androgens in men guideline
TRANSCRIPT
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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References1. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y,
Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer TT, Varonen H, Vist GE, Williams JW, Jr., Zaza S 2004Gradingqualityofevidenceandstrengthofrecommendations.BMJ328:1490
2. Fernández-Balsells HM, Murad MH, Melanie L, Lampro-pulos JF, Albuquerque F, Erwin PJ, Bhasin S, Montori VM 2010adverseeffectsoftestosteronetherapyinadultmen:asystematic review and meta-analysis. J Clin endocrinolMetab,95(6):2560–2575
3 Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM 2007Testosterone and cardiovascular risk in men: a systematicreview and meta-analysis of randomized placebo-controlledtrials.MayoClinProc82:29-39
4. Boloña ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, Caples SM, Erwin PJ, Montori VM 2007Testosteroneuseinmenwithsexualdysfunction:asystematicreview and meta-analysis of randomized placebo-controlledtrials.MayoClinProc82:20-28
5. Matsumoto AM 2001TheTestis.in:FeligP,Frohmanlaeds. endocrinology and Metabolism. 4th ed ed. new York,nY:McGraw-Hill;635-705
6. Bhasin S 2008Testiculardisorders.in:larsenPR,Kronen-bergHM,Melmeds,PolanskiKseds.Williams’Textbookofendocrinology.11theditioned.Philadelphia,Pa:elsevier
7. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB 2002age trends in the level of serum testosterone and otherhormonesinmiddle-agedmen:longitudinalresultsfromtheMassachusetts male aging study. J Clin endocrinol Metab87:589-598
8. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR 2001longitudinal effectsof agingon serum total andfree testosterone levels inhealthymen.Baltimorelongitu-dinalstudyofaging.JClinendocrinolMetab86:724-731
9. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva F, Forti G, Giwercman A, Huhtaniemi IT, Kula K, Punab M, Boonen S, Vander-schueren D 2008 Hypothalamic-pituitary-testicular axisdisruptionsinoldermenaredifferentiallylinkedtoageandmodifiable risk factors: the european Male aging study.JClinendocrinolMetab93:2737-2745
10. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB 2007Prevalence of symptomatic androgen deficiency in men.JClinendocrinolMetab92:4241-4247
11. Zitzmann M, Faber S, Nieschlag E 2006 association ofspecific symptoms and metabolic risks with serum testos-teroneinoldermen.JClinendocrinolMetab91:4335-4343
12. Hall SA, Esche GR, Araujo AB, Travison TG, Clark RV, Williams RE, McKinlay JB 2008Correlatesof lowtestos-teroneandsymptomaticandrogendeficiencyinapopulation-basedsample.JClinendocrinolMetab93:3870-3877
13. Travison TG, Araujo AB, Kupelian V, O’Donnell AB, McKinlay JB 2007 The relative contributions of aging,health,andlifestylefactorstoserumtestosteronedeclineinmen.JClinendocrinolMetab92:549-555
14. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C 2006 Prevalence of hypogonadism in malesagedatleast45years:theHiMstudy.internationalJournalofClinicalPractice60:762-769
15. Kelleher S, Conway AJ, Handelsman DJ 2004Bloodtestos-terone threshold for androgen deficiency symptoms. J ClinendocrinolMetab89:3813-3817
16. Bremner WJ, Vitiello MV, Prinz PN 1983lossofcircadianrhythmicityinbloodtestosteronelevelswithaginginnormalmen.JClinendocrinolMetab56:1278-1281
17. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB 2007intraindividualvariation in levelsof serumtestos-teroneandotherreproductiveandadrenalhormonesinmen.Clinendocrinol(Oxf)67:853-862
18. Bhasin S, Zhang A, Coviello A, Jasuja R, Ulloor J, Singh R, Vesper H, Vasan RS 2008The impactofassayqualityand reference ranges on clinical decision making in thediagnosisofandrogendisorders.steroids73:1311-1317
19. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H 2007utility, limitations and pitfalls in measuring testosterone:anendocrinesocietyPositionstatement.JClinendocrinolMetab92:405-413
20. Vermeulen A, Verdonck L, Kaufman JM 1999acriticalevaluationofsimplemethodsfortheestimationoffreetestos-teroneinserum.JClinendocrinolMetab84:3666-3672
21. Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ 2009 Predictive accuracy and sources of variability incalculated free testosterone estimates. ann Clin Biochem46(Pt2):137-43.
