffectsoftestosteronetreatmentinmenwhofailedtorespondtoaPde5inhibitor(87–93).someofthesestudieswerenotplacebocontrolled,andthedegreeoftestosterone deficiency varied among trials (87–93,112, 113). several trials reported on the impact oftestosteronetherapyonothersexualoutcomes,namely,orgasmic and ejaculatory function, intercourse, andoverallsatisfaction(4).Generally,theeffectoftestos-teronewaspositive,butsmallsamplesizes,inconsistentfindings, and incomplete reporting yielded impreciseestimates.(Quality of evidence: )

2.2.C. Values

Ourrecommendationtooffertestosteronetherapytomenwith lowlibidooredwhohaveunequivocallylowtestosteronelevelsplacesarelativelyhighervalueonimprovingthesecomplaintsandarelativelylowervalueonavoidingtheburdenoftestosteronetherapyand itsunclear long-termsafety.adecision to treatoldermendependsonthephysician’sandthepatient’sassessment of risks and benefits and costs. Olderpatients with a greater potential for adverse effectsmayopttoavoidtestosteronetherapy.

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didnotdiffer significantlybetweengroups (–0.6kg;95%Ci,–2.0,0.8)(125).

Muscle strength and physical function. Testosteronetherapywasassociatedwithagreaterimprovementingripstrengththanplacebo(3.3kg;95%Ci,0.7,5.8)(125). Changes in lower-extremity muscle strengthand measures of physical function were reported inonlyafewstudiesandwereinconsistent.somestudiesreported no changes in performance-based measuresofphysicalfunction(68,119,121),whereasonestudyreported improvement in a composite measure ofphysicalfunction(121).Mostofthestudiesincludedmen who had no functional limitations and usedmeasuresofphysicalfunctionthathadalowceiling.

Sexual function. Twoplacebo-controlledtrialsyieldedimprecise results regarding the effectof testosteroneonoverallsexualsatisfaction(0.2sdunits;95%Ci,–0.02,0.57)(4).

Quality of life. Fourplacebo-controlled randomizedtrials reported on testosterone’s effect on quality oflife(119,129,133,134).Theresultswereinconsis-tent across trials and imprecise. However, testos-terone therapy was associated with significantlygreaterimprovementinthephysicalfunctiondomainscorethanwasplacebo(0.5sdunits;95%Ci,0.03,0.9)(125).

Depression. The effects of testosterone therapy ondepression have been inconsistent across trials. arecentsystematicreviewofrandomizedtrialsreportedsignificantly greater improvements in depressionscores in testosterone-treated men than in placebo-treated men (135). However, several randomizedtrialshavefoundnosignificanteffectsoftestosteronetherapy on depression in older men with low orlow-normal testosterone levels (127–133). Theinconsistentandimpreciseresultslimittheinferentialstrength.

Cognition. Three placebo-controlled randomizedtrials(130,133,136),oneofwhichstudiedpatientswith alzheimer’s dementia and low testosteronelevels (136), reported imprecise effects on severaldimensions of cognition,noneofwhich was signifi-cantafterpooling.

2.3.B. Evidence

several cross-sectional and longitudinal studiesdemonstrate that serum total and free testosteroneconcentrationsinmenfallwithincreasingage(7–9,84,103,104,114,115).althoughthefallisgradual,bytheeighthdecade,accordingtoonestudy,30%ofmenhadtotaltestosteronevaluesinthehypogonadalrange,and50%hadlowfreetestosteronevalues(8).Therateofage-relateddeclineinserumtestosteronelevels varies in different individuals and is affectedbychronicdisease,adiposity,andmedications(7,9,114–117).

Testosterone trials in older men. in randomized,placebo-controlled trials of 3 months to 3 years inolder men with low-normal to low testosteroneconcentrations,testosteroneadministrationwasasso-ciated with varying degrees of elevation in testos-terone levels (68, 119–131). Overall, testosteronetrialsinoldermenwerecharacterizedbysmallsamplesize,inclusionofhealthyoldermenwithloworlow-normal testosterone levels who were asymptomatic,variable dosing regimens, and the use of surrogateoutcomes;thesestudiesdidnothavesufficientpowerto detect either meaningful gains in patient-impor-tantoutcomesorchanges inprostateandcardiovas-culareventrates(68,119–131).

