International Journal of Endocrinology

International Journal of Endocrinology / 2012 / Article
Special Issue

Endocrine Function in Aging

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Review Article | Open Access

Volume 2012 |Article ID 280724 | 17 pages | https://doi.org/10.1155/2012/280724

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

Academic Editor: Huan Cai
Received13 Jan 2012
Revised08 Apr 2012
Accepted10 Apr 2012
Published07 Jun 2012

Abstract

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).

1. Introduction

Testosterone deficiency or hypotestosteronemia is a widely recognized hormonal alteration associated with male aging [13]. 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 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].

It is controversial whether aging is to be considered as the only variable linked to age-related T decline [14, 15]: several factors do seem to interfere in different ways with T metabolism, like genetic factors [16], chronic diseases [1719], chronic medications [20], obesity [7, 21, 22], and lifestyle factors [23, 24].

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 [3032], 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 [3541].

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 ( ), and a matched nondepressed control group ( ). 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.

2. 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.

3. Results

3.1. T Levels and Depression

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 [4663] (see Tables 1 and 2).


Author, yearType of studySample sizeAgeOutcome measuresResults

Barrett-Connor et al. [64]Cross-sectional population-based study856 menRange: 50–89 yrsAssociation between BDI and BT or DHTBDI 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. [105]Naturalistic236 male outpatients in 1997 and 192 in 2000All patients were 70+ yrs. Range: 73.5–78.5 yrs in 1997; 76.0–81.0 yrs in 2000Association between GDS and TT, FT, estradiol, DHEAS, AR gene CAG-repeat lengthNo 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. [55]Naturalistic48 patients with cancer who had received no major antineoplastic intervention for at least 2 weeksRange: 20–79 yrs; Median: 59 yrsAssociation between HAM-D and hypogonadism64% of patients had hypogonadism, which was correlated with HAM-D score.

Spetz et al. [43]Cross sectional370 menRange: 55 to 75 yrs; median: 62 yrsBlood concentrations of T and BTMen 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. [54]Naturalistic669 manual workersRange: 43–67 yearsAssociation between BT, BMI and BDI scoresThere 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. [53]Prospective cohort udy2855 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 scoresSignificant 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. [52]Naturalistic157 men referred to an erectile dysfunction specialty clinicRange: 21–85 yrs; Median = 53 yrsScores 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. [50]Cross-sectional108 men and 100 womenRange: 70–95 yrs; Mean: yrs (men); yrs (women)Associations between GDS and TT, FT, DHEA, DHEAS, EstradiolLinear 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. [47]Naturalistic59 men with adverse mental symptoms (AMS) and 57 asymptomatic (AS) men from the Finnish National Population RegisterMean: yrs for AMS and yrs for ASHypogonadism (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. [7]NaturalisticRandom population sample of 3,369 men at eight European centersMean: yrsAssociations between TT and FT, and items from the SF-36 and the BDISadness (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. [49]Cross-sectionalStudy population: 163 men with stable systolic chronic heart failure (CHF), and 316 healthy men living in the same areaRange: 35–80 yrs (controls) Mean: yrs (CHF)Associations between BDI and TT or DHEASThere 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. [106]Naturalistic1147 community-dwelling elderly men, aged65+ yrsAssociations between GDS, DHEA, TT, FT, estradiol, and SHBGDHEA was significantly associated with GDS score. No association was seen between depressive symptoms and TT, FT, estradiol levels or SHBG levels.

Berglund et al. [56]Naturalistic3413 men participating in the fifth Tromsø study in 2001Range: yrsAssociations between the Hopkins Symptom Checklist-10 (SCL-10) scores and TMen 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. [63]Cross-sectional104 men with COPD; 36 of whom had significant depressive symptoms (GDS ≥ 11)All 55+ yrs. Mean:
(depressed),
(nondepressed):
Associations between GDS and hypogonadismPrevalence 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.

Author, yearType of studySample sizeAgeOutcome measuresResults

Steiger et al. [61]Pre-post analyses12 male patients with MDDMean: yrsChange in nocturnal secretion of TNocturnal secretion of T increased after remission of depression.

Booth et al. [71]Naturalistic4,393 men from the Vietnam Experience StudyRange: 30–48 yrs; Mean = 37 yrsAssociations between T and depression measured with the items from the Diagnostic Interview ScheduleT-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. [60]Cross-sectional15 male inpatients with moderate to severe MDD and 22 healthy comparisonsRange: 22–85 yrs; for MDD versus for comparisonsDifferences in T between groupsDaytime T, nighttime T, and 24-hour mean T secretion were significantly lower in the MDD inpatients.

Seidman et al. [62]Cross-sectional32 elderly men with dysthymic disorder, 13 elderly men with MDD, and 175 nondepressed comparisonsRange: 60–82 yrsDifferences in TTTT was lower in elderly men with dysthymic disorder than in men with MDD and men without depressive symptoms.

Shores et al. [67]Naturalistic278 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 period45+ yrsDifferences in prevalence of ICD-9-CM depressive illnessThe hypogonadal men had an increased occurrence of diagnosed depressive illness (21.7% versus 7.1%).

McIntyre et al. [44]Cross-sectional44 depressed and 50 nondepressed menRange: 40–65 yrs; depressed= ; controls= Differences in T levelsDepressed 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. [51]Naturalistic247 men of a population-based studyMean: 75.7 yrsDifferences in T levels and DHEAST 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. [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 middle-aged 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; ) in the entire sample.