22. Daniell HW, Lentz R, Mazer NA 2006 Open-label pilotstudy of testosterone patch therapy in men with opioid-inducedandrogendeficiency.JPain7:200-210
23. Kim TW, Alford DP, Malabanan A, Holick MF, Samet JH. lowbonedensityinpatientsreceivingmethadonemain-tenancetreatment.drugalcoholdepend.2006;85:258-62
24. Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmuller D 2005 Plasma testosteroneandsexualfunctioninmenreceivingbuprenorphinemainte-nance for opioid dependence. J Clin endocrinol Metab90:203-206
25. Basaria S 2008 androgen deprivation therapy, insulinresistance, and cardiovascular mortality: an inconvenienttruth.Jandrol29:534-539
an e
ndo
crin
e so
cieT
y cl
inic
al p
racT
ice
guid
elin
e
26
26. Citron JT, Ettinger B, Rubinoff H, Ettinger VM, Minkoff J, Hom F, Kan P, Alloo R 1996Prevalenceofhypothalamic-pituitary imaging abnormalities in impotent men withsecondaryhypogonadism.Jurol155:529-533
27. Buvat J, Lemaire A 1997endocrinescreeningin1,022menwith erectile dysfunction: clinical significance and cost-effectivestrategy.Jurol158:1764-1767
28. Handelsman DJ, Liu PY 2006 Klinefelter’s syndrome—amicrocosmofmalereproductivehealth.JClinendocrinolMetab91:1220-1222
29. Riggs BL, Khosla S, Melton LJ, 3rd 2002sexsteroidsandthe construction and conservation of the adult skeleton.endocrRev23:279-302
30. Ebeling PR 2008 Clinical practice. Osteoporosis in men.nenglJMed358:1474-1482
31. shores MM, Matsumoto AM, Sloan KL, Kivlahan DR 2006lowserumtestosteroneandmortalityinmaleveterans.archinternMed166:1660-1665
32. Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB 2007sexsteroidsandall-causeand cause-specific mortality in men. arc interl Med167:1252-1260
33. Laughlin GA, Barrett-Connor E, Bergstrom J 2008lowserum testosterone and mortality in older men. J ClinendocrinolMetab93:68-75
34. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C 2009 low serumtestosteroneandestradiolpredictmortality in elderlymen.JClinendocrinolMetab94:2482-2488
35. Liverman CT, Blazer DG 2004 Testosterone and aging,clinical research directions. Washington, d.C.: nationalacademiesPress,2004.
36. Bhasin S, Buckwalter JG 2001Testosteronesupplementa-tion in older men: a rational idea whose time has not yetcome.Jandrol22:718-731
37. Dobs AS, Few WL, 3rd, Blackman MR, Harman SM, Hoover DR, Graham NM 1996 serum hormones in menwith human immunodeficiency virus-associated wasting.JClinendocrinolMetab81:4108-4112
38. Arver S, Sinha-Hikim I, Beall G, Guerrero M, Shen R, Bhasin S 1999serumdihydrotestosteroneandtestosteroneconcentrations in human immunodeficiency virus-infectedmenwithandwithoutweightloss.Jandrol20:611-618
39. Reid IR 1987 serum testosterone levels during chronicglucocorticoidtherapy.anninternMed106:639-640
40. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P 2004 Frequent occurrence ofhypogonadotropic hypogonadism in type 2 diabetes.JClinendocrinolMetab89:5462-5468
41. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM, 3rd 2000Validationofascreening
questionnaire for androgen deficiency in aging males.Metabolism49:1239-1242
42. Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM 2004TheagingMales’symptomsscale(aMs) as outcome measure for treatment of androgendeficiency.eururol46:80-87
43. Smith KW, Feldman HA, McKinlay JB 2000Constructionandfieldvalidationofaself-administeredscreenerfortestos-terone deficiency (hypogonadism) in ageing men. Clinendocrinol(Oxf)53:703-711
44. Morley JE, Perry HM 3rd, Kevorkian RT, Patrick P 2006Comparison of screening questionnaires for the diagnosisofhypogonadism.Maturitas53:424-9.
