Hypogonadism vs eugonadism. Based on the study’s inclusion criteria, trials were divided into 3 categories: hypogonadal, eugonadal, and trials with both subjects. Of 16 trials, 9 trials with 577 hypogonadal subjects and 3 trials with 171 eugonadal subjects were identified. We categorized 4 trials as having a mixture of hypogonadal and eugonadal participants in both categories. By comparison, there was a significant, positive effect size in the hypogonadal subgroup (z=4.192; P < .0001) However, effect size in the eugonadal subpopulation was negative and did not reach significance. (z=-1.024; P=.306) This comparison is summarized in FIGURE 4.
Level of depression. Of the 16 selected studies, 5 trials (n=184) studied the effect of testosterone on subjects with major depressive disorder (MDD) diagnosed based on DSM-IV criteria. Four of these 5 trials28,35,37,41 used testosterone to augment the effect of other antidepressants, and 1 trial42 used testosterone as monotherapy. Three trials (n=83) among these 16 trials studied the impact of testosterone on subthreshold depression, including dysthymia and minor depression.40,43,44 Shores et al (2009)44 and Rabkin et al (2006)40 had the mixture of dysthymia and minor depression in their participants; however, Seidman et al (2009) only studied this effect in patients diagnosed with dysthymia. Three trials (n=125) had varieties of participants, from normal mood to diagnosed MDD (defined as Mixed in FIGURE 5), and 5 trials (n=452) did not describe the level of depression in their participants, but those trials predominantly recruited subjects with normal mood to minor depression. As shown in FIGURE 5, the strongest effect was observed in subjects with subthreshold depression (z=4.480; P < .0001). In the category of MDD, the effect size was smaller than that for subthreshold depression but was still was significant and large (z=2.080; P=.038). The effect of testosterone on the last 2 subgroups was positive but did not reach statistical significance.
HIV/AIDS. Four trials (n=258) out of the 16 selected trials studied the impact of testosterone in HIV-positive subjects.32,38-40 For patients who were HIV positive, the impact of testosterone was slightly larger numerically than for participants with negative HIV status (z=3.570, P < .0001 in HIV-positive patients vs z=3.223, P=.001 in HIV-negative patients) (FIGURE 6).
Duration of treatment. The 16 selected studies are categorized by 6, 8, 12, 24, 30, and 52 weeks based on their duration of treatment. We compared the impact of testosterone on mood in these 6 subgroups. Five trials (n=230) in the category of 6 weeks, 3 trials (n=214) of 8 weeks, 3 trials (n=62) of 12 weeks, 3 trials (n=210) of 24 weeks, 1 trial (n=170) of 30 weeks, and another trial (n=58) of 52 weeks were compared in this subgroup meta-analysis. The effect size of testosterone in trials with a duration of 6 weeks was positive but nonsignificant (z=1.926; P=.054). This number peaks at 8 weeks (z=3.095; P=.002) to 12 weeks (z=2.944; P=.003), and continues to 24 weeks (z=2.497; P=.013), and then declines at 30 weeks (z=2.104; P=.035). However, the impact was negative in the only trial with 52 weeks’ duration treated with oral testosterone (z=–2.090; P=.037). The results of this subgroup meta-analysis are summarized in FIGURE 7.
Route of administration. Of the 16 selected trials, 8 trials31,32,36,38,39,41-43 with IM administration of testosterone, 5 trials28,34,35,37,44 with testosterone gel, 2 trials33,45 with oral testosterone, and 1 trial40 with oral DHEA were compared in a subgroup meta-analysis. The number of subjects in each category was 427, 166, 218, and 133, respectively. The effect size was 3.069 (P=.002) in the gel subgroup; z=2.967 (P=.003) in the IM subgroup; 0.565 (P=.572) in the oral testosterone subgroup; and 3.350 (P=.001) in the oral DHEA subgroup. Oral testosterone, in contrast to oral DHEA, testosterone gel, and IM testosterone, did not show a significant result. The results of this subgroup meta-analysis are summarized in FIGURE 8.
