PLoS One. 2016; 11(9): e0162480.
Published online 2016 Sep 21. doi: 10.1371/journal.pone.0162480
PMCID: PMC5031462
Samantha Huo,1 Anthony R. Scialli,2,3 Sean McGarvey,2 Elizabeth Hill,2 Buğra Tügertimur,4 Alycia Hogenmiller,2 Alessandra I. Hirsch,5 and Adriane Fugh-Berman2,*
Johnson Rajasingh, Editor
Abstract
Testosterone products are recommended by some prescribers in response to a diagnosis or presumption of “low testosterone” (low-T) for cardiovascular health, sexual function, muscle weakness or wasting, mood and behavior, and cognition. We performed a systematic review of 156 eligible randomized controlled trials in which testosterone was compared to placebo for one or more of these conditions. We included studies in bibliographic databases between January 1, 1950 and April 9, 2016, and excluded studies involving bodybuilding, contraceptive effectiveness, or treatment of any condition in women or children. Studies with multiple relevant endpoints were included in all relevant tables. Testosterone supplementation did not show consistent benefit for cardiovascular risk, sexual function, mood and behavior, or cognition. Studies that examined clinical cardiovascular endpoints have not favored testosterone therapy over placebo. Testosterone is ineffective in treating erectile dysfunction and controlled trials did not show a consistent effect on libido. Testosterone supplementation consistently increased muscle strength but did not have beneficial effects on physical function. Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. The prescription of testosterone supplementation for low-T for cardiovascular health, sexual function, physical function, mood, or cognitive function is without support from randomized clinical trials.
1. Introduction
Testosterone and methyltestosterone are marketed in the United States for men with congenital or acquired hypogonadism. Some practitioners have used testosterone preparations to treat a variety of symptoms identified as those of “low testosterone” (low-T), a term that has not been uniformly defined. We present a systematic review of randomized controlled trials (RCTs) that evaluated the use of testosterone therapy against placebo or inactive comparator in adult men for cardiovascular health, sexual function, muscle weakness/wasting, mood and behavior, or cognition. We did not include studies of testosterone in men with missing or damaged testicles, or who had Klinefelter syndrome or other genetic anomalies. We did not include studies on the use of testosterone for any indication in women or in children, the use of androgens in contraception, or the use of androgens for bodybuilding or athletic performance.
2. Methods
2.1 Data Search, Synthesis and Analysis
Computerized literature searches were conducted in PubMed, Embase, and APA PsycNET. Searches were limited to human males but were not restricted by language or date. The PubMed search was conducted using the MeSH term “testosterone” and the modifiers “administration and dosage,” “adverse effects,” “deficiency,” “standards,” “therapeutic use,” or “therapy.” The original PubMed search was conducted for studies published between January 1, 1950 and November 26, 2013. The Embase search was conducted using the Emtree key term “testosterone,” modified by “adverse drug reaction,” “androgen deficiency,” “therapy,” “drug dose,” or “clinical trial.” The original Embase search was conducted for studies published between January 1, 1974 and November 26, 2013. The PsycNET search was conducted using the term “testosterone” modified by “addiction,” “drug dependency,” “therapy,” “treatment,” or “deficiency.” The original PsycNET search was conducted for studies published between January 1, 1806 and November 26, 2013. All searches were repeated on April 9, 2016 to identify clinical trials that had been published since the initial search, so the final search included more than four decades of trials from all databases.
2.2 Study Selection
Search results were combined using EndNote and duplicates were deleted. These results were filtered using the key term “clinical trial.” Titles and abstracts were reviewed to identify RCTs and eliminate irrelevant studies. Relevant studies were retrieved.
2.3 Data Extraction
Data were extracted into tables by 4 independent reviewers according to the presence of information on cardiovascular health, sexual function, muscle weakness/wasting, mood and behavior, or cognition. Studies with multiple relevant endpoints were included in all relevant tables. Review articles were identified and retrieved, and their reference lists were searched for primary publications of RCTs.
Some studies that included randomized controlled designs also included open-label continuation phases. We evaluated and summarized the randomized controlled portions of these studies. Although our primary interest was the use of testosterone for the treatment of hypogonadism, however defined by study authors, we included trials of testosterone in eugonadal men. In some studies, eugonadal subjects were randomized to receive testosterone or a comparator (usually placebo), and hypogonadal subjects were treated with testosterone only. We evaluated and summarized only the randomized portions of these studies.
2.4 Quality Assessment
We assessed quality of studies by a 5-point Jadad score. In order to be as inclusive as possible, we included all studies identified regardless of Jadad score. For clinical endpoints only (angina/ischemia, congestive heart failure, and erectile dysfunction) we also included an analysis of studies restricted to Jadad scores of 4 or 5. We accepted whatever criteria were used by individual study authors to define low testosterone.
