The aim of this review was to summarize current knowledge on the correlation between depressive symptoms with a syndrome called partial androgen deficiency of the aging male (PADAM) and on the potential benefits of testosterone (T) treatment on mood. Despite, the causative nature of the relationship between low T levels and depression is uncertain, many hypogonadal men suffer from depression and vice versa several depressed patients are affected by hypogonadism. Supplementation with testosterone failed to show sound evidence of effectiveness in the treatment of depression. Nevertheless, testosterone supplementation has proved to be effective on some domains significant for the quality of life of aged patients with PADAM (sexual function and cognitive functions, muscular strengths).
Testosterone deficiency or hypotestosteronemia is a widely recognized hormonal alteration associated with male aging [
The joint consensus of International Society of Andrology, the International Society for the Study of the Aging Male (ISSAM) and the European Association of Urology prepared a set of recommendations specifically on the Investigation, treatment, and monitoring of late-onset hypogonadism in males [
In 2010, the Endocrine Society published clinical practice guidelines for testosterone therapy in adult men with androgen deficiency syndrome [
Age-related serum testosterone decline is caused by different simultaneous mechanisms, such as primary structural gonadal impairment, age-related degenerative modifications of the pituitary gland, deficits of the neurohypothalamic system, and primary peripheral metabolic abnormalities such as the age-associated increase in the concentration of serum sex hormone binding globulin (SHBG), with a consequent decrease in FT [
It is controversial whether aging is to be considered as the only variable linked to age-related T decline [
Despite the fact that many men with low testosterone levels are asymptomatic [
In the Endocrine Society Guidelines symptoms are separated into two groups, more specific symptoms and signs of hypogonadism (incomplete or delayed sexual development, sexual disorders, breast discomfort, gynecomastia, loss of body [axillary and pubic] hair, reduced shaving, very small or shrinking testes, inability to father children, low or zero sperm count, height loss, low trauma fracture, low bone mineral density, hot flushes, and sweats) and less specific symptoms (decreased energy, motivation, initiative, self-confidence, feeling sad or blue, depressed mood, dysthymia, poor concentration and memory, sleep disturbance, increased sleepiness, mild anemia, reduced muscle bulk and strength, increased body fat, body mass index, and diminished physical or work performance) [
PADAM as a clinical entity is still controversial, because it is very difficult to distinguish to what extent the symptoms attributed to PADAM are due to the natural and unavoidable consequences of aging and how much to androgen deficiency [
Behavioral aspects of PADAM may overlap with signs of depression. For example, McIntyre et al. [
Thus, the aim of this review was to summarize current knowledge on depressive symptoms correlated with PADAM and on the potential benefits of T treatment on mood.
In order to provide a critical review of the association of PADAM and depression in older males, we performed a PubMed search to identify all papers published in English peer-reviewed journals between 1980 and 2012. The search string was androgen deficiency OR testosterone deficiency OR hypogonadism OR testosterone treatment OR testosterone supplementation AND depress*.
We limited the search to articles reporting data for male aged 45+ years old. All English full-text articles reporting original data about the main topic were included. The reference lists of the articles included in the review were also manually checked to retrieve other relevant studies.
Epidemiological and clinical studies of the connection between age-related low T levels and a reduced feeling of well-being, with unusual anxiety and irritability, nervousness, mood swings, and a depressive state, have produced mixed results [
Naturalistic and cross-sectional studies in nonselected samples of patients.