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 [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 4-fold 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 low-grade 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 cross-sectional, 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 ( ). 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].

3.2. 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 [7981], 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).


Author, yearType of studySample sizeAgeTreatmentOutcome measuresResults

Wang et al. [35]Pre-/postanalyses51 hypogonadal men22–60 yrs old18 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 daysChange in scores in single items on a 7-point Likert rating scale measuring anger, alertness, irritability, energy, sadness, tiredness, friendliness, nervousness, and well-beingT 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. [35]Pre-/postanalyses30 hypogonadal menAll 18+ years oldSublingual T cyclodextrin 5 mg 3 times daily for 6 monthsThe patients were less nervous and more alert, friendly, and energetic during the 6-month treatment period compared with baseline.

Alexander et al. [107]Cross-sectional33 hypogonadal men receiving T replacement. 10 eugonadal men receiving T and 19 eugonadal men not administered TRange: 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 dailyChange 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. [82]Double-blind RCT227 hypogonadal menAbout 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 groupsIn 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 gelSexual 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 applicationAll 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. [93]RCT56 menRange: 20–50 yrsTestosterone cypionate for 6 weeks in doses rising to 600 mg/wk and placebo for 6 weeks, separated by 6 weeks of no treatmentDifferences in YMRS and HAM-D scores84% 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. [108]RCT30 healthy men and 8 hypogonadal male patientsHealthy males: Range: 19–45 yrs; Mean: 28.2 yrs Hypogonadal men: Range: 23–40 yrs; Mean: 30.8 yrs15 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 weeksDifferences in depression-dejection dimension of the POMSSignificant 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. [69]Pre-/postanalyses40 men with prostate cancer treated with androgen blockade therapyRange: 44–83 yrs; Mean = 72.4 yrsAndrogen blockade therapy (flutamide and leuprolide) for 36 weeks and subsequently followed up for another 18 weeks after discontinuationChange in BDI scoresBDI 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. [95]Double-blind RCT31 healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuseRange: 18–45 yrs; Mean:  yrsLeuprolide 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 scoresBDI scores significantly increased during Lupron plus placebo compared with baseline and Lupron plus testosterone.

Kenny et al. [102]RCT11 men with early cognitive decline and bioavailable T levels below 128 ng/dLRange: 73–87 yrs; Mean:  yrsintramuscular testosterone (200 mg every 3 weeks) or placebo for 12 weeksChanges in GDS scoresNo significant changes were found in depression following T supplementation

Haren et al. [90]Double-blind RCT76 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/LRange: 60–86 yrs Mean:  yrs80 mg twice daily of testosterone undecanoate—TU (39 subjects) or identical placebo (37 placebo) for 12 monthsDifferences in GDS scoresFrom 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. [94]RCT60 healthy menRange: 60–75 yrsMonthly 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 weeksChanges in HAM-D and YMRSBaseline 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. [85]Double-blind RCT184 men with TT below 12.0 nmol/L or FT below 225 pmol/L, and a diagnosis of the MetSRange: 35–69 yrs; Mean:  yrs30 weeks with either parenteral testosterone undecanoate (1,000 mg i.m., at baseline, and after 6 and 18 weeks) or placebo injectionsAssociation between BDI and TT. Changes in BDI scoresAt baseline, BDI scores significantly correlated with TT ( ). More improvements in BDI for those treated with T (mean difference versus placebo after 30 weeks: −2.5 points).

Aloisi et al. [88]Open label9 opioid-induced hypogonadic men. T less than 2-3 ng/mL in at least two determinations in the previous 3-4 monthsRange: 38–74 yrs; Mean:  yrsOne-month supply of testosterone gel, a hydroalcoholic compound containing 50 mg testosterone in 5 g gel in each sachet for 1 yearChange in CES-D scores from baselineCES-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.

Author, yearType of studySample sizeAgeTreatmentOutcome measuresResults

Seidman and Rabkin [98]Open-label5 depressed men who had low T levels and had not responded to an adequate SSRI trialRange: 34–50 yrs; Mean: yrs400 mg testosterone replacement biweekly for 8 weeksChanges in HAM-D scores from baselineSignificant recovery from major depression following T augmentation.

Perry et al. [97]RCT15 elderly eugonadal males with MDD (HAM-D > 18)Mean: yrsFollowing 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 weeksChanges in HAM-D scores42% 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. [101]Double-blind RCT22 MDD patients with morning serum TT of 350 ng/dL or less who were receiving antidepressant treatmentRange: 30–65 yrs; Mean: (T group) and (placebo group)12 men received 1% testosterone gel (10 g/day) and 10 received placeboBDI, HAM-D, CGI-SSubjects 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. [99]RCT12 hypogonadal men who were receiving antidepressants (on appropriate dose) for a minimum of 6 weeksRange: 52–80 yrs; Mean: yrsPlacebo or active T gel 1% at a dose of 5 g for 24 weeksDifferences in HAM-D scoresThere 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 [84]Double blind RCT30 men with low and low-normal T levels (i.e., total T <or = 350 ng/dL) and MDDRange: 33–71 yrs; Mean: yrsWeekly intramuscular injections of either T enanthate 200 mg or placebo for 6 weeksDifferences in HAM-D scoresThe HAM-D scores decreased significantly in both T and placebo groups, and there were no significant between-group differences.