3. Results
Fig 1 lists the exclusion criteria used to select 226 qualifying papers from 11,417 reviewed abstracts. Although most studies were described by their authors as randomized, not all indicated the nature of the randomization procedures. Some studies included identical numbers of subjects in treatment and exposed conditions, suggesting that allocation was not random. After further examination, 70 papers did not meet our criteria, so the final data set included 156 papers.
3.1 Cardiovascular Health
Table 1 summarizes extracted studies that focused on the effect of testosterone on cardiovascular endpoints, including 17 studies on ischemia/angina, 6 on congestive heart failure (CHF), 25 on lipids, and 11 on inflammatory and coagulation markers.
3.1.1 Coronary artery disease
In studies that investigated the effect of testosterone on patients with coronary artery disease (CAD), eligible men generally were identified based on stable angina, angiographic evidence of some degree of coronary artery occlusion, or a history of myocardial infarction (MI). Six studies involved men in whom the study authors reported evidence of hypogonadism either clinically [1] or based on plasma testosterone concentration [2–6]; the remainder included men without regard to plasma testosterone concentration. All but three of the studies evaluated ST-segment depression on an exercise stress test using a modification of the Bruce protocol. One of the studies not using the Bruce protocol evaluated findings on electrocardiography (ECG) and Holter monitoring, without specification of an exercise protocol.[7] Another study added single-photon emission computer tomography (SPECT) to evaluate for deficits in myocardial uptake of a labeled perfusion tracer.[8] One study used magnetic resonance imaging (MRI) estimates of myocardial perfusion.[3] One study evaluated change in coronary artery calcium score over time, showing no difference between testosterone and placebo.[6]
Two studies evaluated brachial artery response to release of occlusion as an indicator of sensitivity to local vasodilators in men with CAD and did not directly address the coronary arteries; both reported results favorable to testosterone therapy.[9, 10] Two studies in apparently healthy men with bioavailable testosterone <4.44 nM (128 ng/dL) or total testosterone ≤15 nM (432 ng/dL) found no change in brachial artery reactivity in response to transdermal testosterone or dihydrotestosterone therapy.[5, 11] The study that used MRI showed no effect of 8 weeks of oral testosterone undecanoate therapy on myocardial perfusion, although there was increased perfusion of those segments supplied by an unobstructed coronary artery.[3]
Three studies used acute treatments with intravenous (IV) testosterone just prior to exercise testing. Two of the studies showed favorable effects of treatment on time to ST-segment depression.[2, 12] One study showed no effect on ECG or SPECT evidence of ischemia.[8] A year-long study showed benefits of testosterone treatment on ST-segment depression.[4] The remaining eight studies evaluated treatments of 2 to 24 weeks in duration.[1, 3, 10, 11, 13–17] The 3 studies that looked at time to ST-segment depression found a benefit of testosterone supplementation.[1, 14, 16]
Although 2 studies reported improvements in angina symptoms during or after testosterone treatment,[7, 15] 4 studies showed no effect of treatment on angina.[1, 4, 8, 16] Most studies did not report any measure of angina symptoms. A study on men with leg claudication or trophic ulcers attributed to arteriosclerosis did not show an improvement in subjective symptoms, walking, or plethysmographic estimation of blood flow endpoints after 3 months of testosterone therapy.[13]
There was a decreased incidence of silent MI with testosterone treatment in 1 study.[15] Another study, designed to determine the effect of testosterone supplementation on lower-extremity strength and physical function in men 65 years of age and older, was stopped early by a Data and Safety Monitoring Board due to an excess of cardiovascular adverse events.[17] These adverse events included acute coronary syndrome (ACS), MI, ECG abnormalities, and arrhythmias, among others.
Eleven studies of coronary artery disease scored 4 or 5 on the Jadad scale. Of these, only one of five studies that included angina as an outcome found a benefit. Four of five studies that assessed ST segment depression found a benefit.
