Testosterone Replacement Therapy in Hypogonadal Men:
Assessing the Benefits, Risks, and Best Practices Martin Miner, MD; David J. Canty, PhD; and Ridwan Shabsigh, MD, FACS
DOI: 10.3810/pgm.2008.09.1914
Abstract: Hypogonadism is a common condition, especially among older men, but often goes undiagnosed and untreated. It can be associated with a number of signs and symptoms that affect health and quality of life, including feelings of low energy and fatigue; decreased sex drive and performance; decreased muscle mass and strength; decreased bone mineral density; and increased body fat, particularly abdominal fat, a putative risk factor for metabolic syndrome and type 2 diabetes mellitus. The evidence supporting testosterone replacement therapy (TRT) in improving these and related conditions is strong and consistent for body composition and sexual function; moderately consistent for bone mineral density; inconsistent for insulin sensitivity, glycemic control, and lipid profiles; and weak and inconsistent for mood and cognitive function. The concern of some physicians about the potential for TRT to stimulate prostate cancer is not supported by decades of data accumulated to date, though studies of longer duration (eg, 10 years or more) would be even more convincing. Other research needs are discussed. As the front line of health care delivery, primary care physicians need to be vigilant in diagnosing and treating symptomatic hypogonadism. Based on current guidelines, we recommend assessing testosterone levels when an adult man exhibits signs of hypogonadism, and as part of normal medical screening in men starting at age 40 to 50 years, to establish a baseline. A physician should discuss the possibility of TRT with symptomatic patients who have a serum total testosterone level < 300 ng/dL. If TRT is initiated, a patient's response and adverse events should be assessed every 3 to 6 months, and therapy adjusted accordingly.
Introduction
Hypogonadism due to all causes may affect up to 30% of men,[SUP]1[/SUP] and can have negativeeffects on health and quality of life, including decreased lean body mass and increasedfat mass, decreased bone mineral density, fatigue, decreased libido and sexual function,and negative mood states. Unfortunately, hypogonadism remains underdiagnosedand undertreated, with only about 5% of men with the condition being treated for it,according to one estimate.[SUP]2[/SUP]
Because primary care physicians (PCPs) are on the front line of health care delivery,they are in a unique position to identify symptomatic hypogonadal patients and treatthem appropriately. The decision to treat should be based not only on assessing testosterone(T) status, but on the presence of hypogonadal symptoms and the evidencesupporting testosterone replacement therapy (TRT) having beneficial effects on them.
Hall et al[SUP]3[/SUP] found in an observational study (BACH) in theBoston area over 3 years that of the men who met criteriafor having untreated, symptomatic androgen deficiency,∼88% were not receiving treatment despite adequate accessto care. This review provides an overview of hypogonadism,an assessment of the strength and consistency of theevidence supporting various potential benefits of TRT, andpractical recommendations for treating hypogonadism in theprimary care setting. Additional background on T, TRT, andquality characteristics of studies assessed for this review areincluded in Table 1.
Hypogonadism
For purposes of this review, we will use the traditional term"hypogonadism" as a descriptor of low T status, clarifyingwhere appropriate if it is accompanied by symptoms andsigns. We note, however, that there is growing consensusfor use of other, more descriptive terms, including "lateonsethypogonadism" (LOH) and "testosterone deficiencysyndrome" (TDS), which more specifically refer to a clinicalspectrum of symptoms and signs.
Because different laboratory cut-off values have beenused to define hypogonadism, incidence and prevalenceestimates vary. One study estimated age-related hypogonadismdue to all causes affects 20% to 30% of men.[SUP]1[/SUP] Anotherstudy estimated symptomatic androgen deficiency (low Tand clinical signs) in men 30 to 79 years of age at 5.6%,with higher prevalence in older men (eg, 18.2% in men >70 years), and projected that prevalence would grow 38% by2025 compared to 2000.[SUP]4[/SUP]
In addition to aging, certain conditions are associatedwith an increased risk for hypogonadism: obesity, metabolicsyndrome, type 2 diabetes mellitus, chronic opiate use, chronichepatic disease, and chronic glucocorticoid use. Circulating Tcan be converted to other hormones, eg, dihydrotestosterone(DHT) in the periphery by 5-alpha reductase, and estradiol(E2) by aromatization in adipose tissue. The high levels ofbody fat in obese men results in increased aromatase activityand higher levels of E2. Thus, the prevalence of hypogonadismin men with type 2 diabetes mellitus, which is associated withobesity, is 30% to 55%, depending on age.[SUP]5[/SUP] The inverserelationship between testosterone and obesity, type 2 diabetesmellitus, and metabolic syndrome appears bidirectional:low T predicts the development of these conditions, and theconditions likely perpetuate low T.[SUP]6[/SUP]
Clinical signs of hypogonadism can include:
Many of these signs and symptoms are often attributedto other existing comorbidities, or to "normal" aging, andthere is much interpatient variability on presentation-justsome of the reasons that age-related hypogonadism is underrecognizedand undertreated.[SUP]7[/SUP]Assessing the Benefits of TRT
The clinical question researched for this review was: Whatis the strength of evidence showing various benefits ofTRT? The authors searched MEDLINE for all randomizedcontrolled trials in humans with "testosterone" in the title orabstract. Additional articles were retrieved from referenceslisted in recently published reviews.
The retrieved published studies were assessed forvalidity characteristics based on strength of recommendationtaxonomy (SORT), a practical and simplified system recommendedfor general practice and family practice journals.8In our assessment, we considered the similarity of patientsoverall as well as in intervention and control groups, allocationconcealment, blinding, completion of follow-up, useof intention-to-treat, and adequate statistical power, thoughmany of the reports did not include sufficient information toaccurately determine statistical power. The search resultedin a total of 400 articles, of which 50 met inclusion criteriaand included findings related to the above potential benefits.For each benefit area, the level of support for the benefit areawas assessed:
A = Strong and consistent evidence for benefit.
B = Moderately strong and consistent evidence forbenefit.
C = Weak and/or inconsistent evidence for benefit.
Additionally, we assessed adverse events reported in thestudies. It should be noted that at least some inconsistencyof evidence (generating lower support levels of B and C)is likely due to different TRT preparations used, differentdosing schedules employed, and different populations studied, and may not necessarily reflect a lack of therapeuticof TRT generally.
Improving Body Composition and MuscleStrength: Support Level A and C
The 17 trials that examined the effect of TRT on bodycomposition ranged from 3 months to 3 years in length, andincluded from 12 to more than 400 participants.[SUP]9-25[/SUP] Moststudies were in older men (≥ 60 years), but some were inyounger men and in those with asthma or chronic obstructivepulmonary disease (COPD). Patients with COPD andchronic asthma have been poorly studied in relationship totestosterone levels, but we decided to include these chronicdisease states. Of the 17 trials, 15 found TRT increasedlean body mass and/or decreased fat mass. The effect onstrength was considerably less consistent, with some studiesshowing gains, others showing gains in some musclegroups but not others, and still others showing no gains atall. Based on these studies, we consider the evidence forTRT improving body composition (increasing lean bodymass and/or decreasing fat mass) to be level A, whileevidence showing it increased strength was level C. Thisassessment is also consistent with other recent reviews andmeta-analyses.[SUP]26-28
[/SUP]Increasing Bone Mineral Density:Support Level B
The 8 reviewed studies of TRT and bone mineral densityranged from 3 months to 3 years in length, and included35 to more than 100 participants.[SUP],14,24,29-33[/SUP] The participantswere mostly, but not all, older men (≥ 60 years), and includedthose who were normal and healthy, hypogonadal, with rheumatoidarthritis, or with a history of long-term corticosteroidtherapy. Overall, we consider the evidence supporting TRTbenefiting BMD to be level B, because it is only moderatelystrong and consistent. These findings are consistent withthose in other meta-analyses.[SUP]28,34[/SUP]
Reduced lean body mass, strength, and bone mineraldensity collectively increase frailty and the risk for falling,a common and often debilitating problem associated withaging. Given the effects of T on body composition andpossibly bone density and strength, it is not surprising thatreduced T levels are associated with greater risk for falling.[SUP]35[/SUP] Frailty is typically defined as including 3 or more ofthe following characteristics: low physical activity, muscleweakness, slowed performance, fatigue, or unintentionalweight loss. The possible effects of TRT on frailty is an areaworth investigating, but at this time there are no studies onthe effects of TRT in frail elderly men.Improving Metabolic Syndrome, Type 2Diabetes Mellitus, CardiovascularDisease: Support Level A and C
The 14 reviewed studies of the effects of TRT on glycemiccontrol, serum lipids, and cardiovascular disease were2 months to 3 years in length, and included 18 to morethan 100 participants.[SUP]19,24,36-47[/SUP] The participants rangedfrom young to old adult men, with or without abdominalobesity, type 2 diabetes mellitus, hypogonadism, ordyslipidemia.