Author, year | Type of study | Sample size | Age | Outcome measures | Results |
---|---|---|---|---|---|
Barrett-Connor et al. [ | Cross-sectional population-based study | 856 men | Range: 50–89 yrs | Association between BDI and BT or DHT | BDI scores were inversely associated with BT and DHT. BT were 17% lower for men with categorically defined depression than levels observed in all other men. |
T’Sjoen et al. [ | Naturalistic | 236 male outpatients in 1997 and 192 in 2000 | All patients were 70+ yrs. Range: 73.5–78.5 yrs in 1997; 76.0–81.0 yrs in 2000 | Association between GDS and TT, FT, estradiol, DHEAS, AR gene CAG-repeat length | No relationship between the GDS and FT or TT in 1997. The GDS did not correlate with AR gene CAG-repeat length. The GDS of 1997 correlated significantly with (free) estradiol and with DHEAS. The analysis in 2000 confirmed a lack of association between GDS and androgen levels or AR gene CAG-repeat length. The association between GDS and (free) estradiol and DHEAS was not observed in the subgroup of men studied in 2000. Changes in FT and serum (free) estradiol levels between 1996 and 2000 were not related to GDS score in 2000. |
Strasser et al. [ | Naturalistic | 48 patients with cancer who had received no major antineoplastic intervention for at least 2 weeks | Range: 20–79 yrs; Median: 59 yrs | Association between HAM-D and hypogonadism | 64% of patients had hypogonadism, which was correlated with HAM-D score. |
Spetz et al. [ | Cross sectional | 370 men | Range: 55 to 75 yrs; median: 62 yrs | Blood concentrations of T and BT | Men reporting deterioration in work performance had significantly lower T (16.6 nmol/L) and BT (6.9 nmol/L) than men without this problem (18.8 nmol/L and 7.9 nmol/L, resp.). Men reporting decreased strength and/or endurance had lower concentrations of BT than men without the same complaint (7.2 nmol/L and 8.0 nmol/L, resp.). Men suffering from hot flushes had lower T (15.1 nmol/L) and BT (6.58 nmol/L) compared with men who either had flushes but were not bothered by them or men without any flushes (17.6 nmol/L and 7.63 nmol/L). |
Kratzik et al. [ | Naturalistic | 669 manual workers | Range: 43–67 years | Association between BT, BMI and BDI scores | There was a U-shaped (quadratic) association between BT and BDI. Obese and underweight men with high BT had an increase BDI score. Men with low BT levels had an increased BDI score and eugonadal men with normal T levels have the lowest risk of depression. |
Morsink et al. [ | Prospective cohort udy | 2855 well-functioning elderly men (1406) and women (1449) | All aged aged 70–79 yrs; Mean: 73.8 yrs (men); 73.5 yrs (women) | Associations between TT, FT, DHEAS and CES-D scores | Significant inverse association between DHEAS and the CES-D for men and women. In men, there was a borderline significant inverse association between TT and depressive symptoms. For men, those in the lowest quartile of DHEAS and TT had significantly more depressive symptoms than those in the other quartiles. |
Makhlouf et al. [ | Naturalistic | 157 men referred to an erectile dysfunction specialty clinic | Range: 21–85 yrs; Median = 53 yrs | Scores of 22 or higher on the CES-D (overt depression) | Hypogonadal men were 1.94 times more likely to have overt depression scores compared to eugonadal counterparts. |
Fukai et al. [ | Cross-sectional | 108 men and 100 women | Range: 70–95 yrs; Mean: | Associations between GDS and TT, FT, DHEA, DHEAS, Estradiol | Linear regression model of hormone levels on functional scores unadjusted and adjusted for age, and age and body mass index indicated that in men the GDS was not associated with hormone levels. |
Hintikka et al. [ | Naturalistic | 59 men with adverse mental symptoms (AMS) and 57 asymptomatic (AS) men from the Finnish National Population Register | Mean: | Hypogonadism (FT < 160 pmol/L) | AMS more often had hypogonadism; BDI score and HAM-D correlated negatively with FT in the entire sample. |
Wu et al. [ | Naturalistic | Random population sample of 3,369 men at eight European centers | Mean: | Associations between TT and FT, and items from the SF-36 and the BDI | Sadness (SF-36), loss of energy (BDI), and fatigue were significantly associated with FT but not with TT. The probability of symptoms increased with decreased levels of T. The thresholds for TT were approximately 160 pmol/L for both sadness and fatigue. |
