| Menwithout Psychiatric Disorders |
|
Skakkebaek et al, 1981[45] |
12 men 22–48 years old diagnosed as androgen deficient; one man subsequently found to be normal and excluded. |
T undecanoate 160 mg or placebo daily for 2 months followed by opposite tx; randomization of tx order not described but said to be balanced. |
Improved self-rated anxiety and tension; no statistically significant effect on depression, anger, vigor, or fatigue (authors concluded otherwise based on P = .10). |
3 |
|
Anderson et al, 1992[63] |
31 healthy men 21–41 years old. |
T enanthate 200 mg IM weekly for 8 (n = 16) or 4 weeks with placebo IM weekly for the remaining 4 weeks (n = 15); randomization not discussed. Described as single-blinded. |
No effect on self-assessment of mood (cheerful, lethargic, relaxed, tense, energetic, unhappy, irritable, ready to fight, easily angered) using an unvalidated ranking scale. |
2 |
|
Janowsky et al, 1994[114] |
56 healthy men 60–75 years old. |
T 15-mg scrotal (n = 27) or placebo patch (n = 29) 16 hours daily for 3 months; method of randomization not discussed. |
No effect on self-rated or spouse-rated Profile of Mood States (POMS). |
3 |
|
Kouri et al, 1995[108] |
8 healthy men 20–39 years old; 2 were subsequently excluded from analysis because they did not accept the terms of the test situation. |
Crossover design: 1) T cypionate IM 150 mg/week for 2 weeks, then 300 mg/week for 2 weeks, then 600 mg/week for 2 weeks then no tx for 6 weeks, then placebo IM for 6 weeks, then no tx for 6 weeks or 2) Same design with placebo tx prior to T. |
↑Aggressive response to a button-pushing game involving retaliation against a fictitious opponent. ↑Young Mania Rating Scale score (more aggressive). |
4 |
|
Bhasin et al, 1996[115]; Tricker et al, 1996[116] |
50 healthy men 19–40 years old who had earlier experience with weight-lifting; 7 dropped out prior to randomization, 3 dropped out during tx and were excluded. |
T enanthate 600 mg or placebo IM weekly followed by the opposite tx, tx for 10 weeks followed by washout. Further randomization within tx to exercise or non-exercise. Randomization method not given. |
No effect on Multidimensional Anger Inventory, Mood Inventory, or Observer Mood Inventory administered prior to tx and during weeks 6 and 10, 7 days after previous injection. |
2, 4 |
|
Schiavi et al, 1997[59] |
18 men 46–67 years old (median age 60 years) with ED with or without hypoactive sexual desire; 12 men completed the study, dropouts were excluded from analysis. |
T enanthate 200 mg or placebo IM every 2 weeks for 6 weeks followed by 4-week washout followed by the opposite tx; order was randomized by unstated method; 7 subjects received placebo first, 5 subjects received T first. |
No effect on POMS or psychological symptom profile. |
3 |
|
Sih et al, 1997[104] |
32 men 51–79 years old with free blood T concentration <60 ng/dL (2.1 nM); unclear how dropouts after randomization were handled. |
T cypionate 200 mg (n = 10) or placebo (n = 12) every 14–17 days for 12 months; tx allocation by random number (not otherwise characterized) |
No effect on Yesavage Geriatric Depression Scale (GDS) |
4 |
|
Dobs et al, 1999[113] |
133 men with AIDS age 18–65+ who had lost 5–20% of baseline weight with a morning serum total T concentration ≤400 ng/dL (13.9 nM) or free T concentration ≤16 pg/mL (56 pM); 15 T and 20 placebo did not complete the study. |
T 15-mg (n = 67) or placebo (n = 66) patch applied 20–24 hours/day to shaved scrotal skin for 12 weeks; assessments at weeks 4, 8, and 12; randomization method not given. |
