Partial Androgen Deficiency, Depression, and Testosterone Supplementation in Aging Men

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).


Introduction
Testosterone deficiency or hypotestosteronemia is a widely recognized hormonal alteration associated with male aging [1][2][3]. Its prevalence may be as high as 30% in men aged 40-79 years [4,5], and in up to 12% the hypotestosteronemia it can be associated with clinical symptoms [5]. Nevertheless, different levels of testosterone (T) could be associated with the presence of specific clinical symptoms [6,7].
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 [8,9]. Laboratory diagnosis of hypogonadism is based on the measurement of serum total testosterone (TT). Although there is no uniformly accepted threshold level for T in older men, TT levels above 350 ng/dL are considered normal and do not require substitution therapy, while TT levels below 230 ng/dL usually benefit from testosterone treatment. When TT level is between 230 and 350 ng/dL, it may be useful to calculate free testosterone (FT), particularly in obese men. FT level below 65 pg/mL suggests that testosterone treatment is needed [10,11].
In 2010, the Endocrine Society published clinical practice guidelines for testosterone therapy in adult men with androgen deficiency syndrome [12]. The members of the working group agreed that because the normative ranges for TT and FT in healthy young men vary among laboratories and assays (lower TT limits: 280-300 ng/dL; lower FT limits: 5-9 pg/ mL) [13], clinicians should use the lower limit of normal range for healthy young men established in their laboratory. Members of the working group disagreed on T concentrations below which testosterone supplementation should be offered to older men with symptomatic hypogonadism. Some members of the working group recommended T supplementation in older men with TT level below 300 ng/dL, because this is the threshold at which older men have 2 International Journal of Endocrinology symptoms that might be attributable to low testosterone; others recommended T supplementation only in those with TT level below 200 ng/dL, because higher pretreatment T values are associated with lower beneficial effects of T therapy.
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 [3].
Despite the fact that many men with low testosterone levels are asymptomatic [25], many others have a partial, gradual, and variable decline in T associated with various clinical symptoms, described as a syndrome called partial androgen deficiency of the aging male (PADAM) [26]. PADAM is characterized by sexual, somatic, and behavioral symptoms, with insidious onset and slow progression [27]: diminished sexual desire and erectile quality, particularly nocturnal erections [28,29]; decrease in lean body mass, with associated diminution in muscle volume and strength; increase in visceral fat [30][31][32], decrease in bone mineral density, resulting in osteoporosis [33]; reduction in body hair and skin alterations [34]; weakness, fatigue, depression, lack of motivation and energy, lower psychological vitality, anxiety, irritability, insomnia, decreased work and sport performances; difficulty in concentrating, memory impairment, and low dominance [35][36][37][38][39][40][41].
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) [12]. Serum T concentration has to be measured in patients with the more specific symptoms of hypogonadism and considered in those who report the less specific symptoms. The diagnosis of hypogonadism is possible when serum T level is below lower limits, and reversible illness, drugs, and nutritional deficiency have been excluded.
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 [37,42,43].
Behavioral aspects of PADAM may overlap with signs of depression. For example, McIntyre et al. [44] considered that reduction in physiologically active bioavailable testosterone (BT) concentration is a vulnerability factor for depressive symptoms in middle-aged depressed men. The authors assessed and compared TT and BT levels in two groups of middle-aged men (40-65 years), untreated subjects meeting DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders-4th edition, text revised) [45] criteria for a major depressive episode (N = 44), and a matched nondepressed control group (N = 50). Depressed men had lower mean BT levels and TT levels than the control group. Biochemical hypogonadism (i.e., BT level ≤70 ng/dL or TT level ≤350 ng/dL) was also more prevalent in depressed men than in nondepressed controls (34% versus 6%; 61% versus 14%, resp.).
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.