Shores et al. [86]Double-blind RCT followed by an open-label extension phase33 men with TT levels of ≤280 ng/dL and subthreshold depression (dysthymia or minor depression, according to DSM-IV)All 50+ yrs old; Mean: yrs (T); yrs (placebo)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 gelDifferences in HAM-D scoresAt 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. [87]Double-blind RCT23 men with dysthymic disorder and with low or low-normal T level (i.e, TT < 350 ng/dL)Mean: yrs200 mg of testosterone cypionate im or placebo every 10 days for 6 weeksDifference in HAM-D and CGI-IHAM-D score decreased significantly more in the T group ( ) than in the placebo group ( ). Patients in the T group were more likely to remit (53.8% versus 10%) than patients in the placebo group.

Pope et al. [91]Double-blind RCT100 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/dLMean: and , respectively for those treated wih T and those in the placebo groupPlacebo 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/dayDifference in HAM-D and MADRSNo 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 [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 ( ). 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; ). 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. Mood improved and the improvement was maintained with continued treatment.

Recently, Shores et al. [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 ( ) and a higher remission rate of subthreshold depression (52.9% versus 18.8%, ) 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 ( ).

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 [8991].

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 [98100]. 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 short-term 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].

4. 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, 114116]. 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 [117119] and may be on cognitive functions [57, 120122].

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.

Conflict of Interests

The authors declare that there is no conflict of interest associated with this manuscript.