45. Mauras N, Hayes V, Welch S, Rini A, Helgeson K, Dokler M, Veldhuis JD, Urban RJ 1998Testosteronedeficiencyinyoung men: marked alterations in whole body proteinkinetics, strength, and adiposity. J Clin endocrinol Metab83:1886-1892
46. Kwan M, Greenleaf WJ, Mann J, Crapo L, Davidson JM 1983 The nature of androgen action on male sexuality:a combined laboratory-self-report study on hypogonadalmen.JClinendocrinolMetab57:557-562
47. Wang C, Swedloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N 2000Transdermaltestosteronegelimprovessexualfunction,mood,musclestrength,andbodycompositionparametersinhypogonadal men. Testosterone Gel study Group. J ClinendocrinolMetab85:2839-2853
48. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R 2003 aa2500 testosterone gel normalizesandrogen levels inagingmaleswith improvements inbodycompositionand sexual function. JClinendocrinolMetab88:2673-2681
49. Bancroft J, Wu FC 1983Changesinerectileresponsivenessduring androgen replacement therapy. arch sex Behav12:59-66
50. Carani C, Scuteri A, Marrama P, Bancroft J 1990 Theeffectsoftestosteroneadministrationandvisualeroticstimulionnocturnalpeniletumescenceinnormalmen.HormBehav24:435-441
51. Cunningham GR, Hirshkowitz M, Korenman SG, Karacan I 1990 Testosterone replacement therapy and sleep-relatederections in hypogonadal men. J Clin endocrinol Metab70:792-797
52. Alexander GM, Sherwin BB 1991Theassociationbetweentestosterone,sexualarousal,andselectiveattentionforeroticstimuliinmen.HormBehav25:367-381
53. Bhasin S, Enzlin P, Coviello A, Basson R 2007 sexualdysfunction in men and women with endocrine disorders.lancet369:597-611
54. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R 1997Testos-teronereplacementincreasesfat-freemassandmusclesizeinhypogonadalmen.JClinendocrinolMetab82:407-413
TesTosTero
ne Th
erapy in M
en w
iTh an
drogen
deficiency syn
droM
es
27
55. Brodsky IG, Balagopal P, Nair KS 1996effectsof testos-terone replacement on muscle mass and muscle proteinsynthesis in hypogonadal men--a clinical research centerstudy.JClinendocrinolMetab81:3469-3475
56. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A 1996 increase in bonedensityand leanbodymassduring testosteroneadministra-tioninmenwithacquiredhypogonadism.JClinendocrinolMetab81:4358-4365
57. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL 2000effectsoftestos-teronereplacementinhypogonadalmen.JClinendocrinolMetab85:2670-2677
58. Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E 1997 long-term effect of testosterone therapy on bonemineral density in hypogonadal men. J Clin endocrinolMetab82:2386-2390
59. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS 2004long-termtestosteronegel(androGel)treatmentmaintainsbeneficialeffectsonsexualfunctionandmood,leanandfatmass,andbonemineraldensityinhypo-gonadalmen.JClinendocrinolMetab89:2085-2098
60. Aminorroaya A, Kelleher S, Conway AJ, Ly LP, Handelsman DJ 2005 adequacy of androgen replacementinfluencesbonedensityresponsetotestosteroneinandrogen-deficientmen.eurJendocrinol.2005152:881-886
61. Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS 1996Testosteronereplacement therapy improvesmoodin hypogonadal men--a clinical research center study.JClinendocrinolMetab81:3578-3583
62. Rabkin JG, Rabkin R, Wagner G 1995 Testosteronereplacement therapy in HiV illness. Gen Hosp Psychiatry17:37-42
63. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S 2001 Testosteronesupplementation improves spatial and verbal memory inhealthyoldermen.neurology57:80-88
64. Janowsky JS, Oviatt SK, Orwoll ES 1994 Testosteroneinfluences spatial cognition in older men. Behav neurosci108:325-332
65. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P 1992 The effects oftestosteronetreatmentonbodycompositionandmetabolismin middle-aged obese men. int J Obes Relat Metab disord16:991-997