No effect on health distress or mood assessed by Rand HIV-Medical Outcomes Study-short form or EUROQoL Feeling Thermometer |
3 |
|
Pope et al, 2000[169] |
53 presumed healthy men aged 20–50 years; an additional 13 men were recruited but not randomized or were randomized and not evaluable. |
T or placebo IM every 2 weeks. T dose was 150 mg/week for 2 weeks, 300 mg/week for 2 weeks, and 600 mg/week for 2 weeks. After a 6-week washout period, opposite tx given. Method of randomization not given |
↑Young Mania Rating Scale (↑manic).↑Point Subtraction Aggression Paradigm (↑aggressive). ↑Verbal hostility subscale score on Aggression Questionnaire of Buss and Perry. ↑Phobic anxiety on Symptom Checklist 90-R. No effect on Hamilton Depression Rating Scale (HAM-D) |
4 |
|
Daly et al, 2001[109] |
20 healthy men aged 18–42 years. |
PO placebo daily for 3 days, then PO methyltestosterone 40 mg/day for 3 days, then PO methyltestosterone 240 mg/day for 3 days, then PO placebo for 3 days inpatient. Schedule fixed but unknown to subjects and raters (not clear who the raters were inasmuch as subjects self-rated). |
High-dose methyltestosterone associated with visual analogue scale (VAS) self-rating of ↑Cognitive ability, ↑Distractibility, ↑Energy, ↑Sexual arousal, ↑Aggression, ↑Irritability. |
2 |
|
O’Connor et al, 2002[117] |
30 healthy eugonadal men aged 23–40 years; 8 hypogonadal men included but given only active tx and so not summarized here. One subject dropped out; it is not clear if he was retained in the analysis. |
Testosterone enanthate 200 mg IM or placebo weekly for 8 weeks (n = 15/group). Method of randomization not given |
The authors reported a lack of effect of testosterone on mood and aggression in eugonadal men, but the analyses shown in the paper were chiefly between hypogonadal men and eugonadal men. |
2 |
|
Dabbs et al, 2002[110] |
16 healthy men and 17 women, mean age 20.2 years (women are not further discussed); 5 subjects (sex not indicated) failed screening; 15 men were scored. |
Micronized T 40 mg or placebo gel applied to the skin daily for 5 days |
No difference in personality scores on Gough and Heilbrun Adjective Check List; some differences identified by study authors on post-hoc analysis. ↑Hostility on evaluation by 2 undergraduate judges of a free-text paragraph written by each subject on his mood at the end of tx |
3 |
|
Kunelius et al, 2002[118] |
120 men, age 50–70 years, with “andropause” symptoms, serum T <15 nM (432 ng/dL). Six subjects dropped out; it is not clear whether they were included in the analysis. |
“Randomized” by sealed envelope to 2.5% DHT gel (125 mg/day DHT) or placebo (60 subjects per group) for 30 days after which dose was adjusted on serum DHT concentration to 187.5 or 250 mg/day DHT. Placebo dose was randomly adjusted. Tx duration was 6 months. |
No effect on well-being or mood as assessed by questionnaire. |
5 |
|
O’Connor et al, 2004[67] |
28 healthy eugonadal men 22–44 years old; 4 subjects withdrew on tx and were excluded. |
T undecanoate 1000 mg or placebo IM at the beginning of an 8-week tx phase followed by 8-week washout followed by the opposite tx. Self-assessment each week and psychometric assessments during week 4 of each tx phase |
↑Anger-hostility (during first 2 weeks after injection) and ↓fatigue-inertia scores on POMS. No effect on Aggression Questionnaire, Partner Aggression Questionnaire, or Aggression Provocation Questionnaire, Buss Durkee Hostility Inventory (irritability subscale), Rathus Assertiveness Schedule, or State Self-Esteem Scale |
3 |
|