|Study name||N||Age||Duration (weeks)||Inclusion criteria||Intervention||Depression scale||Conclusion||Reason excluded|
|Cavallini et al, 200446||130||60 to 74||24||HG||Oral T, carnitine||DMS-III||T significantly improved DMS||Different scale|
|Knapp et al, 200847||61||18 to 60||16||HIV with weight loss||IM T||DASS-21||Improvement in mood scores was not significantly different from placebo group||Different scale|
|McNicholas et al, 200348||208||31 to 80||12||HG||Gel and Patch T||Questionnaire rating positive and negative mood||No statistically significant changes in T patch, in contrast to gel, which has a significant improvement||Different scale|
|O’Connor et al, 200449||28||22 to 44||12||Eugonadal||1000 mg single-dose IM T||POMS||T increment was associated with detectable but minor mood changes||Different scale|
|Dean et al, 200550||371||48 to 68||52||HG||Gel T||Questionnaire rating positive and negative mood||Significant improvement in mood were maintained for up to 12 months of treatment||Different scale|
|Steidle et al, 200251||406||50 to 70||12||HG||Gel and patch T||Questionnaire rating positive and negative mood||Although all treatments resulted in improvement in mood scores, no significant differences among the treatments were observed||Different scale|
|Aydogan et al, 201216||40||20 to 26||24||CHH, compared with eugonadal healthy men||IM T||BDI||BDI scores significantly improved after T replacement treatment||Bias in selecting control group|
|Kenny et al, 200452||11||73 to 87||12||HG/mild to moderate cognitive impairment||IM T||GDS||No significant changes were found in depression scores||Lack of necessary statistical data, such as P value|
|Schmidt et al, 200453||31||18 to 45||12||Eugonadal men||IM T following acute induction of hypogonadism by Lupron (leuprolide)||BDI||Significant effect of T on BDI scores was observed||Acute induction of hypogonadism|
|BDI: Beck Depression Inventory; CHH: congenital hypogonadotropic hypogonadism; DASS-21: Depression Anxiety Stress Scales–21; DMS: Diagnostic Melancholia Scale; GDS: Geriatric Depression Scale; HG: hypogonadism; IM: intramuscular; POMS: Profile of Mood States; T: testosterone.|
This meta-analysis indicates that exogenous testosterone has a robust effect on depressed men with hypogonadism but not on eugonadal men. As the world population is progressively aging, with the help of advanced health care and modern medicine, the prevalence of men with hypogonadism is rising. In addition to the increasing rate of hypogonadism, the rate of depression is several times higher in men with low testosterone compared with eugonadal men. Although testosterone replacement therapy (TRT) has a large positive impact on hypogonadal men, our subgroup meta-analysis showed that this effect is not statistically significant in older men. A major limitation is the inability to separate the ages in several studies. Therefore, we used a mean age to compare subgroups of age <60 with older subpopulations with a mean age ≥60. Hence, 3 trials were set in the subgroup of age <60. In addition to age, there may be other confounds to investigate in order to understand the effects of TRT in older adults. In Lu et al (2006), the study investigated the impact of TRT on the combination of hypogonadal and eugonadal patients with Alzheimer’s disease. Haren et al (2005) studied older men (age >60) with low normal testosterone. Finally, Orengo et al (2005) studied the impact on hypogonadal men with major depression. Although this subgroup with a wide range of testosterone levels does not homogeneously reflect subpopulations of older men with hypogonadism, others have shown similar results. Kenny et al (2004) reported that no significant changes from the baseline were found in GDS scores after TRT.52 In addition, Sih et al (1997) reported no effects after treatment with TRT on the GDS scores in hypogonadal older men.54 Moreover, Khera et al (2012) studied the impact of testosterone gel on PHQ-9 scores of 849 hypogonadal men in a 12-month single-arm, multicenter observational study in a US-based registry trial.17 Their subcohort analysis also did not show a clinically meaningful improvement in depression scores in hypogonadal men age ≥60 compared with hypogonadal men age <60.
The effect size of exogenous testosterone on subthreshold depression, including dysthymia and minor depression, was large and unanimously positive across trials. Among all of the selected trials, 3 trials studied this effect in a homogeneous group of subjects with subthreshold depression. Shores et al (2009) studied the effect of testosterone on hypogonadal men with dysthymia and minor depression. Seidman et al (2009) studied this effect on subjects with diagnosed dysthymia. Rabkin et al (2006) studied this impact on HIV-positive patients with dysthymia or minor depression. In addition, the effect of exogenous testosterone on MDD was statistically significant and positive. Of 5 trials with homogenous subjects diagnosed with MDD, 4 trials studied testosterone to augment the effect of other antidepressants. The calculated effect size individually in these trials was positive in all 4 trials.28,35,37,41 However, the effect size was negative in the only trial that used 6 weeks of IM testosterone as monotherapy.42 Because the placebo response in this study was very high, this result needs to be studied in a larger, controlled trial with a longer duration.
Exogenous testosterone had a significant effect on mood among HIV-positive patients. Despite the fact that low baseline testosterone was not set as an inclusion criterion in 3 out of the 4 trials in this subpopulation, the effect size in these patients was larger than that seen in the HIV-negative subpopulation. This result might have occurred because of multiple benefits of treatment with testosterone in these patients. The study by Rabkin et al (2000) indicated that testosterone treatment restores libido and energy, alleviates depressed mood, and increases muscle mass specifically in HIV-positive patients with wasting syndrome. They reported response rates of 74%, 59%, and 58% with testosterone treatment in improving libido, fatigue, and depressed mood, respectively, compared with 19%, 25%, and 14% response rates in the control group, respectively. They also reported an average increase of 2.2 kg in the muscle mass of subjects with wasting syndrome over 12 weeks of treatment with testosterone. However, the effect size of testosterone on HIV-positive patients in the study by Rabkin et al (2004) was much lower than that seen in the 3 other trials conducted with HIV-positive patients. This may have occurred because of the higher (613 [SD=270] pg/dL) mean baseline testosterone level of participants in the Rabkin 2004 study, compared with participants in the other 3 trials in this subpopulation.