Jankowska et al. [ | Cross-sectional | Study population: 163 men with stable systolic chronic heart failure (CHF), and 316 healthy men living in the same area | Range: 35–80 yrs (controls) Mean: | Associations between BDI and TT or DHEAS | There were no differences in serum TT levels between the healthy men and the men with CHF when evaluated according to BDI score. Men with CHF had lower serum DHEAS as compared with healthy men in subsequent groups according to BDI score. Lower TT and DHEAS were associated with depressive symptoms in men with CHF. |
Wong et al. [ | Naturalistic | 1147 community-dwelling elderly men, aged | 65+ yrs | Associations between GDS, DHEA, TT, FT, estradiol, and SHBG | DHEA was significantly associated with GDS score. No association was seen between depressive symptoms and TT, FT, estradiol levels or SHBG levels. |
Berglund et al. [ | Naturalistic | 3413 men participating in the fifth Tromsø study in 2001 | Range: | Associations between the Hopkins Symptom Checklist-10 (SCL-10) scores and T | Men with T levels in the lowest 10th percentile, had increased SCL-10 score compared to men with higher T levels. However, men with more pronounced symptoms indicating mental disorder did not have lower testosterone levels. |
Halabi et al. [ | Cross-sectional | 104 men with COPD; 36 of whom had significant depressive symptoms (GDS ≥ 11) | All 55+ yrs. Mean: | Associations between GDS and hypogonadism | Prevalence of hypogonadism was greater in patients with severe depressive symptoms (GDS ≥ 19) than in those with mild depressive symptoms (GDS = 11–18) (62% versus 26%). After controlling for confounders, however, gonadal state was not associated with severe depressive symptoms. |
T: testosterone; BT: bioavailable testosterone; FT: free testosterone; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulphate; SHBG: sex hormone-binding globulin; BMI: body mass index; HAM-D: Hamilton scale for depression; BDI: Beck depression inventory; CES-D: center for epidemiologic studies depression scale; GDS: geriatric depression scale.
Naturalistic and cross-sectional studies in patients with depressive disorders.
Author, year | Type of study | Sample size | Age | Outcome measures | Results |
---|---|---|---|---|---|
Steiger et al. [ | Pre-post analyses | 12 male patients with MDD | Mean: | Change in nocturnal secretion of T | Nocturnal secretion of T increased after remission of depression. |
Booth et al. [ | Naturalistic | 4,393 men from the Vietnam Experience Study | Range: 30–48 yrs; Mean = 37 yrs | Associations between T and depression measured with the items from the Diagnostic Interview Schedule | T-squared has a significant relationship with depression, indicating a curvilinear relationship. Among men whose testosterone is below 590 ng/dL, each increase in the testosterone level is associated with less depression. Among men whose testosterone is above this value, each increase in the hormone is associated with greater depression. |
Schweiger et al. [ | Cross-sectional | 15 male inpatients with moderate to severe MDD and 22 healthy comparisons | Range: 22–85 yrs; | Differences in T between groups | Daytime T, nighttime T, and 24-hour mean T secretion were significantly lower in the MDD inpatients. |
Seidman et al. [ | Cross-sectional | 32 elderly men with dysthymic disorder, 13 elderly men with MDD, and 175 nondepressed comparisons | Range: 60–82 yrs | Differences in TT | TT was lower in elderly men with dysthymic disorder than in men with MDD and men without depressive symptoms. |
Shores et al. [ | Naturalistic | 278 men with consistently normal or low T levels (TT ≤ 200 ng/dL; or FT ≤ 0.9 ng/dL) at baseline and during a 2-year follow-up period | 45+ yrs | Differences in prevalence of ICD-9-CM depressive illness | The hypogonadal men had an increased occurrence of diagnosed depressive illness (21.7% versus 7.1%). |
McIntyre et al. [ | Cross-sectional | 44 depressed and 50 nondepressed men | Range: 40–65 yrs; depressed= | Differences in T levels | Depressed men had lower BT levels and TT levels than controls. Biochemical hypogonadism (i.e., BT level ≤ 2.4 nmol/L or TT level ≤ 12.14 nmol/L) was also more prevalent in depressed men than in non-depressed controls (34% versus 6% and 61% versus 14%, resp.). |
Ponholzer et al. [ | Naturalistic | 247 men of a population-based study | Mean: 75.7 yrs | Differences in T levels and DHEAS | T levels were not associated to prevalence or incidence of depression or dementia. |
T: testosterone; BT: bioavailable testosterone; FT: free testosterone; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulphate; SHBG: Sex hormone-binding globulin; BMI: body mass index; HAM-D: Hamilton scale for depression; BDI: Beck depression inventory; CES-D: center for epidemiologic studies depression scale; GDS: geriatric depression scale; MDD: major depressive disorder.
