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Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline
Authors: Shalender Bhasin, Glenn R. Cunningham, Frances J. Hayes, Alvin M. Matsumoto, Peter J. Snyder, Ronald S. Swerdloff, and Victor M. Montori Afliations: 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, Washington; University of Pennsylvania School of Medicine (P.J.S.), (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 o assistance to endocrinologists and other health care proessionals by providing guidance and recommendations or particular areas o practice. The Guidelines should not be considered inclusive o all proper approaches or methods, or exclusive o others. The Guidelines cannot guarantee any specifc outcome, nor do they establish a standard o care. The Guidelines are not intended to dictate the treatment o a particular patient. Treatment decisions must be made ma de based on the independent judgment o health care providers and each patient’s individual circumstances. The Endocrine Society makes no warranty, express or implied, regarding the Guidelines and specifcally excludes any warranties o merchantability and ftness or a particular use or purpose. The Society shall not be liable or direct, indirect, special, incidental, or consequential damages related to the use o the inormation contained herein. First published in Journal 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 Deciency Syndromes: An Endocrine Society Clinical Practice Guideline (J Clin Endocrinol Metab 91:1995– 2101l doi: 10.1210/jc.2005–2847) 10.1210/jc.2005–2847) This guideline is also available with CME. Go to http://www.endo-society http://www.endo-society.org/guidelines/Current-C .org/guidelines/Current-Clinical-Practice-Guidelines.cf linical-Practice-Guidelines.cfm m for more details. © The Endocrine Society, 2010
The Endocrine Society’s
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Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline
Table of Contents bstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 ummaryoRecommendations.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 Methodoevelopmentovidence-BasedClinicalPracticeGuidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 iagnosisoHypogonadism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 TreatmentondrogenefciencyWithTestosterone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 Reerences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 cknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31 OrderForm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32 Reprintnormation,Questions&Correspondences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . nsideBackCover
Abstract Objective: Toupdatetheguidelinesortheevalua-
Conclusions: Werecommendmakingadiagnosiso
tionandtreatmentoandrogendefciencysyndromes inadultmenpublishedpreviouslyin2006.
androgen defciency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. Wesuggest the measurement o morningtotaltestosteronelevelbyareliableassayas theinitialdiagnostictest.Werecommendconfrmationothediagnosisbyrepeatingthemeasuremento morningtotaltestosteroneandinsomemeninwhom totaltestosteroneisnearthelowerlimitonormalor in whom sex hormone binding globulin (HBG) abnormality issuspected by measurement oree or bioavailabletestosteronelevel,usingvalidatedassays. We recommend testosterone therapy or men with symptomaticandrogendefciencytoinduceandmaintain secondary sex characteristics and to improve theirsexualunction,senseowell-being,musclemass andstrength,andbonemineraldensity.Werecommendagainststartingtestosteronetherapyinpatients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specifc antigen greaterthan4ng/mlorgreaterthan3ng/mlinmenat highriskorprostatecancersuchasricanmericansormenwithfrst-degreerelativeswithprostate cancerwithouturtherurologicalevaluation,hematocrit>50%,untreatedsevere obstructivesleepapnea, severe lower urinary tract symptoms with nternational Prostate ymptom core (P) > 19, or uncontrolledorpoorlycontrolledheartailure.When testosteronetherapyisinstituted,wesuggestaimingat achievingtestosteronelevelsduringtreatmentinthe mid-normalrangewithanyotheapprovedormulations,chosenonthebasisothepatient’spreerence, considerationopharmacokinetics,treatmentburden, andcost.Menreceivingtestosteronetherapyshould bemonitoredusingastandardizedplan.
Participants: ThendrogensinMenGuidelineTask Forcewascomposedoachair,selectedbytheClinical Guidelines ubcommittee o The ndocrine ociety,fveadditionalexperts,amethodologist,and amedicalwriter.TheTaskForcereceivedno corporateundingorremuneration.
Evidence: Thisevidence-basedguidelinewasdevelopedusingtheGradingoRecommendations,ssessment, evelopment, and valuation (GR) systemtodescribethestrengthorecommendations andthequalityoevidence.
Consensus Process: Consensusothisguidelinewas guidedbysystematicreviewsoevidenceanddiscussionsduringin-persongroupmeetings,severalconerence calls, and e-mail communications. The drats preparedbytheTaskForcewerereviewedsuccessively by The ndocrine ociety’s Clinical Guidelines ubcommittee,ClinicalairsCoreCommittee,and approved by Council. t each stage o review, the TaskForcereceivedwritten commentsand incorporatedneededchanges.TaskForcemembershadfnal responsibilityorandcontrolovercontentpresented inthisguideline.
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SUMMARY OF RECOMMENDATIONS 1.1.
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DIAGNOSIS AND EVALUATION OF PATIENTS WITH SUSPECTED ANDROGEN DEFICIENCY
We recommend making a diagnosis o androgen defciencyonlyinmenwithconsistentsymptomsand signsandunequivocallylowserumtestosteronelevels. (1| ) Wesuggestthatcliniciansmeasureserumtestosteronelevelinpatientswithclinicalmaniestations shown in Table1. We suggest thatclinicians also consider measuring serum testosterone level when patients report the lessspecifc symptoms and signs listedinTable1B.(2| ) We suggest the measurement o morning total testosteronelevelbyareliableassayastheinitialdiagnostic test. (2| ) We recommend confrmation o the diagnosis by repeatingmeasurementototaltestosterone.(1| ) Wesuggestmeasurementoreeorbioavailable testosterone level, using an accurate and reliable assay, in some men in whom total testosterone concentrationsarenearthelowerlimitothenormal rangeandinwhomalterationsoHBGaresuspected. (2| ) Wesuggestthatanevaluationoandrogendefciencyshouldnotbemadeduringanacuteorsubacute illness. (2| )
1.1.1. Further evaluation o men deemed androgen defcient WerecommendmeasurementoserumHandFH levelstodistinguishbetweenprimary(testicular)and secondary (pituitary-hypothalamic) hypogonadism. (1| ) nmenwithsecondaryhypogonadism,wesuggest urtherevaluationtoidentiytheetiologyohypothalamic and/or pituitary dysunction. This evaluation may include measurements o serum prolactin and iron saturation, pituitary unction testing, and magnetic resonance imaging o the sella turcica. (2| )
nmenwithprimarytesticularailureounknown etiology,wesuggestobtainingakaryotypetoexclude Klineeltersyndrome,especiallyinthosewithtesticularvolumelessthan6ml.(2| ) Wesuggestmeasurementobonemineraldensity by using dual-energy x-ray absorptiometry (X) scanninginmenwithsevereandrogendefciencyor lowtraumaracture.(2| )
1.2.
SCREENING FOR ANDROGEN DEFICIENCY (GENERAL POPULATION)
We recommend against screening or androgen defciencyinthegeneralpopulation.(1| )
1.2.2. Case fnding o androgen defciency We suggest that clinicians not use the available case-fnding instruments or detection o androgen defciencyinmenreceivinghealthcareorunrelated reasons. (2| ) We suggest that cliniciansconsider case detection by measurement o total testosterone levels in menwithcertainclinicaldisorders,listedinTable3, inwhichtheprevalenceolowtestosteronelevelsis highororwhomtestosteronetherapyissuggested/ recommendedinection2.0.(2| )
2.0.
TREATMENT OF ANDROGEN DEFICIENCY WITH TESTOSTERONE
Werecommendtestosteronetherapyorsymptomatic men with classical androgen defciency syndromes aimed at inducing and maintaining secondary sex characteristicsandatimprovingtheirsexualunction, sense o well-being, and bone mineral density. (1| ) We recommend against testosterone therapy in patients with breast(1| )orprostatecancer. (1| ) We recommend against testosterone therapy withouturtherurologicalevaluationinpatientswith palpable prostate nodule or induration or prostatespecifcantigen(P)4ng/mlorP3ng/mlin menathighriskoprostatecancer,suchasrican mericans or men with frst-degree relatives with prostatecancer.(1| )
We recommend against testosterone therapy in patientswithhematocritabove50%,untreatedsevere obstructive sleep apnea, severe lower urinary tract symptoms[mericanrologicalssociation()/ nternationalProstateymptomcore(P)19],or uncontrolled orpoorly controlled heart ailure,orin thosedesiringertility.(1| ) We suggest initiating testosterone therapy with anyotheollowingregimens,chosenonthebasiso thepatient’spreerence,considerationopharmacokinetics,treatmentburden,andcost.(2| ) • 75–100 mg o testosterone enanthate or cypionateadministered intramuscularly (M)weekly, or150–200mgadministeredevery2weeks. • Oneortwo5-mgnongenital,testosteronepatches appliednightlyovertheskinotheback,thigh, orupperarm,awayrompressureareas. • 5–10goa1%testosteronegelapplieddailyover acoveredareaonongenitalskin(patientsshould washhandsaterapplication). • 30mgoabioadhesivebuccaltestosteronetablet appliedtobuccalmucosaevery12hours. • Testosteronepelletsimplantedsubcutaneouslyat intervalso3to6months;thedoseandregimen varywiththeormulationused. • Oraltestosteroneundecanoate,injectabletestosterone undecanoate, testosterone-in-adhesive matrix patch, and testosterone pellets where available.
Monitoring strategies and schedule Werecommendevaluatingthepatient3to6months atertreatmentinitiationandthenannuallytoassess whethersymptomshaverespondedtotreatmentand whether the patient is sueringany adverse eects, andtocheckcompliance.(1| ) Wesuggestmonitoringtestosteronelevels3to6 months ater initiation o testosterone therapy. We suggestaimingatachievingserumtestosteronelevels during treatment in the mid-normal range. n men receiving testosterone enanthate or cypionate, we suggest aiming or testosterone levels between 400 and 700 ng/dl one week ater the injection. (2| ) Werecommenddetermininghematocritatbaseline,at3to6months,andthenannually.hematocritis>54%,stoptherapyuntilhematocritdecreases
toasaelevel,evaluatethepatientorhypoxiaand sleepapnea,andreinitiatetherapyatareduceddose. (1| ) Wesuggestrepeatingbonemineraldensityothe lumbarspine,emoralneck,andhipater1to2years o testosterone therapy in hypogonadal men with osteoporosisorlowtraumaracture.(2| ) nmen40yearsoageorolderwhohaveabaselineP>0.6ng/ml,werecommenddigitalexaminationotheprostateandPmeasurementbeore initiating treatment, at3 to6 months, and then in accordancewithevidence-basedguidelinesorprostatecancerscreening,dependingontheageandrace othepatient.(1| ) Werecommendthatcliniciansobtainurological consultationithereis:(1| ) • nincreaseinserumorplasmaPconcentrationgreaterthan1.4ng/mlwithinany12-month periodotestosteronetreatment. • Pvelocityomorethan0.4ng/ml·yrusing the P level ater 6 months o testosterone administration as the reerence. P velocity shouldbeusedonlyitherearelongitudinalP dataormorethan2years. • etection o a prostatic abnormality on digital rectalexamination. • /Pscore>19. We recommend evaluation or symptoms and signs o ormulation-specifc adverse events at each visit: (1| ) • njectable testosterone esters: nquire about uctuationsin mood orlibido, and coughater injection, and evaluate hematocrit to detect excessive erythrocytosis, especially in older patients. • Testosteronepatch: ook orsigns o skin reactionattheapplicationsite. • Testosterone gels: dvise patients to cover the applicationsitewithclothingandwashtheskin beorehavingskin-to-skincontact,becausegels leavea residue otestosteroneon the skin that canbetranserredtoawomanorchildwhocomes inclosecontact. • Buccaltestosteronetablets:nquireaboutalterationsintasteandexaminegumsandoralmucosa orirritation.
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TESTOSTERONE THERAPY IN MEN WITH SEXUAL DYSFUNCTION
We suggestthatcliniciansoer testosteronetherapy tomenwithlowtestosteronelevelsandlowlibidoto improvelibido(2| )andtomenwitherectile dysunction () who have low testosterone levels ater evaluation o underlying causes o and consideration o established therapies or . (2| )
2.3.
OLDER MEN WITH LOW SERUM TESTOSTERONE CONCENTRATION
We recommend against a general policy o oering testosteronetherapytoalloldermenwithlowtestosterone levels. (1| ) We suggest that clinicians consider oering testosterone therapy on an individualized basis to oldermenwithlowtestosteronelevelsonmorethan one occasion and clinicallysignifcant symptoms o androgen defciency, ater explicit discussion o the uncertainty about the risks and benefts o testosteronetherapy. (2| )
2.4.
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PATIENTS WITH CHRONIC ILLNESS AND LOW TESTOSTERONE LEVELS
Wesuggestthatcliniciansconsidershort-termtestosterone therapy as an adjunctive therapy in HVinectedmenwithlowtestosteronelevelsandweight losstopromoteweightmaintenanceandgainsinlean bodymass(BM)andmusclestrength.(2| )
2.4.2. Glucocorticoid-treated men Wesuggestthatclinicians oertestosteronetherapy tomenreceivinghighdosesoglucocorticoidswho havelowtestosteronelevelstopromotepreservation oBMandbonemineraldensity.(2| )
METHOD OF DEVELOPMENT OF EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES The Clinical Guidelines ubcommittee o The ndocrine ociety deemed testosterone therapy in androgen-defcient men a priority area in need o practice guidelines and appointed a Task Force to ormulate evidence-based recommendations. The TaskForceelectedtousetheapproachrecommended by the Grading o Recommendations, ssessment, evelopment,andvaluation(GR)workgroup, aninternationalgroupwithexpertiseindevelopment andimplementationoevidence-basedguidelines(1). The Task Force used systematic reviews o available evidence and two commissioned systematic reviews (2–4) toinormitskey recommendations andconsistent language. The Task Force also used consistent languageandgraphicaldescriptionsoboththestrength oarecommendationandthequalityoevidence.The strength o a recommendation is indicated by the number1(strongrecommendation,associatedwiththe phrase“werecommend”)or2(weakrecommendation, associatedwiththephrase“wesuggest”).Thequalityo theevidenceisindicatedbycross-flledcircles,suchthat denotes very low quality evidence; , low quality; , moderate quality; and , highquality.TheTaskForcehasconfdencethatpersons whoreceivecareaccordingtothestrongrecommendations will derive, on average, more good than harm. Weakrecommendationsrequiremorecareulconsiderationotheperson’scircumstances,values,andpreerencestodeterminethebestcourseoaction. inkedtoeachrecommendationisadescriptionothe evidence, values thatpanelists considered in making therecommendation,andinsomeinstances remarks, a section in which panelists oer technical suggestions or dosing and monitoring. These technical commentsreectthebestavailableevidenceapplied toatypicalpatient.Oten,thisevidencecomesrom the unsystematic observations o the panelists and theirvaluesandpreerences;thereore,theseremarks shouldbeconsideredsuggestions.