66. Marin P, Krotkiewski M, Bjorntorp P 1992 androgentreatmentofmiddle-aged,obesemen:effectsonmetabolism,muscleandadiposetissues.eurJMed1:329-336
67. Kapoor D, Goodwin E, Channer KS, Jones TH 2006Testosterone replacement therapy improves insulin resis-
tance,glycaemiccontrol,visceraladiposityandhypercholes-terolaemia in hypogonadal men with type 2 diabetes.eurJendocrinol154:899-906
68. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT 2008effectoftestosteronesupplementationonfunctionalmobility,cognition,andotherparametersinoldermen:arandomizedcontrolledtrial.JaMa299:39-52
69. Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Wood-house L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S 2002TheeffectsofvaryingdosesofToninsulinsensitivity, plasma lipids, apolipoproteins, and C-reactiveprotein in healthy young men. J Clin endocrinol Metab87:136-143
70. Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C, Rizza RA 2007 effect of 2 years of testosterone replacement oninsulin secretion, insulin action, glucose effectiveness,hepaticinsulinclearance,andpostprandialglucoseturnoverinelderlymen.diabetesCare30:1972-1978
71. Fowler JE, Jr., Whitmore WF, Jr. 1981 The response ofmetastatic adenocarcinoma of the prostate to exogenoustestosterone.Jurol126:372-375
72. Agarwal PK, Oefelein MG 2005Testosteronereplacementtherapy after primary treatment for prostate cancer. J urol173:533-536
73. Kaufman JM, Graydon RJ 2004 androgen replacementafter curative radical prostatectomy for prostate cancer inhypogonadalmen.Jurol172:920-922
74. Khera M, Grober ED, Najari B, Colen JS, Mohamed O, Lamb DJ, Lipshultz LI 2009 Testosterone replacementtherapy following radical prostatectomy. J sex Med6:1165-1170
75. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA, Jr. 2004Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. n engl JMed350:2239-2246
76. Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS, Feng Z, Parnes HL, Coltman CA, Jr. 2006assessing prostate cancer risk: results from the ProstateCancerPreventionTrial.JnatlCancerinst98:529-534
77. Calof O, Singh AB, Lee ML, Urban RJ, Kenny AM, Tenover JL, Bhasin S 2005adverseeventsassociatedwithtestosterone supplementation of older men. J Gerontol aBiolsciMedsci.60:1451-7
78. Seftel AD, Mack RJ, Secrest AR, Smith TM 2004Restor-ative increases inserumtestosterone levelsare significantlycorrelatedtoimprovementsinsexualfunctioning.Jandrol25:963-972
an e
ndo
crin
e so
cieT
y cl
inic
al p
racT
ice
guid
elin
e
28
79. Clopper RR, Voorhess ML, MacGillivray MH, Lee PA, Mills B 1993Psychosexualbehaviorinhypopituitarymen:acontrolled comparison of gonadotropin and testosteronereplacement.Psychoneuroendocrinology18:149-161
80. Allan CA, Forbes EA, Strauss BJ, McLachlan RI 2008Testosterone therapy increases sexual desire in ageing menwith low-normal testosterone levels and symptoms ofandrogendeficiency.intJimpotRes20:396-401
81. Skakkebaek NE, Bancroft J, Davidson DW, Warner P 1981 androgen replacement with oral testosteroneundecanoateinhypogonadalmen:adoubleblindcontrolledstudy.Clinendocrinol(Oxf)14:49-61
82. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G 2004 Carnitine versus androgen administration in thetreatmentofsexualdysfunction,depressedmood,andfatigueassociatedwithmaleaging.urology63:641-646
83. Carani C, Granata AR, Bancroft J, Marrama P 1995Theeffects of testosterone replacement on nocturnal peniletumescenceandrigidityanderectileresponsetovisualeroticstimuli in hypogonadal men. Psychoneuroendocrinology20:743-753
84. Korenman SG, Morley JE, Mooradian AD, Davis SS, Kaiser FE, Silver AJ, Viosca SP, Garza D. 1990secondaryhypogonadism in older men: its relation to impotence.JClinendocrinolMetab71:963-639
85. Jain P, Rademaker AW, McVary KT 2000 Testosteronesupplementation for erectiledysfunction: resultsof ameta-analysis.Jurol164:371-375