Positive results were reported by Hintikka et al. [
The Rancho Bernardo Study examined the association between T and depression in 856 community-dwelling older men aged 50 to 89 years (mean age 70.2 years) during a period of 4 years [
Lee et al. [
In a historical cohort study, the Veterans Affairs Puget Sound Health Care System carried out on 278 men aged 45 years and older without previous depressive diagnosis, hypogonadal men with TT levels of 200 ng/dL or less (compared to eugonadal men) showed an approximate 4-fold increase in the risk of incident depression in the 2-year followup [
In a sample of 32 subjects with dysthymic disorder (mean age 70.5, SD 5.8, range = 60–82 years), Seidman et al. [
Furthermore, there is some evidence that, compared with controls, T secretion is blunted among older men with severe major depressive disorder (MDD), it appears to normalize after major depressive episode remission [
No association between depression and T level has been reported in the Massachusetts Male Aging Study, a cross-sectional, population-based multidisciplinary survey of 1,709 normally aging men (aged 39–70 years) [
The causative nature of the relationship between low T levels and depression is uncertain. For example, investigators of the Massachusetts Male Aging Study found a significant interaction between polymorphic CAG repeats sequence encoding a variable-length glutamine chain in the N-terminal transactivation domain of an androgen receptor genetic polymorphism protein, testosterone level, and depression [
Although the practice of hormone replacement therapy began as long ago as the 18th century, with the use of extractions of reproductive organs of animals to treat a variety of ailments or to enhance the capacity for enjoyment of work and sexual activity [
Intervention studies in samples of patients with depressive symptoms.
Author, year | Type of study | Sample size | Age | Treatment | Outcome measures | Results |
---|---|---|---|---|---|---|
Wang et al. [ | Pre-/postanalyses | 51 hypogonadal men | 22–60 yrs old | 18 received T enanthate 200 mg im every 20 days, 16 received sublingual T cyclodextrin (SLT) at a dose of 2.5 mg three times daily, and 17 received SLT at a dose of 5.0 mg three times daily. The total treatment period was 60 days | Change in scores in single items on a 7-point Likert rating scale measuring anger, alertness, irritability, energy, sadness, tiredness, friendliness, nervousness, and well-being | T replacement led to significant decreases in anger, irritability, sadness, tiredness, and nervousness, and significant improvement in energy, friendliness, and well-being in all subjects as a group. Baseline serum T was positively correlated with friendliness and well-being, and negatively correlated with nervousness, irritability and tiredness. After T replacement these correlations disappeared. |
Wang et al. [ | Pre-/postanalyses | 30 hypogonadal men | All 18+ years old | Sublingual T cyclodextrin 5 mg 3 times daily for 6 months | — | The patients were less nervous and more alert, friendly, and energetic during the 6-month treatment period compared with baseline. |
Alexander et al. [ | Cross-sectional | 33 hypogonadal men receiving T replacement. 10 eugonadal men receiving T and 19 eugonadal men not administered T | Range: 19–60 yrs Mean: 41.1 yrs (hypogonadal); 33.4 yrs (eugonadal men receiving T); 32. 7 (eugonadal men not administered T) | Eugonadal men received weekly i.m. injections of testosterone enanthate (TE) (200 mg). Hypogonadal men were treated either with 200 mg TE every 20 days or with 2.5 or 5.0 mg sublingual testosterone cyclodextrin 3 times daily | Change in POMS scores after 6 weeks of treatment. | T had positive effects on mood in hypogonadal men, but did not have any effects on mood in eugonadal men. |
Wang et al. [ | Double-blind RCT | 227 hypogonadal men | About 3.9–11.0% of the subjects were <35 yrs, 23.3–36.8% were between 35–49 yrs, 55.1–57.5% were between 50–64 yrs, and 3.9–8.2% were 65+ yrs in the 3 initial treatment groups | In the first 3 months the subjects were randomized to receive 50 mg/day T gel in 5 g gel, 100 mg/day T gel in 10 g gel, or 2 nonscrotal patches delivering 5 mg/day (T patch). In the following 3 months, the subjects were administered 1 of the following treatments: 50 mg/day T gel, 100 g/day T gel, 5.0 mg/day T patch, or 75 mg/day T gel in 7.5 g gel | Sexual function and mood were assessed before clinic visits on day 0 and on days 30, 60, 90, 120, 150, and 180 during gel and patch application | All subjects as a group showed improvement in positive mood. Similarly, the negative mood summary scores showed significant decreases without showing between-group differences. |