3.1.2 Congestive heart failure
Six studies evaluated effects of testosterone treatment on CHF.[18–23] In two papers from the same group,[19, 20] it is not clear whether treatments were randomly assigned. Administration of testosterone by the buccal route was associated with beneficial effects on cardiac index and systemic vascular index in the acute catheterization setting, consistent with an acute vasodilatory effect.[19] Intramuscular (IM) testosterone treatment for 12 weeks improved exercise capacity and reduced heart failure symptom scores without identifiable effects on left ventricular size or ejection fraction (EF).[20] Another study of IM testosterone in men with CHF showed an improvement in oxygen consumption, respiratory efficiency (ventilation/carbon dioxide consumption), and distance walked in 10 minutes without changes in EF or left ventricular end-diastolic diameter.[18] The improvements in exercise function appeared attributable to the response of men with baseline plasma testosterone concentration <12 ng/mL (~4 nM). A study of a testosterone patch showed improvement in the shuttle walk test.[23] Another study showed no effect of IM testosterone enanthate on ejection fraction, although there was an improvement in a Doppler-based myocardial performance index.[22]
The only study that scored above a 3 on Jadad found a benefit on CHF measures.[18]
3.1.3 Lipids
Serum or plasma concentrations of cholesterol fractions, triglycerides, and lipoproteins have been used as surrogate endpoints for cardiovascular risk, although they should not be mistaken for markers of cardiovascular adverse events. In 25 studies, testosterone treatment was associated with favorable, unfavorable, or no effects on lipids as summarized in Table 1. Favorable effects in 11 studies included 5–11% decreases in total cholesterol concentration and variable and inconsistent decreases in triglycerides and low-density lipoprotein (LDL) cholesterol. One of the studies counted as showing a favorable effect did not demonstrate a change in total or high-density lipoprotein (HDL) cholesterol or triglycerides but reported a 13% reduction in LDL cholesterol.[24] This finding was based on averages of several repeated measurements over the course of 1 year rather than a determination of improved lipid measurements at the end of the treatment period.
Unfavorable changes were reported in 2 studies [5, 25] and included increases in total cholesterol, LDL cholesterol, and triglycerides and decreases in HDL cholesterol in men evaluated as hypogonadal prior to androgen therapy. Most of the studies that did not report favorable effects of testosterone on lipids reported no effects at all. One of these studies[26] reported a decrease in lipoprotein-a (LP-a), but this finding was transient and occurred in a study with multiple measurements at multiple time points in multiple patient subgroups without adjustment for multiple comparisons. Nine of the 11 studies that had favorable effects on lipids had Jadad scores of 4 or 5. Nine of the 14 studies that lacked favorable effects on lipids had Jadad scores of 4 or 5.
The discordance between studies on the lipid effects of testosterone treatment did not appear to be route dependent. Seven of the 11 studies showing favorable effects used IM injection of testosterone enanthate, esters, or undecanoate. Five of the 14 studies not showing favorable effects on lipids used IM injection of testosterone esters, cypionate, or undecanoate.
3.1.4 Inflammatory or coagulation markers
Eleven studies were identified in which markers that have been associated with atherosclerotic cardiovascular disease risk were measured in men using testosterone or dihydrotestosterone therapy. Three studies reported favorable effects of testosterone on tumor necrosis factor-α (TNF-α), a marker of inflammation.[1, 3, 27] One study in men with CHF showed no effect of testosterone treatment by buccal, IM, or transdermal routes on serum concentration of TNF-α.[21] One of the studies asserted that there was a decrease in the inflammatory marker interleukin-1β (IL-1β), but a statistically significant effect was not shown.[1] Another study showed a decrease in interleukin-6 (IL-6) and C-reactive protein, additional inflammatory markers.[28] Two studies performed in elderly men who were largely without a diagnosis of CAD showed no beneficial effect of testosterone therapy on C-reactive protein[29, 30] as did two studies of men with type 2 diabetes mellitus.[31, 32] Transdermal dihydrotestosterone did not affect inflammatory markers in men with low total pretreatment testosterone concentrations.[33] No change in fibrinogen, plasminogen activator inhibitor-1, or tissue plasminogen activator was shown in men with CAD who used testosterone patches or oral doses.[3, 34]
3.2 Sexual Function
The 48 studies that assessed sexual function or libido as a primary or secondary endpoint are summarized in Table 2. Study populations included men identified by study authors as “hypogonadal,” normal men, and men with erectile dysfunction (ED). Studies included men with depression,[35–37] chronic renal disease,[38] cirrhosis,[39] arterial insufficiency,[40] cancer,[24] diabetes,[26] HIV,[35, 41] Alzheimer disease,[42] and chronic obstructive pulmonary disease (COPD).[43] Preparations included IM (n = 16), oral (n = 11), topical gel or solution (n = 14), patch (n = 5), and buccal (n = 1) formulations. Studies used a variety of questionnaires, including the International Index of Erectile Function (IIEF), Frenken sexual experience scales, Derogatis Sexual Performance Scale (DSPS), the Aging Males’ Symptoms (AMS) scale, Male Sexual Health Questionnaire, Psychosexual Daily Questionnaire, and study-specific questionnaires. Study reports used different language for symptoms, so we grouped, for example, “libido,” “sexual interest,” and “sexual desire.”