86. Carani C, Bancroft J, Granata A, Del Rio G, Marrama P 1992 Testosterone and erectile function, nocturnal peniletumescenceandrigidity,anderectileresponsetovisualeroticstimuliinhypogonadalandeugonadalmen.Psychoneuroen-docrinology17:647-654
87. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A 2003androgensimprovecavernousvasodilationandresponsetosildenafil in patients with erectile dysfunction. Clin endo-crinol(Oxf)58:632-638
88. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H 2004 Randomized study of testosterone gel as adjunctivetherapy to sildenafil in hypogonadal men with erectiledysfunction who do not respond to sildenafil alone. J urol172:658-663
89. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H 2008 Randomized study of testosterone gel as adjunctivetherapy to sildenafil in hypogonadal men with erectiledysfunction who do not respond to sildenafil alone. J urol179:s97-s102
90. Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV 2003Oraltestosteroneundecanoatereverseserectiledysfunc-tionassociatedwithdiabetesmellitus inpatients failingonsildenafilcitratetherapyalone.agingMale6:94-99
91. Shamloul R, Ghanem H, Fahmy I, El-Meleigy A, Ashoor S, Elnashaar A, Kamel I 2005 Testosterone therapy can
enhance erectile function response to sildenafil in patientswithPadaM:apilotstudy.JsexMed2:559-564
92. Hwang TI, Chen HE, Tsai TF, Lin YC 2006Combineduseof androgen and sildenafil for hypogonadal patients unre-sponsivetosildenafilalone.intJimpotRes18:400-404
93. Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J 2005 does sildenafil combined with testosteronegel improve erectile dysfunction in hypogonadal men inwhomtestosteronesupplementtherapyalone failed? Jurol173:530-532
94. Finkel DM, Phillips JL, Snyder PJ 1985stimulationofsper-matogenesis by gonadotropins in men with hypogonado-tropichypogonadism.nenglJMed313:651–655
95. Liu L, Banks SM, Barnes KM, Sherins RJ 1988Two-yearcomparisonoftesticularresponsestopulsatilegonadotropin-releasinghormone and exogenous gonadotropins from theinceptionoftherapyinmenwithisolatedhypogonadotropichypogonadism.JClinendocrinolMetab67:1140–1145
96. Büchter D, Behre HM, Kliesch S, Nieschlag E 1998Pulsa-tileGnRHorhumanchorionicgonadotropin/humanmeno-pausal gonadotropin as effective treatment for men withhypogonadotropichypogonadism:areviewof42cases.eurJendocrinol139:298–303
97. Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, Spratt D, Brentzel J, O’Dea L 2009stimulationof spermatogenesiswith recombinanthuman follicle-stimu-latinghormone(follitropinalfa;GOnal-f):long-termtreat-ment in azoospermic men with hypogonadotropichypogonadism.Fertilsteril92:979–990
98. Bhasin S, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR2003Managingtherisksofprostatediseaseduring testosterone replacement therapy in older men:recommendations for a standardized monitoring plan. Jandrol24:299–311
99. Riehmann M, Rhodes PR, Cook TD, Grose GS, Bruskewitz RC 1993 analysis of variation in prostate-specific antigenvalues.urology42:390–397
100. Scardino PT 2007TheresponsibleuseofantibioticsforanelevatedPsalevel.natClinPracturol4:1
101. Kobayashi M, Nukui A, Morita T 2008 serum Psa andpercent free Psa value changes after antibiotic treatment.adiagnosticmethodinprostatecancersuspectswithasymp-tomaticprostatitis.urolint80:186–192
102. Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS, Vaughan ED, Pappas F, Taylor A, Binkowitz B, Ng J 1992Theeffectoffinasteride inmenwithbenignprostatichyperplasia.TheFinasteridestudyGroup.nenglJMed327:1185–1191
103. Carter HB 1997 Psa variability versus velocity. urology49:305
104. 2009Prostate-specificantigenbestpracticestatement:2009update. linthicum,Md:american urological associationeducationandResearch,inc.