Howell et al, 2001[24] |
35 men mean age 40.9 with some degree of testicular dysfunction after cytotoxic cancer therapy; blood LH ≥8 mIU/L and T <20 nM (576 ng/dL); 2 dropouts were excluded from analysis. |
T 2.5 or 5.0 mg patch (n = 16) or placebo patch (n = 19) daily for 12 months; randomization method not described, study described as single-blinded |
No effect on Hospital Anxiety and Depression Scale (HADS). |
3 |
|
Pugh et al, 2004[20] |
20 men 44–81 years old with impaired LV EF (mean 35%) |
T 100 mg or placebo IM every 2 weeks for 12 weeks. Subjects said to be randomized, but randomization method and the number of subjects per group were not described. |
BDI not affected; improvement identified by authors was not statistically significant. |
3 |
|
Haren et al, 2005[119] |
76 men 60–86 years old, mean age 68.5 years, with at least 2 symptoms on ADAM and total T >8 nM (231 ng/dL); 6 dropouts analyzed by ITT |
T undecanoate 160 mg/day (n = 39) or placebo (n = 37) by mouth for 12 months; dose halved if hematocrit increased above 50%; randomization in blocks of 4 using ADLS |
More GDS improvement in placebo vs T group |
5 |
|
Malkin et al, 2006[23] |
76 men with CHF, mean age 64 years; 34 dropouts were retained for analysis using ITT. |
T 5 mg (n = 37) or placebo (n = 39) patch daily for 12 months; randomization was stratified by ischemic vs non-ischemic heart failure. Method of randomization not given |
No effect on BDI |
3 |
|
Brockenbrough et al, 2006[38] |
40 hemodialysis patients with serum T concentration <400 ng/dL (13.9 nM); 22 subjects completed the study. Analyzed by ITT |
Topical T 100 mg (n = 19) or placebo gel (n = 21) daily for 6 months; block randomized in groups of 4 |
Not possible to evaluate; Likert scale for mood combined with scales for sexual desire and reported as a composite score not affected by tx |
5 |
|
Okun et al, 2006[85] |
Men with Parkinson disease and free T concentration <100 pg/mL (347 pM), mean age 68 years |
T enanthate 200 mg (n = 15) or placebo (n = 15) IM every 2 weeks for 8 weeks; dose could be adjusted upwards based on free T concentration measured every 2 weeks; method of randomization not given |
No effect on GDS, State-Trait Anxiety Inventory (STAI), or Visual Analog Mood Scale (VAMS) |
4 |
|
Knapp et al, 2008[41] |
61 HIV-positive men, mean age 43 years, with involuntary weight loss and/or BMI <20 mg/m2; 4 placebo-assigned and 9 T-assigned subjects dropped out and were analyzed using the last observation carried forward. |
T enanthate 300 mg (n = 31) or placebo (n = 30) weekly for 16 weeks; randomized by computer-generated list in blocks of 6 |
↑Mental health subscale of QoL instrument. ↓Stress, anxiety, and depression subscale scores |
5 |
|
Maki et al, 2007[120] |
15 men age 66–86 years, total blood T >240 ng/dL (8.3 nM) |
T enanthate 200 mg (n = 9) or placebo (n = 6) IM every other week for 90 days followed by 90-day washout followed by the opposite tx; tx order determined by coin toss |
No tx effect on Positive and Negative Affectivity Schedule |
5 |
|
Vaughan et al, 2007[112] |
69 men 65–83 years (mean 70.8 years) with 2 morning serum T concentrations <12.1 nM (350 ng/dL); 23 dropouts were excluded from analysis. |
T enanthate 200 mg IM every 2 weeks + placebo pill (n = 23), T enanthate 200 mg IM every 2 weeks + finasteride 5 mg/day (n = 22), or placebo injection and placebo pill (n = 23), tx for 36 months; block-randomization by computer; possible reduction in T dose if hematocrit >52%; cognitive tests at baseline, 4, and 36 months |
↓Scores in Speilberger Test of Anxiety. No effect on BDI |