Of 47 studies that assessed sexual function or satisfaction, 23 studies reported beneficial effects of testosterone treatment for at least 1 measure of sexual function or satisfaction,[6, 26, 35, 37, 40, 43–60] and 24 studies did not show testosterone-associated improvements in any sexual function endpoint.[24, 36, 38, 39, 41, 42, 61–78] Three studies we counted as positive were mixed: Steidle et al found improvement with 100 but not 40 mg of gel, Legros et al[57] tested 3 dose levels of orally administered testosterone undecanoate (60 mg, 160 mg, and 240 mg) and found a benefit only for the middle dose, and Hackett et al[58] found that testosterone worked in a group with testosterone ≤8.0 nM for intercourse satisfaction but not in a group with testosterone 8.1–12 nM. One study “reported a subjective feeling of increased muscular energy and sexual desire in some subjects”.[79] There was no difference between groups by Fischer exact test (performed by us) and we excluded this study from further analysis. Limiting analysis to the 30 studies with Jadad scores of 4 or 5 yielded similar results; 14 were positive and 16 negative.
Of 31 studies that evaluated erectile function, 15 found no improvement with testosterone therapy,[6, 26, 39, 41, 55, 59, 62, 64, 65, 68, 70–72, 76, 77] and 16 reported a benefit.[35, 37, 43–52, 56, 58, 60] Although the study by Chiang et al[50] reported a benefit of both testosterone and placebo compared to baseline; however, our analysis did not show a difference between treatment groups. Limiting analysis to the 17 studies with Jadad scores of 4 or 5 yielded similar results; 9 were positive and 8 were negative.
Twelve studies included men with ED; 8 found no benefit of testosterone over placebo,[55, 59, 62, 64, 68, 72, 74, 76] and 4 found a benefit.[35, 46, 47, 49] One negative study found that testosterone reduced erectile function when compared to placebo; however, there was no change when each group was compared to its baseline.[76]
Of 23 studies that specifically reported changes in libido, 13 found that testosterone treatment increased libido,[26, 35, 37, 45, 46, 54, 56, 60, 63, 65, 70, 77, 79] eight found no effect,[24, 38, 39, 47, 59, 67, 75, 76] and 1 found an effect after 3 but not 6 months of treatment.[48] Hackett et al[58] found that testosterone improved sexual desire in a group with initial testosterone ≤8.0 nM but not in a group with initial testosterone 8.1–12 nM.
Eleven studies used the Aging Males’ Symptoms scale, which includes 3 questions on libido and sexual function. Five studies found no difference between testosterone and placebo on total scores,[26, 54, 57, 72, 76] and 4 studies found a benefit of testosterone.[52, 57, 58, 66] One paper[53] reported only sexual subscales but not total AMS scores. On the sexual subscale of the AMS scale, this study reported a benefit, Ho et al[73] found no benefit, and Legros et al[57] found a benefit of testosterone on the AMS sexual subscale only in the middle (160 mg) of 3 dose levels at 3 of 4 time points. Hackett et al[58] found that testosterone improved AMS scores in a group with initial testosterone ≤8.0 nM but not in a group with initial testosterone 8.1–12 nM.
Ten of 13 of the studies on libido or desire with a Jadad score of 4 or 5 found a benefit. Seven of 12 studies on erectile dysfunction with a Jadad score of 4 or 5 found a benefit.
3.3 Muscle Weakness/Wasting
Table 3 summarizes 39 studies that evaluated the effect of testosterone on physical function, muscle strength, or HIV-associated muscle wasting, including 19 in men assessed as having low serum testosterone, 9 on HIV-negative men with normal serum testosterone, 1 on healthy men with normal serum testosterone, and 10 on HIV-positive men. Studies that measured testosterone effects only on body composition (other than in HIV-associated wasting) without measures of physical function or muscle strength were excluded. Subjects included both those defined by the authors as hypogonadal and those considered to have normal testosterone concentrations. Common measures of muscle strength included grip strength dynamometry and the 1-repetition maximum for exercises including the bench press and leg press. Physical function was often measured by the 6-minute walk test, the time and number of steps required to walk 25 feet, and the get-up-and-go test, which evaluates the ability to rise from a chair, walk a short distance, and return to sitting.
Twenty studies evaluated subjects described as hypogonadal, with 11 of those evaluating healthy subjects. Five studies examined the effects of testosterone supplementation on physical frailty, functional limitations, or a categorization as “sedentary,”[53, 80–83] and single studies evaluated subjects with COPD,[84] advanced cancer,[75] and Parkinson’s disease.[85] Ten studies evaluated subjects considered to have normal testosterone concentrations; 1 study included healthy, elderly men, and the remainder included subjects with planned knee replacement surgery,[86] stable CHF,[18, 22, 87] leg claudication or ulcers,[13] long-term glucocorticoid therapy,[88] myotonic dystrophy,[89] arterial insufficiency,[40] COPD,[43] or who were planning or undergoing physical rehabilitation.[90]
Ten studies evaluated subjects with HIV; 8 of those studies included subjects with HIV-wasting, 1 included subjects with abdominal obesity, and 1 did not use weight criteria. Most of these papers studied older men. Few studies investigated the use of testosterone supplementation in men younger than 60 years.