Methods
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.
Positive results were reported by Hintikka et al. [47] who examined associations between hypogonadism (laboratory diagnosis was based on FT level <4.6 ng/dL), erectile dysfunction, sexual desire, and long-term and current depressive symptoms in a population-based sample of Finnish middleaged men. The inclusion criteria for this study were based on self-reported adverse mental symptoms prevailing at baseline and at the 3-year followup. At 7 years from the baseline, men who reported long-term adverse mental symptoms had higher depression but lower FT levels than asymptomatic men. Furthermore, depression correlated negatively with FT (rho = −0.20; P < 0.05) in the entire sample.
The Rancho Bernardo Study examined the association between T and depression in 856 community-dwelling older   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. [ [64]. In that study, BT levels decreased with age and were significantly and inversely associated with Beck Depression Inventory (BDI) scores [65], indicating more depressive symptoms associated with lower BT levels.
There was a graded stepwise decrease in BT, with a parallel increasing level of depressed mood; in addition, BT levels were 17% lower in men with categorically defined depression than in controls. Lee et al. [66] investigated the PADAM in a community sample of 311 Chinese men (aged 40-80) attending a family medicine clinic in Hong Kong. A total of 87.8% of the sample was screened PADAM positive using the ADAM questionnaire. PADAM-positive individuals were found to have poorer quality of life, higher depression and anxiety, even after adjusting for age and number of current diseases.
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 4fold increase in the risk of incident depression in the 2-year followup [67]. The risk of depression was inversely related to T levels, with statistically significant findings observed at T levels lower than 280 ng/dL.
In a sample of 32 subjects with dysthymic disorder (mean age 70.5, SD 5.8, range = 60-82 years), Seidman et al. [62] found that most elderly men with dysthymic disorder had TT levels in the hypogonadal range (i.e., ≤300 ng/dL). Furthermore, their TT levels were lower than in patients with MDD or healthy controls. The authors hypothesized that dysthymic disorder in elderly men may be related to HPG axis hypofunction. This association is believed to be the result of either chronic depression leading to HPG axis blunting, or to HPG axis hypofunctioning leading to lowgrade depression [68].
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 [60,61]. A significant increase in depression during the androgen deprivation treatment period, and a tendency to decline after chemical castration was discontinued has been observed in eugonadal men at risk for prostate cancer who are treated with androgen blockade therapy [69].
No association between depression and T level has been reported in the Massachusetts Male Aging Study, a crosssectional, population-based multidisciplinary survey of 1,709 normally aging men (aged 39-70 years) [70]. Partially positive results were also reported more recently in the Tromso Study [56]. In this study, lower testosterone levels were associated with subthreshold symptoms of anxiety and depression. The Veterans' Experience Study [71], which investigated a sample of 4,393 veterans who served the U.S. military (mean age 37 years), found small but significant associations between depression and T Level (r = 0.04; P < 0.01). However, in this latter study, the authors pointed out that the relationship between T level and depression may actually be curvilinear [71].
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 [72]. The CAG repeat length appears to have modulatory effects on androgen action [73,74], and the associations between depression and testosterone concentration may be mediated by different androgen sensitivity. The psychiatric effects of T may be also mediated through modulation of brain monoamine levels and, in particular, of the serotonergic function [75,76]. In animal models, T increases cortical serotonin 2A receptor binding densities [77] and, in humans, cortical serotonin 2A receptors decrease with depression and aging [78].