TesTosTero
ne Th
erapy in M
en w
iTh an
drogen
deficiency syn
droM
es
29
105. Bretton PR 1994Prostate-specificantigenanddigitalrectalexaminationinscreeningforprostatecancer:acommunity-basedstudy.southMedJ87:720–723
106. Muschenheim F, Omarbasha B, Kardjian PM, Mondou EN 1991screening forcarcinomaof theprostatewithprostatespecificantigen.annClinlabsci21:371–380
107. Richie JP, Catalona WJ, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, MacFarlane MT, Southwick PC 1993effectofpatientageonearlydetectionof prostate cancerwith serumprostate-specific antigen anddigitalrectalexamination.urology42:365–374
108. Gosselaar C, Roobol MJ, Roemeling S, de Vries SH, Cruijsen-Koeter I, van der Kwast TH, Schröder FH 2006screeningforprostatecancerwithoutdigitalrectalexamina-tionandtransrectalultrasound:resultsafterfouryearsintheeuropean Randomized study of screening for ProstateCancer(eRsPC),Rotterdam.Prostate66:625–631
109. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha-Hikim I, Shen R, Storer TW 2001Testosteronedose-responserelationshipsinhealthyyoung men. am J Physiol endocrinol Metab 281:e1172–e1181
110. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW 2005Oldermenareasresponsiveasyoungmentotheanaboliceffectsofgradeddosesoftestos-terone on the skeletal muscle. J Clin endocrinol Metab90:678–688
111. Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S 2008 effects of graded doses of testosterone onerythropoiesisinhealthyyoungandoldermen.JClinendo-crinolMetab93:914–919
112. O’Carroll R, Bancroft J 1984Testosteronetherapy for lowsexualinterestanderectiledysfunctioninmen:acontrolledstudy.BrJPsychiatry145:146–151
113. Schiavi RC, White D, Mandeli J, Levine AC 1997effectoftestosteroneadministrationonsexualbehaviorandmoodinmenwitherectiledysfunction.archsexBehav26:231–241
114. Simon D, Preziosi P, Barrett-Connor E, Roger M, Saint-Paul M, Nahoul K, Papoz L 1992Theinfluenceofagingonplasmasexhormonesinmen:theTelecomstudy.amJepide-miol135:783–791
115.Dai WS, Kuller LH, LaPorte RE, Gutai JP, Falvo-Gerard L, Caggiula A 1981 The epidemiology of plasma testosteronelevelsinmiddle-agedmen.amJepidemiol114:804–816
116. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH 1997longitudinalrelationbetweenendogenoustestosteroneandcardiovasculardiseaseriskfactorsinmiddle-agedmen.a13-yearfollow-upofformerMultipleRiskFactorinterventionTrialparticipants.amJepidemiol146:609–617
117.Mohr BA, Bhasin S, Link CL, O’Donnell AB, McKinlay JB 2006Theeffectofchangesinadiposityontestosteronelevels
in older men: longitudinal results from the MassachusettsMaleagingstudy.eurJendocrinol155:443–452
118. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad Jr JG, Strom BL 1999 effect of testos-terone treatment on bone mineral density in men over 65yearsofage.JClinendocrinolMetab84:1966–1972
119. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL 1999 effect of testosterone treatment on bodycompositionandmusclestrengthinmenover65yearsofage.JClinendocrinolMetab84:2647–2653
120. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL 2004exogenoustestosterone or testosterone with finasteride increases bonemineral density in older men with low serum testosterone.JClinendocrinolMetab89:503–510
121. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL 2005exogenoustestosterone(T)aloneorwithfinasterideincreasesphysicalperformance,grip strength, and lean body mass in older men with lowserumT.JClinendocrinolMetab90:1502–1510
122. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG 2001effectsof transdermal testosteroneonboneandmuscleinoldermenwithlowbioavailabletestosteronelevels.JGerontolaBiolsciMedsci56:M266–M272
123. Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla ManC, Tindall DJ, Melton 3rd LJ, Smith GE, Khosla S, Jensen MD 2006dHeainelderlywomenand-dHeaor testosterone in elderly men. n engl J Med355:1647–1659
124. Sih R, Morley JE, Kaiser FE, Perry 3rd HM,Patrick P, Ross C 1997Testosteronereplacementinolderhypogonadalmen:a 12-month randomized controlled trial. J Clin endocrinolMetab82:1661–1667
125. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT 2006 drug insight:testosterone and selective androgen receptor modulators asanabolic therapies for chronic illness and aging. nat ClinPractendocrinolMetab2:146–159
126. Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieberman SA, Tipton K, Wolfe RR, Urban RJ 2002 Testosterone administration to older menimproves muscle function: molecular and physiologicalmechanisms. am J Physiol endocrinol Metab 282:e601–e607
127. Tenover JS 1992effectsof testosteronesupplementation intheagingmale.JClinendocrinolMetab75:1092–1098
128. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE 2003Oraltestosteronesupplementationincreases muscle and decreases fat mass in healthy elderlymaleswithlow-normalgonadalstatus.JGerontolaBiolsciMedsci58:618–625
an e
ndo
crin
e so
cieT
y cl
inic
al p
racT
ice
guid
elin
e
30
129. Reddy P, White CM, Dunn AB, Moyna NM, Thompson PD 2000Theeffectoftestosteroneonhealth-relatedqualityof life in elderly males—a pilot study. J Clin Pharm Ther25:421–426
130. Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S 2004 effects of testosterone on behavior, depression, andcognitive function inoldermenwithmildcognitive loss. JGerontolaBiolsciMedsci59:75–78
131. Blackman MR, Sorkin JD, Mu¨ nzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst KM, Harman SM 2002 Growth hormone and sexsteroid administration in healthy aged women and men: arandomizedcontrolledtrial.JaMa288:2282–2292
132. Tracz MJ, Sideras K, Boloña ER, Haddad RM, Kennedy CC, Uraga MV, Caples SM, Erwin PJ, Montori VM 2006Testosterone use in men and its effects on bone health. asystematicreviewandmeta-analysisofrandomizedplacebo-controlledtrials.JClinendocrinolMetab91:2011–2016
133. Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prest-wood KM 2002effectsoftransdermaltestosteroneoncogni-tive functionandhealthperception inoldermenwith lowbioavailabletestosteronelevels.JGerontolaBiolsciMedsci57:M321–M325
134. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS 2000 low-dose transdermal testosterone therapy improvesangina threshold in men with chronic stable angina: arandomized,double-blind,placebo-controlledstudy.Circula-tion102:1906–1911
135.Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M 2009Testosterone and depression: systematic review and meta-analysis.JPsychiatrPract15:289–305
136. Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL 2006effectsoftestosteroneoncognitionandmoodinmalepatients with mild alzheimer disease and healthy elderlymen.archneurol63:177–185