Pope et al. [ | RCT | 56 men | Range: 20–50 yrs | Testosterone cypionate for 6 weeks in doses rising to 600 mg/wk and placebo for 6 weeks, separated by 6 weeks of no treatment | Differences in YMRS and HAM-D scores | 84% of those who received 600 mg/wk of testosterone cypionate exhibited minimal psychiatric effects (YMRS ≤ 10), 12% became mildly hypomanic (YMRS= 10–19), and 4% became markedly hypomanic (YMRS ≥ 20). The HAM-D remained low, with no changes during T administration or withdrawal. |
O’Connor et al. [ | RCT | 30 healthy men and 8 hypogonadal male patients | Healthy males: Range: 19–45 yrs; Mean: 28.2 yrs Hypogonadal men: Range: 23–40 yrs; Mean: 30.8 yrs | 15 eugonadal-men received 200 mg i.m. T enanthate once weekly for 8 weeks, 15 received 200 mg i.m. 0.9% sodium chloride solution weekly for 8 weeks. The hypogonadal group received 200 mg i.m. T enanthate biweekly for 8 weeks | Differences in depression-dejection dimension of the POMS | Significant main effects were found for time, group, and for time x group interaction. Multiple comparisons found that the significant group effect was accounted for by significantly higher levels of total mood disturbance in the hypogonadal group than the eugonadal-treated and eugonadal-placebo groups. However, there was a significant reduction in total mood scores in the hypogonadal group by weeks 1-2 explaining the significant interaction effect. |
Almeida et al. [ | Pre-/postanalyses | 40 men with prostate cancer treated with androgen blockade therapy | Range: 44–83 yrs; Mean = 72.4 yrs | Androgen blockade therapy (flutamide and leuprolide) for 36 weeks and subsequently followed up for another 18 weeks after discontinuation | Change in BDI scores | BDI scores increased significantly during the active treatment and declined somewhat thereafter. However, the number of people with clinically significant depressive symptoms did not change significantly. |
Schmidt et al. [ | Double-blind RCT | 31 healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuse | Range: 18–45 yrs; Mean: | Leuprolide acetate (Lupron) 7.5 mg im every 4 weeks for 3 months. After the first month of Lupron alone, all men received (in addition to Lupron) testosterone enanthate (200 mg i.m.) or placebo every 2 weeks for 1 month each in a crossover design. | Changes in BDI scores | BDI scores significantly increased during Lupron plus placebo compared with baseline and Lupron plus testosterone. |
Kenny et al. [ | RCT | 11 men with early cognitive decline and bioavailable T levels below 128 ng/dL | Range: 73–87 yrs; Mean: | intramuscular testosterone (200 mg every 3 weeks) or placebo for 12 weeks | Changes in GDS scores | No significant changes were found in depression following T supplementation |
Haren et al. [ | Double-blind RCT | 76 healthy men with at least two symptoms on the ADAM, a FT index (FTI) of 0.3–0.5 and TT greater than 8 nmol/L | Range: 60–86 yrs Mean: | 80 mg twice daily of testosterone undecanoate—TU (39 subjects) or identical placebo (37 placebo) for 12 months | Differences in GDS scores | From baseline to month-6 there was a significant effects of treatment on depression. No clinically relevant differences on the GDS between the testosterone and placebo group. |
Gray et al. [ | RCT | 60 healthy men | Range: 60–75 yrs | Monthly injections of long-acting GnRH agonist to suppress endogenous T production and randomization to one of five doses (25, 50, 125, 300, and 600 mg) of testosterone enanthate weekly for 20 weeks | Changes in HAM-D and YMRS | Baseline depression and mania were not correlated with log FT levels. Changes in mood did not differ by group and were not significantly correlated with FT or TT. |
Giltay et al. [ | Double-blind RCT | 184 men with TT below 12.0 nmol/L or FT below 225 pmol/L, and a diagnosis of the MetS | Range: 35–69 yrs; Mean: | 30 weeks with either parenteral testosterone undecanoate (1,000 mg i.m., at baseline, and after 6 and 18 weeks) or placebo injections | Association between BDI and TT. Changes in BDI scores | At baseline, BDI scores significantly correlated with TT ( |
Aloisi et al. [ | Open label | 9 opioid-induced hypogonadic men. T less than 2-3 ng/mL in at least two determinations in the previous 3-4 months | Range: 38–74 yrs; Mean: | One-month supply of testosterone gel, a hydroalcoholic compound containing 50 mg testosterone in 5 g gel in each sachet for 1 year | Change in CES-D scores from baseline | CES-D showed no significant change from baseline to follow-up assessments at 3, 6 and 12 months. |
T: testosterone; BT: bioavailable testosterone; FT: free testosterone; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulphate; SHBG: Sex hormone-binding globulin; BMI: body mass index; HAM-D: Hamilton scale for depression; BDI: Beck depression inventory; CES-D: center for epidemiologic studies depression scale; GDS: geriatric depression scale; POMS: profile of mood states; YMRS: young mania rating scale; MDD: major depressive disorder; MetS: metabolic syndrome.