Based on our subgroup meta-analysis, the maximum effect size was observed in studies of 8 weeks’ duration. It was interesting that the effect of 6 weeks of testosterone treatment was not statistically significant. The reason may be the lack of homogenous participants in this subpopulation. However, this result was consistent with studies by Pope et al (2003 and 2010). Both these trials had similar inclusion criteria, including participants with MDD with partial response or resistant to antidepressants and testosterone level <350 pg/dL, but they had almost opposite results. The first study had a significant difference in HAM-D scores, whereas the second study did not have a significant change compared with placebo. The only difference between these 2 studies was the duration and dose of testosterone. The first study was with 8 weeks in duration with 10 g/d of testosterone gel, and the second study was 6 weeks in duration with 5 g/d of testosterone gel. In the study by Pope et al (2010), it is possible that had they continued their trial for 2 more weeks, they would have observed a significant difference in the HAM-D score. The other interesting result in this subgroup meta-analysis was that treatment duration of 1 year showed a negative effect size. But our meta-analysis was limited in that we had only 1 study in this subgroup—that of Haren et al (2005). This trial was conducted with subjects with low normal testosterone and a mean baseline GDS of 6. Therefore, this effect size cannot be interpreted as a whole. Dean et al (2005) studied the effect of testosterone treatment on negative and positive mood over 12 months of treatment. They reported an improvement in mood scores, which was maintained through month 12.50
Our subgroup meta-analysis regarding route of administration showed that the effects of testosterone gel and IM injection are not comparable to oral testosterone because some oral testosterone formulations have proven to have variable absorption and poor bioavailability due to the first-pass effect in the liver.55 In addition, this subgroup meta-analysis showed that oral DHEA has a slightly larger effect size than testosterone gel and injection. DHEA is classified by the FDA as a nutritional supplement that can be used in both sexes.40 Our results were based on only 1 trial, by Rabkin et al (2006), studying the effect of this supplement in both men and women with HIV. This slightly larger effect size of DHEA might be because of the slightly larger effect of exogenous testosterone in patients with HIV. More studies investigating the effects of DHEA are needed to observe its effect on depressed individuals.
The results of this meta-analysis support the use of TRT in middle-aged, depressed men with low testosterone. This treatment can be used as monotherapy in dysthymia and minor depression or as augmentation therapy in MDD in this population. Therefore, we recommend checking total testosterone levels as a screening tool in depressed middle-aged men, particularly in those individuals whose depression is associated with poor morning erection, low sexual desire, and erectile dysfunction.56,57 In this meta-analysis, 7 of 9 trials conducted with hypogonadal men set their threshold for low total testosterone level at 350 ng/dL. Shores et al (2009) set a threshold of 280 ng/dL, and Zhang et al (2012) defined low testosterone as a total testosterone level of <230 ng/dL. For levels between 230 and 350 ng/dL, they checked free testosterone level and considered a free testosterone level <65 pg/mL as hypogonadism. Within the latest Endocrine Society guidelines, it is recommended that TRT be initiated in men with 2 morning total testosterone levels <280 to 300 ng/dL plus symptoms of androgen deficiency such as low libido, decreased energy, decreased spontaneous erection, and depressed mood.56
Because most antidepressants have adverse side effects, these side effects are the major reason for medication discontinuation. An important side effect of most antidepressants is sexual dysfunction. Selective serotonin reuptake inhibitors are the most commonly used medications in depression and are estimated to cause sexual dysfunction in one-third of patients.58 Because maintenance of satisfying sexual performance in patients with depression is important, TRT—with its dual effects on mood and sexual function—may be a better choice for hypogonadal men. In addition, there were no cases of prostate cancer reported with short-term use of testosterone in 16 selected trials in this meta-analysis. Most of the side effects reported in these trials were minor, comparable with the placebo group, and reversible after discontinuing treatment. As recommended by the Endocrine Society, prostate-specific antigen (PSA) and hematocrit levels should be checked at the beginning of treatment and monitored after 3 to 6 months of treatment. This treatment should be withheld in the case of a PSA level of >4 ng/mL (>3 ng/dL in men at high risk of prostate cancer, such as African American men or men with first-degree relatives with prostate cancer), a hematocrit level >50%, untreated severe obstructive sleep apnea, or uncontrolled or poorly controlled heart failure.11 Surprisingly, the effects of TRT in hypogonadal men may persist for an extended period of time after the treatment is discontinued. Taniguchi et al followed up 33 men with symptomatic androgen deficiency who had received TRT for 6 months in the past. The mean duration from the last treatment was 55 months. Scores of the International Index of Erectile Function (IIEF-5) and SF-36 were improved significantly in the early stages of treatment and remained unchanged for a long period of time after TRT was discontinued.59 Therefore, depressed men with low testosterone may experience long-term benefit from a short trial of TRT.
DISCLOSURES: Dr. Seo is an employee of AbbVie. Drs. Amanatkar, Chibnall, Manepalli, and Grossberg report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
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CORRESPONDENCE: Hamid Reza Amanatkar, MD Department of Neurology and Psychiatry 1438 South Grand Blvd St. Louis, MO 63104 USA E-MAIL: firstname.lastname@example.org
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