1.0. DIAGNOSIS OF HYPOGONADISM Denition of hypogonadism.Hypogonadisminmen isaclinicalsyndromethatresultsromailureothe testis toproduce physiologicallevels otestosterone (androgendefciency)andanormalnumberospermatozoaduetodisruptionooneormorelevelsothe hypothalamic-pituitary-testicular(HPT)axis.
Classication of hypogonadism. bnormalities o the HPT axis at the testicular level cause primary testicular ailure, whereas central deects o the hypothalamusorpituitarycausesecondarytesticular ailure. Hypogonadism also can reect dual deects thataectboththetestisandthepituitary. • Primary testicular ailure results in low testosterone levels, impairment o spermatogenesis, andelevatedgonadotropinlevels. • econdarytesticularailureresultsinlowtestosterone levels, impairment o spermatogenesis, andloworlow-normalgonadotropinlevels. •
Combined primary and secondary testicular ailureresults inlow testosteronelevels,impairment o spermatogenesis, and variable gonadotropinlevels,dependingonwhetherprimaryor secondarytesticularailurepredominates.
Thisclassifcationhastherapeuticimplicationsbecause ertility can be restored with appropriate hormonal stimulationinpatientswithsecondaryhypogonadism, butnotinmostpatientswithprimaryhypogonadism. Fertilityoptionsormenwithprimarytesticularailure arelimitedtotheuseodonorsperm,adoption,or,in somepatients,assistedreproductivetechnologies,such as intracytoplasmic sperm injection. lso, urther evaluation o secondary hypogonadism may uncover apituitarytumororsystemicillness. Combined primary and secondary hypogonadism occurs with hemochromatosis, sickle cell disease, thalassemia, glucocorticoid treatment, alcoholism, andX-1mutations,andinoldermen(5,6).
The age-related decline in testosterone levels, confrmedinseveralcross-sectionalandlongitudinal studies (7–9), results rom deects in bothtesticular and hypothalamic-pituitary unction. The average declineinserumtestosteronelevelswithaginginmen is1–2%peryear(7,8).signifcantractionoolder menhavelevelsbelowthelowerlimitothenormal rangeorhealthy,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 deficiency 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 testosterone level by a reliable assay as the initial diagnostic test. (2| ) We recommend confirmation of th e diagnosis by repeating measurement of total t estosterone. (1| ) We suggest measurement of free or bioavailable testosterone 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 o hypogonadism in men dependsontheageoonsetoandrogendefciency. Onset in adulthood leads to a clinical syndrome
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TABLE 1. Symptoms and signs suggestive of androgen deciency in men
A.Morespecifcsymptomsandsigns • Incompleteordelayedsexualdevelopment, eunuchoidism • Reducedsexualdesire(libido)andactivity • Decreasedspontaneouserections • Breastdiscomort,gynecomastia • Lossobody(axillaryandpubic)hair,reducedshaving • Verysmall(especially<5ml)orshrinkingtestes • Inabilitytoatherchildren,loworzerospermcount • Heightloss,lowtraumaracture,lowbone mineraldensity • Hotushes,sweats B.Otherlessspecifcsymptomsandsigns • Decreasedenergy,motivation,initiative,and sel-confdence • Feelingsadorblue,depressedmood,dysthymia • Poorconcentrationandmemory • Sleepdisturbance,increasedsleepiness • Mildanemia(normochromic,normocytic,inthe emalerange) • Reducedmusclebulkandstrength • Increasedbodyat,bodymassindex • Diminishedphysicalorworkperormance
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substantiallydierentromthatresultingromonset intheetalorprepubertalperiod.ncontrasttomen whose hypogonadism is o postpubertal onset, men whosehypogonadismisoprepubertalonsetandwho were not adequately treated will exhibit eunuchoid proportions, delayed development o secondary sex characteristics,andhighpitchedvoice.
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iagnosisoandrogendefciencyinmenposesseveral challenges.ymptomsandsignsarenonspecifcand modifedbyage,comorbidillness,severityandduration o androgen defciency, variation in androgen sensitivity, and previous testosterone therapy. The signsandsymptomslistedinTable1arebasedonthe panelists’ experience in clinic-based populations o androgen-defcientmenwhoare likelytohavemore severeandrogendefciency;population-basedsurveys osymptomsandsignsinmenwithclassicalandrogen defciencyhavenotbeenconducted.
n population-based surveys o community-dwelling middle-agedandoldermen,lowlibido,andhot ushes,aswellaslessspecifcsymptomssuchasatigue or loss o vigor, irritability or depressed mood,poor concentration,reducedphysicalperormance,orsleep disturbance, were associated with low testosterone levels(10–12).nthesesurveys,thecrudeprevalence osymptomaticandrogendefciencywas~6%inthe populationomiddle-agedtooldermenandincreased withage,waistcircumerence,andpoorsel-reported healthstatus,butwasunrelatedtoraceandethnicity (12). n other population-based studies, the prevalence o low testosterone irrespective o symptoms wasassociatedwithage,obesity,diabetes,andcomorbidities or health status (9, 12, 13). The overall prevalenceolowtestosteronewasoundtobehigher inaprimarycarepractice–basedpopulationopatients than that reported in populations o communitydwellingmen(14). Thethresholdtestosteronelevel below which symptoms o androgen defciency and adverse health outcomes occur and testosterone administration improvesoutcomesinthegeneralpopulationisnot known.However,inhealthymenaswellasinreerral patient populations, the threshold o testosterone levelsvariedorvarioussymptomsoandrogendefciency and target organs, and among individuals (11,12,15).Formostsymptoms,theaveragetestosterone threshold corresponded to thelower limit o the normal range or young men, i.e., ~300 ng/dl (10.4 nmol/l) with a greater likelihood o having symptomsbelowthisthresholdthanaboveit(11,15). erumtestosteronelevelsvarysignifcantlyasaresult ocircadianandcircannualrhythms,episodicsecretion, and measurement variations (16–19). Testosteroneconcentrationsmaybe aectedbyillnessand certain medications (e.g., opiates and glucocorticoids). Total testosterone concentrations are also inuencedbyalterationsinHBGconcentrations. erum testosterone levels exhibit a circadian variationwithpeakvaluesinthemorning;thiscircadian rhythm is blunted with aging (16). Because o this circadianvariationintestosteronelevelsandtheact thatnormalrangesorserumtestosteroneareusually establishedusingmorningbloodsamples,testosterone
measurementorthediagnosisoandrogendefciency should be perormed in the morning. t has been argued thatmorning testosterone measurements are not needed in older men in whom the circadian rhythmisblunted.However,asubstantialractiono oldermen,65to80yearsoage,haslowserumtestosteronelevelsintheaternoonwillhavenormaltestosteroneconcentrationsinthemorning(17). tisimportanttoconfrmlowtestosteroneconcentrationsinmenwithaninitialtestosteronelevelinthe mildlyhypogonadalrange,because30%osuchmen may have a normal testosterone level on repeat measurement(17).lso,15%ohealthyyoungmen mayhaveatestosteronelevelbelowthenormalrange in a 24-hour period. n a community-based, multiethniccohortomiddle-agedtooldermen,day-to-day variationsinserumtestosteroneconcentrationswere oundtobesufcientlylargethatsingletestosterone measurements were inadequate to characterize an individual’s levels, and at least two testosterone measurementswereneededtodiagnoseandrogendefciencywithgreaterconfdence(17). erumtotaltestosteroneconcentrationrepresentsthe sum o unbound and protein-bound testosterone in circulation. Most o the circulating testosterone is boundtoHBGandtoalbumin(18,19);only0.5–3% ocirculatingtestosteroneisunboundor“ree.”The term “bioavailable testosterone” reers to unbound testosterone plus testosterone bound loosely to albumin;thistermreectsthehypothesisthatinaddition to the unbound testosterone, albumin-bound testosteroneisreadilydissociableandthusbioavailable.Freeorbioavailabletestosteroneconcentrations shouldbemeasuredwhentotaltestosteroneconcentrations are close to the lower limit o the normal range and when altered HBG levels are suspected e.g.,inoldermenandinmenwithobesity,diabetes mellitus, chronic illness, or thyroid disease (conditionslistedinTable2). Total testosterone concentrations are measured by radioimmunoassay (R), immunometric assays, or liquid chromatography tandem mass spectrometry. utomatedassaysortotaltestosteroneareavailable in most hospital laboratories and usually are sufcientlyaccuratetodistinguisheugonadalromhypo-
TABLE 2. Conditions associated with alterations in SHBG concentrations
ConditionsassociatedwithdecreasedSHBG concentrations • Moderateobesity* • Nephroticsyndrome* • Hypothyroidism • Useoglucocorticoids,progestins,andandrogenic steroids* • Acromegaly • Diabetesmellitus* ConditionsassociatedwithincreasedSHBG concentrations •Aging* • Hepaticcirrhosisandhepatitis* • Hyperthyroidism • Useoanticonvulsants* • Useoestrogens • HIVdisease * Particularlycommonconditionsassociatedwithalterationsin SHBGconcentrations
gonadalmen(18,19).Totaltestosteronelevelsare aectedbyalterationsinHBGthatoccurinobesity, oldage,diabetesmellitus,hyper-andhypothyroidism, andacromegaly,andinmentakingcertainmedications(Table2).ccurateandreliableassaysorree orbioavailabletestosteronemeasurementsusuallyare not available in local laboratories, and these tests should be perormed in a reliable reerence laboratory. Free testosterone measurements by analog methods are requently available in local laboratories, but these measurements areaectedby alterationsinHBGandareinaccurate(19).Theiruseis not recommended. Free testosterone level can be measuredaccuratelybyequilibriumdialysisorcalculated rom total testosterone, HBG, and albumin (20).Thecalculatedreetestosteroneconcentrations aredependentonthequalityototaltestosteroneand HBG assays. The calculated ree testosterone concentrations dier systematically rom those measured byequilibrium dialysisand vary with the algorithmusedorcalculatingreetestosterone(21). Bioavailabletestosteroneismeasuredbyammonium sulateprecipitationorcalculatedromtotaltestosteroneandHBG.
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Thenormativerangesortotalandreetestosterone levelsinhealthyyoungmenvaryamonglaboratories andassays(18).nsomelaboratories,thelowerlimit o the normal range or total testosterone level in healthyyoungmenis280-300ng/dl(9.8-10.4nmol/l). imilarly, in some reerence laboratories, the lower limitothe normalrangeorserumreetestosterone level,measuredbytheequilibriumdialysismethod,is 5–9pg/ml(0.17-0.31nmol/l).The clinicians should usethelowerlimitonormalrangeorhealthyyoung menestablishedintheirlaboratory.
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Theassessmentomenorandrogendefciencyshould includeageneralhealthevaluationtoexcludesystemic illness, use o certain medications (e.g., opiates or high-dose glucocorticoid therapy) and recreational drugs that aect testosterone productionormetabolism,eatingdisorders,andexcessiveexercisebecause these conditions can lower testosterone levels transiently(5).ong-actingopioidanalgesicssuppressthe hypothalamic-pituitary-gonadal (HPG) axis in men, produce symptomatic androgen defciency, and are associatedwithincreasedriskoosteoporosis(22,23). Thesuppressionotestosteroneisparticularlyproound inmenonmethadonemaintenancetherapybecauseo itslongdurationoaction;buprenorphinesuppresses plasmatestosteronetoalesserextentthanmethadone (24). ndrogen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogs in men with prostate cancer has emerged as an important causeotherapeuticallyinducedandrogendefciency thatisassociatedwithincreasedriskosexualdysunction, atigue, ractures, cardiovascular disease, and diabetes (25). The diagnosis o androgen defciency shouldnotbemadeduringanacuteillness.
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1.1.C. Values Ourproposed diagnostic strategy reects ourpreerence to avoid labeling men with low testosterone levelsduetoHBGabnormalities,naturalvariations in testosterone levels, or transient disorders as requiring testosterone therapy. Our strategy also reects our preerence to avoid treatment in men without unequivocally low testosterone levels and symptomsin whom the benefts and riskso testosteronetherapyremainunclear.