5 |
|
Zak et al, 2009[122] |
25 male students, mean 20.8 years old. |
T 1% gel 10 g or placebo given prior to playing game; each man served as his own control. Randomization of tx order not discussed |
↑Selfishness in game designed to test selfishness |
4 |
|
Giltay et al, 2010[75] |
184 men age 35–69 (mean 52.1) with T concentration <12.0 nM (346 ng/dL) or calculated free T concentration <225 pM (6.5 ng/dL) who had metabolic syndrome; 14 dropouts (8 T, 6 placebo) analyzed with last observation carried forward |
T undecanoate 1000 mg (n = 113) or placebo (n = 71) IM given at week 0, 6, 18, and 24; evaluations at week 30. Randomization method not given except to say that T was over-assigned in a 7:3 ratio |
↑Improvement in BDI |
4 |
|
Borst et al, 2014[102] |
Men aged 60 or more with total T ≤300 ng/dL (10.4 nM) or bioavailable T ≤70 ng/dL (2.4 nM) |
T enanthate 125 (n = 14) or 0 (n = 16) mg/week IM for 23 months. There also were finasteride + T arms that we ignore here. |
T-associated reduction of a mean of 0.74 items on the 15-item Geriatric Depression Scale short form |
1 |
|
Mirdamadi et al, 2014[22] |
50 males, age 50–70, with CHF |
T enanthate 250 mg IM or saline placebo IM every 4 weeks for 12 weeks |
No difference between groups in BDI |
3 |
|
Hackett et al, 2014[58] |
199 men aged 18–80 with T2DM with total T between 8.1–12 nM (233–346 ng/dL) or total T ≤8.0 nM (231 ng/mL). 9 patients did not complete the study; 4 because of serious adverse events (3 treatment unrelated deaths, 1 prostate cancer in placebo), and 5 withdrew their consent. |
Subjects were block randomized to receive testosterone undecanoate 1000 (n = 97) or 0 (n = 102) mg IM at week 0, 6, and 18. |
No improvement in Hospital Anxiety and Depression score (HADS) in men with baseline T ≤8.0 nM; ↑HADS-depression score but not HADS-anxiety in men with baseline T 8.1–12 nM |
5 |
|
Malkin et al, 2004[1] |
12 men 60.8 ± 4.6 years old (mean ± SD) with CAD and “clinical need for T replacement.” One man failed screening and another withdrew at unspecified point in the study. |
100 mg T or placebo IM every 2 weeks for 4 weeks, 1 month washout, then tx switch; randomization by computer; single-blinded |
↓BDI score |
5 |
| Menwith Psychiatric Disorders |
| HIV-Positive |
|
Grinspoon et al, 2000[129] |
52 men, mean age 41.6, with AIDS-associated wasting (weight <90% of ideal or weight loss >10%) and serum free T concentration <12 pg/mL (416 pM); 21 of these men had baseline BDI >18; 13 subjects died or withdrew and were not evaluated. |
T 300 mg (n = 21) or placebo (n = 18) IM every 3 weeks for 6 months. |
Improved BDI by a mean of 5.8 points; improvement was associated with increased weight. BDI did not change with placebo. Men with BDI >18 at baseline were not analyzed separately. |
3 |
|
Rabkin et al, 2000[35] |
72 HIV-positive men, mean age 39, with serum T <17.4 nM (501 ng/dL) with sexual dysfunction and at least one “hypogonadal” mood symptom; 2 dropped out and were excluded from analysis. Among 70 remaining, 26 had MDD, dysthymia, “minor” depression, or MDD in remission. |
Randomization in blocks of 4 by computer-generated numbers to T cypionate (n = 38 overall, 26 with depression diagnosis) or placebo (n = 32 overall, 7 with a depression diagnosis) injected biweekly (presumably IM) for 6 weeks; the first T dose was 200 mg, subsequent doses were 400 mg. Open-label phase with T followed the 6-week double-blind study, not summarized here |