Bone mineral density. We did not find any trialsreportingtheeffectoftestosteroneonbonefractures.a systematic review of randomized, placebo-controlledtrialsof1-to3-year’sdurationthatevalu-ated effects on bone mineral density and werepublishedbeforeMarch2005yieldedinconsistentandimprecise results (118, 120, 122, 132); these trialsshowedamoderatetreatmenteffectonlumbarbonemineral density (0.4 sd units; 95% Ci, 0.1, 0.7),equivalent toan increase in lumbarbonedensityof2%(95%Ci,0.5,3.3)(132).Thesetrialsruledoutamoderate-to-largetestosteroneeffectonfemoralneckbonedensity(0.0sdunits;95%Ci,–0.3,0.3).

Body composition. in our systematic review, testos-terone therapy was associated with a significantlygreaterincreaseinlBM(2.7kg;95%Ci,1.6,3.7)andagreaterreductioninfatmass(–2.0kg;95%Ci,–3.1,–0.8) than placebo (125). The body weight change

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patientschoosetestosteronetherapy,wesuggestthatcliniciansaimatachievingtotaltestosteronelevelsinthe lower part of the normal range of young men(400–500ng/dl[14.0–17.5nmol/l]).

2.4. PATIENTS WITH CHRONIC ILLNESS AND LOW TESTOSTERONE LEVELS

2.4.1. HIV-infected men with weight loss

2.4.1.A. Recommendation

We suggest that clinicians consider short-term testos-terone therapy as an adjunctive therapy in HIV-infected men with low testosterone levels and weight loss to promote weight maintenance and gains in lean body mass and muscle strength. (2| )

2.4.1.B. Evidence

ThereisahighprevalenceoflowtestosteronelevelsinHiV-infectedmen(37,38,137):20–25%ofHiV-infectedmenonhighlyactiveantiretroviraltherapyhavelowtestosteronelevels(137).lowtestosteronelevelsareassociatedwithweight loss,progressiontoaids (138), wasting (139), depression, and loss ofmusclemassandexercisecapacity(139).

Body weight and LBM. in a systematic review ofrandomized,placebo-controlled trialsof testosteronetherapyinHiV-infectedpatientswithweightlossthatreported body composition (125), 3 to 6 months oftestosteronetherapywasassociatedwithgreatergainsinbodyweight (+1.54kg; 95%Ci, 0.03, 3.10) andlBM(+1.22kg;95%Ci,0.2,2.2)thanwasplacebo.differenceinlBMbetweenplaceboandtestosteronegroups was greater in trials that used testosteroneesters(+3.34kg)(140).

Muscle strength. inthreeoffourtrialsthatmeasuredmuscle strength (141–145), testosteroneadministra-tion was associated with improvements in maximalvoluntarystrength.

Other outcomes. in a systematic reviewof placebo-controlled trials,we found four reportingondepres-sioninpatientswithHiVinfection(62,146–148).alarge loss to follow-up in one trial, inconsistencyacrosstrials,incompletedatareporting,andimpreci-

Adverse outcomes associated with testosterone therapy.inasystematicreviewof19randomizedtrialsto determine the risks of adverse events associatedwith testosterone therapy in older men (77), thecombinedrateofallprostateeventswassignificantlygreaterintestosterone-treatedmenthaninplacebo-treated men (odds ratio, 1.78; 95% Ci, 1.07, 2.95).Ratesofprostatecancer,Psagreater than4ng/ml,andprostatebiopsieswerehigherinthetestosteronegroupthanintheplacebogroup,althoughdifferencesbetweengroupswerenotstatisticallysignificant(77).Testosterone-treatedmenwerenearlyfourtimesmorelikelythanplacebo-treatedmentoexperiencehema-tocrit>50%(oddsratio,3.69;95%Ci,1.82,7.51).Thefrequencyofcardiovascularevents,sleepapnea,ordeathdidnotdiffer significantlybetweengroups.Thus, testosterone therapy of older men was associ-ated with a higher risk of detecting prostate eventsandhematocritabove50%thanwasplacebo(77).