References

  1. A. Nardozza Jr., S. Szelbracikowski Sdos, A. C. Nardi, and J. C. Almeida, “Age-related testosterone decline in a Brazilian cohort of healthy military men,” International Brazilian Journal of Urology, vol. 37, pp. 591–597, 2011. View at: Google Scholar
  2. A. B. Araujo, A. B. O'Donnell, D. J. Brambilla et al., “Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts male aging study,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 12, pp. 5920–5926, 2004. View at: Publisher Site | Google Scholar
  3. G. Valenti, “The pathway of partial androgen deficiency of aging male,” Journal of Endocrinological Investigation, vol. 28, no. 11, pp. 28–33, 2005. View at: Google Scholar
  4. C. A. Allan and R. I. McLachlan, “Age-related changes in testosterone and the role of replacement therapy in older men,” Clinical Endocrinology, vol. 60, no. 6, pp. 653–670, 2004. View at: Publisher Site | Google Scholar
  5. C. C. Liu, W. J. Wu, Y. C. Lee et al., “The prevalence of and risk factors for androgen deficiency in aging Taiwanese men,” Journal of Sexual Medicine, vol. 6, no. 4, pp. 936–946, 2009. View at: Publisher Site | Google Scholar
  6. J. E. Lackner, E. Rucklinger, G. Schatzl, G. Lunglmayr, and C. W. Kratzik, “Are there symptom-specific testosterone thresholds in aging men?” British Journal of Urology International, vol. 108, pp. 1310–1315, 2011. View at: Google Scholar
  7. F. C. W. Wu, A. Tajar, J. M. Beynon et al., “Identification of late-onset hypogonadism in middle-aged and elderly men,” New England Journal of Medicine, vol. 363, no. 2, pp. 123–135, 2010. View at: Publisher Site | Google Scholar
  8. E. Nieschlag, R. Swerdloff, H. M. Behre et al., “Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations,” Journal of Andrology, vol. 27, no. 2, pp. 135–137, 2006. View at: Publisher Site | Google Scholar
  9. C. Wang, E. Nieschlag, R. Swerdloff et al., “Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations,” European Journal of Endocrinology, vol. 159, no. 5, pp. 507–514, 2008. View at: Publisher Site | Google Scholar
  10. A. Vermeulen, “Hormonal cut-offs of partial androgen deficiency: a survey of androgen assays,” Journal of Endocrinological Investigation, vol. 28, no. 3, pp. 28–31, 2005. View at: Google Scholar
  11. W. Rosner, R. J. Auchus, R. Azziz, P. M. Sluss, and H. Raff, “Position statement: utility, limitations, and pitfalls in measuring testosterone: an endocrine society position statement,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 2, pp. 405–413, 2007. View at: Publisher Site | Google Scholar
  12. S. Bhasin and A. M. Matsumoto, “Patient information page from The Hormone Foundation. Patient guide to testosterone therapy in adult men with androgen deficiency syndromes,” The Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 6, pp. 2–3085, 2010. View at: Google Scholar
  13. S. Bhasin, A. Zhang, A. Coviello et al., “The impact of assay quality and reference ranges on clinical decision making in the diagnosis of androgen disorders,” Steroids, vol. 73, no. 13, pp. 1311–1317, 2008. View at: Publisher Site | Google Scholar
  14. S. M. Harman, E. J. Metter, J. D. Tobin, J. Pearson, and M. R. Blackman, “Longitudinal effects of aging on serum total and free testosterone levels in healthy men,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 724–731, 2001. View at: Publisher Site | Google Scholar
  15. S. A. Hall, G. R. Esche, A. B. Araujo et al., “Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 10, pp. 3870–3877, 2008. View at: Publisher Site | Google Scholar
  16. A. W. Meikle, D. T. Bishop, J. D. Stringham, and D. W. West, “Quantitating genetic and nongenetic factors that determine plasma sex steroid variation in normal male twins,” Metabolism, vol. 35, no. 12, pp. 1090–1095, 1986. View at: Google Scholar
  17. H. E. Turner and J. A. H. Wass, “Gonadal function in men with chronic illness,” Clinical Endocrinology, vol. 47, no. 4, pp. 379–403, 1997. View at: Google Scholar
  18. V. Rochira, L. Zirilli, G. Orlando, D. Santi, G. Brigante, and C. Diazzi, “Premature decline of serum total testosterone in HIV-infected men in the HAART-Era,” PLoS ONE, vol. 6, Article ID e28512, 2011. View at: Google Scholar
  19. M. M. Miner, M. Khera, R. K. Bhattacharya, G. Blick, and H. Kushner, “Baseline data from the TRiUS registry: symptoms and comorbidities of testosterone deficiency,” Postgraduate Medicine, vol. 123, no. 3, pp. 17–27, 2011. View at: Google Scholar
  20. M. R. MacAdams, R. H. White, and B. E. Chipps, “Reduction of serum testosterone levels during chronic glucocorticoid therapy,” Annals of Internal Medicine, vol. 104, no. 5, pp. 648–651, 1986. View at: Google Scholar
  21. A. Vermeulen, J. M. Kaufman, and V. A. Giagulli, “Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 5, pp. 1821–1826, 1996. View at: Publisher Site | Google Scholar
  22. S. G. Anderson, A. Heald, N. Younger, S. Bujawansa, R. P. Narayanan, A. McCulloch et al., “Screening for hypogonadism in diabetes 2008/9: results from the Cheshire Primary Care cohort,” Primary Care Diabetes, vol. 6, no. 2, pp. 143–148, 2011. View at: Google Scholar
  23. T. G. Travison, A. B. Araujo, V. Kupelian, A. B. O'Donnell, and J. B. McKinlay, “The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 2, pp. 549–555, 2007. View at: Publisher Site | Google Scholar
  24. P. B. Gray, C. F. Yang, and H. G. Pope, “Fathers have lower salivary testosterone levels than unmarried men and married non-fathers in Beijing, China,” Proceedings of the Biological Sciences, vol. 273, no. 1584, pp. 333–339, 2006. View at: Publisher Site | Google Scholar
  25. A. B. Araujo, G. R. Esche, V. Kupelian et al., “Prevalence of symptomatic androgen deficiency in men,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 11, pp. 4241–4247, 2007. View at: Publisher Site | Google Scholar