Clinical Global Impression (CGI) scale response (not defined) in 74% T and 19% placebo (P < 0.001). No effect of tx on CGI in subjects with a depression diagnosis (P = .08). Improvement in total and vegetative scores on HAM-D, but not the affective scale. No change in the BDI (P = .052) |
4 |
|
Rabkin et al, 2004[130] |
123 HIV-positive men, mean age 41, with MDD or dysthymia; 33 men dropped out and were retained for ITT analysis. |
Randomization in blocks of 6 by computer-generated numbers to T cypionate IM biweekly + daily PO placebo (n = 38), placebo IM biweekly + fluoxetine PO (20–40 mg) daily (n = 46), or placebo IM biweekly + placebo PO daily (n = 39). Initial T dose was 200 mg, subsequent doses were 400 mg. Within tx groups, subjects were also randomized to fluoxetine or placebo daily by mouth. Tx were given for 8 weeks. Eight of the subjects were randomized only to fluoxetine or placebo due to transient unavailability of T. |
No difference in response on HAM-D or BDI by ITT and by considering only completers. Improvement in Chalder Fatigue Scale compared to placebo and to fluoxetine |
4 |
| HIV-Negative |
|
Reddy et al, 2000[121] |
22 men ≥65 years old; 8 dropouts at different times were analyzed only for those forms they completed. |
T enanthate 200 mg (n = 14) or placebo (n = 8) IM every 2 weeks for a total of 4 doses. |
No effect on Short-Form 36 (SF-36) or Psychological General Well-Being |
3 |
|
Seidman et al, 2001[36]Seidman & Roose, 2006.[164] |
32 men 33–71 years old with MDD (DSM-IV criteria) and serum T ≤350 ng/dL (12.1 nM); 2 dropouts were excluded from analysis. |
T enanthate 200 mg (n = 13) or placebo (n = 17) IM weekly for 6 weeks |
Improved QoL score. HAM-D and BDI described as improved in both groups; no intergroup difference. No difference between groups in response rate, defined as a ≥50% decrease in the HAM-D or as defined by CGI |
4, 4 |
|
Pope et al, 2003[125] |
23 men with tx-refractory MDD (DSM-IV criteria) and serum T ≤350 ng/dL (12.1 nM); 22 randomized (1 man who responded to run-in placebo gel excluded) |
T gel 1% (n = 12) or placebo gel (n = 10) for 8 weeks; valid randomization procedure described. T dose reduced if serum T exceeded 1070 ng/dL; sham reductions performed in placebo gel. Usual antidepressants continued during trial |
↑Rate of decrease in HAM-D and CGI scores; no difference in rate of change in BDI ↑Response as evaluated by HAM-D but no significant change in CGI or BDI |
5 |
|
Kenny et al, 2004[124] |
11 men with MMSE scores of 14–28, cognitive impairment by Dementia Rating Scale, and serum free T <128 ng/dL (4.44 nM); none discontinued. |
T enanthate 300 mg (n = 6) or placebo (n = 5) IM every 3 weeks for 9 weeks; testing at 10 weeks. Method of randomization not given. |
No effects on behavior with Behave AD or mood with GDS |
3 |
|
Cavallini et al, 2004[48] |
150 men 60–74 years old with symptoms of androgen decline, including decreased libido and erectile quality, depressed mood and concentration, irritability, and fatigue; free T <6 pg/mL (21 pM); 20 dropouts excluded |
T undecanoate 160 mg/day (n = 40), carnitine (n = 45, not further considered here), or placebo (n = 45) taken PO for 6 months; randomization by color-coded boxes |
HAM-D improved at 3 but not at 6 months |
4 |
|
Seidman et al, 2005[127] |
26 men, mean age 46.4 years, with MDD partially or nonresponsive to 2 adequate antidepressant trials |
T group (n = 13) received IM T enanthate 200 mg/week IM × 2 weeks, then 400 mg, then 400 mg (if responsive) or 600 mg (if not responsive) for the final injection; placebo group (n = 13) received weekly IM saline for 4 weeks. Tx allocation by random number table. Antidepressants continued. Evaluation at 6 weeks |