ameta-analysisbyHaddadetal.(3)ofstudiesfoundthroughOctober2004enrollingoldermenwithlowtestosterone levels yielded insignificant changes inmajor lipid fractions (total cholesterol standardizedmean difference [sMd] -0.22 (-0.71 to 0.27) ; ldlcholesterol sMd 0.06 [-0.30 to 0.42]; Hdl choles-terol sMd 0.04 [-0.39 to 0.40]; triglycerides sMd,-0.27[-0.61to0.08]).

2.3.C. Values

Therecommendationnottotreatasymptomaticoldermen with age-related decline in testosterone levelplacesalowervalueontheunproven,potentialbene-fits of testosterone therapy and a higher value onavoidingtheburdensof testosteroneadministration,monitoring, and cost, as well as on unknown long-termrisks.

2.3.D. Remarks

Physicians should recognize considerable disagree-mentamongexpertsonthisissuebecauseofthelackofevidencebasetoreachconsensusrecommendations(35,36,125).nonspecificage-relatedsymptomsandlow T levels often co-exist in older men without aclearcausallink.neitherthesafetynortheefficacyofT therapy in older men with low testosterone levelhas been demonstrated. should clinicians and their

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2.4.2.B. Evidence

Testosteronelevelsareloweringlucocorticoid-treatedmen than in age-matched controls (39). There is ahigh prevalence of low testosterone levels in gluco-corticoid-treatedmendue toglucocorticoid-inducedsuppression of all components of the hypothalamic-pituitary-testicular axis. Typically, administration ofmorethan5–7.5mg/dofprednisoneoritsequivalentincreases the risk of gonadotropin and testosteronesuppression and alterations in muscle and bonemass(149).

in two placebo-controlled trials (150, 151), testos-teronetherapyofmenreceivingglucocorticoidtreat-ment for bronchial asthma or chronic obstructivepulmonarydiseasewasassociatedwithagreatergainin lBM (2.3 kg; 95% Ci, 2.0, 3.6) and a greaterdecrease in fat mass (–3.1 kg; 95% Ci, –3.5, –2.8)thanwasplacebo.Thesetwotrialsreportedsignificantincrease in lumbar bone mineral density in associa-tionwithtestosteronetherapy(4%;95%Ci,2,7%);theeffectonfemoralbonemineraldensitywasincon-sistentandnotsignificant.Therearenobonefracturedatainthispopulation.

Testosteroneadministrationwasassociatedwithalowfrequency of adverse events. However, these infer-encesareweakenedbythesmallsizeofthesestudies,theirshortduration,andtheirinconsistentresults.

2.4.2.C. Values

Ourrecommendationtooffertestosteronetherapytoglucocorticoid-treated men with low testosteronelevelsplacesarelativelyhighervalueonthepotentialbenefitofmaintainingmusclemassandbonemineraldensityandarelativelylowervalueonavoidingthepotentialforadverseeffectsandtheburdensoftestos-teroneadministration,monitoring,andcost,andontheunclearlong-termsafetyofthetherapy.

2.4.2.D. Remarks

diagnostic and treatment recommendations are thesameasforpatientswithclassicalandrogendeficiency.

sionlimitthestrengthofinferences.Overall,testos-terone therapy had a moderate effect on depression(–0.6sdunits;95%Ci,–1.0,–0.2).Therewerenosignificanttestosteroneeffectsonqualityoflife.

Adverse outcomes. Theadverseeventratesdidnotdiffersignificantly between placebo and testosterone groups.ChangesinCd4+Tlymphocytecounts,HiVviralload,Psa, and plasma high-density lipoprotein cholesterolwerenotsignificantlydifferentbetweengroups.