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 f luid 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 o H and FH concentrations can help distinguish between primary and secondary hypogonadism. Men with primary hypogonadism have low testosterone levels in association with elevated H and FH levels, while men with secondaryhypogonadismhavelowtestosteronelevels inassociationwithloworinappropriatelynormalH levels.BecauseHissecretedinapulsatilemannerby thepituitary,serumHlevelsinmenwithsecondary hypogonadismmaybebelowthenormalrangeorin low-normalrangebutclearlyinappropriateinrelation tothelowtestosteroneconcentrations.nindividuals withcompleteidiopathichypogonadotropichypogonadism(e.g.,Kallmannsyndrome)andseveregonadaotropinsuppressionordefciency,Hpulsatilitymay be absent or markedly suppressed and these men
FIG. 1. An approach for the diagnostic evaluation of adult men suspected of having androgen deciency. FSH = folliclestimulating hormone; LH = luteinizing hormone; MRI=magnetic r esonance imaging; SFA,=seminal uid analysis; SHBG = sex hormone-binding globulin; T = testosterone History and physical (symptoms and signs)
Morning Total T
Normal T
Low T #
Follow up
Exclude reversible illness, drugs, nutritional defciency Repeat T [use free or bioavailable T, if suspect altered SHBG^] LH+FSH SFA [If fertility issue]
Confrmed 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
# Insomelaboratories,thelowerlimitofthenormaltestosteronerangeinhealthyyoungmenisapproximately280–300ng/dl(9.8–10.4 nmol/l);however,thisrangemayvaryindifferentlaboratories.Usethelowerlimitoftherangeestablishedinyourreferencelaboratory. @ Insomereferencelaboratories,thelowerlimitofthenormalfreetestosteronerangeinhealthyyoungmenisapproximately5–9ng/dL (0.17–0.31nmol/liter)usingequilibriumdialysisorcalculatedfromtotaltestosteroneandSHBG;however,thisrangemayvaryindifferent laboratories,dependingonthespecicequilibriumdialysisorcalculatedfromtotaltestosteroneandSHBGassaysandthereference populationused.Usethelowerlimitoftherangeestablishedinyourreferencelaboratory. ^ ConditionsinwhichSHBGlevelsmaybealteredarelistedinTable2. * PerformpituitaryimagingMRItoexcludepituitaryand/orhypothalamictumororinltrativedisease,ifseveresecondaryhypogonadism(serum T<150ng/dl),panhypopituitarism,persistenthyperprolactinemia,orsymptomsorsignsoftumormasseffect,suchasheadache,visual impairment,orvisualelddefect,arepresent.
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usuallyhaveverylowtestosteroneandHlevels.n most clinical laboratories, H levels are measured usingnonradioactiveimmunometricassaysthathave sufcient sensitivity to distinguish between normal andlowlevels. n men deemed to have secondary hypogonadism, additional diagnostic evaluation may be needed to exclude pituitary neoplasia, hyperprolactinemia, hemochromatosis and other infltrative diseases,
obstructivesleepapnea,andgeneticdisordersassociatedwithgonadotropindefciency.Themeasurement oserumprolactinandironsaturationcanhelpdeterminethepresenceo hyperprolactinemiaandhemochromatosis, respectively. ssessment o anterior pituitary unction, i clinically indicated or in the presence o severe secondary hypogonadism (testosteronelevel<150ng/dl[<5.2nmol/l]),canuncover otherpituitaryhormonedefciencies.diagnosiso
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idiopathic hypogonadotropic hypogonadism is made ater excluding other causes o hypogonadotropic hypogonadism. Patients with hypogonadotropic hypogonadism should be examined or dysmorphic eatures—suchas extremeobesity(e.g., Prader-Willi yndrome), polydactyly, anosmia (e.g., Kallmann syndrome),shortstature(e.g.,contiguousgene deletions o chromosome X), or kidney abnormalities (e.g.,Kallmannsyndrome)—toacilitaterecognition ospecifcsyndromesbypatternrecognition. n the evaluation o men with secondary hypogonadism, the cost-eectiveness o pituitary imaging MRtoexcludepituitaryand/orhypothalamictumor isunknown.urveysomenwithsecondaryhypogonadism and sexual dysunction haverevealed a low prevalence o hypothalamic-pituitary abnormalities (26,27).Thediagnosticyieldopituitaryimagingto excludepituitaryand/orhypothalamictumorcanbe improvedbyperormingthisprocedureinmenwith serumtestosteronebelow150ng/dl(26),panhypopituitarism,persistenthyperprolactinemia,orsymptoms otumormasseect(headache,visualimpairment,or visualfelddeect).
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Karyotype can be useul in excluding Klineelter syndrome ─ a common identifable cause o primary testicular ailure ─ in men with primary testicular ailure,especiallyinthosewithtesticularvolumeless than 6 ml, although men with mosaic Klineelter syndrome may have larger testicular volumes. The karyotype obtained rom peripheral blood lymphocytesmaybenormal(46,XY)inmenwithKlineelter syndrome who have mosaicism (46, XY/ 47, XXY). Men with Klineelter syndrome can beneft rom geneticcounselingandneedsurveillanceorcertain disordersorwhichtheyareatincreasedrisk(28). Testosteronestimulatesboneormationandinhibits bone resorption through multiple mechanisms that involve both androgen and estrogen receptormediated processes (29,30). However, the cost- eectivenessomeasuringbonemineraldensityand the requency at which it should be perormed are stillbeingdebated.
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ertilityisapressingclinicalissuetopatientsand their partners, at least two seminal uid analyses
separatedby aninterval oseveralweeks should be perormedonsemensamplescollectedwithin1hour oejaculationateratleast48hoursoabstinence. The cost-eectiveness o these diagnostic strategies hasnotbeenevaluatedinclinicaltrials.
1.1.1.C. Values Ourrecommended diagnostic strategy places a relatively higher value in detecting conditions (e.g., pituitary neoplasiaor other treatablepituitarydisorders)or which eectivetreatmentor counseling is available. This strategy places a relatively lower valuein avoidingthe burden and cost otests with unknownyield.
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 deficien cy in the general population. (1| )
1.2.1.B. Evidence Becauseothelackoconsensusonacasedefnition andtheextenttowhichandrogendefciencyisan importanthealthproblem,aswellasthelackodata on the perormance characteristics o candidate screening tools, the useulness o population screeningcannotbeevaluatedatpresent.Thelongtermhealthconsequencesolowtestosteronelevels areunknowninthetwolargestsubsetsomenwith low testosterone levels—older men and men with chronic illness.The impact o untreated androgen defciencyonmortalityisunclear,althoughseveral, butnotall,epidemiologicstudieshave reported an associationolowtestosteronelevelswithhigherallcausemortality,particularlymortalityduetocardiovasculardisease(31–34).Thebeneftsandadverse consequenceso long-term testosteronetherapyon patient-important outcomes in asymptomatic men with presumed hypogonadism remain unclear (35, 36). Thereore, screening or androgen defciency doesnotulfllanyothenecessarycriteriatojustiy
it.oclinical trialshaveassessed theeectiveness oscreeningstrategies.
1.2.1.C. Values The recommendation not to screen men in the general population places a high value on avoiding labelingandmedicalizationootherwisehealthymen orwhomtesting,treatment,andmonitoringwould representaburdenwithunclearbeneft.Thisrecommendationalsoplacesahighvalueonavoidinginterventionswithunclearoutcomes.tplacesalowvalue onthepotentialbeneftsoearlydetectionandtreatment oandrogendefciency inmen who have not soughtmedicalattention.
1.2.2. Case Finding o Androgen Defciency 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 deally,casedetectionshouldidentiyromtheclinic populationpatientswhopresentwithmedicalproblemsapparentlyunrelatedtoandrogendefciency,but who are likely to beneft rom testosterone therapy. Candidategroupsinwhomthereishighprevalenceo low testosterone levels and in whom we suggest measurementoserumtestosteronelevelarelistedin Table3;theseincludemenwithchronicillness,such as those with HV-associated weight loss, end- stage renal disease on dialysis, chronic obstructive pulmonary disease, osteoporosis or racture ater lowtraumaatayoungage,type2diabetesmellitus, andmenreceivingchronicglucocorticoidandopioids (5, 6, 37–40). Most surveys o men with chronic illnessincludedrelativelysmall,conveniencesamples. The inormation about the benefts and risks o
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,orother diseasesothesellarregion • Treatmentwithmedicationsthataecttestosterone productionormetabolism,suchasglucocorticoidsand opioids • HIV-associatedweightloss • End-stagerenaldiseaseandmaintenancehemodialysis • Moderatetoseverechronicobstructivelungdisease • Inertility • Osteoporosisorlowtraumaracture,especiallyina youngman • Type2diabetesmellitus Inmenwithchronicdiseasessuchasdiabetesmellitus, end-stagerenaldisease,chronicobstructivelungdisease, measurementotestosteronemaybeindicatedby symptomssuchassexualdysunction,unexplainedweight loss,weakness,ormobilitylimitation.Inmenwithsome otherconditions,suchasapituitarymass,HIV-associated weightloss,lowtraumaracture,ortreatmentwith medicationsthataecttestosteroneproduction,measurementotestosteronemaybeindicatedregardlesso symptoms.
testosterone therapy in these conditions is either limitedornotavailable. There is limited inormation about the perormance properties o case-detection instruments that rely on sel-report, namely, ndrogen efciency in ging Males (M) (41), the ging Males’ ymptoms (M)Ratingcale(42),andtheMassachusettsMale gingtudyQuestionnaire(43).Therearenotrialso case-detectionstrategiesinthesepatientpopulations, and the cost-eectiveness o the use o case-fnding instruments over measurement o serumtestosterone levelsisunknownandtheirspecifcityispoor(44).
1.2.2.C. Values Our recommendation in avor o case detection by measurementotestosteronelevelsplacesarelatively highvalueonthepotentialbeneftsandarelatively lowvalueontheburdenotestosteronetherapyand uncertaintyaboutitslong-termsaety.
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2.0. TREATMENT OF ANDROGEN DEFICIENCY WITH TESTOSTERONE
tate and PSA measurement before initiating treatment, at 3 to 6 months, and then in accordance w ith evidence-based guidelines for prostate cancer screening, depending on the age and race of the patient. (1| )
2.1.B. Evidence
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 characteristics and at improving their sexual functi on, sense of wellbeing, and bone mineral d ensity. (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 prostate cancer. (1| )
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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 d osing interval; we suggest aiming for testosterone levels between 400 and 700 ng/dl midway between injections. (2| )
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In men 40 years of age or older who have a baseline PSA > 0.6 ng/ml, we recommend digital examination of the pros-
2.1.1. Non–placebo-controlled studies. oweringotestosteroneconcentrationsinadultmen bysurgicalorchiectomyorbyGnRHagonistorantagonist administration is associated with rapid and markedlossobonemineraldensity(29),increasein atmass(45),andalossomusclemassandstrength (45). owering o testosterone concentrations also resultsinhotushesandadecreaseinoverallsexual activity,thoughts,andantasies. Testosterone therapy o young, hypogonadalmen is associated with improvements in overall sexual activity scores, requency o sexual thoughts and antasies,anincreaseinattentivenesstoeroticstimuli, and an increase in the requency and duration o nighttime erections (46–53). Testosterone therapy increases hair growth in several androgen-sensitive areas. Testosterone therapy o healthy, hypogonadal menalsoincreasesat-reemass(47,48,54–57)and musclestrength(47,54)anddecreasesatmass(47, 48, 57). lthough testosterone therapy o healthy, hypogonadal men increases bone mineral density depending on compliance (58–60), the eects o testosteroneonractureriskareunknown. Testosteronetherapyimprovesthepositiveandreduces thenegativeaspects omood(60,61).ncontrolled studies report improvements in energy and sense o well-beingatertestosteronetherapy(62).nasmall open-labeltrial,testosteronetherapyhasbeenreported toimprovesomequality-o-liemeasuressuchassexual unction,well-being,andmoodinmenwithopioidinduced androgen defciency (22). The eects o testosterone oncognitiveunction arepoorlyunderstood;somestudiesreportsmalleectsonvisuospatial cognitionandverbalmemoryanduency(63,64). ata onthe impact otestosterone replacement on insulin sensitivity have yielded conicting results. omestudieshave demonstratedavorableeectsin
menwithobesity(65,66)ortype2diabetes(67),and inhealthyoldermen(68).n contrast,otherstudies haveshownnochangesininsulinsensitivityollowing androgenadministrationtohealthyyoung(69)and oldermen(70). Testosterone therapy may be associated with increasedriskoseriousadverseeectsinmenwith somedisorders(Table4).Metastaticprostatecancer and breast cancer are hormone-dependent cancers that maybe stimulated togrowduring testosterone treatment(71);testosteroneshouldnotbeadministered to men with these cancers. lthough some clinicians have suggested that patients with organconfnedprostatecancerwhohaveundergoneradical prostatectomyandhavebeendisease-ree2ormore yearsaterradicalprostatectomyandwhohaveundetectable P levels may be considered or testosterone replacement on an individualized basis (72–74),butthelackodataromrandomizedtrials precludesageneralrecommendation. prostatenoduleorindurationoraP>4.0ng/ml mayindicateapreviouslyunrecognizedprostatecancer. n addition to P and digital rectal examination (R)results,theassessmentoprostatecancerrisk TABLE 4. Conditions in which testosterone administration is associated with a high risk of adverse outcome and for which we recommend against using testosterone
Veryhighriskoseriousadverseoutcomes • Metastaticprostatecancer • Breastcancer Moderatetohighriskoadverseoutcomes • Unevaluatedprostatenoduleorinduration • PSA>4ng/ml(>3ng/mlinindividualsathighrisk orprostatecancer,suchasAricanAmericansormen withfrst-degreerelativeswhohaveprostatecancer) • Hematocrit>50% • Severelowerurinarytractsymptomsassociatedwith benignprostatichypertrophyasindicatedbyAUA/ IPSSscore>19 • Uncontrolledorpoorlycontrolledcongestiveheart ailure AUA/IPSS=AmericanUrologicalAssociation/InternationalProstate SymptomScore
shouldincludeconsiderationoadditionalriskactors, suchasage,amilyhistory(greaterriskinmenhaving a frst-degree relative with prostate cancer), race (greater risk in rican mericans), prior biopsy history,comorbidities,andPvelocityanddensity (75,76).Wesuggestestimatingprostatecancerrisk using the prostate cancer risk calculator (http:// deb.uthscsa.edu/RORiskCalc/Pages/calcs.jsp), which takes intoconsideration age, ethnicity, P, fndingsodigitalrectalexamination,amilyhistory, theuseoa5-αreductaseinhibitor,andpriorbiopsy history. Men in the placebo arm o the Prostate Cancer Prevention Trial were observed to have increased risk o an occult prostate cancer even i theirPwas<4.0ng/ml,andtheriskincreasedas thePincreasedabove0.5ng/ml(75).Theprostate cancerriskcalculatorprovidesameansorevaluating prostate cancer risk in men who are considering testosteronetreatment(76),butitcanonlybeused ormen55to95yearsoage(76).nmendeemedto be at high risk or prostate cancer, such as rican mericans and men with frst-degree relatives with prostatecancer,aPlevel>3ng/mlshouldprompt a urological consultation beore consideration o testosteronetherapy.Furthermore,inmenwithhematocrit>50%,untreatedobstructivesleepapnea,severe lower urinary tract symptoms, or severe congestive heartailure,testosteronemayworsenthesecondition (77).Testosteronetherapymaysuppressspermatogenesisandisnotappropriateinmenwhodesireertility. Open-labelstudiesinyoung,hypogonadalmenhave oundalowrequencyoadverseeventswithreplacement doses o testosterone. Common drug-related adverseeventsincludeincreaseinhematocrit,acne, oilinessoskin,andbreasttenderness(Table5).The requency o breast enlargement, sleep apnea, and prostateeventsislowintrialsoyoung,hypogonadal men.systematicreviewotestosteronetherapyin men with low or low normal testosterone levels included37randomizedcontrolledtestosteronetrials in hypogonadal men, healthy oldermen, men with sexual dysunction, HV-inected men with weight loss,and inmen with a variety o otherconditions (2).Thismeta-analysisolowqualityevidence,mostly because o large loss to ollow-up and inconsistent resultsacrossstudies,oundthattestosteronetherapy
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wasassociatedwithgreaterincreasesinhemoglobin, hematocrit,andP,andagreaterdecreaseinhighdensity lipoprotein (H) cholesterol level than placebo(2).Theseeectsweremostmarkedinstudies enrollingolderpatientswithlowtestosteronelevels usingintramusculartestosteronepreparations.Overall mortality,cardiovasculareventrates,prostatecancer, lowerurinarytractsymptomscores,andsystolicand diastolicbloodpressuredidnotdieramongtestosterone-andplacebo-treatedmen(2).