  26. E. Nieschlag, R. Swerdloff, H. M. Behre et al., “Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations,” International Journal of Andrology, vol. 28, no. 3, pp. 125–127, 2005. View at: Publisher Site | Google Scholar
  27. J. B. Shelton and J. Rajfer, “Androgen deficiency in aging and metabolically challenged men,” Urologic Clinics of North America, vol. 39, pp. 63–75, 2012. View at: Google Scholar
  28. A. S. Burris, S. M. Banks, C. S. Carter, J. M. Davidson, and R. J. Sherins, “A long-term, prospective study of the physiologic and behavioral effects of hormone replacement in untreated hypogonadal men,” Journal of Andrology, vol. 13, no. 4, pp. 297–304, 1992. View at: Google Scholar
  29. A. Hamidi Madani, A. Heidarzadeh, N. Akbari Parsa, F. Khosravi Darestani, and Z. Hamidi Madani, “A survey on relative frequency of metabolic syndrome and testosterone deficiency in men with erectile dysfunction,” International Urology and Nephrology, vol. 44, no. 3, pp. 667–672, 2012. View at: Google Scholar
  30. R. J. Urban, Y. H. Bodenburg, C. Gilkison et al., “Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis,” American Journal of Physiology, vol. 269, no. 5, pp. E820–E826, 1995. View at: Google Scholar
  31. J. S. Tenover, “Androgen administration to aging men,” Endocrinology and Metabolism Clinics of North America, vol. 23, no. 4, pp. 877–892, 1994. View at: Google Scholar
  32. N. Itoh and T. Tsukamoto, “Clinical aspects of partial androgen deficiency of aging male (PADAM),” Clinical Calcium, vol. 13, pp. 1432–1437, 2003. View at: Google Scholar
  33. E. O. Abu, A. Horner, V. Kusec, J. T. Triffitt, and J. E. Compston, “The localization of androgen receptors in human bone,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 10, pp. 3493–3497, 1997. View at: Publisher Site | Google Scholar
  34. N. A. Hibberts, A. E. Howell, and V. A. Randall, “Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp,” Journal of Endocrinology, vol. 156, no. 1, pp. 59–65, 1998. View at: Publisher Site | Google Scholar
  35. C. Wang, G. Alexander, N. Berman et al., “Testosterone replacement therapy improves mood in hypogonadal men—a clinical research center study,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 10, pp. 3578–3583, 1996. View at: Publisher Site | Google Scholar
  36. D. R. Rubinow and P. J. Schmidt, “Androgens, brain, and behavior,” American Journal of Psychiatry, vol. 153, no. 8, pp. 974–984, 1996. View at: Google Scholar
  37. A. A. Werner, “The male climacteric,” Journal of the American Medical Association, vol. 132, pp. 188–194, 1946. View at: Google Scholar
  38. R. B. Greenblatt, C. Nezhat, R. A. Roesel, and P. K. Natrajan, “Update on the male and female climacteric,” Journal of the American Geriatrics Society, vol. 27, no. 11, pp. 481–490, 1979. View at: Google Scholar
  39. Y. Sato, S. Kato, S. Ohnishi et al., “Analysis of clinical manifestations and endocrinological aspects of patients having PADAM-like symptoms,” Japanese Journal of Urology, vol. 95, no. 1, pp. 8–16, 2004. View at: Google Scholar
  40. G. M. Alexander, R. S. Swerdloff, C. Wang et al., “Androgen-behavior correlations in hypogonadal men and eugonadal men. II. Cognitive abilities,” Hormones and Behavior, vol. 33, no. 2, pp. 85–94, 1998. View at: Publisher Site | Google Scholar
  41. K. Walker, “The male climacteric,” Postgraduate Medical Journal, vol. 14, pp. 120–123, 1938. View at: Google Scholar
  42. W. W. Hochreiter, D. K. Ackermann, and H. P. Brütsch, “Andropause,” Therapeutische Umschau, vol. 62, no. 12, pp. 821–826, 2005. View at: Publisher Site | Google Scholar
  43. A. C. E. Spetz, L. Palmefors, R. S. P. Skobe et al., “Testosterone correlated to symptoms of partial androgen deficiency in aging men (PADAM) in an elderly Swedish population,” Menopause, vol. 14, no. 6, pp. 999–1005, 2007. View at: Publisher Site | Google Scholar
  44. R. S. McIntyre, D. Mancini, B. S. Eisfeld et al., “Calculated bioavailable testosterone levels and depression in middle-aged men,” Psychoneuroendocrinology, vol. 31, no. 9, pp. 1029–1035, 2006. View at: Publisher Site | Google Scholar
  45. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, Washington, DC, USA, 4th edition, 2000.
  46. L. Di, P. Sgrò, V. Fierro et al., “Prevalence of undiagnosed testosterone deficiency in aging athletes: does exercise training influence the symptoms of male hypogonadism?” Journal of Sexual Medicine, vol. 7, no. 7, pp. 2591–2601, 2010. View at: Publisher Site | Google Scholar
  47. J. Hintikka, L. Niskanen, H. Koivumaa-Honkanen et al., “Hypogonadism, decreased sexual desire, and long-term depression in middle-aged men,” Journal of Sexual Medicine, vol. 6, no. 7, pp. 2049–2057, 2009. View at: Publisher Site | Google Scholar
  48. M. Markianos, J. Tripodianakis, C. Istikoglou et al., “Suicide attempt by jumping: a study of gonadal axis hormones in male suicide attempters versus men who fell by accident,” Psychiatry Research, vol. 170, no. 1, pp. 82–85, 2009. View at: Publisher Site | Google Scholar
  49. E. A. Jankowska, A. Drohomirecka, B. Ponikowska et al., “Deficiencies in circulating testosterone and dehydroepiandrosterone sulphate, and depression in men with systolic chronic heart failure,” European Journal of Heart Failure, vol. 12, no. 9, pp. 966–973, 2010. View at: Publisher Site | Google Scholar
  50. S. Fukai, M. Akishita, S. Yamada et al., “Association of plasma sex hormone levels with functional decline in elderly men and women,” Geriatrics and Gerontology International, vol. 9, no. 3, pp. 282–289, 2009. View at: Publisher Site | Google Scholar