The level of evidence supporting TRT in the treatmentof metabolic syndrome, type 2 diabetes mellitus, and cardiovasculardisease varies because TRT has varying impactson different aspects of treatment. Specifically, reduction ofbody fat, especially intra-abdominal fat, is a key componentin treating most individuals with metabolic syndrome or type2 diabetes mellitus, as well as many patients with atheroscleroticcardiovascular disease and dyslipidemia. As describedabove, we consider the evidence supporting TRT in helpingreduce fat mass to be level A. On the other hand, evidenceshowing that TRT improves glycemic control and lipid profile is somewhat weaker and less consistent. Five of 8 studiesshowed TRT improved various measures of glycemiccontrol,[SUP]24,36,39,40,42-45[/SUP] and 5 of 10 studies showed TRT improvedone or more serum lipid components,[SUP]19,24,36,39,40,42-44,46,47[/SUP]mostly total cholesterol and triglyceride levels; a numberalso showed it reduced HDL levels. Thus, we consider theevidence on improving glycemic control and serum lipids inpatients with metabolic syndrome to be level C. The overallneutral-to-positive effects of TRT on serum lipids neithersupport contraindicating it in men with hypogonadism andpreexisting CVD, nor administering it solely for cardiovascularbenefits. This conclusion is consistent with those in otherrecent reviews and analyses of prospective studies.[SUP]48,49
[/SUP]Improving Sexual Desire, Functionand Performance: Support Level A
Studies on the effect of T therapy on sexual function andperformance varied greatly in quality, though findings weregenerally consistent. The 10 studies reviewed ranged from1 to 6 months in length, and included from 12 to more than400 participants.[SUP]22,23,[/SUP] We also included studies of hypogonadalmen who were prior PDE5 failures and then reassessedfollowing testosterone repletion. Most of the studies showed that TRT increased sexual awareness and arousal, erectilefunction, and the frequency of spontaneous erections, butwas less consistent in enhancing actual sexual behavior andperformance. Overall, we consider the evidence showingTRT benefits on at least some aspects of sexual desire, functionand performance to be strong and consistent, and assessit as level A. Our assessment is consistent with a recentlypublished review58 and meta-analyses of randomized, placebocontrolledtrials of TRT in men with sexual dysfunction andvarying endogenous T levels.[SUP]59,60[/SUP]s It is also worth noting that,because vasculopathy is the most common cause of erectiledysfunction, the condition can also serve as an early markerfor CVD.[SUP]61[/SUP] In conclusion, it is important to screen all menwith ED for hypogonadism, especially those with a historyof inadequate response to prior PDE5 inhibitors.
Improving Cognitive Function and Mood:Support Level C
Studies on T therapy and cognitive function and mood variedgreatly in quality as well as findings. The 12 studies reviewedranged from 1 to 12 months in length, and included from 10 tomore than 400 participants. Only 6 of the 13 studies showedTRT improved at least some aspects of cognitive functionand/or mood,[SUP]20,22,24,50,53,62-69[/SUP] though effects on mood weresomewhat more consistent. Because of the inconsistency infindings overall and the fact that no study was longer than12 months, we considered the support for TRT improvingcognitive function and mood to be level C.
Assessing the Risks of TRT
Risks of TRT include expense, the ambiguity of testosterone'simpact on occult prostate cancer, and the potentialexacerbation of erythropoiesis and obstructive sleep apnea,as reported in the literature.
Serious adverse effects were rarely reported in the studiesreviewed. Among studies reporting various adverse effects,levels of prostate-specific antigen (PSA) did not significantly change in most (18 of 23), BPH symptoms/volumeand urinary flow did not change in most (7 of 9), hemoglobin/hematocrit increased in approximately half (8 of 15),HDLs decreased in 4 of 18, blood pressure increased in 1 of5, and liver function enzyme levels increased in 1 of 7.Many practitioners are concerned about TRT increasingthe risk of prostate disease. Although prostate tumors areandrogen sensitive and prostate growth is stimulated by T andparticularly DHT, decades of accumulated data do not demonstratethat endogenous or exogenous T plays a causativerole in prostate cancer, nor that TRT will convert subclinicalprostate cancer to detectable prostate cancer. Indeed, in thiscontext it is worth noting that, when prostate cancer is presentin hypogonadal men, it is often more aggressive than ineugonadal men.[SUP]70[/SUP] Nonetheless, studies to date on TRT havegenerally been limited to less than 3 years in duration, andTRT is generally prescribed for life. Carpenter and others inthe Endogenous Hormones and Prostate Cancer CollaborativeGroup presented an impressive pooled analysis of 18studies analyzing 3886 men with prostate cancer and 6438control subjects, and concluded that there are no associationsbetween prostate cancer risk and serum concentrations of testosterone,calculated free testosterone, dihydrotestosterone,and other androgens or calculated free estradiol. By confirmingthe lack of evidence to support an androgen-prostatecancer hypothesis, the study obliges the scientific communityto move past the biologically plausible androgen-prostatecancer hypothesis and begin the task of characterizing themodifiable risk factors of prostate cancer.[SUP]71,72[/SUP]
In summary, additional large studies of longer durationare needed to confirm that TRT does not increase the riskfor prostate disease. For now, it is prudent to prescribe TRTonly for symptomatic hypogonadal men who have normalPSA levels and digital rectal exam (DRE) findings. Prostatecancer or male breast cancer are absolute contraindicationsfor TRT; severe obstructive uropathy is considered a relativecontraindication. However, men successfully treated forprostate cancer and suffering from confirmed symptomatichypogonadism are potential candidates for TRT after a prudentinterval, if there is no clinical or laboratory evidenceof residual cancer (more long-term outcome data are beingcollected in this population of men).Diagnosing Hypogonadism
Diagnosing hypogonadism can be challenging because clinicalsymptoms may not be obvious or due to other causes;there is not complete agreement on laboratory cutoff valuesof T that define it; and T levels in men vary with time of day,season, certain medications, stress, illness and other factors.Nevertheless, the clinical signs noted earlier should triggerevaluation of serum T levels.
Diagnosing hypogonadism also can be facilitated throughscreening questionnaires such as the ADAM questionnaire(Figure 1). As with most such instruments, it is not 100%sensitive nor specific, but at least can serve as the basis fordiscussion with the patient. In practice, diminished libido anderectile dysfunction are the primary symptoms on the ADAMthat reflect symptomatic hypogonadism in older men (alsosometimes referred to as LOH, as noted earlier).