2.1.2. Placebo-controlled, randomized trials.
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systematicreviewoundnorandomized,placebocontrolledtrialsotheeectotestosteronetherapy ondepression,cognition,ragilityractures,qualityo lie, or cardiovascular outcomes in young, hypogonadal men (3). n trials that reported the eect o testosteroneonlibido(3,4,46,78–80)anderectile unction(81–87) in hypogonadalmen, testosterone therapywasassociatedwithgreaterimprovementsin libido (dierence between testosterone and placebo groups1.2;95%confdenceinterval[C],0.3,2.2)but nosignifcantimprovementsinsel-reportederectile unction (0.8; 95% C, –0.05, 1.6.) compared with placebo (4). n a systematic review o testosterone trials that werepublished beore October 2004 and that enrolled men with low testosterone levels (4), testosteronetherapywasassociatedwithamoderate nonsignifcantandinconsistenteectonsatisaction witherectileunction(random eects pooled eect size,0.80;95%C–0.10,1.60),alargeeectonlibido (pooledeectsize,1.31,95%C,0.40,2.25),andno signifcant eect on overall sexual satisaction (4). Trials thatenrolledpatients withloworlow-normal testosteronelevelsatbaselineshowedasmalleect on satisaction with erectile unction(pooled eect size,0.34;95%C,0.03,0.65),moderatenonsignifcanteectonlibido(pooledeectsize,0.41;95%C, –0.01, 0.83), and no signifcant eect on overall sexualsatisaction.Theinconsistencyacrosstrialsand imprecision o pooled estimatesweaken theseinerences (4). The trials o the eects o testosterone therapyonerectileresponsetoselectivephosphodiesterase 5 (P-5) inhibitors have beeninconclusive (87–93).
TABLE 5. Potential adverse effects of testosterone replacement
Adverseeventsorwhichthereisevidenceoassociation withtestosteroneadministration • Erythrocytosis • Acneandoilyskin • Detectionosubclinicalprostatecancer • Growthometastaticprostatecancer • Reducedspermproductionandertility Uncommonadverseeventsorwhichthereisweak evidenceoassociationwithtestosteroneadministration • Gynecomastia • Malepatternbalding(amilial) • Growthobreastcancer • Inductionorworseningoobstructivesleepapnea Formulation-specifcadverseeects • Intramuscularinjectionsotestosteroneenanthate, cypionateorundecanoate – Fluctuationinmoodorlibido – Painatinjectionsite – Excessiveerythrocytosis(especiallyinolderpatients) – Coughingepisodesimmediatelyaterthe intramuscularinjection* • Transdermalpatches – Frequentskinreactionsatapplicationsite • Transdermalgel – Potentialriskortestosteronetransertopartneror anotherpersonwhoisinclosecontact(needto remindpatienttocoverapplicationsiteswithclothing andtowashskinandhandswithsoapbeore havingskin-to-skincontactwithanotherperson) – Skinirritation • Buccaltestosteronetablets – Alterationsintaste – Irritationogums • Pelletimplants – Inection,expulsionopellet • Oraltablets – Eectsonliverandcholesterol(methyltestosterone)† * Themechanismofcough,whichhasbeenreportedrarelyafter intramuscularinjectionsoftestosteroneundecanoateandeven morerarelyaftertestosteroneenanthateandcypionate,is unknown,butithasbeenattributedtooilembolization. † Livertoxicityhasbeenreportedmostlywithoral17-alpha alkylatedandrogens.Thefrequencyofskinreactionsishigher withthetestosteronepatchthanwiththetransdermalgels.
Most studies o testosterone therapy in young, hypogonadalmenhavebeenopenlabelanddidnot include a placebo group. The observations rom theseopen-labelstudiesareconsistentwiththesparse dataromrandomizedtrialsandwiththeexperience othepanelists.(Quality of evidence: )
2.1.C . Values Therecommendationtooertestosteronetherapyto healthy,hypogonadalmenwithclassicandrogen-defciencysyndromesplacesa relativelyhighervalueon alleviatinghypogonadalsymptomsandotherbenefts otestosteronetherapyandarelativelylowervalueon avoidingthepotentialburdenolong-termtreatment, monitoring,cost,anditsunclearlong-termsaety.
2.1.D. Remarks Table6 summarizesthe clinical pharmacologyothe available testosterone ormulations. When clinicians recommendtestosteronetherapy,wesuggestaimingat achieving testosterone levels in a range that is midnormalorhealthy,youngmen.nmenreceiving testosterone enanthate or cypionate, serum testosteronelevelsvaryduringthedosinginterval;wesuggest aimingortestosteronelevelsbetween350and750ng/ dloneweekatertheinjection.Testosteronetherapy canbeinitiatedwithanyothesuggestedregimensin accordwithconsiderationsothepatient’spreerence, pharmacokinetics o testosterone ormulation, treatmentburden,andcost(Table7).Outsidethenited tates,oraltestosteroneundecanoate,amatrixtransdermaltestosteronepatch,andinjectabletestosterone undecanoate are available or clinical use in many countries;physiciansinthosecountrieswhowishtouse these ormulations should ollow the drug regimens approved in those countries. ee Tables 6 and 8 or additionalsaetyandpharmacokineticsinormation. Whenthegoalotreatmentistoreplacetestosterone, treatmentomenwhosehypogonadismisoprepubertal onset issimilarto that omen with hypogonadismopostpubertalonset,asdescribedabove.n contrast, when the goal o treatment is to restore ertility,menwithhypogonadismoprepubertalonset aremorelikelytorequirereplacementoFHaswell asH,whereasmenwithpostpubertalonsetaremore likelytorequirereplacementoHonly(94–97).
Monitoring androgen-decient men receiving testosterone therapy. ndrogen-defcient men receivingtestosteronetherapywhoare>40yearso age with a baseline P > 0.6 ng/ml should be ollowed using a standardized, monitoring plan (Table 8) to acilitate early detection o adverse eventsandtopreventunnecessaryprostatebiopsies thatmightleadtodetectionosubclinicalprostate cancer(77,98).difcultissueintheollow-upo hypogonadal men receiving testosterone therapy relatestothecriteriathatshouldbeusedtoguide the decision to perorm prostate biopsy. P measurements have considerable test-retest variability(99).TransientPelevationsmaybedue to other prostatic disorders. P levels may be increased by prostatitis, benign prostatic hyperplasia, prostate trauma, urinary tract inections, prostatecancer,andassayvariability.prostatitisis suspected, appropriate antibiotic treatment has been reported to decrease P by approximately 30% (100, 101). Thereore, we recommend that Pelevationsbeconfrmedbyrepeatingthetest. The 90% confdence limit or the change in P levels between two tests perormed 3 to 6 months apartinastudyomenwithbenignprostatichyperplasiawas1.4ng/ml(102).nasystematicreview,the averagePincrease ater initiation otestosterone therapy was 0.3 ng/ml in young, hypogonadal men and0.44ng/mlinoldermen(98).Theincreasesin P levels ater testosterone therapy in androgendefcient men in excess o 1.4 ng/ml over a 3- to 6-monthperiodareunusual.Theseconsiderationsled ustosuggesturologicalconsultationorevaluationo confrmed P increments > 1.4 ng/ml during any 1-yearperiodaterinitiationotestosteronetherapy. nmenorwhomsequentialPmeasurementsare available or more than 2 years, Carter (103) has proposedtheuseoPvelocitytoidentiymenat higher risk or prostate cancer. For periods omore than 2 years, P velocity > 0.4 ng/ml·yr should warrant a urological evaluation and more intensive uturesurveillanceorprostatecancer(103). Becausetheriskoprostatecancerisverylowinmen younger than age 40, they may not need prostate monitoring. The merican rological ssociation’s
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TABLE 6. Clinical pharmacology of some testosterone formulations Formulation
e
Regimen
Correctssymptomso androgendefciency; relativelyinexpensive, isel-administered; exibilityodosing
RequiresIMinjection; peaksandvalleysin serumTlevels
1%Testosterone gel
Availableinsachets, tubesandpumps5–10 gTgelcontaining 50–100mgTqd
RestoresserumT andE2levelsto thephysiological malerange
SerumDHTlevelsare higherandT:DHTratios arelowerin hypogonadalmen treatedwiththeTgel thaninhealthy eugonadalmen
Correctssymptomso androgendefciency, providesexibility odosing,easeo application,goodskin tolerability
Potentialotranserto aemalepartneror childbydirect skin-to-skincontact;skin irritationinasmall proportionotreated men;moderatelyhigh DHTlevels
Transdermal 1or2patches, testosteronepatch designedtonominally deliver5–10mgTover 24happliedqdon nonpressureareas
RestoresserumT, DHT,andE2levels tothephysiological malerange
T:DHTandT:E2levels Easeoapplication, areinthephysiological correctssymptomso malerange androgendefciency
Buccal, bioadhesive, Ttablets
30mgcontrolled release,bioadhesive tabletsbid
Absorbedromthe buccalmucosa
NormalizesserumT andDHTlevelsin hypogonadalmen
Tpellets
3-6 pelle tsimplanted sc;doseandregimen varywithormulation
SerumTpeaksat1mo T:DHTandT:E2ratios andthenissustained donotchange innormalrangeor 3–6mo,depending onormulation
17-α methyl T
This17-α alkylated compoundshould notbeusedbecause opotentialorliver toxicity.
Orally active
OralT undecanoate*
40to80mgpobid ortidwithmeals
Whenadministered HighDHTwithTratio inoleicacid,T undecanoateis absorbedthroughthe lymphatics,bypassing theportalsystem; considerablevariability inthesameindividual ondierentdaysand amongindividuals
Convenienceooral administration
Notapprovedinthe USA;variableclinical responses,variable serumTlevels,high DHT:Tratio
Injectable long-acting Tundecanoate inoil*
Europeanregimen 1000mgIM,ollowed by1000mgat6wk, and1000mgq 10–14wk
Whenadministered atadoseo750to 1000mgIM,serumT levelsaremaintainedin thenormalrangeina majorityotreatedmen
DHTandE2levelsrise inproportiontothe increaseinTlevels; T:DHTandT:E2ratios donotchange
Correctssymptomso androgendefciency; requiresinrequent administration.
RequiresIMinjection oalargevolume (4ml);coughreported immediatelyater injectioninaverysmall numberomen
Testosterone in-adhesive matrixpatch*
2X60cm2patches deliveringapproximately4.8mgT/d
RestoresserumT, DHTandE2tothe physiologicalrange
T:DHTandT:E2are inthephysiological range
Lasts 2 d
Some skin irritation
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Disadvantages
DHTandE2levelsrise inproportiontothe increaseinTlevels; T:DHTandT:E2ratios donotchange
u
y T e i c
Advantages
150–200mgIMq2 AterasingleIM wkor75–100mg/wk injection,serumTlevels riseintothesupraphysiologicalrange,then declinegradually intothehypogonadal rangebytheendo thedosinginterval
d i
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DHT and E2
Tenanthate orcypionate
n i l e
l a c i
Pharmacokinetic prole
SerumTlevelsinsome androgen-defcient menmaybeinthe low-normalrange; thesemenmayneed applicationo2 patchesdaily;skin irritationatthe applicationsiteoccurs requentlyinmany patients
Correctssymptoms Gum-relatedadverse oandrogendefciency eventsin16%o inhealthy,hypogotreatedmen nadalmen Correctssymptomso androgendefciency
Requiressurgical incisionorinsertions; pelletsmayextrude spontaneously Clinical responses are variable;potentialor livertoxicity;shouldnot beusedortreatmento androgendefciency
DHT=dihydrotestosterone;E 2 =estradiol;T=testosterone * TheseformulationsarenotapprovedforclinicaluseintheUSA,butareavailableoutsidetheUSAinmanycountries.Physiciansincountrieswherethese formulationsareavailableshouldfollowtheapproveddrugregimens.