137. Rietschel P, Corcoran C, Stanley T, Basgoz N, Klibanski A, Grinspoon S 2000Prevalenceofhypogonadismamongmenwith weight loss related to human immunodeficiency virusinfection who were receiving highly active antiretroviraltherapy.Clininfectdis31:1240–1244
138. Salehian B, Jacobson D, Swerdloff RS, Grafe MR, Sinha-Hikim I, McCutchan JA 1999Testicularpathologicchangesandthepituitary-testicularaxisduringhumanimmunodefi-ciencyvirusinfection.endocrPract5:1–9
139. Grinspoon S, Corcoran C, Lee K, Burrows B, Hubbard J, Katznelson L, Walsh M, Guccione A, Cannan J, Heller H, Basgoz N, Klibanski A 1996lossof leanbodyandmusclemass correlates with androgen levels in hypogonadal menwith acquired immunodeficiency syndrome and wasting. JClinendocrinolMetab81:4051–4058
140. Kong A, Edmonds P 2002 Testosterone therapy in HiVwasting syndrome: systematic review and meta-analysis.lancetinfectdis2:692–699
141. Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I, Shen R, Arver S, Beall G 1998 effects oftestosterone replacement with a nongenital, transdermalsystem, androderm, in human immunodeficiency virus-infectedmenwithlowtestosteronelevels.JClinendocrinolMetab83:3155–3162
142. Bhasin S, Storer TW, Javanbakht M, Berman N, Yarasheski KE, Phillips J, Dike M, Sinha-Hikim I, Shen R, Hays RD, Beall G 2000Testosteronereplacementandresistanceexer-cise in HiVinfected men with weight loss and low testos-teronelevels.JaMa283:763–770
143. Grinspoon S, Corcoran C, Parlman K, Costello M, Rosen-thal D, Anderson E, Stanley T, Schoenfeld D, Burrows B, Hayden D, Basgoz N, Klibanski A 2000 effects of testos-teroneandprogressiveresistancetrainingineugonadalmenwith aids wasting. a randomized, controlled trial. anninternMed133:348–355
144. Knapp PE, Storer TW, Herbst KL, Singh AB, Dzekov C, Dzekov J, LaValley M, Zhang A, Ulloor J, Bhasin S 2008effectsofasupraphysiologicaldoseoftestosteroneonphys-icalfunction,muscleperformance,mood,andfatigueinmenwith HiV-associated weight loss. am J Physiol endocrinolMetab294:e1135–e1143
145. Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, Klibanski A 2000effectsofhypogonadismandtestosteroneadministrationondepressionindicesinHiV-infectedmen.JClinendocrinolMetab85:60–65
146. Rabkin JG, Wagner GJ, McElhiney MC, Rabkin R, Lin SH 2004TestosteroneversusfluoxetinefordepressionandfatigueinHiV/aids:aplacebo-controlledtrial.JClinPsychophar-macol24:379–385
147. Rabkin JG, Wagner GJ, Rabkin R 1999Testosteronetherapyfor human immunodeficiency virus-positive men with andwithouthypogonadism.JClinPsychopharmacol19:19–27
148. Rabkin JG, Wagner GJ, Rabkin R 2000 a double-blind,placebocontrolledtrialoftestosteronetherapyforHiV-posi-tivemenwithhypogonadalsymptoms.archGenPsychiatry57:141–147;discussion155–146
149. van Staa TP, Leufkens HG, Cooper C 2002Theepidemi-ologyofcorticosteroid-inducedosteoporosis:ameta-analysis.Osteoporosint13:777–787
150. Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ 2003 Randomized placebo-controlled trial of androgeneffects on muscle and bone in men requiring long-termsystemicglucocorticoidtreatment.JClinendocrinolMetab88:3167–3176
151. Reid IR, Wattie DJ, Evans MC, Stapleton JP 1996Testos-terone therapy in glucocorticoid-treated men. arch internMed156:1173–1177
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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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