Intervention studies in samples of patients with depressive disorders.
Author, year | Type of study | Sample size | Age | Treatment | Outcome measures | Results |
---|---|---|---|---|---|---|
Seidman and Rabkin [ | Open-label | 5 depressed men who had low T levels and had not responded to an adequate SSRI trial | Range: 34–50 yrs; Mean: | 400 mg testosterone replacement biweekly for 8 weeks | Changes in HAM-D scores from baseline | Significant recovery from major depression following T augmentation. |
Perry et al. [ | RCT | 15 elderly eugonadal males with MDD (HAM-D > 18) | Mean: | Following a single-blind 2-week placebo lead-in, patients were randomly assigned to treatment with either a physiologic dose of testosterone cypionate (TC), 100 mg/week, or supraphysiologic dose of 200 mg/week i.m. for 6 weeks | Changes in HAM-D scores | 42% decrease in the mean HAM-D scores. However, the majority of the change was due to improvement in the late-onset depression patients. The TC dose did not affect the response. |
Pope et al. [ | Double-blind RCT | 22 MDD patients with morning serum TT of 350 ng/dL or less who were receiving antidepressant treatment | Range: 30–65 yrs; Mean: | 12 men received 1% testosterone gel (10 g/day) and 10 received placebo | BDI, HAM-D, CGI-S | Subjects receiving testosterone gel had significantly greater improvement on the HAM-D than subjects receiving placebo. These changes were noted on both the vegetative and affective subscales of the HAM-D. A significant difference was also found on the CGI-S but not on the BDI. |
Orengo et al. [ | RCT | 12 hypogonadal men who were receiving antidepressants (on appropriate dose) for a minimum of 6 weeks | Range: 52–80 yrs; Mean: | Placebo or active T gel 1% at a dose of 5 g for 24 weeks | Differences in HAM-D scores | There was a significant improvement in HAM-D at 12 weeks of testosterone treat- ment as compared to baseline. However, there was no statistical difference between placebo and testosterone treatments. |
Seidman and Roose [ | Double blind RCT | 30 men with low and low-normal T levels (i.e., total T <or = 350 ng/dL) and MDD | Range: 33–71 yrs; Mean: | Weekly intramuscular injections of either T enanthate 200 mg or placebo for 6 weeks | Differences in HAM-D scores | The HAM-D scores decreased significantly in both T and placebo groups, and there were no significant between-group differences. |
Shores et al. [ | Double-blind RCT followed by an open-label extension phase | 33 men with TT levels of ≤280 ng/dL and subthreshold depression (dysthymia or minor depression, according to DSM-IV) | All 50+ yrs old; Mean: | Either 7.5 g of testosterone gel (17 men) or placebo gel (16 men) daily for 12 weeks, followed by a 12-week open-label extension phase during which all subjects received 7.5 g of testosterone gel | Differences in HAM-D scores | At the end of the double-blind phase, testosterone-treated men had a greater reduction in HAM-D scores and a higher remission rate of subthreshold depression (52.9% versus 18.8%) than did placebo-treated men. At the end of the extension phase, there were no significant between-group differences in the remission rate of depression between the original testosterone group and the original placebo group (58.8% versus 68.8%, resp.). . |
Seidman et al. [ | Double-blind RCT | 23 men with dysthymic disorder and with low or low-normal T level (i.e, TT < 350 ng/dL) | Mean: | 200 mg of testosterone cypionate im or placebo every 10 days for 6 weeks | Difference in HAM-D and CGI-I | HAM-D score decreased significantly more in the T group ( |
Pope et al. [ | Double-blind RCT | 100 medically healthy adult men with MDD showing partial response or no response to an adequate SSRI trial during the current episode and a screening TT ≤ 350 ng/dL | Mean: | Placebo gel (50 men) or testosterone gel (50 men) at 5 g/day. If the testosterone level at week 1 exceeded the physiologic range (91070 ng/dL), the investigator reduced the dose of gel to 2.5 g/day; if the level was 500 ng/dL or lower, then the investigator issued instructions to raise the dose to 10 g/day | Difference in HAM-D and MADRS | No significant difference in the antidepressant effects of T and placebo gel augmentation |