View: Table 1
Validity Characteristics, Design, and Findings of Trials on Testosterone Therapy
Many experts argue that levels of free or bioavailable T(vs total T, which includes T bound to sex hormone bindingglobulin [SHBG], a nonbioavailable form of T) more accuratelyreflect a man's androgen status. While some methodsto estimate free and bioavailable T are available,[SUP]73[/SUP] standardmethods and normative values do not yet exist. On the otherhand, many practitioners favor total T assessment becauseit is less expensive and SHBG levels are rarely abnormalenough to significantly change the level of bioavailable T.Complicating matters, various groups and organizations,including the Endocrine Society and the InternationalSociety of Andrology, have proposed somewhat differentnormative values for total T and different treatment algorithms(Figures 2, 3).[SUP]74-76[/SUP] A number of experts point outthat these algorithms are too complicated and not widelyused, and recommend simply using the US Food and DrugAdministration (FDA) cutoff to define hypogonadism(total T level ≤ 300 ng/dL) in symptomatic men as indicatingthe need for further testing (eg, free T, SHBG, andother hormones) and for consideration of TRT.[SUP]77[/SUP] If T levelsare below a certain threshold (in author MM's experience,T < 200 ng/dL, though some guidelines suggest T < 150ng/dL[SUP]74,75[/SUP]), then luteinizing hormone and prolactin levels should be obtained to exclude any secondary cause ofhypogonadism, particularly pituitary microadenoma.
Testosterone Replacement Therapy
If TRT is deemed appropriate based on clinical signsand results of T testing, what should the goal T level be?Unfortunately, there also are no definitive standards for goal Tlevels with TRT, though the Endocrine Society recommendsaiming for a "mid-normal range," with levels < 350 ng/dLor > 700 ng/dL prompting dosage adjustment.[SUP]74[/SUP] Practitionerscan consider narrowing the target range closer to about600 ng/dL based on recent findings showing that, in hypogonadalmen given TRT, threshold functional plasma levelswere approximately 400 ng/dL for increase in nighttimeerections, 500 ng/dL for increase in frequency of sexualintercourse, and 600 ng/dL for increased sexual desire.[SUP]78[/SUP]Based on the studies we reviewed, it appears that highlevels of DHT are not essential for the beneficial effect of Tin older men. A clinician could therefore consider the additionof an alpha reductase inhibitor in older hypogonadalmen with an enlarged prostate (PSA > 1.5) to both ensureadequate levels of T (since conversion of T to DHT wouldbe inhibited) and prostate safety.[SUP]79[/SUP]
View: Figure 1
ADAM Questionnaire (A diagnosis of ADAM [androgen decline in the aging male] is suspected if there are "yes" answers to questions 1 and 7, or any 3 other questions.)[SUP]85[/SUP]
Different TRT preparations are available, each havingadvantages and disadvantages (Tables 2, 3). Injectable agentsare often used. These preparations contain T esters which,in fat depot injections, provide a "timed-release" form ofT over a period of weeks. A dosing schedule of 200 mgIM every 2 weeks is used initially, and adjusted based onthe patient's response. Levels for efficacy measurement aredrawn mid-cycle, or 1 week following the injection. Topicalor transdermally delivered TRT can minimize the cyclicalhighs and lows of serum T that often accompany TRTinjections, and most studies have found few or no adverseeffects[SUP]22[/SUP] other than local irritation with some formulations.Their main disadvantage is high cost ($100 to $150 per monthvs $30/month for self-administered injection therapy). Theinjectable T ester formulation testosterone undecanoate isdosed less frequently (approximately every 10-12 weeks)than other T ester formulations and results in smaller cyclicalhighs and lows,[SUP]80[/SUP] but is currently not yet approved in theUnited States.
Generally, oral agents should not be used because firstpassmetabolism in the liver results in very small amountsreaching the peripheral circulation, and also in greater HDLreductions and liver toxicity.[SUP]81,82[/SUP] The only exception is oralT undecanoate (taken 4 times per day) which is absorbedvia the lymph system; however, it is currently not availablein the United States.
Monitoring and Follow-Up
Before beginning TRT, patient assessments shouldinclude:
Additionally, prior to initiating TRT, a man's risk forprostate cancer should be assessed based on PSA value,family history, race, and DRE. Determination of risk can befacilitated through online tools (eg, National Cancer Institute:www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp).After a TRT formulation has been agreed upon, morningT levels should be assessed within 2 to 3 weeks of starting agel, patch, or buccal TRT; and at approximately 8 weeks if aninjectable form is used. When treating with injectable preparations, again, T levels should be checked midway betweeninjections, to confirm that the dosage is appropriate.
View: Figure 2
Endocrine Society's recommended approach for the diagnostic evaluation of adult men suspected of having androgen deficiency.[SUP]74[/SUP](copyright 2006, the Endocrine Society).
Monitoring for side effects is obviously important,including:[SUP]70[/SUP]
View: Figure 3
Recommended approach of the International Society of Andrology, International Society for the Study of the Aging Male, and European Urology Association for the diagnostic evaluation of adult men suspected of having androgen deficiency.[SUP]76[/SUP]
After 3 months, the patient's response should be assessed,including the above measures as well as morning total T levelfor patch users. The patient's reports of the effects of thetherapy are also important indicators of response. If thepatient exhibits no adverse changes in repeat blood tests andreports symptom improvements, he can be followed every6 months. Once TRT is initiated, it is likely to be lifelong.
Table 3 illustrates a practical implementation and management guideline for testosterone deficiency syndrome.
Discussion
Overall, our review found the evidence for the variouspotential benefits of TRT in symptomatic hypogonadal mento range from level A to C. Strengths of our review includethe large number of studies examined and integration of ourassessment with findings and conclusions from other reviewsand meta-analyses. Weaknesses of our review include lack ofmore formalized meta-analysis techniques to combine findingsfrom different studies and assess the evidence in aggregate;and the widely varying characteristics of the individualstudies, including the different types of TRT administered(eg, IM injections, patches, and oral formulations).
Summary
Hypogonadism is a fairly common, yet underdiagnosed andundertreated condition in men-especially older men-thatcan affect both health status and quality of life.Research to date strongly and consistently shows TRT,at least over the short term (up to ∼3 years), has positive effects on body composition-decreasing fat mass, andincreasing muscle mass-which in turn can reduce the riskfor metabolic syndrome and type 2 diabetes. Notwithstandingthese benefits, the evidence is less consistent for TRTdirectly improving insulin sensitivity and glycemic control,lipid profiles, and cardiovascular disease risk. Evidence ismoderately consistent for TRT improving bone mineraldensity. Research to date also is strong showing TRT haspositive effects on various aspects of sexual function, thoughthe specific effects differ from study to study. The evidenceis weak and/or inconsistent for beneficial effects on moodand cognitive function.
View: Table 2
Testosterone Replacement Algorithm: Men's Health Center, The Miriam Hospital, Warren Alpert School of Medicine, Brown University
Patients at risk for adverse outcomes with TRT includethose with erythrocytosis, hyperviscosity, untreated obstructivesleep apnea, severe benign prostatic hyperplasia symptoms(AUA prostate symptom score > 19), or uncontrolledsevere heart failure. Contraindications include men withknown or suspected carcinoma of the prostate gland orbreast.
Because primary care physicians generally see patientsfirst, they need to be vigilant in diagnosing symptomatichypogonadism, and treat it appropriately. Assessment oftotal T should be considered: 1) when a patient exhibitssymptoms consistent with low T, and 2) as part of normalmedical screening in men starting at age 40 to 50 years,for a baseline. The FDA's definition of hypogonadism(total T < 300 ng/dL) in symptomatic men can be used asindicating the need for further testing and considerationof TRT. If a diagnosis of symptomatic hypogonadism isconfirmed, the physician and patient should discuss TRTand formulation options that best meet the patient's needs.After TRT is initiated, the patient should be monitored every3 to 6 months for his response and any adverse effects, anddosages adjusted or therapy discontinued accordingly. Aswith any therapy, TRT carries risks, but the risks appear tobe fairly minimal when the goal of therapy is normalizationof T levels, and manageable with proper patient monitoringand follow-up. Indeed, from a benefit-risk standpoint, physicians need to consider the risks of not treating symptomatichypogonadism.
