The prevalence of testosteronedeficiency is reported to be40%–60% among men ondialysis. Although there isinsufficient information regarding theprevalence of testosterone deficiencyin men with non-dialysis dependentchronic kidney disease (CKD), it appearsto increase as renal function declines. Testosterone deficiency is associatedwith higher levels of inflammatory markers(interleukin-6, C-reactive protein)and also with all-cause and cardiovascular(CV)-related mortality amongpatients with end-stage renal disease. With this in mind, consensus on thediagnosis and management of testosteronedeficiency in CKD patients remainsimportant and is still evolving.
Most testosterone in the circulation isbound to sex hormone-binding globulin(SHBG) or to albumin, with approximately0.5%–3% present as free testosterone,the biologically active hormone.Under most circumstances, measuringtotal testosterone is adequate for diagnosingtestosterone deficiency. Total testosterone,however, can provide inaccurateestimates of bioactive testosterone in situationswhere SHBG values are altered,including several that are common amongpatients with CKD. Specifically, SHBGconcentration may be low in patients withobesity, diabetes, and nephrotic syndromeand may be high in older patients. TheEndocrine Society suggests measuringfree testosterone levels in some men wheretotal testosterone concentrations are nearthe lower limit of normal but alterationsof SHBG are suspected.
The diagnosis of hypogonadism is usuallybased on at least 2 consecutivemorning (when levels are highest) lowserum testosterone levels in conjunctionwith clinical symptoms.3 Because serumtestosterone concentrations decline withage, some argue that the reference rangeshould be age-specific. For example,consider 2 studies that measure testosteronein young and elderly men.Bhasin et al. found the 2.5th percentileof total testosterone to be 348.3 ng/dL ina sample of young men compared with184 ng/dL for a sample of elderly menstudied by Yeap et al.5 Therefore, usingthe standard reference range could leadto over diagnosis in the elderly populationif symptoms are not considered aspart of the diagnosis.
The diagnosis of hypogonadism is challengingbecause the signs and symptomsare non-specific and can vary basedon age and comorbidities. Commonsymptoms that should be clearly definedinclude decreased libido, or the lack ofsexual desire, and erectile dysfunction,the inability to acquire or maintain anerection needed for sexual intercourse.Other relatively specific signs includegynecomastia, loss of body hair, shrinkingof testes, low sperm count, low bonemineral density, and hot flushes. Lessspecific symptoms include decreasedenergy, motivation, self confidence,depressed mood, poor concentrationand memory, sleep disturbances, anemia,reduced muscle mass and strength,increased body fat and body mass index,and decreased physical performance.Therefore, a thorough history and physicalexamination should be performedto assess for these signs and symptoms.
Clinical observations have suggested thatlow testosterone levels may have severaladverse consequences, but the effectof testosterone replacement remainsunclear. Trials have been limited by smallsample size, different inclusion criteria,and variable testosterone regimens.There are even fewer data for the CKDpopulation, so extrapolation from thegeneral population is often necessary.
In the general population, a meta-analysisof 17 randomized controlled trialsof testosterone replacement with 862participants showed moderate improvementsin libido with only a small effecton erectile dysfunction.6 In addition,2 small studies that evaluated effectsof testosterone on sexual function inESRD patients found that most patientsexperienced improvement in but notnormalization of sexual function.
Although not specifically aimed atpatients with hypogonadism, there havebeen a few trials evaluating the effectsof androgen therapy on physical functionin patients with ESRD. In 1 study,researchers showed that administrationof nandrolone deconate, a synthetic testosteronederivative, improved physicalperformance and increased lean bodymass.9 In addition, studies of testosteronereplacement among elderly menhave generally shown improvement inthe lean body mass, strength and physicalfunction.
Bone mineral density
Studies of the effects of testosterone onoutcomes related to bone mineral densityin patients with CKD are also limited,but some data are available in the generalelderly population. Although results ofthese studies are mixed, improvementsare more pronounced for patients withlower pre-treatment testosterone levels. Given that the causes of bonedisease in patients with CKD are multifactorial,with secondary hyperparathyroidismas a major underlying mechanism, itmay not be reasonable to generalize fromthe general elderly population to the CKDpopulation.
Treatment with testosterone has knownside effects, which include acne, malepattern baldness, gynecomastia, as wellas more serious side effects, such asworsening sleep apnea, adverse CV outcomes,and accelerated growth of prostatecancer. With regard to CV outcomes, ina meta-analysis of 51 clinical trials, testosteronetreatment was not associatedwith higher CV risk.14 Other evidencehas been more concerning, however. Arandomized controlled trial evaluatingtestosterone treatment in elderly men withmobility limitations and chronic diseasewas halted due to adverse CV events inthe testosterone group.
In addition, 2retrospective studies showed a higher riskof myocardial infarction (MI) in patientstreated with testosterone, although theabsolute risks were low.16,17 These retrospectivestudies were limited by the lackof available data on total testosteroneconcentrations and the indications for,and doses of, testosterone treatment. Asyet, the FDA has not concluded that testosteronetherapy increases the risk of MIor mortality; however, it warns cliniciansto be aware of the concerns while investigationsare underway.
Given the possible risk, especially amongCKD patients who are already at highrisk of cardiovascular disease, low testosteronelevels should not be routinelytreated among patients with CKD.However, treatment can be consideredon an individual basis in symptomaticpatients with poor physical function,fracture risk, and documented low testosteronelevels. Patients receiving testosteronereplacement therapy shouldbe reassessed frequently, and therapyshould be discontinued if benefit is notobserved after a 3- to 6-month trial.