  51. A. Ponholzer, S. Madersbacher, M. Rauchenwald, S. Jungwirth, P. Fischer, and K. H. Tragl, “Serum androgen levels and their association to depression and Alzheimer dementia in a cohort of 75-year-old men over 5 years: results of the VITA study,” International Journal of Impotence Research, vol. 21, no. 3, pp. 187–191, 2009. View at: Publisher Site | Google Scholar
  52. A. A. Makhlouf, M. A. Mohamed, A. D. Seftel, and C. Neiderberger, “Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction,” International Journal of Impotence Research, vol. 20, no. 2, pp. 157–161, 2008. View at: Publisher Site | Google Scholar
  53. L. F. J. Morsink, N. Vogelzangs, B. J. Nicklas et al., “Associations between sex steroid hormone levels and depressive symptoms in elderly men and women: results from the Health ABC study,” Psychoneuroendocrinology, vol. 32, no. 8–10, pp. 874–883, 2007. View at: Publisher Site | Google Scholar
  54. C. W. Kratzik, G. Schatzl, J. E. Lackner et al., “Mood changes, body mass index and bioavailable testosterone in healthy men: results of the Androx Vienna Municipality Study,” BJU International, vol. 100, no. 3, pp. 614–618, 2007. View at: Publisher Site | Google Scholar
  55. F. Strasser, J. L. Palmer, L. R. Schover et al., “The impact of hypogonadism and autonomic dysfunction on fatigue, emotional function, and sexual desire in male with advanced center: a pilot study,” Cancer, vol. 107, no. 12, pp. 2949–2957, 2006. View at: Publisher Site | Google Scholar
  56. L. H. Berglund, H. S. Prytz, A. Perski, and J. Svartberg, “Testosterone levels and psychological health status in men from a general population: the Tromsø study,” Aging Male, vol. 14, no. 1, pp. 37–41, 2011. View at: Publisher Site | Google Scholar
  57. S. D. Moffat, A. B. Zonderman, E. Jeffrey Metter, M. R. Blackman, S. Mitchell Harman, and S. M. Resnick, “Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 11, pp. 5001–5007, 2002. View at: Publisher Site | Google Scholar
  58. A. Mazur, “Biosocial models of deviant behavior among male army veterans,” Biological Psychology, vol. 41, no. 3, pp. 271–293, 1995. View at: Publisher Site | Google Scholar
  59. J. M. Dabbs Jr., C. H. Hopper, and G. J. Jurkovic, “Testosterone and personality among college students and military veterans,” Personality and Individual Differences, vol. 11, no. 12, pp. 1263–1269, 1990. View at: Google Scholar
  60. U. Schweiger, M. Deuschle, B. Weber et al., “Testosterone, gonadotropin, and cortisol secretion in male patients with major depression,” Psychosomatic Medicine, vol. 61, no. 3, pp. 292–296, 1999. View at: Google Scholar
  61. A. Steiger, U. Von Bardeleben, K. Wiedemann, and F. Holsboer, “Sleep EEG and nocturnal secretion of testosterone and cortisol in patients with major endogenous depression during acute phase and after remission,” Journal of Psychiatric Research, vol. 25, no. 4, pp. 169–177, 1991. View at: Publisher Site | Google Scholar
  62. S. N. Seidman, A. B. Araujo, S. P. Roose et al., “Low testosterone levels in elderly men with dysthymic disorder,” American Journal of Psychiatry, vol. 159, no. 3, pp. 456–459, 2002. View at: Publisher Site | Google Scholar
  63. S. Halabi, E. G. Collins, N. Thorevska, M. J. Tobin, and F. Laghi, “Relationship between depressive symptoms and hypogonadism in men with COPD,” COPD, vol. 8, pp. 346–353, 2011. View at: Google Scholar
  64. E. Barrett-Connor, D. G. Von Mühlen, and D. Kritz-Silverstein, “Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 2, pp. 573–577, 1999. View at: Publisher Site | Google Scholar
  65. A. T. Beck, R. A. Steer, R. Ball, and W. F. Ranieri, “Comparison of Beck depression inventories -IA and -II in psychiatric outpatients,” Journal of Personality Assessment, vol. 67, no. 3, pp. 588–597, 1996. View at: Publisher Site | Google Scholar
  66. A. M. Lee, L. W. Chu, C. S. Y. Chong et al., “Relationship between symptoms of androgen deficiency and psychological factors and quality of life among Chinese men,” International Journal of Andrology, vol. 33, no. 5, pp. 755–763, 2010. View at: Publisher Site | Google Scholar
  67. M. M. Shores, K. L. Sloan, A. M. Matsumoto, V. M. Moceri, B. Felker, and D. R. Kivlahan, “Increased incidence of diagnosed depressive illness in hypogonadal older men,” Archives of General Psychiatry, vol. 61, no. 2, pp. 162–167, 2004. View at: Publisher Site | Google Scholar
  68. S. N. Seidman and B. T. Walsh, “Testosterone and depression in aging men,” American Journal of Geriatric Psychiatry, vol. 7, no. 1, pp. 18–33, 1999. View at: Google Scholar
  69. O. P. Almeida, A. Waterreus, N. Spry, L. Flicker, and R. N. Martins, “One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men,” Psychoneuroendocrinology, vol. 29, no. 8, pp. 1071–1081, 2004. View at: Publisher Site | Google Scholar
  70. A. B. Araujo, R. Durante, H. A. Feldman, I. Goldstein, and J. B. Mckinlay, “The relationship between depressive symptoms and male erectile dysfunction: cross-sectional results from the Massachusetts male aging study,” Psychosomatic Medicine, vol. 60, no. 4, pp. 458–465, 1998. View at: Google Scholar
  71. A. Booth, D. R. Johnson, and D. A. Granger, “Testosterone and men's depression: the role of social behavior,” Journal of Health and Social Behavior, vol. 40, no. 2, pp. 130–140, 1999. View at: Google Scholar
  72. S. N. Seidman, A. B. Araujo, S. P. Roose, and J. B. McKinlay, “Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men,” Biological Psychiatry, vol. 50, no. 5, pp. 371–376, 2001. View at: Publisher Site | Google Scholar
  73. E. Nieschlag and H. Behre, Testosterone: Action, Deficiency, Substitution, Cambridge University Press, 2004.