As noted by Harman,[SUP]83[/SUP] an increasing number of hypogonadalmen (symptomatic or not) embark on a regimen oftestosterone replacement as a preventive measure to slowprogression, or even avoid onset of, age-related debilitiessuch as diminished sexual capacity and loss of muscle mass,strength, and bone loss. This approach is consistent with theparadigm that low T levels precede the cascade of eventsleading to obesity, metabolic syndrome, type 2 diabetes mellitus,and cardiovascular disease (notwithstanding that theseconditions also appear to perpetuate low T levels). As notedby Harman,[SUP]83[/SUP] this preventive approach should be verified bya large, long-term clinical trial (eg, thousands of patients followedfor 10 years, such as the proposed ESTEEM trial) toestablish the preventive value of long-term TRT and confirmits safety. Unfortunately, an Institute of Medicine committeerecommended against investing in such a large undertakingto demonstrate safety based on the grounds that the benefitsof such preventive therapy have not been proven.[SUP]84[/SUP] Thus,for the time being, practitioners will have to use their bestclinical judgment for each individual patient who wants toundergo preventive T therapy.
Beyond the need for such a large, long-term trial, morewell-controlled studies are needed on benefits that currentlyare only moderately or weakly supported to determine if findingsdiffer across different TRT preparations and dosages,and across different population groups, and to determinewhether benefits are maintained long-term (eg, > 3 years).Further research is needed to determine the association oflong-term (eg, > 3 years) TRT as well as uncorrected lowendogenous T levels with prostate disease risk. Finally,additional research is also needed to establish standards forfree and bioavailable T.
View: Table 3
Testosterone Replacement Therapy Preparations[SUP]74
[/SUP]
Conflict of Interest Statement
Martin M. Miner, MD discloses a conflict of interest withAuxilium, Indevus, and GSK. David Canty, MD has no conflict of interest to disclose. Ridwan Shabsigh, MD discloses aconflict of interest with Pfizer, Eli Lilly, Johnson & Johnson,Bayer Schering Pharma, Indevus, Auxilium, BoehringerIngelheim, and American Medical Systems.
References
Assessing the Benefits, Risks, and Best Practices Martin Miner, MD; David J. Canty, PhD; and Ridwan Shabsigh, MD, FACS
DOI: 10.3810/pgm.2008.09.1914
Abstract: Hypogonadism is a common condition, especially among older men, but often goes undiagnosed and untreated. It can be associated with a number of signs and symptoms that affect health and quality of life, including feelings of low energy and fatigue; decreased sex drive and performance; decreased muscle mass and strength; decreased bone mineral density; and increased body fat, particularly abdominal fat, a putative risk factor for metabolic syndrome and type 2 diabetes mellitus. The evidence supporting testosterone replacement therapy (TRT) in improving these and related conditions is strong and consistent for body composition and sexual function; moderately consistent for bone mineral density; inconsistent for insulin sensitivity, glycemic control, and lipid profiles; and weak and inconsistent for mood and cognitive function. The concern of some physicians about the potential for TRT to stimulate prostate cancer is not supported by decades of data accumulated to date, though studies of longer duration (eg, 10 years or more) would be even more convincing. Other research needs are discussed. As the front line of health care delivery, primary care physicians need to be vigilant in diagnosing and treating symptomatic hypogonadism. Based on current guidelines, we recommend assessing testosterone levels when an adult man exhibits signs of hypogonadism, and as part of normal medical screening in men starting at age 40 to 50 years, to establish a baseline. A physician should discuss the possibility of TRT with symptomatic patients who have a serum total testosterone level < 300 ng/dL. If TRT is initiated, a patient's response and adverse events should be assessed every 3 to 6 months, and therapy adjusted accordingly.
Introduction
Hypogonadism due to all causes may affect up to 30% of men,[SUP]1[/SUP] and can have negativeeffects on health and quality of life, including decreased lean body mass and increasedfat mass, decreased bone mineral density, fatigue, decreased libido and sexual function,and negative mood states. Unfortunately, hypogonadism remains underdiagnosedand undertreated, with only about 5% of men with the condition being treated for it,according to one estimate.[SUP]2[/SUP]
Because primary care physicians (PCPs) are on the front line of health care delivery,they are in a unique position to identify symptomatic hypogonadal patients and treatthem appropriately. The decision to treat should be based not only on assessing testosterone(T) status, but on the presence of hypogonadal symptoms and the evidencesupporting testosterone replacement therapy (TRT) having beneficial effects on them.
Hall et al[SUP]3[/SUP] found in an observational study (BACH) in theBoston area over 3 years that of the men who met criteriafor having untreated, symptomatic androgen deficiency,∼88% were not receiving treatment despite adequate accessto care. This review provides an overview of hypogonadism,an assessment of the strength and consistency of theevidence supporting various potential benefits of TRT, andpractical recommendations for treating hypogonadism in theprimary care setting. Additional background on T, TRT, andquality characteristics of studies assessed for this review areincluded in Table 1.
Hypogonadism
For purposes of this review, we will use the traditional term"hypogonadism" as a descriptor of low T status, clarifyingwhere appropriate if it is accompanied by symptoms andsigns. We note, however, that there is growing consensusfor use of other, more descriptive terms, including "lateonsethypogonadism" (LOH) and "testosterone deficiencysyndrome" (TDS), which more specifically refer to a clinicalspectrum of symptoms and signs.
Because different laboratory cut-off values have beenused to define hypogonadism, incidence and prevalenceestimates vary. One study estimated age-related hypogonadismdue to all causes affects 20% to 30% of men.[SUP]1[/SUP] Anotherstudy estimated symptomatic androgen deficiency (low Tand clinical signs) in men 30 to 79 years of age at 5.6%,with higher prevalence in older men (eg, 18.2% in men >70 years), and projected that prevalence would grow 38% by2025 compared to 2000.[SUP]4[/SUP]
In addition to aging, certain conditions are associatedwith an increased risk for hypogonadism: obesity, metabolicsyndrome, type 2 diabetes mellitus, chronic opiate use, chronichepatic disease, and chronic glucocorticoid use. Circulating Tcan be converted to other hormones, eg, dihydrotestosterone(DHT) in the periphery by 5-alpha reductase, and estradiol(E2) by aromatization in adipose tissue. The high levels ofbody fat in obese men results in increased aromatase activityand higher levels of E2. Thus, the prevalence of hypogonadismin men with type 2 diabetes mellitus, which is associated withobesity, is 30% to 55%, depending on age.[SUP]5[/SUP] The inverserelationship between testosterone and obesity, type 2 diabetesmellitus, and metabolic syndrome appears bidirectional:low T predicts the development of these conditions, and theconditions likely perpetuate low T.[SUP]6[/SUP]
Clinical signs of hypogonadism can include:
- Decreased energy/increased fatigue.
- Decreased libido and erection firmness and durationof erection.
- Oligospermia or azoospermia.
- Decreased lean body mass and muscle strength.
- Increased body fat (especially visceral).
- Decreased body hair over chest and pubic area.
- Decreased bone mineral density and possibleosteoporosis.
- Changes in mood (eg, fatigue, depression, anger,irritability).
Many of these signs and symptoms are often attributedto other existing comorbidities, or to "normal" aging, andthere is much interpatient variability on presentation-justsome of the reasons that age-related hypogonadism is underrecognizedand undertreated.[SUP]7[/SUP]Assessing the Benefits of TRT
The clinical question researched for this review was: Whatis the strength of evidence showing various benefits ofTRT? The authors searched MEDLINE for all randomizedcontrolled trials in humans with "testosterone" in the title orabstract. Additional articles were retrieved from referenceslisted in recently published reviews.
The retrieved published studies were assessed forvalidity characteristics based on strength of recommendationtaxonomy (SORT), a practical and simplified system recommendedfor general practice and family practice journals.8In our assessment, we considered the similarity of patientsoverall as well as in intervention and control groups, allocationconcealment, blinding, completion of follow-up, useof intention-to-treat, and adequate statistical power, thoughmany of the reports did not include sufficient information toaccurately determine statistical power. The search resultedin a total of 400 articles, of which 50 met inclusion criteriaand included findings related to the above potential benefits.For each benefit area, the level of support for the benefit areawas assessed:
A = Strong and consistent evidence for benefit.