Twenty-seven studies measured the effects of testosterone treatment on muscle mass, with 22 (81%) of these studies showing a significant increase in muscle mass associated with treatment.[41, 43, 53, 80–84, 88, 89, 91–102] Nineteen of 22 (86.3%) of these studies had a Jadad score of 4 or 5. Twenty-five studies assessed the effects of testosterone treatment on fat mass, with 15 (60%) of these studies showing a decrease in fat mass associated with treatment.[11, 43, 53, 81, 83, 84, 88, 91, 93, 94, 96, 97, 99, 102, 103] Twelve of these studies had a Jadad score of 4 or 5.
Some studies did not measure muscle and fat mass specifically but used other body composition endpoints. Two studies showed no changes in body weight or BMI,[22, 104] but another showed an increase in body weight and BMI.[18] One study, with a Jadad score of 3, showed no change in weight or estimates of body fat (triceps and scapula skinfold thickness).[105] In studies of HIV-positive men with weight loss, 3 of 6 studies (all of which had Jadad scores of 4 or 5) showed an increase in weight with testosterone treatment,[99, 101, 106] and all 4 studies that measured muscle mass showed an increase.[41, 99–101]
Of the 30 studies that assessed muscle strength as a primary or secondary endpoint, 13 studies (43%) reported an improvement in at least 1 measure of muscle strength.[11, 18, 53, 81, 83, 84, 88, 93, 94, 101, 102, 104, 107] Eleven of 13 of these studies had a Jadad score of 4 or 5. Three of these 12 studies (all with Jadad scores of 4 or 5) reported improvements in fewer than 25% of the measurements.[11, 53, 81] In studies of men without HIV, 11 of 24 studies (45.8%) reported an improvement in at least 1 measure of muscle strength. In studies of men with HIV, 2[101, 107] of 5 studies reported an improvement in at least 1 measure of muscle strength; 3 showed no effect.[41, 99, 103]
Twenty-four studies evaluated the effects of testosterone treatment on physical function endpoints and, of these, 5 found an improvement in at least 1 measure of function.[18, 22, 81, 83, 86] Neither of the 2 studies of HIV patients measuring physical function showed an improvement in function.[41, 100] Six of these studies had a Jadad score of 4 or 5.[18, 41, 81, 83, 86, 100]
In summary, the majority of studies show increased muscle mass but no effect of testosterone on muscle strength or function.
3.4 Mood and Behavior
Forty-five studies evaluating the effect of testosterone on mood and behavior are summarized in Table 4. Twenty-nine of these studies focused on men without psychiatric disorders, and 16 on men with psychiatric disorders.
3.4.1 Healthy men
Some studies of mood and behavior were designed to evaluate the potential adverse effects of anabolic steroid abuse. For example, men abusing anabolic steroids have been described as having “Roid Rage.” We did not evaluate steroid abuse studies, but we reviewed studies on testosterone preparations and their association with anger, aggression, and other mood alterations. There was little consistency among the studies we reviewed.
Five studies reported treatment-associated increases in anger, aggression, or hostility.[67, 108–111] Only two of these studies had a Jadad score of 4 or 5.[108, 111] One study,[110] with a Jadad score of 3, determined that testosterone gel applied to the skin increased hostility based on evaluations by 2 undergraduate judges of a free-text paragraph written by each subject to describe his mood at the end of treatment. We do not know the reliability of this assessment. Two studies (Jadad score 3 and 5) reported a decrease in anxiety after testosterone treatment.[45, 112]
Seventeen of 29 studies reported no effect of testosterone treatment on personality, psychological well-being, or mood.[22, 24, 38, 59, 63, 85, 104, 113–121] Seven of 17 studies had a Jadad score of 4 or 5. One of these studies could not be evaluated because only a composite score for mood and sexual function was reported.[38] The study that used hostility assessments by undergraduate judges found no change in personality as assessed by the Gough and Heilbrun Adjective Check List.[110] Another study in this group reported that elevation of testosterone serum concentrations above normal using testosterone gel was associated with an increase in selfishness on a computer game that evaluated the willingness to give away small amounts of money.[122] Two additional studies from the same group in non-depressed men with CHF did not show an effect of testosterone on the Beck Depression Inventory (BDI),[20, 27] although the earlier of these studies concluded otherwise based on a finding that was not statistically significant. A study in non-depressed men with metabolic syndrome reported an improvement in the BDI in testosterone-treated compared to placebo-treated subjects.[52] A study found non-depressed men older than 60 years to have a mean 5% decrease in a geriatric depression scale when administered testosterone.[102] This study had a Jadad score of 1. Another study [58] found that testosterone treatment had no effect on the Hospital Anxiety Depression score (HADS) in men with testosterone ≤8.0 nM but improved the depression subset of the HADS in men with testosterone of 8.1–12 nM. Malkin et al.[1] found that 100 mg testosterone every 2 weeks improved the BDI score. This study had a Jadad score of 5.