TABLE 7. Some recommended regimens* for testosterone replacement therapy
• 150to200mgadministeredevery2wk,or75–100 mgotestosteroneenanthateorcypionateadministered IMweekly • Oneortwo5-mgtestosteronepatchesappliednightly overtheskinotheback,thigh,orupperarm,away rompressureareas • 5to10gotestosteronegelapplieddailyovera coveredareaoskin • 30mgoabioadhesive,buccaltestosteronetablet appliedtobuccalmucosatwicedaily • Testosteronepellets(doseandregimenvarywiththe ormulationused) * FormulationsavailableinothercountriesbutnotintheUnited Statesinclude:1)oraltestosteroneundecanoate(typicallyused atadoseof40to80mgorallytwoorthreetimesdailywith meals);2)twotestosteronematrixpatches30,45,or60cm2 appliedevery2days;3);Injectabletestosteroneundecanoate 1000mgfollowedbyasecond1000mginjection6weeks later,andthen1000mgevery10to14weeks.Physiciansin thosecountrieswheretheseformulationsareavailableshould followtheapproveddrugregimens.SeeTables6and8for additionalsafetyandpharmacokineticsinformation.
Best Practice tatement (2009) (104) recommends obtainingabaselinePatage40,andthentodetermineuturescreeningintervalsbasedonthisvalue. Menatleast40yearsoagewhohaveabaselineP value above the median (0.6 ng/ml) and who are receivingtestosteronetherapyshouldundergoprostate monitoring by digital rectal examination and P measurement3to6monthsaterinitiatingtherapyand theninaccordancewiththerecommendedguidelines takingintoaccounttheage,race,amilyhistory,and otherriskactors.ThecombinedapplicationoP anddigitalprostateexaminationimprovestheprostate cancerdetectionratewhencomparedwitheithertest alone(105–108). Testosterone administration in hypogonadal men is associatedwithadose-dependentincreaseinhemoglobinlevels(109–111);theincreasein hemoglobin isgreater inolder men than in young hypogonadal men(110–111).Baselinehematocrit>50%isarelativecontraindicationtotestosteronetherapybecause someothesemenwilldevelopahematocrit>54% whentreatedwithtestosterone.Menwithhematocrit level>50%shouldundergourtherclinicalevaluation
beore consideration o testosterone therapy. Men receivingtestosterone therapy should havehematocritmeasuredatbaselineand3to6monthsaterinitiationotestosteronetherapy.
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 underlying causes of ED and consideration of established therapies for ED. (2| )
2.2.B. Evidence pontaneous and experimentally induced androgen defciencyisassociatedwithadecreasedrequencyo sexual thoughts and antasies, nighttime erections. overall sexual activity, and attentiveness to erotic stimuli(4,46–53,59,78–83).ndrogendefciencyis an important cause o hypoactive sexual desire disorder. However, androgen defciency and are twoindependentlydistributedclinicaldisorderswith distinct pathophysiology; the two disorders may coexistinmiddle-agedandoldermen(53,84).
Libido. mongrandomizedtrialsthatenrolledpatients withtotaltestosteronelevels<300ng/dl(10.4nmol/l), twoparalleltrials(48,82)andthreecrossovertrials(49, 79, 83) reported eects on libido; the longest trial ollowedparticipantsor6months(4,79).Theresults othese trials were inconsistent but revealed a large improvementinlibido(1.3units;95%C,0.4,2.2) (4).(Quality of evidence: ) mong trials that enrolled men with total testosterone levels > 300 ng/dl (10.4 nmol/l), a meta- analysisreportedourtrialsthatevaluatedeectson libido (4). ot included in the meta-analysis is a recent placebo-controlled study o men > 55 years o age with total testosterone levels < 430 ng/dl (<15 nmol/l); in this trial, testosterone treatment improvedsexualdesire(80).However,inthemetaanalysis, the pooled eect o testosterone on libido
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TABLE 8. Monitoring men receiving testosterone therapy
1.Evaluatethepatient3to6monthsatertreatmentinitiationandthenannuallytoassesswhethersymptomshaveresponded totreatmentandwhetherthepatientissueringromanyadverseeects. 2.Monitortestosteronelevel3to6monthsaterinitiationotestosteronetherapy: • Therapyshouldaimtoraiseserumtestosteronelevelintothemid-normalrange. • Injectabletestosteroneenanthateorcypionate:Measureserumtestosteronelevelmidwaybetweeninjections.Itestosterone is>700ng/dl(24.5nmol/l)or<400ng/dl(14.1nmol/l),adjustdoseorrequency. • Transdermalpatches:Assesstestosteronelevel3–12haterapplicationothepatch;adjustdosetoachievetestosterone levelinthemidnormalrange. • Buccaltestosteronebioadhesivetablet:Assesslevelimmediatelybeoreoraterapplicationoreshsystem. • Transdermalgels:Assesstestosteronelevelanytimeaterpatienthasbeenontreatmentoratleast1wk;adjustdoseto achieveserumtestosteronelevelinthemidnormalrange. • Testosteronepellets:Measuretestosteronelevelsattheendothedosinginterval.Adjustthenumberopelletsand/orthe dosingintervaltoachieveserumtestosteronelevelsinthenormalrange. • Oraltestosteroneundecanoate*:Monitorserumtestosteronelevel3to5hateringestion. • Injectabletestosteroneundecanoate*:Measureserumtestosteroneleveljustpriortoeachsubsequentinjectionandadjust thedosingintervaltomaintainserumtestosteroneinmid-normalrange. 3.Checkhematocritatbaseline,at3to6months,andthenannually.Ihematocritis>54%,stoptherapyuntilhematocrit decreasestoasaelevel;evaluatethepatientorhypoxiaandsleepapnea;reinitiatetherapywithareduceddose. 4.Measurebonemineraldensityolumbarspineand/oremoralneckater1–2yrotestosteronetherapyinhypogonadalmen withosteoporosisorlowtraumaracture,consistentwithregionalstandardocare. 5.Inmen40yearsoageorolderwithbaselinePSAgreaterthan0.6ng/ml,perormdigitalrectalexaminationandcheck PSAlevelbeoreinitiatingtreatment,at3to6months,andtheninaccordancewithguidelinesorprostatecancerscreening dependingontheageandraceothepatient. 6.Obtainurologicalconsultationithereis: • AnincreaseinserumPSAconcentration>1.4ng/mlwithinany12-monthperiodotestosteronetreatment. • APSAvelocityo>0.4ng/ml·yrusingthePSAlevelater6monthsotestosteroneadministrationasthereerence (onlyapplicableiPSAdataareavailableoraperiodexceeding2yr). • Detectionoaprostaticabnormalityondigitalrectalexamination. • AnAUA/IPSSprostatesymptomscoreo>19.
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7.Evaluateormulation-specifcadverseeectsateachvisit: • Buccaltestosteronetablets:Inquireaboutalterationsintasteandexaminethegumsandoralmucosaorirritation. • Injectabletestosteroneesters(enanthate,cypionate,andundecanoate):Askaboutuctuationsinmoodorlibido,and rarelycoughaterinjections. • Testosteronepatches:Lookorskinreactionattheapplicationsite. • Testosteronegels:Advisepatientstocovertheapplicationsiteswithashirtandtowashtheskinwithsoapandwater beorehavingskin-to-skincontact,becausetestosteronegelsleaveatestosteroneresidueontheskinthatcanbetranserred toawomanorchildwhomightcomeinclosecontact.Serumtestosteronelevelsaremaintainedwhentheapplicationsite iswashed4–6haterapplicationothetestosteronegel. • Testosteronepellets:Lookorsignsoinection,fbrosis,orpelletextrusion. * NotapprovedforclinicaluseintheUnitedStates. AUA/IPSS=AmericanUrologicalAssociationInternationalProstateSymptomScore;PSA=prostate-specicantigen
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wasnotsignifcant(0.4units;95%C,–0.01,0.8) (76).ackoprecisionaroundthisestimateweakens thisinerence.(Quality of evidence: )
Erectile dysfunction. meta-analysis by Jain et al. (85)evaluatedtheeectsotestosteronetherapyin menwith.mong16publishedstudies(85),57%
o subjects experienced an improvement in erectile unction.nalatersystematicrevieworandomized placebo-controlledtrials thatenrolledpatientswith totaltestosterone<300ng/dl(10.4nmol/l)(4),two paralleltrialsandtwocrossovertrialsreportedeects on erectile unction. The results were inconsistent acrosstrials,andthepooledestimatewasnotsignifcant(0.8units;95%C,–0.1,1.6)(4).(Quality of evidence: ) mong trials that enrolled men with total testosterone>300ng/dl(10.4nmol/l),severalparalleltrials enrolledmenwithinwhomsildenaflhadailed (87–93)andthreecrossovertrialsinmenwitheither low libido or (112, 113). These trials reported inconsistent and nonsignifcant eects on erectile unction(0.3units;95%C,–0.03,0.65)(4).The inconsistencyacrosstrialsandtheimprecisionothe pooled estimateweaken ourinerences. (Quality of evidence: )
Other sexual outcomes. everalstudieshaveevaluated theeectsotestosteronetreatmentinmenwhoailed torespondtoaP5inhibitor(87–93).omeothese studieswerenotplacebocontrolled,andthedegreeo testosterone defciency varied among trials (87–93, 112, 113). everal trials reported on the impact o testosteronetherapyonothersexualoutcomes,namely, orgasmic and ejaculatory unction, intercourse, and overallsatisaction(4).Generally,theeectotestosteronewaspositive,butsmallsamplesizes,inconsistent fndings, and incomplete reporting yielded imprecise estimates.(Quality of evidence: )
2.2.C. Values Ourrecommendationtooertestosteronetherapyto menwithlowlibidoorwhohaveunequivocally lowtestosteronelevelsplacesarelativelyhighervalue onimprovingthesecomplaintsandarelativelylower valueonavoidingtheburdenotestosteronetherapy anditsunclearlong-termsaety.decisiontotreat oldermendependsonthephysician’sandthepatient’s assessment o risks and benefts and costs. Older patients with a greater potential or adverse eects mayopttoavoidtestosteronetherapy.
2.2.D. Remarks iagnosticand treatment recommendationsare the sameasorpatientswithclassicalandrogendefciency (Sections 1.1. and 2.1.).Menwithsexualdysunction should be evaluated or 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 testosterone 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 clinically significant symptoms of androgen deficiency, after explicit discussion of the uncertainty about the risks and benefits of t estosterone therapy. (2| ) Thepanelistsdisagreedonserumtestosteronelevels belowwhichtestosteronetherapyshouldbeoeredto oldermenwithsymptoms.ependingontheseverity o clinical maniestations, some panelists avored treatingsymptomatic older men with a testosterone level below the lower limit o normal or healthy youngmen(280–300ng/dl[9.7–10.4nmol/l]);others avored a level below 200 ng/dl (6.9 nmol/l). The panelistswhoavoredtreatingmenwhohadvalues <300ng/dlweremoreinuencedbytheobservation thatmenwhohavevaluesbelowthatlevelotenhave symptoms that might be attributable to low testosterone.Thepanelistswhoavorednottreatingunless theserumtestosteronewasaslowas200ng/dlwere moreinuencedbythelackotestosteronetreatment eectsinrandomizedclinicaltrialswhensubjectshad pretreatment values o 300 ng/dl but suggestions o benefcialeectswhenthepretreatmentvalueswere closer to 200 ng/dl. The lack o defnitive studies precludes an unequivocal recommendation and emphasizestheneedoradditionalresearch.
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2.3.B. Evidence everal cross-sectional and longitudinal studies demonstrate that serum total and ree testosterone concentrationsinmenallwithincreasingage(7–9, 84,103,104,114,115).lthoughtheallisgradual, bytheeighthdecade,accordingtoonestudy,30%o menhadtotaltestosteronevaluesinthehypogonadal range,and50%hadlowreetestosteronevalues(8). Therateoage-relateddeclineinserumtestosterone levels varies in dierent individuals and is aected bychronicdisease,adiposity,andmedications(7,9, 114–117).
Testosterone trials in older men. n randomized, placebo-controlled trials o 3 months to 3 years in older men with low-normal to low testosterone concentrations,testosteroneadministrationwasassociated with varying degrees o elevation in testosterone levels (68, 119–131). Overall, testosterone trialsinoldermenwerecharacterizedbysmallsample size,inclusionohealthyoldermenwithloworlownormal testosterone levels who were asymptomatic, variable dosing regimens, and the use o surrogate outcomes;thesestudiesdidnothavesufcientpower to detect either meaningul gains in patient-importantoutcomesorchangesinprostateandcardiovasculareventrates(68,119–131).
Bone mineral density. We did not fnd any trials
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reportingtheeectotestosteroneonboneractures. systematic review o randomized, placebocontrolledtrialso1-to3-year’sdurationthatevaluated eects on bone mineral density and were publishedbeoreMarch2005yieldedinconsistentand imprecise results (118, 120, 122, 132); these trials showedamoderatetreatmenteectonlumbarbone mineral density (0.4 units; 95% C, 0.1, 0.7), equivalenttoanincreaseinlumbarbonedensityo 2%(95%C,0.5,3.3)(132).Thesetrialsruledouta moderate-to-largetestosteroneeectonemoralneck bonedensity(0.0units;95%C,–0.3,0.3).
Body composition. n oursystematic review, testosterone therapy was associated with a signifcantly greaterincreaseinBM(2.7kg;95%C,1.6,3.7)and agreaterreductioninatmass(–2.0kg;95%C,–3.1, –0.8)thanplacebo(125).Thebodyweightchange
didnotdiersignifcantlybetweengroups(–0.6kg; 95%C,–2.0,0.8)(125).
Muscle strength and physical function. Testosterone therapywasassociatedwithagreaterimprovementin gripstrengththanplacebo(3.3kg;95%C,0.7,5.8) (125). Changes in lower-extremity muscle strength and measures o physical unction were reported in onlyaewstudiesandwereinconsistent.omestudies reportednochangesinperormance-basedmeasures ophysicalunction(68,119,121),whereasonestudy reported improvement in a composite measure o physicalunction(121).Mostothestudiesincluded men who had no unctional limitations and used measuresophysicalunctionthathadalowceiling.