B = Moderately strong and consistent evidence forbenefit.
C = Weak and/or inconsistent evidence for benefit.
Additionally, we assessed adverse events reported in thestudies. It should be noted that at least some inconsistencyof evidence (generating lower support levels of B and C)is likely due to different TRT preparations used, differentdosing schedules employed, and different populations studied, and may not necessarily reflect a lack of therapeuticof TRT generally.
Improving Body Composition and MuscleStrength: Support Level A and C
The 17 trials that examined the effect of TRT on bodycomposition ranged from 3 months to 3 years in length, andincluded from 12 to more than 400 participants.[SUP]9-25[/SUP] Moststudies were in older men (≥ 60 years), but some were inyounger men and in those with asthma or chronic obstructivepulmonary disease (COPD). Patients with COPD andchronic asthma have been poorly studied in relationship totestosterone levels, but we decided to include these chronicdisease states. Of the 17 trials, 15 found TRT increasedlean body mass and/or decreased fat mass. The effect onstrength was considerably less consistent, with some studiesshowing gains, others showing gains in some musclegroups but not others, and still others showing no gains atall. Based on these studies, we consider the evidence forTRT improving body composition (increasing lean bodymass and/or decreasing fat mass) to be level A, whileevidence showing it increased strength was level C. Thisassessment is also consistent with other recent reviews andmeta-analyses.[SUP]26-28
[/SUP]Increasing Bone Mineral Density:Support Level B
The 8 reviewed studies of TRT and bone mineral densityranged from 3 months to 3 years in length, and included35 to more than 100 participants.[SUP],14,24,29-33[/SUP] The participantswere mostly, but not all, older men (≥ 60 years), and includedthose who were normal and healthy, hypogonadal, with rheumatoidarthritis, or with a history of long-term corticosteroidtherapy. Overall, we consider the evidence supporting TRTbenefiting BMD to be level B, because it is only moderatelystrong and consistent. These findings are consistent withthose in other meta-analyses.[SUP]28,34[/SUP]
Reduced lean body mass, strength, and bone mineraldensity collectively increase frailty and the risk for falling,a common and often debilitating problem associated withaging. Given the effects of T on body composition andpossibly bone density and strength, it is not surprising thatreduced T levels are associated with greater risk for falling.[SUP]35[/SUP] Frailty is typically defined as including 3 or more ofthe following characteristics: low physical activity, muscleweakness, slowed performance, fatigue, or unintentionalweight loss. The possible effects of TRT on frailty is an areaworth investigating, but at this time there are no studies onthe effects of TRT in frail elderly men.Improving Metabolic Syndrome, Type 2Diabetes Mellitus, CardiovascularDisease: Support Level A and C
The 14 reviewed studies of the effects of TRT on glycemiccontrol, serum lipids, and cardiovascular disease were2 months to 3 years in length, and included 18 to morethan 100 participants.[SUP]19,24,36-47[/SUP] The participants rangedfrom young to old adult men, with or without abdominalobesity, type 2 diabetes mellitus, hypogonadism, ordyslipidemia.
The level of evidence supporting TRT in the treatmentof metabolic syndrome, type 2 diabetes mellitus, and cardiovasculardisease varies because TRT has varying impactson different aspects of treatment. Specifically, reduction ofbody fat, especially intra-abdominal fat, is a key componentin treating most individuals with metabolic syndrome or type2 diabetes mellitus, as well as many patients with atheroscleroticcardiovascular disease and dyslipidemia. As describedabove, we consider the evidence supporting TRT in helpingreduce fat mass to be level A. On the other hand, evidenceshowing that TRT improves glycemic control and lipid profile is somewhat weaker and less consistent. Five of 8 studiesshowed TRT improved various measures of glycemiccontrol,[SUP]24,36,39,40,42-45[/SUP] and 5 of 10 studies showed TRT improvedone or more serum lipid components,[SUP]19,24,36,39,40,42-44,46,47[/SUP]mostly total cholesterol and triglyceride levels; a numberalso showed it reduced HDL levels. Thus, we consider theevidence on improving glycemic control and serum lipids inpatients with metabolic syndrome to be level C. The overallneutral-to-positive effects of TRT on serum lipids neithersupport contraindicating it in men with hypogonadism andpreexisting CVD, nor administering it solely for cardiovascularbenefits. This conclusion is consistent with those in otherrecent reviews and analyses of prospective studies.[SUP]48,49
[/SUP]Improving Sexual Desire, Functionand Performance: Support Level A
Studies on the effect of T therapy on sexual function andperformance varied greatly in quality, though findings weregenerally consistent. The 10 studies reviewed ranged from1 to 6 months in length, and included from 12 to more than400 participants.[SUP]22,23,[/SUP] We also included studies of hypogonadalmen who were prior PDE5 failures and then reassessedfollowing testosterone repletion. Most of the studies showed that TRT increased sexual awareness and arousal, erectilefunction, and the frequency of spontaneous erections, butwas less consistent in enhancing actual sexual behavior andperformance. Overall, we consider the evidence showingTRT benefits on at least some aspects of sexual desire, functionand performance to be strong and consistent, and assessit as level A. Our assessment is consistent with a recentlypublished review58 and meta-analyses of randomized, placebocontrolledtrials of TRT in men with sexual dysfunction andvarying endogenous T levels.[SUP]59,60[/SUP]s It is also worth noting that,because vasculopathy is the most common cause of erectiledysfunction, the condition can also serve as an early markerfor CVD.[SUP]61[/SUP] In conclusion, it is important to screen all menwith ED for hypogonadism, especially those with a historyof inadequate response to prior PDE5 inhibitors.
Improving Cognitive Function and Mood:Support Level C
Studies on T therapy and cognitive function and mood variedgreatly in quality as well as findings. The 12 studies reviewedranged from 1 to 12 months in length, and included from 10 tomore than 400 participants. Only 6 of the 13 studies showedTRT improved at least some aspects of cognitive functionand/or mood,[SUP]20,22,24,50,53,62-69[/SUP] though effects on mood weresomewhat more consistent. Because of the inconsistency infindings overall and the fact that no study was longer than12 months, we considered the support for TRT improvingcognitive function and mood to be level C.
Assessing the Risks of TRT
Risks of TRT include expense, the ambiguity of testosterone'simpact on occult prostate cancer, and the potentialexacerbation of erythropoiesis and obstructive sleep apnea,as reported in the literature.
Serious adverse effects were rarely reported in the studiesreviewed. Among studies reporting various adverse effects,levels of prostate-specific antigen (PSA) did not significantly change in most (18 of 23), BPH symptoms/volumeand urinary flow did not change in most (7 of 9), hemoglobin/hematocrit increased in approximately half (8 of 15),HDLs decreased in 4 of 18, blood pressure increased in 1 of5, and liver function enzyme levels increased in 1 of 7.Many practitioners are concerned about TRT increasingthe risk of prostate disease. Although prostate tumors areandrogen sensitive and prostate growth is stimulated by T andparticularly DHT, decades of accumulated data do not demonstratethat endogenous or exogenous T plays a causativerole in prostate cancer, nor that TRT will convert subclinicalprostate cancer to detectable prostate cancer. Indeed, in thiscontext it is worth noting that, when prostate cancer is presentin hypogonadal men, it is often more aggressive than ineugonadal men.[SUP]70[/SUP] Nonetheless, studies to date on TRT havegenerally been limited to less than 3 years in duration, andTRT is generally prescribed for life. Carpenter and others inthe Endogenous Hormones and Prostate Cancer CollaborativeGroup presented an impressive pooled analysis of 18studies analyzing 3886 men with prostate cancer and 6438control subjects, and concluded that there are no associationsbetween prostate cancer risk and serum concentrations of testosterone,calculated free testosterone, dihydrotestosterone,and other androgens or calculated free estradiol. By confirmingthe lack of evidence to support an androgen-prostatecancer hypothesis, the study obliges the scientific communityto move past the biologically plausible androgen-prostatecancer hypothesis and begin the task of characterizing themodifiable risk factors of prostate cancer.[SUP]71,72[/SUP]
In summary, additional large studies of longer durationare needed to confirm that TRT does not increase the riskfor prostate disease. For now, it is prudent to prescribe TRTonly for symptomatic hypogonadal men who have normalPSA levels and digital rectal exam (DRE) findings. Prostatecancer or male breast cancer are absolute contraindicationsfor TRT; severe obstructive uropathy is considered a relativecontraindication. However, men successfully treated forprostate cancer and suffering from confirmed symptomatichypogonadism are potential candidates for TRT after a prudentinterval, if there is no clinical or laboratory evidenceof residual cancer (more long-term outcome data are beingcollected in this population of men).Diagnosing Hypogonadism
Diagnosing hypogonadism can be challenging because clinicalsymptoms may not be obvious or due to other causes;there is not complete agreement on laboratory cutoff valuesof T that define it; and T levels in men vary with time of day,season, certain medications, stress, illness and other factors.Nevertheless, the clinical signs noted earlier should triggerevaluation of serum T levels.