3.4.2 Men with psychiatric diagnoses
Twelve studies (3 in HIV-positive men) evaluated testosterone supplementation in men with a diagnosis of depression or dysthymia (sometimes also called, “minor depression”), 1 study evaluated the use of testosterone in men with schizophrenia, and 2 studies were conducted in men with Alzheimer disease or cognitive impairment. The study in schizophrenic men used testosterone or placebo gel in addition to whatever treatment the subject was already using.[123] There were improvements in the negative symptom scores on a standardized scale but no change in the Calgary Depression Scale for Schizophrenia. The authors used an intention-to-treat (ITT) analysis and implied that better results were seen among subjects who completed the study; however, there were no significant differences in the depression scores between testosterone and placebo among completers. Two studies in men with cognitive impairment or Alzheimer disease (Jadad score 3) found no effect of treatment on neuropsychiatric symptoms, depression, behavior, or quality of life (QoL).[42, 124] Caregiver-assessed QoL was improved in 1 of these studies.[42]
The response of depression and dysthymia to testosterone was mixed and inconsistent. Among HIV-negative men, four studies (all with a Jadad score of 4 or 5) showed testosterone-associated improvements in standard scoring systems for depression and/or in the proportion of subjects who achieved remission of their psychiatric disorder.[37, 51, 125, 126] Four other studies (2 with a Jadad score of 4 or 5) showed no improvement in depression or dysthymia with testosterone compared to placebo.[36, 111, 127, 128] One study (Jadad score 4) showed a transient improvement in depression and melancholia after 3 months of treatment that was no longer apparent after 6 months of treatment.[48]
Because it has been noted that HIV-positive men can be depressed and “hypogonadal,” 3 studies administered testosterone to HIV-positive men with depression or dysthymia.[35, 129, 130] Two of the studies had a Jadad score of 4[35, 130] and one study had a Jadad score of 3.[129] Testosterone treatment had inconsistent effects on measures of depression; one study showed a 5.8-point improvement in the Beck Depression Inventory (BDI) in men with HIV-associated wasting, although the improvement may have been explained by an increase in weight.[129] Another study showed a testosterone-associated improvement in HIV-positive men overall in the Clinical Global Impression (CGI) scale but not among subjects with a depression diagnosis.[35] This study also showed improvement in the total and vegetative symptom scores of the Hamilton Rating Scale for Depression (HAM-D) but not in the affective scale, and there was no significant change in BDI scores. A subsequent, larger study by the same group showed no difference in response of depression measured by HAM-D or BDI in men given testosterone compared to placebo.[130]
Authors attributed the mixed responses in the literature to the considerable placebo response in most studies and to the possibility of an idiosyncratic response to testosterone, with putative subgroups of responders who were difficult to identify a priori.[111, 127] The studies, however, did not show consistent responses in subgroups of men who had low serum testosterone concentrations, depression resistant to standard therapy, or men characterized as middle-aged or elderly. In studies in which serum testosterone concentrations were measured on therapy (both with a Jadad score of 5), response of depression or dysthymia was not consistently associated with serum hormone concentration.
3.5 Cognition
Twenty-two studies evaluating the effects of testosterone on cognition are summarized in Table 5. Seventeen focused on men without cognitive impairment and 4 focused on men with cognitive impairment.
3.5.1 Men described as normal
Ten studies evaluated the effects of testosterone treatment on cognitive endpoints in healthy men. Spatial cognition/memory was reported to be improved with testosterone supplementation in 3 studies,[114, 131, 132] unchanged in 2 studies,[42, 133] and poorer with supplementation in 1 study.[134] Although 1 study reported improved working memory[135] and 1 study found improved verbal fluency,[134] most other studies found no improvement in verbal fluency, memory, or other cognitive endpoints in healthy men given testosterone.[42, 91, 120, 131, 133, 134, 136] Two of 5 studies that showed improvement and 4 of 7 of the studies that showed no improvement had a Jadad score of 4 or 5.
3.5.2 men described as hypogonadal
Hypogonadal men, variously defined, were found in 1 study to have better verbal learning and reversal of digits on number sequencing with testosterone supplementation,[112] but no effect on the same domain was found in another study.[137] The study showing an advantage used injected testosterone enanthate 200 mg while the negative study used a daily 5 mg patch. Another injection study found no effect of supplementation on memory in hypogonadal men.[104] One study reported a possible disadvantage of treatment with dihydrotestosterone compared to placebo in performance on the Modified Mini-Mental State Examination (MMSE),[11] but data were not shown and the putative difference could not be evaluated. Another study showed no improvement in visuospatial cognition or MMSE with testosterone treatment for 12 months.[119] All studies had Jadad scores of 4 or 5.