Sexual function. Twoplacebo-controlledtrialsyielded impreciseresultsregardingtheeectotestosterone onoverallsexualsatisaction(0.2units;95%C, –0.02,0.57)(4).
Quality of life. Fourplacebo-controlledrandomized trialsreportedontestosterone’seectonqualityo lie(119,129,133,134).Theresultswereinconsistent across trials and imprecise. However, testosterone therapy was associated with signifcantly greaterimprovementinthephysicalunctiondomain scorethanwasplacebo(0.5units;95%C,0.03, 0.9)(125).
Depression. The eects o testosterone therapy on depression have been inconsistent across trials. recentsystematicrevieworandomizedtrialsreported signifcantly greater improvements in depression scores in testosterone-treatedmen than in placebotreated men (135). However, several randomized trialshaveoundnosignifcanteectsotestosterone therapy on depression in older men with low or low-normal testosterone levels (127–133). The inconsistentandimpreciseresultslimittheinerential strength.
Cognition. Three placebo-controlled randomized trials(130,133,136),oneowhichstudiedpatients with lzheimer’s dementia and low testosterone levels (136), reported imprecise eects on several dimensionsocognition,noneowhichwassignifcantaterpooling.
Adverse outcomes associated with testosterone therapy.nasystematicreviewo19randomizedtrials to determine the risks o adverse events associated with testosterone therapy in older men (77), the combinedrateoallprostateeventswassignifcantly greaterin testosterone-treatedmenthanin placebotreated men (oddsratio, 1.78;95% C, 1.07,2.95). Ratesoprostatecancer,Pgreaterthan4ng/ml, andprostatebiopsieswerehigherinthetestosterone groupthanintheplacebogroup,althoughdierences betweengroupswerenotstatisticallysignifcant(77). Testosterone-treatedmenwerenearlyourtimesmore likelythanplacebo-treatedmentoexperiencehematocrit>50%(oddsratio,3.69;95%C,1.82,7.51). Therequencyocardiovascularevents,sleepapnea, ordeathdidnotdiersignifcantlybetweengroups. Thus,testosteronetherapyooldermenwasassociated with a higher risk odetecting prostate events andhematocritabove50%thanwasplacebo(77). meta-analysisbyHaddadetal.(3)ostudiesound throughOctober2004enrollingoldermenwithlow testosterone levels yielded insignifcant changes in major lipid ractions (total cholesterol standardized mean dierence [M]-0.22 (-0.71 to0.27) ; cholesterolM 0.06 [-0.30 to0.42]; H cholesterol M 0.04 [-0.39 to 0.40]; triglycerides M, -0.27[-0.61to0.08]).
2.3.C. Values Therecommendationnottotreatasymptomaticolder men with age-related decline in testosterone level placesalowervalueontheunproven,potentialbenefts o testosterone therapy and a higher value on avoidingthe burdenso testosteroneadministration, monitoring, and cost, as well ason unknown longtermrisks.
2.3.D. Remarks Physicians should recognize considerable disagreementamongexpertsonthisissuebecauseothelack oevidencebasetoreachconsensusrecommendations (35,36,125).onspecifcage-relatedsymptomsand low T levels oten co-exist in older menwithouta clearcausallink.eitherthesaetynortheefcacyo T therapy inolder men with low testosterone level has beendemonstrated. hould cliniciansand their
patientschoosetestosteronetherapy,wesuggestthat cliniciansaimatachievingtotaltestosteronelevelsin the lower part o the normal range o young men (400–500ng/dl[14.0–17.5nmol/l]).
2.4.
PATIENTS WITH CHRONIC ILLNESS AND LOW TESTOSTERONE LEVELS
2.4.1. HIV-inected men with weight loss 2.4.1.A. Recommendation We suggest that clinicians consider short-term testosterone 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 Thereisahighprevalenceolowtestosteronelevels inHV-inectedmen(37,38,137):20–25%oHVinectedmen onhighlyactiveantiretroviraltherapy havelowtestosteronelevels(137).owtestosterone levelsareassociatedwithweightloss,progressionto (138), wasting (139), depression, and loss o musclemassandexercisecapacity(139).
Body weight and LBM. n a systematic review o randomized,placebo-controlledtrialsotestosterone therapyinHV-inectedpatientswithweightlossthat reportedbodycomposition(125),3to6monthso testosteronetherapywasassociatedwithgreatergains inbody weight (+1.54 kg; 95% C, 0.03,3.10) and BM(+1.22kg;95%C,0.2,2.2)thanwasplacebo. ierenceinBMbetweenplaceboandtestosterone groups was greater in trials that used testosterone esters(+3.34kg)(140).
Muscle strength. nthreeoourtrialsthatmeasured muscle strength(141–145),testosteroneadministration was associated with improvements in maximal voluntarystrength.
Other outcomes. nasystematicreviewoplacebocontrolledtrials,weoundourreportingondepressioninpatientswithHVinection(62,146–148). large loss to ollow-up in one trial, inconsistency acrosstrials,incompletedatareporting,andimpreci-
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sionlimitthestrengthoinerences.Overall,testosteronetherapyhadamoderateeectondepression (–0.6units;95%C,–1.0,–0.2).Therewereno signifcanttestosteroneeectsonqualityolie.
Adverse outcomes. Theadverseeventratesdidnotdier signifcantly between placebo and testosterone groups. ChangesinC4+Tlymphocytecounts,HVviralload, P, and plasma high-density lipoprotein cholesterol werenotsignifcantlydierentbetweengroups. There was considerable heterogeneity across trials (varyingdegreesoweightloss,diseaseseverity,testosteroneregimens,treatmentduration,andmethodsto assessbodycomposition).Therearenodataontestosterone’seectsonphysicalunction,riskodisability, or long-term saety. Overall, short-term (3- to 6-month)testosteroneuseinHV-inectedmenwith low testosterone levels and weight loss can lead to smallgains inbody weight and BM with minimal changeinqualityolieandmood.Thisinerenceis weakenedbyinconsistentresultsacrosstrials.
2.4.1.C. Values Therecommendationtooershort-termtestosterone therapy to HV-inectedmen with low testosterone levelsandweightlossplacesarelativelyhighervalue ongainingBMandmusclestrengthandarelatively lowervalueonavoidingthepotentialortestosteronerelated adverse eects, cost, and unclear long-term saety. Patients with a dierentvalue structuremay decidetoavoidtestosteronetherapy. e n i l e d i u g e c i T c a r p
2.4.1.D. Remarks iagnosticand treatment recommendations are the sameasorpatientswithclassicalandrogendefciency (Sections 1.1. and 2.1.). dditionally, appropriate counselingorsaesexpracticesshouldbeprovided.
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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 wh o have low testosterone levels to promote preservation of lean body mass and bo ne mineral density. (2| )
2.4.2.B. Evidence Testosteronelevelsareloweringlucocorticoid-treated men than inage-matchedcontrols (39). Thereis a highprevalence olowtestosteronelevels inglucocorticoid-treatedmenduetoglucocorticoid-induced suppressionoallcomponentso thehypothalamicpituitary-testicular axis. Typically, administration o morethan5–7.5mg/doprednisoneoritsequivalent increases the risk o gonadotropin and testosterone suppression and alterations in muscle and bone mass(149). n two placebo-controlled trials (150, 151), testosteronetherapyomenreceivingglucocorticoidtreatment or bronchial asthma or chronic obstructive pulmonarydiseasewasassociatedwithagreatergain in BM (2.3 kg; 95% C, 2.0, 3.6) and a greater decrease in at mass (–3.1 kg; 95% C, –3.5, –2.8) thanwasplacebo.Thesetwotrialsreportedsignifcant increaseinlumbarbonemineraldensityinassociationwithtestosteronetherapy(4%;95%C,2,7%); theeectonemoralbonemineraldensitywasinconsistentandnotsignifcant.Therearenoboneracture datainthispopulation. Testosteroneadministrationwasassociatedwithalow requency o adverse events. However, these inerencesareweakenedbythesmallsizeothesestudies, theirshortduration,andtheirinconsistentresults.
2.4.2.C. Values Ourrecommendationtooertestosteronetherapyto glucocorticoid-treated men with low testosterone levelsplacesarelativelyhighervalueonthepotential beneftomaintainingmusclemassandbonemineral densityandarelativelylowervalueonavoidingthe potentialoradverseeectsandtheburdensotestosteroneadministration,monitoring,andcost,andon theunclearlong-termsaetyothetherapy.
2.4.2.D. Remarks iagnostic and treatment recommendations are the sameasorpatientswithclassicalandrogendefciency.
References 1.
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 2004Gradingqualityo evidenceandstrengthorecommendations.BMJ328:1490
2. Fernández-Balsells HM, Murad MH, Melanie L, Lampropulos JF, Albuquerque F, Erwin PJ, Bhasin S, Montori VM 2010dverseeectsotestosteronetherapyinadultmen:a systematic review and meta-analysis. J Clin ndocrinol Metab,95(6):2560–2575 3
4.
5.
6.
Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM 2007 Testosterone and cardiovascular risk in men: a systematic review andmeta-analysiso randomizedplacebo-controlled trials.MayoClinProc82:29-39 Boloña ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, Caples SM, Erwin PJ, Montori VM 2007 Testosteroneuseinmenwithsexualdysunction:asystematic review andmeta-analysiso randomizedplacebo-controlled trials.MayoClinProc82:20-28 Matsumoto AM 2001TheTestis.n:FeligP,Frohman eds.ndocrinology andMetabolism.4th eded. ewYork, Y:McGraw-Hill;635-705 Bhasin S 2008Testicularisorders.n:arsenPR,KronenbergHM,Melmed,PolanskiKeds.Williams’Textbooko ndocrinology.11thditioned.Philadelphia,P:lsevier
7. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinl ay JB 2002 ge trends in the level o serum testosterone and other hormonesinmiddle-agedmen:longitudinalresultsromthe Massachusetts male aging study. J Clin ndocrinol Metab 87:589-598 8.
12. Hall SA, Esche GR, Araujo AB, Travison TG, Clark RV, Williams RE, McKinlay JB 2008Correlatesolowtestosteroneandsymptomaticandrogendefciencyinapopulationbasedsample.JClinndocrinolMetab93:3870-3877 13. Travison TG, Araujo AB, Kupelian V, O’Donnell AB, McKinlay JB 2007 The relative contributions o aging, health,andliestyleactorstoserumtestosteronedeclinein men.JClinndocrinolMetab92:549-555 14. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C 2006Prevalence o hypogonadism inmales agedatleast45years:theHMstudy.nternationalJournalo ClinicalPractice60:762-769 15. Kelleher S, Conway AJ, Handelsman DJ 2004Bloodtestosterone thresholdor androgen defciencysymptoms.J Clin ndocrinolMetab89:3813-3817 16. Bremner WJ, Vitiello MV, Prinz PN 1983ossocircadian rhythmicityinbloodtestosteronelevelswithaginginnormal men.JClinndocrinolMetab56:1278-1281 17. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB 2007ntraindividualvariationinlevelsoserumtestosteroneandotherreproductiveandadrenalhormonesinmen. Clinndocrinol(Ox)67:853-862 18. Bhasin S, Zhang A, Coviello A, Jasuja R, Ulloor J, Singh R, Vesper H, Vasan RS 2008Theimpactoassayquality and reerence ranges on clinical decision making in the diagnosisoandrogendisorders.teroids73:1311-1317 19. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H 2007 tility, limitations and pitalls in measuring testosterone: nndocrineocietyPositiontatement.JClinndocrinol Metab92:405-413 20. Vermeulen A, Verdonck L, Kaufman JM 1999critical evaluationosimplemethodsortheestimationoreetestosteroneinserum.JClinndocrinolMetab84:3666-3672
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR 2001ongitudinaleectsoagingonserumtotaland reetestosteronelevelsinhealthymen.Baltimoreongitudinaltudyoging.JClinndocrinolMetab86:724-731
21. Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ 2009 Predictive accuracy and sources o variability in calculated ree testosterone estimates. nn Clin Biochem 46(Pt2):137-43.
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, Vanderschueren D 2008 Hypothalamic-pituitary-testicular axis disruptionsinoldermenaredierentiallylinkedtoageand modifable risk actors: the uropean Male ging tudy. JClinndocrinolMetab93:2737-2745
22. Daniell HW, Lentz R, Mazer NA 2006Open-labelpilot study o testosterone patch therapy in men with opioidinducedandrogendefciency.JPain7:200-210
10. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB 2007 Prevalence o symptomatic androgen defciency in men. JClinndocrinolMetab92:4241-4247
24. Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmuller D 2005Plasmatestosterone andsexualunctioninmenreceivingbuprenorphinemaintenance or opioid dependence. J Clin ndocrinol Metab 90:203-206
9.
11. Zitzmann M, Faber S, Nieschlag E 2006 ssociation o specifc symptoms and metabolic risks with serum testosteroneinoldermen.JClinndocrinolMetab91:4335-4343
23. Kim TW, Alford DP, Malabanan A, Holick MF, Samet JH. owbonedensityinpatientsreceivingmethadonemaintenancetreatment.ruglcoholepend.2006;85:258-62
25. Basaria S 2008 ndrogen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth.Jndrol29:534-539
T e s T o s T e r o n e T h e r a p y i n
M e n w i T h
a n d r o g e n d e f i c i e n c y s y n d r o M e s
25
26. Citron JT, Ettinger B, Rubinoff H, Ettinger VM, Minkoff J, Hom F, Kan P, Alloo R 1996Prevalenceohypothalamicpituitary imaging abnormalities in impotent men with secondaryhypogonadism.Jrol155:529-533 27. Buvat J, Lemaire A 1997ndocrinescreeningin1,022men with erectile dysunction: clinical signifcance and cost- eectivestrategy.Jrol158:1764-1767 28. Handelsman DJ, Liu PY 2006 Klineelter’s syndrome— amicrocosmomalereproductivehealth.JClinndocrinol Metab91:1220-1222 29. Riggs BL, Khosla S, Melton LJ, 3rd 2002exsteroidsand the construction and conservation o the adult skeleton. ndocrRev23:279-302
44. Morley JE, Perry HM 3rd, Kevorkian RT, Patrick P 2006 Comparison o screening questionnaires or the diagnosis ohypogonadism.Maturitas53:424-9.