Diagnosing hypogonadism also can be facilitated throughscreening questionnaires such as the ADAM questionnaire(Figure 1). As with most such instruments, it is not 100%sensitive nor specific, but at least can serve as the basis fordiscussion with the patient. In practice, diminished libido anderectile dysfunction are the primary symptoms on the ADAMthat reflect symptomatic hypogonadism in older men (alsosometimes referred to as LOH, as noted earlier).
View: Table 1
Validity Characteristics, Design, and Findings of Trials on Testosterone Therapy
Many experts argue that levels of free or bioavailable T(vs total T, which includes T bound to sex hormone bindingglobulin [SHBG], a nonbioavailable form of T) more accuratelyreflect a man's androgen status. While some methodsto estimate free and bioavailable T are available,[SUP]73[/SUP] standardmethods and normative values do not yet exist. On the otherhand, many practitioners favor total T assessment becauseit is less expensive and SHBG levels are rarely abnormalenough to significantly change the level of bioavailable T.Complicating matters, various groups and organizations,including the Endocrine Society and the InternationalSociety of Andrology, have proposed somewhat differentnormative values for total T and different treatment algorithms(Figures 2, 3).[SUP]74-76[/SUP] A number of experts point outthat these algorithms are too complicated and not widelyused, and recommend simply using the US Food and DrugAdministration (FDA) cutoff to define hypogonadism(total T level ≤ 300 ng/dL) in symptomatic men as indicatingthe need for further testing (eg, free T, SHBG, andother hormones) and for consideration of TRT.[SUP]77[/SUP] If T levelsare below a certain threshold (in author MM's experience,T < 200 ng/dL, though some guidelines suggest T < 150ng/dL[SUP]74,75[/SUP]), then luteinizing hormone and prolactin levels should be obtained to exclude any secondary cause ofhypogonadism, particularly pituitary microadenoma.
Testosterone Replacement Therapy
If TRT is deemed appropriate based on clinical signsand results of T testing, what should the goal T level be?Unfortunately, there also are no definitive standards for goal Tlevels with TRT, though the Endocrine Society recommendsaiming for a "mid-normal range," with levels < 350 ng/dLor > 700 ng/dL prompting dosage adjustment.[SUP]74[/SUP] Practitionerscan consider narrowing the target range closer to about600 ng/dL based on recent findings showing that, in hypogonadalmen given TRT, threshold functional plasma levelswere approximately 400 ng/dL for increase in nighttimeerections, 500 ng/dL for increase in frequency of sexualintercourse, and 600 ng/dL for increased sexual desire.[SUP]78[/SUP]Based on the studies we reviewed, it appears that highlevels of DHT are not essential for the beneficial effect of Tin older men. A clinician could therefore consider the additionof an alpha reductase inhibitor in older hypogonadalmen with an enlarged prostate (PSA > 1.5) to both ensureadequate levels of T (since conversion of T to DHT wouldbe inhibited) and prostate safety.[SUP]79[/SUP]
View: Figure 1
ADAM Questionnaire (A diagnosis of ADAM [androgen decline in the aging male] is suspected if there are "yes" answers to questions 1 and 7, or any 3 other questions.)[SUP]85[/SUP]
Different TRT preparations are available, each havingadvantages and disadvantages (Tables 2, 3). Injectable agentsare often used. These preparations contain T esters which,in fat depot injections, provide a "timed-release" form ofT over a period of weeks. A dosing schedule of 200 mgIM every 2 weeks is used initially, and adjusted based onthe patient's response. Levels for efficacy measurement aredrawn mid-cycle, or 1 week following the injection. Topicalor transdermally delivered TRT can minimize the cyclicalhighs and lows of serum T that often accompany TRTinjections, and most studies have found few or no adverseeffects[SUP]22[/SUP] other than local irritation with some formulations.Their main disadvantage is high cost ($100 to $150 per monthvs $30/month for self-administered injection therapy). Theinjectable T ester formulation testosterone undecanoate isdosed less frequently (approximately every 10-12 weeks)than other T ester formulations and results in smaller cyclicalhighs and lows,[SUP]80[/SUP] but is currently not yet approved in theUnited States.
Generally, oral agents should not be used because firstpassmetabolism in the liver results in very small amountsreaching the peripheral circulation, and also in greater HDLreductions and liver toxicity.[SUP]81,82[/SUP] The only exception is oralT undecanoate (taken 4 times per day) which is absorbedvia the lymph system; however, it is currently not availablein the United States.
Monitoring and Follow-Up
Before beginning TRT, patient assessments shouldinclude:
- Serum testosterone. Done before 11 AM. Tests canbegin with a screening total T, and repeat can includetotal T, bioavailable T (which includes Total T, bioavailableT and sex hormone binding globulin, allowingfor calculation of free androgen index) or free T.
- Urinary voiding history.
- Digital rectal exam.
- PSA level.
- History of sleep apnea.
- Blood pressure.
- Fasting blood lipid profile.
- Complete blood count.
- Liver function tests.
- Fluid retention (eg, edema, seen most often in frail,elderly men).
Additionally, prior to initiating TRT, a man's risk forprostate cancer should be assessed based on PSA value,family history, race, and DRE. Determination of risk can befacilitated through online tools (eg, National Cancer Institute:www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp).After a TRT formulation has been agreed upon, morningT levels should be assessed within 2 to 3 weeks of starting agel, patch, or buccal TRT; and at approximately 8 weeks if aninjectable form is used. When treating with injectable preparations, again, T levels should be checked midway betweeninjections, to confirm that the dosage is appropriate.
View: Figure 2
Endocrine Society's recommended approach for the diagnostic evaluation of adult men suspected of having androgen deficiency.[SUP]74[/SUP](copyright 2006, the Endocrine Society).
Monitoring for side effects is obviously important,including:[SUP]70[/SUP]
- Prostate disease. Practitioners should realize that PSAlevels in hypogonadal men are often abnormally low,so an increase up to 15% within 12 months of initiatingTRT reflects normalization; however, increases abovethat should be a signal for a repeat DRE and possiblebiopsy.
- Changes in serum lipids.
- Fluid retention. More often seen in frail or ill elderlymen, this usually resolves after the first few monthsof treatment.
- Liver toxicity. The risk of liver toxicity with TRT isgreatest with oral preparations, less so with injections,and very low with topical preparations. Nonetheless,because of the potential risk, regular liver functiontests are part of ongoing monitoring.
- Polycythemia. This risk appears to be higher withinjectable preparations, probably because of thesupraphysiologic T levels immediately followinginjection. The risk is also greater in patients withconditions associated with increased erythropoiesis,such as chronic obstructive lung disease. If hemoglobin/hematocrit elevations reach above-normal levels,TRT should be stopped or reduced, and phlebotomyconsidered.