3.5.3 Men with cognitive impairment
Treatment of men with suspected or diagnosed Alzheimer disease or cognitive impairment was reported in five studies, two of which had a Jadad score above 3. Although 1 injection study found an improvement on the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-COG),[138] another study using testosterone gel found no effect on the same instrument or on other cognitive function tests.[42] Spatial and verbal memory were improved after 6 weekly injections of testosterone enanthate in 1 study, but the effect did not persist during a 6-week washout period without treatment.[132] A fourth study found no effect of testosterone injections on behavior, activities of daily living (ADLs), or cognition.[124] The fifth study found that transdermal testosterone gel was not associated with statistically significant changes in measures of cognition, mood, or quality of life.[139]
3.5.4 Proposed explanations for inconsistent results
Because study results have been varied and inconsistent, some authors have proposed that testosterone is not the only factor or even the most important factor in cognitive function. Janowsky et al[114] found improved spatial cognition in men treated with scrotal testosterone patches, but there was an imbalance between placebo and testosterone groups in baseline blood concentrations of 17β-estradiol, which these authors attributed to chance. The effect of testosterone and 17β-estradiol on spatial cognition testing was explored using post-hoc testing, and the putative testosterone effect on spatial cognition appeared to be associated with suppression of 17β-estradiol by testosterone supplementation rather than a direct effect of testosterone. This study had a Jadad score of 3.
Most authors with an interest in 17β-estradiol have suggested that the effectiveness of testosterone, when it has shown effectiveness, is due to aromatization to 17β-estradiol. Cherrier et al[131] measured testosterone and 17β-estradiol concentrations after injection of testosterone supplements in healthy men and reported that both testosterone and 17β-estradiol concentrations were associated with recall of a test story, but only 17β-estradiol concentrations were associated with performance on the Stroop test. In another study, Cherrier et al reported that only men with an increase in 17β-estradiol concentration after testosterone supplementation showed improvements in verbal memory testing.[136] This study used administration of the aromatase inhibitor anastrozole to differentiate between effects attributable to testosterone and those that might be due to 17β-estradiol. Another study without anastrozole found 17β-estradiol serum concentrations after testosterone therapy to be a significant predictor of performance on verbal memory testing.[140] All three studies had a Jadad score of 5.
It has also been suggested that testosterone supplementation has produced inconsistent results in cognitive function studies because the blood concentrations achieved by supplementation need to be in an optimum range for effectiveness. Under this hypothesis, over-supplementation is as ineffective as under-supplementation. Cherrier et al[140] administered testosterone enanthate IM at 0, 50, 100, or 300 mg weekly and administered tests of verbal and spatial memory. Results were not reported according to treatment group; rather, subjects were divided into those with no, moderate, or large increases in serum testosterone concentrations over baseline. These response categories were defined based on 1 standard deviation above the control response and 1 standard deviation above the response to 100 mg. Subjects with a moderate increase in serum testosterone concentration over baseline (defined as 11–50 nM) performed better on cognitive testing than those with “no increase” (0–10 nM) or a large increase (>51 nM). Seventeen of the 22 men in this moderate-increase group had received testosterone 100 mg/week with the balance evenly divided between the 50 mg and 300 mg doses. The authors explained that they did not use tertiles or quartiles, because using quartiles or tertiles resulted in some placebo patients with significant changes from baseline, raising the question of whether men on placebo with an increase in their serum testosterone concentration were distinguishable on cognitive testing from men who received testosterone supplementation. This study had a Jadad score of 5.
In summary, there is no support for the use of testosterone to enhance cognition in normal or cognitively impaired men.
4. Discussion
This systematic review examined published RCTs of testosterone supplementation for cardiovascular disease or surrogates of cardiovascular disease, sexual function, muscle strength, mood, and cognition. The review was limited to published studies in English and to trials indexed before April 9, 2016. The evidence supporting the use of testosterone for preventing or treating cardiovascular disease is inconsistent and, on balance, unconvincing. Some evidence supported an acute and chronic effect of testosterone therapy on increasing time to ST-segment depression, and there is evidence of improvement in some measures of congestive heart failure. Most studies showed no effect of testosterone therapy on inflammatory markers, and the effects on lipids were inconsistent.
Studies that examined clinical effects have not favored testosterone therapy over placebo. Two of 3 studies that assessed angina showed no effect. Three studies from the same group found a benefit for symptoms associated with CHF. One study was stopped early for cardiovascular adverse effects.
Testosterone supplementation did not demonstrate consistent effectiveness for improving sexual function or satisfaction. Testosterone is ineffective in treating ED. Controlled trials were mixed on libido, with more positive than negative studies.
Substantial evidence supports a favorable effect of testosterone treatment on muscle mass in both healthy men and men with HIV, and a majority of studies showed a decrease in fat mass. Testosterone did not affect most measures of muscle strength. While decreasing frailty and increasing strength in older men might be beneficial, testosterone supplementation does not improve physical function in older men.
Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. Although 2 studies showed decreased anxiety, treatment of depression showed mixed and inconsistent results. Even if testosterone did benefit mood, social adverse events might ensue; 5 studies noted treatment-related increases in anger, aggression, or hostility. Testosterone did not benefit cognitive impairment or Alzheimer disease; neither did it benefit verbal fluency, memory, or other cognitive endpoints in normal men.
In summary, evidence from RCTs does not support treatment of so-called low-T for improving physical function, sexual function, mood, or cognition. Testosterone increases muscle mass, but not strength, and while some improvement is seen in some surrogate markers of cardiovascular risk, there is little evidence of clinical benefit.
There is conflicting evidence on the association between testosterone supplementation and cardiovascular events. RCTs have reported increased cardiovascular risk with testosterone therapy. One such trial that specifically examined cardiovascular disease and mortality endpoints was stopped early because of an increased risk of cardiovascular events.[17] A meta-analysis of 2994 men in 27 randomized controlled trials through 2012 found that testosterone therapy increased the risk of cardiovascular events (OR, 1.54; 95% CI, 1.09–2.18).[141]
Observational studies examining the effect of testosterone treatment have shown conflicting results on risk. A Veterans Administration study evaluated men who had undergone coronary angiography and had a total testosterone concentration (presumably plasma) less than 300 ng/dL (10.4 nM).[142] Men who were treated with testosterone had an increased risk of all-cause mortality, MI, and stroke compared to men who did not use testosterone (HR, 1.29; 95% CI, 1.05–1.58), based on a mean of 27.5 months of follow-up. Another retrospective cohort study using Veterans Administration data showed a lower rate of all-cause mortality, myocardial infarction, and stroke among testosterone-treated men whose testosterone concentrations “normalized” after treatment.[143] Another observational study of men in a large, integrated health care organization found that death rates were reduced over 3 years, but there was no effect on myocardial infarction or stroke.[144]
A Medicare-based study identified testosterone exposures and MI outcomes using claims data and matched testosterone-treated with untreated subjects using an empirically derived propensity score and found no increased risk.[145] The adjusted HR for testosterone therapy and MI was 0.84 (95% CI 0.69–1.02). Analysis of subjects in the highest quartile propensity score range suggested a protective effect of testosterone treatment, with a HR of 0.69 (95% CI 0.53–0.92). An observational study in men with low testosterone found that treatment was associated with reduced mortality;[146] another in diabetics[147] reported benefit on all-cause mortality but excluded men who had received testosterone for less than one year and excluded deaths occurring before six months. A large cohort study found that myocardial infarction rates were significantly increased within three months of testosterone treatment initiation; testosterone-treated men over 65 experienced double the rate of myocardial infarctions compared to men who did not received testosterone.[148]
Testosterone treatment has been considered for disease prevention because men who are obese, diabetic, hypertensive, or chronically ill have lower plasma concentrations of testosterone.[149] However, the direction of causality is unclear; it is possible that obesity or lack of exercise and chronic disease lower testosterone rather than low testosterone concentrations causing disease. It is also possible that another mechanism both lowers testosterone concentrations and increases the risk of some diseases. Observational studies attributing positive health effects to testosterone may be affected by an increased likelihood of healthier men being prescribed testosterone rather than testosterone improving health.
There are parallels between the recommendation of testosterone and of menopausal hormone therapy in women. Physicians prescribed estrogen and estrogen-progestin preparations to menopausal women to prevent cardiovascular disease because observational studies showed that women who took menopausal hormones had less heart disease than women who did not. RCTs, however, showed that menopausal hormone therapy increased the risk of heart attacks and stroke.[150–153] It is likely that healthier women chose to take menopausal hormone therapy, but menopausal hormone administration did not improve health.
In 2012, sales for testosterone therapies exceeded $2 billion, and sales continue to grow in dozens of countries.[154] To the extent that this increase in use of testosterone supplementation is based on anticipated improvements in cardiovascular health, sexual function, physical functioning, mood, or cognition, we suggest that it might represent therapy without adequate clinical trial support. We identified no population of normal men for whom the benefits of testosterone use outweigh its risk. Given the known risks of testosterone therapy and the lack of evidence for clinical benefits in normal men, we do not think further trials of testosterone are necessary.
Acknowledgments
We thank Matthew Puretz, Anastassia Reznik, and Nicole Dubowitz for their research assistance in the preparation of this paper.
Funding Statement
There were no funding sources for this study. Dr. Scialli is the sole participant in Scialli Consulting LLC. Scialli Consulting LLC has no employees and did not support this study with either salary or any other funding. Scialli Consulting LLC did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.
Data Availability
This is a systematic review. Studies we reference are available in the public domain.
References
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