30. Ebeling PR 2008 Clinical practice. Osteoporosis in men. nglJMed358:1474-1482
45. Mauras N, H ayes V, Welch S, Rini A, Helgeson K, Dokler M, Veldhuis JD, Urban RJ 1998Testosteronedefciencyin young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clinndocrinol Metab 83:1886-1892
32. Araujo AB, Kupelian V, Page ST, Handelsman DJ, Bremner WJ, McKinlay JB 2007exsteroidsandall-cause and cause-specifc mortality in men. rc nterl Med 167:1252-1260 33. Laughlin GA, Barrett-Connor E, Bergstrom J 2008ow serum testosterone and mortality in older men. J Clin ndocrinolMetab93:68-75 34. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C 2009ow serum testosteroneandestradiolpredictmortalityinelderlymen. JClinndocrinolMetab94:2482-2488
n i l e d i u g e c i T c a r p l a c i n i l c y T e i c o s e n i r c o d n e n a
26
42. Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM 2004ThegingMales’ymptomsscale (M) as outcome measure or treatment o androgen defciency.urrol46:80-87 43. Smith KW, Feldman HA, McKinlay JB 2000Construction andfeldvalidationoasel-administeredscreenerortestosterone defciency (hypogonadism) in ageing men. Clin ndocrinol(Ox)53:703-711
31. hores MM, Matsumoto AM, Sloan KL, Kivlahan DR 2006owserumtestosteroneandmortalityinmaleveterans. rchnternMed166:1660-1665
e
questionnaire or androgen defciency in aging males. Metabolism49:1239-1242
46. Kwan M, Greenleaf WJ, Mann J, Crapo L, Davidson JM 1983 The nature o androgen action on male sexuality: a combined laboratory-sel-report study on hypogonadal men.JClinndocrinolMetab57:557-562 47. Wang C, Swedloff RS, Iran manesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N 2000Transdermaltestosteronegelimprovessexualunction, mood,musclestrength,andbodycompositionparametersin hypogonadal men. Testosterone Gel tudy Group. J Clin ndocrinolMetab85:2839-2853
35. Liverman CT, Blazer DG 2004 Testosterone and aging, clinical research directions. Washington, .C.: ational cademiesPress,2004.
48. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R 2003 2500 testosterone gel normalizes androgenlevelsinagingmaleswithimprovementsinbody compositionandsexualunction.JClinndocrinolMetab 88:2673-2681
36. Bhasin S, Buckwalter JG 2001Testosteronesupplementationin oldermen:a rationalideawhose timehas not yet come.Jndrol22:718-731
49. Bancroft J, Wu FC 1983Changesinerectileresponsiveness during androgen replacement therapy. rch ex Behav 12:59-66
37. Dobs AS, Few WL, 3rd, Blackman MR, Harman SM, Hoover DR, Graham NM 1996erumhormonesinmen with human immunodefciency virus-associated wasting. JClinndocrinolMetab81:4108-4112
50. Carani C, Scuteri A, Marrama P, Bancroft J 1990The eectsotestosteroneadministrationandvisualeroticstimuli onnocturnalpeniletumescenceinnormalmen.HormBehav 24:435-441
38. Arver S, Sinha-Hikim I, Beall G, Guerrero M, Shen R, Bhasin S 1999erumdihydrotestosteroneandtestosterone concentrations in human immunodefciency virus-inected menwithandwithoutweightloss.Jndrol20:611-618
51. Cunning ham GR, Hirshkowitz M, Korenman SG, Karacan I 1990Testosteronereplacement therapy andsleep-related erections in hypogonadal men. J Clin ndocrinol Metab 70:792-797
39. Reid IR 1987 erum testosterone levels during chronic glucocorticoidtherapy.nnnternMed106:639-640
52. Alexander GM, Sherwin BB 1991Theassociationbetween testosterone,sexualarousal,andselectiveattentionorerotic stimuliinmen.HormBehav25:367-381
40. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P 2004 Frequent occurrence o hypogonadotropic hypogonadism in type 2 diabetes. JClinndocrinolMetab89:5462-5468
53. Bhasin S, Enzlin P, Coviello A, Basson R 2007 exual dysunction in men and women with endocrine disorders. ancet369:597-611
41. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM, 3rd 2000Validationoascreening
54. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R 1997Testosteronereplacementincreasesat-reemassandmusclesizein hypogonadalmen.JClinndocrinolMetab82:407-413
55. Brodsky IG, Balagopal P, Nair KS 1996ectsotestosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men--a clinical research center study.JClinndocrinolMetab81:3469-3475 56. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A 1996 ncrease in bone densityandleanbodymassduringtestosteroneadministrationinmenwithacquiredhypogonadism.JClinndocrinol Metab81:4358-4365 57. Snyder PJ, Peachey H, Berlin JA, Ha nnoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL 2000ectsotestosteronereplacementinhypogonadalmen.JClinndocrinol Metab85:2670-2677 58. Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E 1997 ong-term eect o testosterone therapy on bone mineral density in hypogonadal men. J Clin ndocrinol Metab82:2386-2390 59. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS 2004ong-termtestosteronegel(ndroGel) treatmentmaintainsbenefcialeectsonsexualunctionand mood,leanandatmass,andbonemineraldensityinhypogonadalmen.JClinndocrinolMetab89:2085-2098 60. Aminorroaya A, Kelleher S, Conway AJ, Ly LP, Handelsman DJ 2005dequacyo androgen replacement inuencesbonedensityresponsetotestosteroneinandrogendefcientmen.urJndocrinol.2005152:881-886 61. Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS 1996Testosteronereplacementtherapyimprovesmood in hypogonadal men--a clinical research center study. JClinndocrinolMetab81:3578-3583 62. Rabkin JG, Rabkin R, Wagner G 1995 Testosterone replacementtherapy in HV illness. Gen Hosp Psychiatry 17:37-42 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 Testosterone supplementation improves spatial and verbal memory in healthyoldermen.eurology57:80-88 64. Janowsky JS, Oviatt SK, Orwoll ES 1994 Testosterone inuencesspatial cognitionin oldermen. Behav eurosci 108:325-332 65. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P 1992 The eects o testosteronetreatmentonbodycompositionandmetabolism inmiddle-aged obesemen.nt J ObesRelatMetab isord 16:991-997 66. Marin P, Krotkiewski M, Bjorntorp P 1992 ndrogen treatmentomiddle-aged,obesemen:eectsonmetabolism, muscleandadiposetissues.urJMed1:329-336 67. Kapoor D, Goodwin E, Channer KS, Jones TH 2006 Testosterone replacement therapy improves insulin resis-
tance,glycaemiccontrol,visceraladiposityandhypercholesterolaemia in hypogonadal men with type 2 diabetes. urJndocrinol154:899-906 68. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT 2008ectotestosteronesupplementationon unctionalmobility,cognition,andotherparametersinolder men:arandomizedcontrolledtrial.JM299:39-52 69. Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S 2002TheeectsovaryingdosesoToninsulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin ndocrinol Metab 87:136-143 70. Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, K lee G, Toffolo G, Cobelli C, Ri zza RA 2007ect o 2 yearso testosteronereplacement on insulin secretion, insulin action, glucose eectiveness, hepaticinsulinclearance,andpostprandialglucoseturnover inelderlymen.iabetesCare30:1972-1978 71. Fowler JE, Jr., Whitmore WF, Jr. 1981 The response o metastatic adenocarcinoma o the prostate to exogenous testosterone.Jrol126:372-375 72. Agarwal PK, Oefelein MG 2005Testosteronereplacement therapy aterprimarytreatmentor prostate cancer. J rol 173:533-536 73. Kaufman JM, Graydon RJ 2004 ndrogen replacement ater curative radical prostatectomy or prostate cancer in hypogonadalmen.Jrol172:920-922 74. Khera M, Grober ED, Najari B, Colen JS, Mohamed O, Lamb DJ, Lipshultz LI 2009 Testosterone replacement therapy ollowing radical prostatectomy. J ex Med 6:1165-1170 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. 2004 Prevalenceo prostate cancer among menwith a prostatespecifcantigenlevel <or =4.0ng per milliliter. nglJ Med350:2239-2246 76. Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS, Feng Z, Parnes HL, Coltman CA, Jr. 2006 ssessing prostate cancer risk: results rom the Prostate CancerPreventionTrial.JatlCancernst98:529-534 77. Calof O, Singh AB, Lee ML, Urban RJ, Kenny AM, Tenover JL, Bhasin S 2005dverseeventsassociatedwith testosterone supplementation o older men. J Gerontol BiolciMedci.60:1451-7 78. Seftel AD, Mack RJ, Secrest AR, Smith TM 2004Restorativeincreasesinserumtestosteronelevelsare signifcantly correlatedtoimprovementsinsexualunctioning.Jndrol 25:963-972
T e s T o s T e r o n e T h e r a p y i n
M e n w i T h
a n d r o g e n d e f i c i e n c y s y n d r o M e s
27
79. Clopper RR, Voorhess ML, MacGillivray MH, Lee PA, Mills B 1993Psychosexualbehaviorinhypopituitarymen:a controlled comparison o gonadotropin and testosterone replacement.Psychoneuroendocrinology18:149-161 80. Allan CA, Forbes EA, Strauss BJ, McLachlan RI 2008 Testosteronetherapyincreasessexualdesire inageing men with low-normal testosterone levels and symptoms o androgendefciency.ntJmpotRes20:396-401 81. Skakkebaek NE, Bancroft J, Davidson DW, Warner P 1981 ndrogen replacement with oral testosterone undecanoateinhypogonadalmen:adoubleblindcontrolled study.Clinndocrinol(Ox)14:49-61 82. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G 2004 Carnitine versus androgen administration in the treatmentosexualdysunction,depressedmood,andatigue associatedwithmaleaging.rology63:641-646 83. Carani C, Granata AR, Bancroft J, Marrama P 1995The eects o testosterone replacement on nocturnal penile tumescenceandrigidityanderectileresponsetovisualerotic stimuli in hypogonadal men. Psychoneuroendocrinology 20:743-753 84. Korenman SG, Morley JE, Mooradian AD, Davis SS, Kaiser F E, Silver AJ, Viosca SP, Garza D. 1990econdary hypogonadism in older men: its relation to impotence. JClinndocrinolMetab71:963-639 85. Jain P, Rademaker AW, McVary KT 2000 Testosterone supplementationorerectiledysunction:resultsoametaanalysis.Jrol164:371-375 86. Carani C, Bancroft J, Granata A, Del Rio G, Marrama P 1992 Testosterone and erectile unction, nocturnal penile tumescenceandrigidity,anderectileresponsetovisualerotic stimuliinhypogonadalandeugonadalmen.Psychoneuroendocrinology17:647-654 87. Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A 2003 ndrogensimprovecavernousvasodilationandresponseto sildenaflin patients with erectile dysunction. Clin ndocrinol(Ox)58:632-638 e n i l e d i u g e c i T c a r p l a c i n i l c y T e i c o s e n i r c o d n e n a
28
88. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H 2004 Randomized study o testosterone gel as adjunctive therapy to sildenafl in hypogonadal men with erectile dysunction whodo notrespondto sildenaflalone.J rol 172:658-663 89. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H 2008 Randomized study o testosterone gel as adjunctive therapy to sildenafl in hypogonadal men with erectile dysunction whodo notrespondto sildenaflalone.J rol 179:97-102 90. Kalinchen ko SY, Kozlov GI, Gontcharov NP, Katsiya GV 2003Oraltestosteroneundecanoatereverseserectiledysunctionassociatedwithdiabetesmellitusinpatientsailingon sildenaflcitratetherapyalone.gingMale6:94-99 91. Shamloul R, Ghanem H, Fahmy I, El-Meleigy A, Ashoor S, Elnashaar A, Kamel I 2005 Testosterone therapy can
enhance erectile unctionresponseto sildenaflin patients withPM:apilotstudy.JexMed2:559-564 92. Hwang TI, Chen H E, Tsai TF, Lin YC 2006Combineduse o androgen and sildenafl or hypogonadal patients unresponsivetosildenaflalone.ntJmpotRes18:400-404 93. Greenstein A, Mabjeesh NJ, Sofer M, Kaver I, Matzkin H, Chen J 2005 oes sildenafl combined with testosterone gel improve erectile dysunction in hypogonadal men in whom testosterone supplementtherapyaloneailed?Jrol 173:530-532 94. Finkel DM, Phillips JL, Snyder PJ 1985timulationospermatogenesis by gonadotropins in men with hypogonadotropichypogonadism.nglJMed313:651–655 95. Liu L, Banks SM, Barnes KM, Sherins RJ 1988Two-year comparisonotesticularresponsestopulsatilegonadotropinreleasinghormone and exogenous gonadotropins rom the inceptionotherapyinmenwithisolatedhypogonadotropic hypogonadism.JClinndocrinolMetab67:1140–1145 96. Büchter D, Behre HM, Kliesch S, Nieschlag E 1998PulsatileGnRHorhumanchorionicgonadotropin/humanmenopausal gonadotropin as eective treatment or men with hypogonadotropichypogonadism:areviewo42cases.urJ ndocrinol139:298–303 97. Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, Spratt D, Brentzel J, O’Dea L 2009timulation ospermatogenesiswithrecombinanthumanollicle-stimulatinghormone(ollitropinala;GO-):long-termtreatment in azoospermic men with hypogonadotropic hypogonadism.Fertilteril92:979–990 98. Bhasin S, Singh AB, Mac RP, Carter B, Lee MI, Cunningham GR 2003Managingtherisksoprostatedisease during testosterone replacement therapy in older men: recommendations or a standardized monitoring plan. J ndrol24:299–311 99. Riehmann M, Rhodes PR, Cook T D, Grose GS, Bruskewitz RC 1993nalysiso variation in prostate-specifc antigen values.rology42:390–397 100. Scardino PT 2007Theresponsibleuseoantibioticsoran elevatedPlevel.atClinPractrol4:1 101. Kobayashi M, Nukui A, Morita T 2008 erumP and percent reeP valuechangesater antibiotictreatment. diagnosticmethodinprostatecancersuspectswithasymptomaticprostatitis.rolnt80:186–192 102. 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 1992Theeectofnasterideinmenwithbenign
prostatichyperplasia.TheFinasteridetudyGroup.nglJ Med327:1185–1191 103. Carter HB 1997 P variability versus velocity. rology 49:305 104.2009Prostate-specifcantigenbestpracticestatement:2009 update. inthicum,M:merican rological ssociation ducationandResearch,nc.