No difference between groups in improvement by HAM-D or BDI |
5 |
|
Orengo et al, 2005[128] |
18 men >50 years old with residual depression (≥12 on HAM-D) in spite of at least 6 weeks of antidepressant therapy and serum T ≤350 ng/dL (12.1 nM); 6 men dropped out and were not included in the analysis. |
Random number generator used to randomize men to T 1% gel 5 g/day or placebo gel for 12 weeks followed by crossover to the other tx; 5 subjects received placebo first and 7 subjects received T first. Evaluations every 6 weeks |
Improvement in HAM-D scores after 12 weeks of T compared to baseline, but no difference between T and placebo. No effect of tx on QoL Satisfaction Questionnaire or POMS |
3 |
|
Lu et al, 2006[42] |
18 men with AD; 2 dropouts were excluded from analysis; last observation carried forward for ITT analysis was reported not to change the results. |
T gel 75 mg/day (n = 9) or placebo gel (n = 9) for 24 weeks |
No tx effect on Neuropsychiatric Inventory, BDI, or self-assessed QoL-AD. Improvement in caregiver-assessed QoL-AD |
3 |
|
Ko et al, 2008[123] |
30 schizophrenic men, 20–49 years old, on antipsychotic medication; 4 of these subjects withdrew and were retained for ITT analysis. |
T 1% gel 5 g (n = 15) or placebo (n = 15) applied daily for 4 weeks; method of tx assignment not discussed |
Improvement in the negative symptom scores on the Positive and Negative Syndrome Scale. No change in the Calgary Depression Scale for Schizophrenia; the authors implied better results for completers, but there was still no significant difference from placebo. |
3 |
|
Seidman et al, 2009[51] |
23 men, mean age 50.6 years, with dysthymia and serum T concentration <350 ng/dL (12.1 nM). |
T cypionate 200 mg (n = 13) or placebo (n = 10) IM every 10 days for 6 weeks; randomization by computer |
Greater improvement in HAM-D and BDI than with placebo. ↑Remission (CGI of 1 or 2 or HAM-D < 8) for 7 men on T (n = 13) compared to 1 man on placebo (n = 10). |
5 |
|
Shores et al, 2009[126] |
33 men ≥50 years old (mean age 59 years) with dysthymia or “minor depression” and T concentration ≤280 ng/dL (9.7 nM); 6 subjects discontinued and were included in ITT analysis. |
T gel 7.5 g (n = 17) or placebo (n = 16) for 12 weeks; “randomization” by computer using 1:1 ratio |
Greater improvement in HAM-D than placebo. ↑Remission (HAM-D ≤7): 9/17 men in T group vs. 3/16 men in placebo group. No effect on Hopkins Symptom Checklist, SF-36, or QoL Enjoyment and Satisfaction Questionnaire. |
5 |
|
Pope et al, 2010[111] |
100 men, 30–65 years old, with MDD with partial or no response to antidepressant therapy and serum T ≤350 ng/dL (12.1 nM); 81 men completed at least 4 weeks of tx, 74 men completed the study. ITT analysis used for 95 subjects who had at least 1 post-baseline evaluation. |
T gel 5 g/day or placebo for up to 6 weeks (n = 50/group); the dose could be altered based on serum T concentration. “Randomization” by sealed envelope |
No effect on HAM-D, CGI, or Montgomery Asberg Depression Rating Scale (MADRS) |
5 |
|
Amiaz et al, 2011[37] |
100 depressed men 30–65 years old with MDD (DSM-IV criteria), with a HAM-D score ≥12 in spite of currently taking a serotonergic antidepressant for at least 4 weeks, serum testosterone ≤350 ng/dL (12.1 nM); 37 subjects were not evaluable due to loss of data and withdrawal. |
T (n = 31) or placebo (n = 32) gel for 6 weeks; allocation using table of random numbers blocked at 50/group; tx period varied from 15 days to 6 weeks. |
Improvement in HAM-D and MADRS |
5 |