T Treatment of Depression in Older Men.
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 [79][80][81], the role of T therapy for middle-aged and older men with depression is still uncertain (see Tables  3 and 4). T replacement in hypogonadal males generally decreases anger, nervousness, irritability and anxiety [35], and consistently leads to increased sexual interest and activity ( [82,83], see [84] for negative results).
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 [85]. Depression was assessed at the baseline and at 18 and 30 weeks with the BDI. At baseline, depression significantly correlated with the total testosterone level (r = −0.16; P = 0.03). When comparing the changes over time in patients treated with TU versus the placebo group, there was a significant improvement in depression (mean difference versus placebo after 30 weeks: −2.5 points; 95% CI: −0.9; −4.1; P = 0.003). Effects were strongest in men with the lowest baseline total testosterone (<222 ng/dL).
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 [35]. Direct correlations between serum T and dihydrotestosterone (DHT) with mood scores were only observed in the baseline period, when serum androgen levels were below the normal range. This observation may indicate that it is possible that, once a minimally adequate serum T/DHT level is achieved by T replacement therapy, further increases in serum T/DHT levels do not further contribute to the improvement in mood variables. In a subsequent trial, Wang et al. [82] administered a transdermal T gel formulation to hypogonadal men (227 men aged 19 to 68 years) over a period of 180 days.   Aloisi et al. [88] Open label 9 opioid-induced hypogonadic men. T    [86] examined the effect of testosterone treatment in older, hypogonadal men (50+ years old) with subthreshold depression in a double-blind randomized controlled trial. Participants received either 7.5 g of testosterone gel or placebo gel daily for 12 weeks, followed by a 12-week open-label extension phase during which all subjects received 7.5 g of testosterone gel. At the end of the double-blind phase, testosterone-treated men had a greater reduction in depression (P < 0.05) and a higher remission rate of subthreshold depression (52.9% versus 18.8%, P < 0.05) than did placebo-treated men. At the end of the open-label phase, the testosterone group had sustained improvement, while patients who had received placebo in the previous 12 weeks improved, and there were no differences between groups on the number of depressive symptoms reported.
Seidman et al. [87] conducted a six-week double-blind placebo-controlled clinical trial in 23 men with mid-life onset male dysthymic disorder and with low or low-normal testosterone level (TT < 350 ng/dL). After the intervention, the depression decreased significantly more in the testosterone group than in the placebo group (P < 0.01).
However, some studies have shown that, in the short and long term [88], T replacement is not superior to placebo in elderly men with low-normal gonadal status, or in men with the lowest BT levels [89][90][91].
Androgen treatment in eugonadal men has demonstrated subtle changes in sexual arousal, cognition, and mood [36], with a significant increase in manic and aggressive symptoms [92,93]. However, two studies failed to observe effects of T on mood in healthy men with induced hypogonadism who were given T [94,95].
To date, little evidence supports the use of androgen therapy in older depressed men [96]. In a study by Perry et al. [97], a subgroup of elderly depressed males (aged 70 and over) improved with T therapy. In a study of 15 elderly eugonadal males with major depressive disorder (MDD, according to the DSM-IV criteria), 5 with early onset MDD, and 10 with late onset MDD, treatment with T cypionate (100 mg/week or 200 mg/week IM for 6 weeks) was efficacious only in some cases of late-onset depression.
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 [98][99][100]. T augmentation in men with major depression refractory to SSRIs treatment and low or borderline TT levels (200-350 ng/dL) produced significant positive results in shortterm treatment (12 weeks) [98,101], but doubts arose about longer-term treatment (20 weeks) [99].
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 [102], and the current clinical guidelines for men with low serum T concentration stress that T therapy for depression is irrelevant [12,103,104].
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 [12,104]. Other, uncommon, adverse events for which there is weak evidence of association with testosterone administration are gynecomastia, male pattern balding (familial), and induction or worsening of obstructive sleep apnea. Formulation-specific adverse effects include fluctuation in mood or libido, pain at injection site, excessive erythrocytosis (especially in older patients), and coughing episodes immediately after the intramuscular injection for intramuscular injections of testosterone enanthate, cypionate, or undecanoate, as well as frequent skin reactions at application site for transdermal patches, and potential risk for testosterone transfer to partner or others in close contact with the individual, and skin irritation for transdermal gel [12].

Discussion
As Western populations represent an aging society with continuing gains in life expectancy [4], hypogonadism in older men may have significant public health implications [67,109,110]. For example, over the last decade, this has led to a significant market growth in T therapies for men 40 years and older [4].
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 [111], and up to 20% of users may suffer from sexual dysfunction [112]. Sexual dysfunction may also be associated with discontinuation of antidepressants treatment [113]. T treatment may have beneficial effects on sexual functions [83,89,94,103,[114][115][116]. Recently, Amiaz et al. [83] conducted a 6-week, double-blind, placebo-controlled clinical trial of testosterone gel versus placebo gel in men with MDD who were currently taking a serotonergic antidepressant and exhibited low or low-normal testosterone level. The results indicated that those taking testosterone improved in sexual functions as measured through the International Index of Erectile Function more than those in the placebo arm. Furthermore, the results indicated that the improvement in sexual functioning did not appear to be attributable to improvement in depression.
T treatment may be particularly useful to improve quality of life in elderly hypogonadal men, because its effect on muscular strength [117][118][119] and may be on cognitive functions [57,[120][121][122].
International Journal of Endocrinology 13 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 [123,124], prostatic carcinoma, an androgen sensitive-tumor, and in cases of mammary carcinoma in men [12,103].
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.