View: Figure 3
Recommended approach of the International Society of Andrology, International Society for the Study of the Aging Male, and European Urology Association for the diagnostic evaluation of adult men suspected of having androgen deficiency.[SUP]76[/SUP]
- Sleep apnea. In some men, TRT appears to affectcentral breathing control, and may worsen sleep apneain patients who have the condition.
- Impairment of spermatogenesis. TRT can causeoligospermia or azoospermia that may not be reversible,which can be an important concern for men whowish to preserve their fertility. These men should beconsidered for oral therapy including estrogen receptorantagonists such as clomiphene or anastrozole(Arimidex[SUP]®[/SUP]).
- Other side effects associated with TRT include gynecomastia,acne, and weight gain.
After 3 months, the patient's response should be assessed,including the above measures as well as morning total T levelfor patch users. The patient's reports of the effects of thetherapy are also important indicators of response. If thepatient exhibits no adverse changes in repeat blood tests andreports symptom improvements, he can be followed every6 months. Once TRT is initiated, it is likely to be lifelong.
Table 3 illustrates a practical implementation and management guideline for testosterone deficiency syndrome.
Discussion
Overall, our review found the evidence for the variouspotential benefits of TRT in symptomatic hypogonadal mento range from level A to C. Strengths of our review includethe large number of studies examined and integration of ourassessment with findings and conclusions from other reviewsand meta-analyses. Weaknesses of our review include lack ofmore formalized meta-analysis techniques to combine findingsfrom different studies and assess the evidence in aggregate;and the widely varying characteristics of the individualstudies, including the different types of TRT administered(eg, IM injections, patches, and oral formulations).
Summary
Hypogonadism is a fairly common, yet underdiagnosed andundertreated condition in men-especially older men-thatcan affect both health status and quality of life.Research to date strongly and consistently shows TRT,at least over the short term (up to ∼3 years), has positive effects on body composition-decreasing fat mass, andincreasing muscle mass-which in turn can reduce the riskfor metabolic syndrome and type 2 diabetes. Notwithstandingthese benefits, the evidence is less consistent for TRTdirectly improving insulin sensitivity and glycemic control,lipid profiles, and cardiovascular disease risk. Evidence ismoderately consistent for TRT improving bone mineraldensity. Research to date also is strong showing TRT haspositive effects on various aspects of sexual function, thoughthe specific effects differ from study to study. The evidenceis weak and/or inconsistent for beneficial effects on moodand cognitive function.
View: Table 2
Testosterone Replacement Algorithm: Men's Health Center, The Miriam Hospital, Warren Alpert School of Medicine, Brown University
Patients at risk for adverse outcomes with TRT includethose with erythrocytosis, hyperviscosity, untreated obstructivesleep apnea, severe benign prostatic hyperplasia symptoms(AUA prostate symptom score > 19), or uncontrolledsevere heart failure. Contraindications include men withknown or suspected carcinoma of the prostate gland orbreast.
Because primary care physicians generally see patientsfirst, they need to be vigilant in diagnosing symptomatichypogonadism, and treat it appropriately. Assessment oftotal T should be considered: 1) when a patient exhibitssymptoms consistent with low T, and 2) as part of normalmedical screening in men starting at age 40 to 50 years,for a baseline. The FDA's definition of hypogonadism(total T < 300 ng/dL) in symptomatic men can be used asindicating the need for further testing and considerationof TRT. If a diagnosis of symptomatic hypogonadism isconfirmed, the physician and patient should discuss TRTand formulation options that best meet the patient's needs.After TRT is initiated, the patient should be monitored every3 to 6 months for his response and any adverse effects, anddosages adjusted or therapy discontinued accordingly. Aswith any therapy, TRT carries risks, but the risks appear tobe fairly minimal when the goal of therapy is normalizationof T levels, and manageable with proper patient monitoringand follow-up. Indeed, from a benefit-risk standpoint, physicians need to consider the risks of not treating symptomatichypogonadism.
As noted by Harman,[SUP]83[/SUP] an increasing number of hypogonadalmen (symptomatic or not) embark on a regimen oftestosterone replacement as a preventive measure to slowprogression, or even avoid onset of, age-related debilitiessuch as diminished sexual capacity and loss of muscle mass,strength, and bone loss. This approach is consistent with theparadigm that low T levels precede the cascade of eventsleading to obesity, metabolic syndrome, type 2 diabetes mellitus,and cardiovascular disease (notwithstanding that theseconditions also appear to perpetuate low T levels). As notedby Harman,[SUP]83[/SUP] this preventive approach should be verified bya large, long-term clinical trial (eg, thousands of patients followedfor 10 years, such as the proposed ESTEEM trial) toestablish the preventive value of long-term TRT and confirmits safety. Unfortunately, an Institute of Medicine committeerecommended against investing in such a large undertakingto demonstrate safety based on the grounds that the benefitsof such preventive therapy have not been proven.[SUP]84[/SUP] Thus,for the time being, practitioners will have to use their bestclinical judgment for each individual patient who wants toundergo preventive T therapy.
Beyond the need for such a large, long-term trial, morewell-controlled studies are needed on benefits that currentlyare only moderately or weakly supported to determine if findingsdiffer across different TRT preparations and dosages,and across different population groups, and to determinewhether benefits are maintained long-term (eg, > 3 years).Further research is needed to determine the association oflong-term (eg, > 3 years) TRT as well as uncorrected lowendogenous T levels with prostate disease risk. Finally,additional research is also needed to establish standards forfree and bioavailable T.
View: Table 3
Testosterone Replacement Therapy Preparations[SUP]74
[/SUP]
Conflict of Interest Statement
Martin M. Miner, MD discloses a conflict of interest withAuxilium, Indevus, and GSK. David Canty, MD has no conflict of interest to disclose. Ridwan Shabsigh, MD discloses aconflict of interest with Pfizer, Eli Lilly, Johnson & Johnson,Bayer Schering Pharma, Indevus, Auxilium, BoehringerIngelheim, and American Medical Systems.
References
- Allan CA, McLachlan RI. Age-related changes in testosterone and the role of replacement therapy in older men. J Clin Endocrinol (Oxf). 2004;60(6):653-670.
- The Food and Drug Administration. Updates: Skin Patch Replaces Testosterone. FDA Consumer Magazine. Published January/February 1996. http://www.fda.gov/fdac/departs/196_upd.html.
- Hall, SA, Araujo AB, Esche GR, et al. Treatment of symptomatic androgen deficiency: results from the Boston Area Community Survey. Arch Intern Med. 2008;168(10):1070-1076.
- Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241-4247.
- Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(11):5462-5468.
- Dandona P, Dhindsa S, Chaudhuri A, Bhatia V, Topiwala S, Mohanty P. Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. Curr Molec Med. In Press.
- Ohl DA, Quallich SA. Clinical hypogonadism and androgen replacement therapy: an overview. Urol Nurs. 2006;26(4):253-259,269.
- Ebell MH, Siwek J, Weiss BD, et al. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. J Am Board Fam Pract. 2004;17(1):59-67.
- Casaburi R, Bhasin S, Cosentino L, et al. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170(8):870-878.
- Blackman MR, Sorkin JD, Münzer T, et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002;288(18):2282-2292.
- Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab. 2003;88(7):3167-3176.
- Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab. 2003;88(1):358-362.
- Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab. 2002;282(3):E601-E607.
- Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2001;56(5):M266-M272.
- Katznelson L, Robinson MW, Coyle CL, Lee H, Farrell CE. Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men. Eur J Endocrinol. 2006;155(6):867-875.
- Münzer T, Harman SM, Hees P, et al. Effects of GH and/or sex steroid administration on abdominal subcutaneous and visceral fat in healthy aged women and men. J Clin Endocrinol Metab. 2001;86:3604-3610.
- Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab. 2005;90(3):1502-1510.
- Reid IR, Wattie DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated men. Arch Intern Med. 1996;156(11):1173-1177.
- Schroeder ET, Singh A, Bhasin S, et al. Effects of an oral androgen on muscle and metabolism in older, community-dwelling men. Am J Physiol Endocrin Metab. 2003;284(1):E120-E128.
- Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;82(6):1659-1660.
- Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84(8):2647-2653.
- Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab. 2003;88(6):2673-2681.
- Svartberg J, Aasebo U, Hjalmarsen A, Sundsfjord J, Jorde R. Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial. Respir Med. 2004;98(9):906-913.
- Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res. 2008;20(4):378-387.
- Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci. 2003;58(7):618-625.
- Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. Testosterone and Aging: Clinical Research Directions. Institute of Medicine. Washington, DC: National Academies Press, 2003.
- Miner MM, Seftel AD. Testosterone and aging: what have we learned since the Institute of Medicine report and what lies ahead? Int J Clin Pract. 2007;61(4):622-632.
- Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf ). 2005;63(3):280-293.
- Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004;89(2):503-510.
- Christmas C, O'Connor KG, Harman SM, et al. Growth hormone and sex steroid effects on bone metabolism and bone mineral density in healthy aged women and men. J Gerontol A Biol Sci Med Sci. 2002;57(1):M12-M18.
- Hall GM, Larbre JP, Spector TD, Perry LA, DaSilva JA. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Br J Rheumatol. 1996;35(6):568-573.
- Meier C, Liu PY, Ly LP, et al. Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab. 2004;89(6):3033-3041.
- Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999;84(6):1966-1972.
- Tracz MJ, Sideras K, Boloña ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. 2006;91(6):2011-2016.
- Orwoll E, Lambert LC, Marshall LM, et al. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med. 2006;166(19):2124-2131.
- Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male. 2003;6(1):1-7.
- Chung T, Kelleher S, Liu PY, Conway AJ, Kritharides L, Handelsman DJ. Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study. Clin Endocrinol (Oxf). 2007;66(2):235-245.
- English KM, Steeds RP, Jones TH, Diver MJ, Channer KS. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation. 2000;102(6):1906-1911.
- Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154(6):899-906.
- Kenny AM, Prestwood KM, Gruman CA, Fabregas G, Biskup B, Mansoor G. Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2002;57(7):M460-M465.
- Malkin CJ, Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone improves functional capacity and symptoms in men with heart failure. Heart. 2004;90:446-447.
- Mårin P, Holmäng S, Gustafsson C, et al. Androgen treatment of abdominally obese men. Obes Res. 1993;1(4):245-251.
- Mårin P, Holmäng S, Jönsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord. 1992;16(12):991-997.
- Mårin P. Testosterone and regional fat distribution. Obes Res. 1995;3 Suppl 4:609S-612S.
- Simon D, Charles MA, Lahlou N, et al. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care. 2001;24:2149-2151.
- Snyder PJ, Peachey H, Berlin JA, et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med. 2001;111(4):255-260.
- Uyanik BS, Ari Z, Gümüs B, Yigitoglu MR, Arslan T. Beneficial effects of testosterone undecanoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study. Jpn Heart J. 1997;38(1):73-82.
- Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol. 2005;96(12B):67M-72M.
- Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev. 2003;24(2):183-217.
- Anderson RA, Bancroft J, Wu FC. The effects of exogenous testosterone on sexuality and mood of normal men. J Clin Endocrinol Metab. 1992;75(6):1503-1507.
- Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf). 2003;58(5):632-638.
- Benkert O, Witt W, Adam W, Leitz A. Effects of testosterone undecanoate on sexual potency and the hypothalamic-pituitary-gonadal axis of impotent males. Arch Sex Behav. 1979;8(6):471-479.
- Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004;63(4):641-646.
- Kunelius P, Lukkarinen O, Hannuksela ML, Itkonen O, Tapanainen JS. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab. 2002;87(4):1467-1472.
- Park NC, Yan BQ, Chung JM, Lee KM. Oral testosterone undecanoate (Andriol) supplement therapy improves the quality of life for men with testosterone deficiency. Aging Male. 2003;6(2):86-93.
- Schiavi RC, White D, Mandeli J, Levine AC. Effect of testosterone administration on sexual behavior and mood in men with erectile dysfunction. Arch Sex Behav. 1997;26(3):231-241.
- Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol. 2004;172(2):658-663.
- Shabsigh R. Testosterone therapy in erectile dysfunction and hypogonadism. J Sex Med. 2005;2(6):785-792.
- Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82(1):20-28.
- Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf). 2005;63(4):381-394.
- Miner MM, Kuritzky L. Erectile dysfunction: a sentinel marker for cardiovascular disease in primary care. Cleve Clin J Med. 2007;74 Suppl 3:S30-S37.
- Cherrier MM, Asthana S, Plymate S, et al. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001;57(1):80-88.
- Janowsky JS, Chavez B, Orwoll E. Sex steroids modify working memory. J Cogn Neurosci. 2000;12(3):407-4.
- Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci. 1994;108(2):325-332.
- Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S. Effects of testosterone on behavior, depression and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci. 2004;59(1):75-78.
- Kenny AM, Bellantonio S, Gruman CA, Acosta RD, Prestwood KM. Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2002;57(5):M321-M325.
- Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(1):105-111.
- Reddy P, White CM, Dunn AB, Moyna NM, Thompson PD. The effect of testosterone on health-related quality of life in elderly males-a pilot study. J Clin Pharm Ther. 2000;25(6):421-426.
- Seidman SN, Spatz E, Rizzo C, Roose SP. Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial. J Clin Psychiatry. 2001;62(6):406-412.
- Rhoden EL, Morgentaler A. Risks of testosterone replacement therapy and recommendations for monitoring. New Engl J Med. 2004;350(5):482-492.
- Endogenous Hormones, Prostate Cancer Collaborative Group; Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3):170-183.
- Carpenter WR, Robinson WR, Godley PA. Getting over testosterone: postulating a fresh start for etiologic studies of prostate cancer. J Natl Cancer Inst. 2008;100(3):158-159.
- International Society for the Study of the Aging Male (ISSAM). Free and bioavailable testosterone calculator. Ghent, Belgium: University Hospital of Ghent, Belgium. Free & Bioavailable Testosterone calculator
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. http://jcem.endrojournals.org.cgi/reprint/91/6/1995. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
- Wang C, Nieschlag E, Swerdloff RS, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lenenfeld B, Morales A, Morley JE, Schulman C, Thompson I, Weidner W, Wu F. ISA, ISSAM, EAU, EAA, and ASA Recommendations for the Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males. [Published online ahead of print September 4, 2008]. J Androl.
- Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM, and EAU recommendations for the investigation, treatment, and monitoring of late-onset hypogonadism in males: scientific background and rationale. Aging Male. 2005;8(2):59-74.
- Rosen RC. Optimizing testosterone replacement therapy in hypogonadal men. Contemporary Urology. 2007;19(5):30-34.
- Seftel AD, Mack RJ, Secrest AR, Smith TM. Restorative increases in serum testosterone levels are significantly correlated to improvements in sexual functioning. J Androl. 2004;25(6):963-972.
- Amory JK, Page ST, Bremmer WJ. Oral testosterone in oil: pharmacokinetic effects of 5alpha reduction by finasteride or dutasteride and food intake in men. J Androl. 2006;27(1):72-78.
- Saad F, Kamischke A, Yassin A, et al. More than eight years' hands-on experience with the novel long-acting parenteral testosterone undecanoate. Asian J Androl. 2007;9(3):291-217.
- Bagatell CJ. Bremner WJ. Androgen and progestagen effects on plasma lipids. Prog Cardiovasc Dis. 1995;38(3):255-271.
- Yoshida EM, Erb SR, Scudamore CH, Owen DA. Severe cholestasis and jaundice secondary to an esterifi ed testosterone, a non-C17 alkylated anabolic steroid. J Clin Gastroenterol. 1994;18(3):268-270.
- Harman SM. Testosterone in older men after the Institute of Medicine Report: where do we go from here? Climateric. 2005;8(2):124-135.
- Liverman CT, Blazer DG, eds. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press, 2004.
- Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9):1239-1242.