  74. M. Zitzmann and E. Nieschlag, “The CAG repeat polymorphism within the androgen receptor gene and maleness,” International Journal of Andrology, vol. 26, no. 2, pp. 76–83, 2003. View at: Publisher Site | Google Scholar
  75. J. S. Janowsky, “Thinking with your gonads: testosterone and cognition,” Trends in Cognitive Sciences, vol. 10, no. 2, pp. 77–82, 2006. View at: Publisher Site | Google Scholar
  76. M. Robichaud and G. Debonnel, “Oestrogen and testosterone modulate the firing activity of dorsal raphe nucleus serotonergic neurones in both male and female rats,” Journal of Neuroendocrinology, vol. 17, no. 3, pp. 179–185, 2005. View at: Publisher Site | Google Scholar
  77. B. E. H. Sumner and G. Fink, “Testosterone as well as estrogen increases serotonin2A receptor mRNA and binding site densities in the male rat brain,” Molecular Brain Research, vol. 59, no. 2, pp. 205–214, 1998. View at: Publisher Site | Google Scholar
  78. G. Fink, B. Sumner, R. Rosie, H. Wilson, and J. McQueen, “Androgen actions on central serotonin neurotransmission: relevance for mood, mental state and memory,” Behavioural Brain Research, vol. 105, no. 1, pp. 53–68, 1999. View at: Publisher Site | Google Scholar
  79. C. E. Brown-Séquard, “Effects in man of subcutaneous injections of freshly prepared liquid from guinea pig and dog testes,” Comptes Rendus des Séances et Mémoires de la Société de Biologie, vol. 9, pp. 415–149, 1889. View at: Google Scholar
  80. C. E. Brown-Séquard, “On a new therapeutic method consisting in the use of organic liquids extracted from glands and other organs,” The Lancet, vol. 134, no. 3438, pp. 105–107, 1889. View at: Google Scholar
  81. C. E. Brown-Séquard, “On a new therapeutic method consisting in the use of organic liquids extracted from glands and other organs,” British Medical Journal, vol. 1, pp. 1212–1214, 1893. View at: Google Scholar
  82. C. Wang, R. S. Swerdloff, A. Iranmanesh et al., “Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men,” Journal of Clinical Endocrinology and Metabolism, vol. 85, pp. 2839–2853, 2000. View at: Google Scholar
  83. R. Amiaz, H. G. Pope, T. Mahne et al., “Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial,” Journal of Sex and Marital Therapy, vol. 37, no. 4, pp. 243–254, 2011. View at: Publisher Site | Google Scholar
  84. S. N. Seidman and S. P. Roose, “The sexual effects of testosterone replacement in depressed men: randomized, placebo-controlled clinical trial,” Journal of Sex and Marital Therapy, vol. 32, no. 3, pp. 267–273, 2006. View at: Publisher Site | Google Scholar
  85. E. J. Giltay, Y. A. Tishova, G. J. Mskhalaya, L. J. Gooren, F. Saad, and S. Y. Kalinchenko, “Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome,” Journal of Sexual Medicine, vol. 7, no. 7, pp. 2572–2582, 2010. View at: Publisher Site | Google Scholar
  86. M. M. Shores, D. R. Kivlahan, T. I. Sadak, E. J. Li, and A. M. Matsumoto, “A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression),” Journal of Clinical Psychiatry, vol. 70, no. 7, pp. 1009–1016, 2009. View at: Publisher Site | Google Scholar
  87. S. N. Seidman, G. Orr, G. Raviv et al., “Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial,” Journal of Clinical Psychopharmacology, vol. 29, no. 3, pp. 216–221, 2009. View at: Publisher Site | Google Scholar
  88. A. M. Aloisi, I. Ceccarelli, M. Carlucci et al., “Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients,” Reproductive Biology and Endocrinology, vol. 9, article 26, 2011. View at: Publisher Site | Google Scholar
  89. M. Haren, I. Chapman, P. Coates, J. Morley, and G. Wittert, “Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly males with low-normal gonadal status,” Age and Ageing, vol. 34, no. 2, pp. 125–130, 2005. View at: Publisher Site | Google Scholar
  90. M. T. Haren, G. A. Wittert, I. M. Chapman, P. Coates, and J. E. Morley, “Effect of oral testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status,” Maturitas, vol. 50, no. 2, pp. 124–133, 2005. View at: Publisher Site | Google Scholar
  91. H. G. Pope Jr., R. Amiaz, B. P. Brennan et al., “Parallel-group placebo-controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment,” Journal of Clinical Psychopharmacology, vol. 30, no. 2, pp. 126–134, 2010. View at: Publisher Site | Google Scholar
  92. R. C. Daly, T. P. Su, P. J. Schmidt, M. Pagliaro, D. Pickar, and D. R. Rubinow, “Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers,” Psychoneuroendocrinology, vol. 28, no. 3, pp. 317–331, 2003. View at: Publisher Site | Google Scholar
  93. H. G. Pope Jr., E. M. Kouri, and J. I. Hudson, “Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial,” Archives of General Psychiatry, vol. 57, no. 2, pp. 133–140, 2000. View at: Google Scholar
  94. P. B. Gray, A. B. Singh, L. J. Woodhouse et al., “Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 7, pp. 3838–3846, 2005. View at: Publisher Site | Google Scholar
  95. P. J. Schmidt, K. L. Berlin, M. A. Danaceau et al., “The effects of pharmacologically induced hypogonadism on mood in healthy men,” Archives of General Psychiatry, vol. 61, no. 10, pp. 997–1004, 2004. View at: Publisher Site | Google Scholar
  96. N. T. Shamlian and M. G. Cole, “Androgen treatment of depressive symptoms in older men: a systematic review of feasibility and effectiveness,” Canadian Journal of Psychiatry, vol. 51, no. 5, pp. 295–299, 2006. View at: Google Scholar
  97. P. J. Perry, W. R. Yates, R. D. Williams et al., “Testosterone therapy in late-life major depression in males,” Journal of Clinical Psychiatry, vol. 63, no. 12, pp. 1096–1101, 2002. View at: Google Scholar
  98. S. N. Seidman and J. G. Rabkin, “Testosterone replacement therapy for hypogonadal men with SSRI- refractory depression,” Journal of Affective Disorders, vol. 48, no. 2-3, pp. 157–161, 1998. View at: Publisher Site | Google Scholar