There was considerable heterogeneity across trials(varyingdegreesofweightloss,diseaseseverity,testos-teroneregimens,treatmentduration,andmethodstoassessbodycomposition).Therearenodataontestos-terone’seffectsonphysicalfunction,riskofdisability,or long-term safety. Overall, short-term (3- to6-month)testosteroneuseinHiV-infectedmenwithlow testosterone levels and weight loss can lead tosmall gains in body weight and lBM with minimalchangeinqualityoflifeandmood.Thisinferenceisweakenedbyinconsistentresultsacrosstrials.

2.4.1.C. Values

Therecommendationtooffershort-termtestosteronetherapy to HiV-infected men with low testosteronelevelsandweightlossplacesarelativelyhighervalueongaininglBMandmusclestrengthandarelativelylowervalueonavoidingthepotentialfortestosterone-related adverse effects, cost, and unclear long-termsafety. Patients with a different value structure maydecidetoavoidtestosteronetherapy.

2.4.1.D. Remarks

diagnostic and treatment recommendations are thesameasforpatientswithclassicalandrogendeficiency(Sections 1.1. and 2.1.). additionally, appropriatecounselingforsafesexpracticesshouldbeprovided.

2.4.2. GLUCOCORTICOID-TREATED MEN

2.4.2.A. Recommendation

We suggest that clinicians offer testosterone therapy to men receiving high doses of glucocorticoids who have low testosterone levels to promote preservation of lean body mass and bone mineral density. (2| )

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AcknowledgmentsThemembersoftheTaskForcethankTheendocrinesociety’sClinicalGuidelinessubcommittee,ClinicalaffairsCore Committee and Council for their careful, critical review of earlier versions of this manuscript and theirhelpfulcommentsandsuggestions.Wealsothankthestaffatthesocietyofficefortheirhelpfulsupportduringthedevelopmentofthisguideline.

Financial Disclosure of Task ForceShalender Bhasin, M.D. (Chair)—Consultation or advisement: GlaxosmithKline (GsK), Merck; Grant orOther Research support: abbott laboratories, ligand, Merck; Financial or Business/Organizational interests:american Board of internal Medicine. Glenn R. Cunningham, M.D.—Consultation or advisement: Clarus,Columbia lab, GsK, endo Pharmaceuticals, abbott laboratories; Grant or Other Research support: abbottlaboratories; Columbia lab, GsK; speakers list: Columbia lab, endo Pharmaceuticals, abbott laboratories;FinancialorBusiness/Organizationalinterests:upTodate;significantFinancialinterestorleadershipPosition:none declared. Frances J. Hayes, M.B., FRCPI—Consultation or advisement: auxilium Pharmaceuticals,GsK,newenglandResearchinstitute;speakersBureauforabbottlaboratories;FinancialorBusiness/Organiza-tional interests:nonedeclared;significantFinancial interestorleadershipPosition:nonedeclared.Alvin M. Matsumoto, M.D.—Consultation or advisement: abbott laboratories, Merck, endo Pharmaceuticals, Tokai;Grant or Other Research support: GsK, abbott laboratories; Financial or Business/Organizational interests:upTodate,u.s.anti-dopingagency/PCC;significantFinancialinterestorleadershipPosition:nonedeclared.Peter J. Snyder, M.D.—Consultationoradvisement:nonedeclared;GrantorOtherResearchsupport:abbottlaboratories;FinancialorBusiness/Organizationalinterests:abbottlaboratories,upTodate;significantFinan-cialinterestorleadershipPosition:upTodate.Ronald S. Swerdloff, M.D.—Consultationoradvisement:Clarus,abbottlaboratories,endoPharmaceuticals;GrantorOtherResearchsupport:actelionPharma,aRYxThera-peutics, inc., auxilium, Bayer Corp., Besins/ascend, Bristol-Myers squibb, Clarus, Columbia, Corcept, GsK,eli lilly &Co., MacroChem Corp., Organon, schering aG, abbott laboratories; Financial or Business/Organizational interests: none declared; significant Financial interest or leadership Position: none declared.*Victor M. Montori, M.D.—FinancialorBusiness/Organizationalinterests:nonedeclared;significantFinancialinterestorleadershipPosition:nonedeclared.

* Evidence-based reviews for this guideline were prepared under contract with The Endocrine Society.

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