T: testosterone; BT: bioavailable testosterone; FT: free testosterone; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulphate; SHBG: Sex hormone-binding globulin; BMI: body mass index; HAM-D: Hamilton scale for depression; BDI: Beck depression inventory; CES-D: center for epidemiologic studies depression scale; GDS: geriatric depression scale; POMS: profile of mood states; YMRS: young mania rating scale; CGI-S: clinical global impression scale-severity; CGI-I: clinical global impression scale-improvement; MDD: major depressive disorder; MetS: metabolic syndrome.
In a randomized, placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT00696748), 184 men suffering from both the metabolic syndrome and hypogonadism were treated for 30 weeks with either parenteral testosterone undecanoate (TU; 1,000 mg IM TU) or placebo injections [
In a sample of 51 hypogonadal men (aged 22 to 60 years) studied for 60 days, T replacement improved positive mood parameters, such as energy, well-being and friendliness, and decreased negative mood parameters including anger, nervousness, and irritability [
Recently, Shores et al. [
Seidman et al. [
However, some studies have shown that, in the short and long term [
Androgen treatment in eugonadal men has demonstrated subtle changes in sexual arousal, cognition, and mood [
To date, little evidence supports the use of androgen therapy in older depressed men [
Androgen administration in open and blind clinical trials to chronically depressed men or to hypogonadal men with depression refractory to selective serotonin reuptake inhibitors (SSRIs) improved depressive symptoms. Human and animal studies have demonstrated that T treatment may facilitate the antidepressant drug response [
At the present time, available data do not suggest the use of T in the treatment of depression in PADAM. Data on older men suffering from depression and PADAM are still few and inadequate [
Furthermore, T supplementation may be associated with some adverse effects, such as erythrocytosis, acne and oily skin, detection of subclinical prostate cancer, growth of metastatic prostate cancer, and reduced sperm production and fertility [
As Western populations represent an aging society with continuing gains in life expectancy [
PADAM includes behavioral and depressive symptoms that vary greatly from individual to individual, being the result not only of biological and psychosocial changes, but also of personal ability to adapt to such changes. The efficacy of T therapy in the treatment of depression in elderly hypogonadal men is inconclusive. Research on T replacement therapy for depressive symptoms of PADAM reveals the great variability of the results.
Nonetheless, androgens supplementation may be a useful as adjunctive therapy in depressed hypogonadal men. Several study reported that antidepressants may be associated with sexual dysfunction in adult patients [
T treatment may be particularly useful to improve quality of life in elderly hypogonadal men, because its effect on muscular strength [
However, due to adverse effects associated with T therapy, pretreatment screening for parameters related to potential risks of testosterone supplementation is essential. T supplementation is contraindicated in individuals with hematocrit of 52% and over [
In conclusion, despite the causative nature of the relationship between low T levels and depression is uncertain, many hypogonadal men suffer from depression and vice versa. Supplementation with testosterone failed to show sound evidence of effectiveness in the treatment of depression. Nevertheless, T supplementation has proved to be effective on some domains significant for the quality of life of patients with PADAM. Those effects may partially mediate the effects on depressive symptomatology reported in some trials. Thus, the overall improvement in well-being and health, related to the quality of life in aging males with partial androgen deficiency, may have a positive impact on their mood.
The authors declare that there is no conflict of interest associated with this manuscript.