105. Bretton PR 1994Prostate-specifcantigenanddigitalrectal examinationinscreeningorprostatecancer:acommunitybasedstudy.outhMedJ87:720–723 106. Muschenheim F, Omarbasha B, Kardjian PM, Mondou EN 1991creeningorcarcinomaotheprostatewithprostate specifcantigen.nnClinabci21:371–380 107. Richie JP, Catalona WJ, Ahmann FR, Hudson MA,
in older men: longitudinal results rom the Massachusetts Malegingtudy.urJndocrinol155:443–452 118. 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 1999ecto testos-
terone treatmenton bonemineraldensityin menover 65 yearsoage.JClinndocrinolMetab84:1966–1972
Scardino PT, Flanigan RC, deKernion JB, Ratliff TL, Kavoussi LR, Dalkin BL, Waters WB, MacFarlane MT, Southwick PC 1993ectopatientageonearlydetection
119. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L,
oprostatecancerwithserumprostate-specifcantigenand digitalrectalexamination.rology42:365–374
compositionandmusclestrengthinmenover65yearsoage. JClinndocrinolMetab84:2647–2653
108. Gosselaar C, Roobol MJ, Roemeling S, de Vries SH, Cruijsen-Koeter I, van der Kwast TH, Schröder FH 2006 creeningorprostatecancerwithoutdigitalrectalexaminationandtransrectalultrasound:resultsaterouryearsinthe uropean Randomized tudy o creening or Prostate Cancer(RPC),Rotterdam.Prostate66:625–631
120. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL 2004xogenous testosteroneor testosterone withfnasteride increases bone mineraldensityin older menwith lowserumtestosterone. JClinndocrinolMetab89:503–510
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-responserelationshipsinhealthy
young men. m J Physiol ndocrinol Metab 281:1172– 1181 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 2005Oldermenareasresponsiveas
Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL 1999 ect o testosterone treatment on body
121. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL 2005xogenoustestosterone (T)aloneorwithfnasterideincreasesphysicalperormance, grip strength, and lean body mass inolder men with low serumT.JClinndocrinolMetab90:1502–1510 122. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG 2001ectsotransdermaltestosteroneonbone andmuscleinoldermenwithlowbioavailabletestosterone levels.JGerontolBiolciMedci56:M266–M272
youngmentotheanaboliceectsogradeddosesotestosterone on the skeletal muscle. J Clin ndocrinol Metab 90:678–688
123. Nair KS, Rizza RA, O’Brien P, Dhatariya K, Short KR,
111. Coviello AD, Kaplan B, Lakshman K M, Chen T, Singh AB, Bhasin S 2008 ects o graded doses o testosterone on erythropoiesisinhealthyyoungandoldermen.JClinndocrinolMetab93:914–919
Hor testosterone in elderly men. ngl J Med 355:1647–1659
112. O’Carroll R, Bancroft J 1984Testosteronetherapyorlow sexualinterestanderectiledysunctioninmen:acontrolled study.BrJPsychiatry145:146–151 113. Schiavi RC, White D, Mandeli J, Levine AC 1997ecto testosteroneadministrationonsexualbehaviorandmoodin menwitherectiledysunction.rchexBehav26:231–241 114. Simon D, Preziosi P, Barrett-Connor E, Roger M, SaintPaul M, Nahoul K, Papoz L 1992Theinuenceoagingon plasmasexhormonesinmen:theTelecomtudy.mJpidemiol135:783–791 115.Dai WS, Kuller LH, LaPorte RE, Gutai JP, Falvo-Gerard L, Caggiula A 1981The epidemiology oplasma testosterone levelsinmiddle-agedmen.mJpidemiol114:804–816 116. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH 1997ongitudinalrelationbetweenendogenous testosteroneandcardiovasculardiseaseriskactorsinmiddleagedmen.13-yearollow-upoormerMultipleRiskFactor nterventionTrialparticipants.mJpidemiol146:609–617 117.Mohr BA, Bhasin S, Link CL, O’Donnell AB, McKinlay JB 2006Theeectochangesinadiposityontestosteronelevels
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 2006Hinelderlywomenand-
124. Sih R, Morley JE, Kaiser FE, Perry 3rd HM,Patrick P, Ross C 1997Testosteronereplacementinolderhypogonadalmen: a12-monthrandomizedcontrolledtrial.JClinndocrinol Metab82:1661–1667 125. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT 2006 rug insight: testosterone and selective androgen receptor modulators as anabolic therapies or chronic illness and aging. at Clin PractndocrinolMetab2:146–159 126. 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 men
improves muscle unction: molecular and physiological mechanisms. m J Physiol ndocrinol Metab 282: 601–607 127. Tenover JS 1992ectso testosteronesupplementationin theagingmale.JClinndocrinolMetab75:1092–1098 128. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE 2003Oraltestosteronesupplementation increases muscle and decreases at mass inhealthyelderly maleswithlow-normalgonadalstatus.JGerontolBiolci Medci58:618–625
T e s T o s T e r o n e T h e r a p y i n
M e n w i T h
a n d r o g e n d e f i c i e n c y s y n d r o M e s
29
129. Reddy P, White CM, Dunn AB, Moyna NM, Thompson PD 2000Theeectotestosteroneonhealth-relatedquality oliein elderly males—a pilotstudy. J Clin Pharm Ther 25:421–426 130. Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S 2004 ects o testosterone on behavior, depression, and cognitiveunctioninoldermenwithmildcognitiveloss.J GerontolBiolciMedci59:75–78 131. Blackman MR, Sorkin JD, Mu¨ nzer T, Bellantoni MF,
thal D, Anderson E, Stanley T, Schoenfeld D, Burrows B, Hayden D, Basgoz N, Klibanski A 2000ectso testos-
135. Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M 2 009 Testosterone and depression: systematic review and metaanalysis.JPsychiatrPract15:289–305 136. Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL
2006ectsotestosteroneoncognitionandmoodinmale patients with mild lzheimer disease and healthy elderly men.rcheurol63:177–185
u g e c i T c a r p
137. Rietschel P, Corcoran C, Stanley T, Basgoz N, Klibanski A, Grinspoon S 2000Prevalenceohypogonadismamongmen with weight lossrelatedto human immunodefciencyvirus inection who were receiving highly active antiretroviral therapy.Clinnectis31:1240–1244
l a c i
138. Salehian B, Jacobson D, Swerdloff RS, Grafe MR, SinhaHikim I, McCutchan JA 1999Testicularpathologicchanges andthepituitary-testicularaxisduringhumanimmunodefciencyvirusinection.ndocrPract5:1–9
n i l c
139. Grinspoon S, Corcoran C, Lee K, Burrows B, Hubbard J,
y T e i c o s e n i r c o d n e n a
30
cise inHVinectedmen with weight loss and low testosteronelevels.JM283:763–770 143. Grinspoon S, Corcoran C, Parlman K, Costello M, Rosen-
134. English KM, Steeds RP, Jones TH, Diver MJ, Channer KS 2000 ow-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized,double-blind,placebo-controlledstudy.Circulation102:1906–1911
d i
KE, Phillips J, Dike M, Sinha-Hikim I, Shen R, Hays RD, Beall G 2000Testosteronereplacementandresistanceexer-
steroid administration inhealthy aged women andmen: a randomizedcontrolledtrial.JM288:2282–2292
133. Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prest wood KM 2002ectsotransdermaltestosteroneoncognitiveunctionandhealthperceptioninoldermenwithlow bioavailabletestosteronelevels.JGerontol BiolciMed ci57:M321–M325
n i l e
142. Bhasin S, Storer TW, Javanbakht M, Berman N, Yarasheski
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 sex
132. Tracz MJ, Sideras K, Boloña ER, Haddad RM, Kennedy CC, Uraga MV, Caples SM, Erwin PJ, Montori VM 2006 Testosteroneuse inmen andits eects onbone health. systematicreviewandmeta-analysisorandomizedplacebocontrolledtrials.JClinndocrinolMetab91:2011–2016
e
141. Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I, Shen R, Arver S, Beall G 1998ectso testosterone replacement with a nongenital, transdermal system, ndroderm, in human immunodefciency virusinectedmenwithlowtestosteronelevels.JClinndocrinol Metab83:3155–3162
Katznelson L, Walsh M, Guccione A, Cannan J, Heller H, Basgoz N, Klibanski A 1996ossoleanbodyandmuscle
mass correlates with androgen levels in hypogonadal men with acquired immunodefciency syndrome and wasting. J ClinndocrinolMetab81:4051–4058 140. Kong A, Edmonds P 2002 Testosterone therapy in HV wasting syndrome: systematic review and meta-analysis. ancetnectis2:692–699
teroneandprogressiveresistancetrainingineugonadalmen with wasting. randomized, controlled trial. nn nternMed133:348–355 144. Knapp PE, Storer TW, Herbst KL, Singh AB, Dzekov C, Dzekov J, LaValley M, Zhang A, Ulloor J, Bhasin S 2008 ectsoa supraphysiologicaldoseotestosteroneonphysicalunction,muscleperormance,mood,andatigueinmen withHV-associatedweight loss.m J Physiol ndocrinol Metab294:1135–1143 145. Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, Klibanski A 2000ectsohypogonadismandtestosterone administrationondepressionindicesinHV-inectedmen.J ClinndocrinolMetab85:60–65 146. Rabkin JG, Wagner GJ, McElhiney MC, Rabkin R, Lin SH 2004Testosteroneversusuoxetineordepressionandatigue inHV/:aplacebo-controlledtrial.JClinPsychopharmacol24:379–385 147. Rabkin JG, Wagner GJ, Rabkin R 1999Testosteronetherapy or human immunodefciency virus-positive men withand withouthypogonadism.JClinPsychopharmacol19:19–27 148. Rabkin JG, Wagner GJ, Rabkin R 2000 double-blind, placebocontrolledtrialotestosteronetherapyorHV-positivemenwithhypogonadalsymptoms.rchGenPsychiatry 57:141–147;discussion155–146 149. van Staa TP, Leufkens HG, Cooper C 2002 The epidemiologyocorticosteroid-inducedosteoporosis:ameta-analysis. Osteoporosnt13:777–787 150. Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ 2003 Randomized placebo-controlled trial o androgen eects on muscle and bone in men requiring long-term systemicglucocorticoidtreatment.JClinndocrinolMetab 88:3167–3176 151. Reid IR, Wattie DJ, Evans MC, Stapleton JP 1996Testosterone therapy in glucocorticoid-treatedmen. rchntern Med156:1173–1177
Acknowledgments ThemembersotheTaskForcethankThendocrineociety’sClinicalGuidelinesubcommittee,Clinicalairs CoreCommitteeandCouncilortheircareul,criticalreviewoearlierversionsothismanuscriptandtheir helpulcommentsandsuggestions.Wealsothankthestaattheocietyofceortheirhelpulsupportduringthe developmentothisguideline.
Financial Disclosure of Task Force Shalender Bhasin, M.D. (Chair)—Consultation or dvisement: GlaxomithKline (GK), Merck; Grant or Other Research upport: bbott aboratories, igand, Merck; Financial or Business/Organizational nterests: merican Board o nternal Medicine.Glenn R. Cunningham, M.D.—Consultationor dvisement: Clarus, Columbia ab, GK, ndo Pharmaceuticals, bbott aboratories; Grant or Other Research upport: bbott aboratories; Columbia ab, GK;peakers ist: Columbia ab, ndoPharmaceuticals, bbott aboratories; FinancialorBusiness/Organizationalnterests:pToate;ignifcantFinancialnterestoreadershipPosition: none declared. Frances J. Hayes, M.B., FRCPI—Consultation or dvisement: uxilium Pharmaceuticals, GK,ewnglandResearchnstitute;peakersBureauorbbottaboratories;FinancialorBusiness/Organizationalnterests:nonedeclared;ignifcantFinancialnterestoreadershipPosition:nonedeclared.Alvin M. Matsumoto, M.D.—Consultation or dvisement: bbott aboratories, Merck, ndo Pharmaceuticals, Tokai; Grant or Other Research upport: GK, bbott aboratories; Financial or Business/Organizational nterests: pToate,..nti-opinggency/PCC;ignifcantFinancialnterestoreadershipPosition:nonedeclared. Peter J. Snyder, M.D.—Consultationordvisement:nonedeclared;GrantorOtherResearchupport:bbott aboratories;FinancialorBusiness/Organizationalnterests:bbottaboratories,pToate;ignifcantFinancialnterestoreadershipPosition:pToate.Ronald S. Swerdloff, M.D.—Consultationordvisement:Clarus, bbottaboratories,ndoPharmaceuticals;GrantorOtherResearchupport:ctelionPharma,RYxTherapeutics, nc., uxilium, Bayer Corp., Besins/scend, Bristol-Myers quibb, Clarus, Columbia,Corcept, GK, li illy &Co., MacroChem Corp., Organon, chering G, bbott aboratories; Financial or Business/ Organizational nterests: none declared; ignifcant Financial nterest or eadership Position: none declared. *Victor M. Montori, M.D.—FinancialorBusiness/Organizationalnterests:nonedeclared;ignifcantFinancial nterestoreadershipPosition:nonedeclared. * Evidence-based reviews for this gui deline were prepared under contract with The Endocrine Society.
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