  99. C. A. Orengo, L. Fullerton, and M. E. Kunik, “Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy,” Journal of Geriatric Psychiatry and Neurology, vol. 18, no. 1, pp. 20–24, 2005. View at: Publisher Site | Google Scholar
  100. L. Martínez-Mota and A. Fernández-Guasti, “Testosterone-dependent antidepressant-like effect of noradrenergic but not of serotonergic drugs,” Pharmacology Biochemistry and Behavior, vol. 78, no. 4, pp. 711–718, 2004. View at: Publisher Site | Google Scholar
  101. H. G. Pope Jr., G. H. Cohane, G. Kanayama, A. J. Siegel, and J. I. Hudson, “Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial,” American Journal of Psychiatry, vol. 160, no. 1, pp. 105–111, 2003. View at: Publisher Site | Google Scholar
  102. A. M. Kenny, G. Fabregas, C. Song, B. Biskup, and S. Bellantonio, “Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss,” Journals of Gerontology, vol. 59, no. 1, pp. 75–78, 2004. View at: Google Scholar
  103. S. Bhasin, G. R. Cunningham, F. J. Hayes et al., “Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 6, pp. 1995–2010, 2006. View at: Publisher Site | Google Scholar
  104. “Testosterone replacement therapy for male aging: ASA position statement,” Journal of Andrology, vol. 27, pp. 133–134, 2006. View at: Google Scholar
  105. G. G. T'Sjoen, S. De Vos, S. Goemaere et al., “Sex steroid level, androgen receptor polymorphism, and depressive symptoms in healthy elderly men,” Journal of the American Geriatrics Society, vol. 53, no. 4, pp. 636–642, 2005. View at: Publisher Site | Google Scholar
  106. S. Y. Wong, J. C. Leung, T. Kwok, C. Ohlsson, L. Vandenput, P. C. Leung et al., “Low DHEAS levels are associated with depressive symptoms in elderly Chinese men: results from a large study,” Asian Journal of Andrology, vol. 13, pp. 898–902, 2011. View at: Google Scholar
  107. G. M. Alexander, R. S. Swerdloff, C. Wang et al., “Androgen-behavior correlations in hypogonadal men and eugonadal men: I. Mood and response to auditory sexual stimuli,” Hormones and Behavior, vol. 31, no. 2, pp. 110–119, 1997. View at: Publisher Site | Google Scholar
  108. D. B. O'Connor, J. Archer, W. M. Hair, and F. C. W. Wu, “Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men,” Physiology and Behavior, vol. 75, no. 4, pp. 557–566, 2002. View at: Publisher Site | Google Scholar
  109. A. M. Matsumoto, “Andropause: clinical implications of the decline in serum testosterone levels with aging in men,” Journals of Gerontology, vol. 57, no. 2, pp. M76–M99, 2002. View at: Google Scholar
  110. R. L. Ferrini and E. Barrett-Connor, “Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men,” American Journal of Epidemiology, vol. 147, no. 8, pp. 750–754, 1998. View at: Google Scholar
  111. H. D. Anderson, W. D. Pace, A. M. Libby, D. R. West, and R. J. Valuck, “Rates of 5 common antidepressant side effects among new adult and adolescent cases of depression: a retrospective US claims study,” Clinical Therapeutics, vol. 34, no. 1, pp. 113–123, 2012. View at: Google Scholar
  112. M. A. Whooley and G. E. Simon, “Managing depression in medical outpatients,” New England Journal of Medicine, vol. 343, no. 26 I, pp. 1942–1950, 2000. View at: Publisher Site | Google Scholar
  113. K. Kroenke, S. L. West, R. Swindle et al., “Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial,” Journal of the American Medical Association, vol. 286, no. 23, pp. 2947–2955, 2001. View at: Google Scholar
  114. A. D. Seftel, R. J. Mack, A. R. Secrest, and T. M. Smith, “Restorative increases in serum testosterone levels are significantly correlated to improvements in sexual functioning,” Journal of Andrology, vol. 25, no. 6, pp. 963–972, 2004. View at: Google Scholar
  115. X. H. Zhang, A. Morelli, M. Luconi et al., “Testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum,” European Urology, vol. 47, no. 3, pp. 409–416, 2005. View at: Publisher Site | Google Scholar
  116. A. Morelli, S. Filippi, R. Mancina et al., “Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa,” Endocrinology, vol. 145, pp. 2253–2263, 2004. View at: Google Scholar
  117. I. Sinha-Hikim, M. Cornford, H. Gaytan, M. L. Lee, and S. Bhasin, “Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 8, pp. 3024–3033, 2006. View at: Publisher Site | Google Scholar
  118. S. Bhasin, L. Woodhouse, R. Casaburi et al., “Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 2, pp. 678–688, 2005. View at: Publisher Site | Google Scholar
  119. S. T. Page, J. K. Amory, F. D. Bowman et al., “Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 3, pp. 1502–1510, 2005. View at: Publisher Site | Google Scholar
  120. P. P. Thilers, S. W. S. MacDonald, and A. Herlitz, “The association between endogenous free testosterone and cognitive performance: a population-based study in 35 to 90 year-oldmen and women,” Psychoneuroendocrinology, vol. 31, no. 5, pp. 565–576, 2006. View at: Publisher Site | Google Scholar
  121. M. M. Cherrier, A. M. Matsumoto, J. K. Amory et al., “The role of aromatization in testosterone supplementation: effects on cognition in older men,” Neurology, vol. 64, no. 2, pp. 290–296, 2005. View at: Google Scholar
  122. A. M. Kenny, S. Bellantonio, C. A. Gruman, R. D. Acosta, and K. M. Prestwood, “Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels,” Journals of Gerontology, vol. 57, no. 5, pp. M321–M325, 2002. View at: Google Scholar
  123. A. Vermeulen, “Andropause,” Maturitas, vol. 34, no. 1, pp. 5–15, 2000. View at: Publisher Site | Google Scholar
  124. J. K. Amory, N. B. Watts, K. A. Easley et al., “Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 2, pp. 503–510, 2004. View at: Publisher Site | Google Scholar

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