ArticleLiterature Review

Testosterone Supplementation for Depressed Men: Current Research and Suggested Treatment Guidelines

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Abstract

Several lines of accumulating evidence suggest that testosterone might be effective for the treatment of depression, especially in older men who exhibit low testosterone levels. However, despite the potential promise of this approach, the available literature of controlled studies of testosterone in depression remains extremely limited. Therefore, testosterone treatment of depression must still be considered an experimental procedure. At the present state of research, it appears that testosterone might most likely show benefit as an augmentation strategy in men who exhibit low or borderline testosterone levels and who show only a partial response to conventional antidepressants. In this article, we provide some suggested practical guidelines for the treatment of such individuals. However, it should be recognized that these suggestions are tentative and will likely require revision as additional data become available.

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... Some studies have found that testosterone replacement therapy (TRT) can relieve depression symptoms associated with hypogonadism [11][12][13]. A meta-analysis of 7 clinical studies showed that TRT significantly improved symptoms of depression in hypogonadal men when compared with placebo [12]. ...
... However, total PHQ-9 scores did not statistically correlate with any testosterone laboratory measures (TT, FT, or SHBG). At baseline, 17.3% (132/762) of the population had moderately severe to severe depression symptoms (score ≥15), 52% (396/762) had mild to moderate symptoms (score [5][6][7][8][9][10][11][12][13][14], and 31% (234/762) had minimal to no symptoms (score <5). The percentages of patients with moderately severe to severe depression symptoms was significantly higher in subcohorts defined by antidepressant or opioid use, self-reported depression history, age <60 years, TT levels <250 ng/dl (<8.68 nmol/l), and HIV/AIDS ( Figure 2), but not obesity (data not shown). ...
... Maximum benefit was seen at 12 months following TRT with a mean PHQ-9 score decrease of 5.62 ± 6.24 points, representing a clinical improvement (≥5 points [18]) in depression symptoms. After initiation of TRT, the percentage of patients with no or minimal depression symptoms (score <5) increased whereas the percentages of patients with mild to moderate (score [5][6][7][8][9][10][11][12][13][14] and moderately severe to severe (score 15-27) depression symptoms decreased ( Figure 4). Maximum benefit was seen at 12 months, when the percentage of patients with no or minimal symptoms increased significantly (p < 0.0001) from 31% (234/762) at baseline to 60% (140/233), and the percentage of patients with moderately severe to severe depression decreased significantly (p < 0.0001) from 17% (132/762) at baseline to 2% (5/233). ...
Article
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Objective: To determine the effect of long-term testosterone replacement therapy (TRT) on depression symptoms in hypogonadal men. Methods: Data were from TRiUS, a multicenter, 12-month observational registry (N = 849) of hypogonadal men prescribed 1% testosterone gel. Measures including total testosterone (TT) were assessed at baseline and months 3, 6, and 12. Depression symptoms were measured with Patient Health Questionnaire-9 (PHQ-9), a validated self-report questionnaire. A PHQ-9 score decrease of ≥5 represents clinical improvement. Results PHQ-9 scores were available for 762/849 TRiUS participants at baseline. Overall, 92.4% (704/762) demonstrated some level of depressive symptoms, with 17.3% (132/762) having moderately severe (score 15–19) to severe (score 20–27) symptoms. Subcohorts with significantly (p ≤ 0.03) more moderately severe to severe symptoms were: <60 years old, TT levels <250 ng/dl (<8.68 nmol/l), HIV/AIDS-positive, or used antidepressants or opioids. TT levels and PHQ-9 scores improved significantly (p < 0.01) by 3 months of TRT. At 12 months PHQ-9 scores showed a clinically meaningful mean improvement of 5.62 points, patients with moderately severe to severe symptoms decreased from 17.3% to 2.1% (5/233), and subcohorts, including those defined by age (<60 years) and antidepressant use, had improved PHQ-9 scores ≥5. Conclusion: TRT may reduce depression symptoms in hypogonadal men, including middle-aged men and those using antidepressants.
... Some studies have found that testosterone replacement therapy (TRT) can relieve depression symptoms associated with hypogonadism [11][12][13]. A meta-analysis of 7 clinical studies showed that TRT significantly improved symptoms of depression in hypogonadal men when compared with placebo [12]. ...
... However, total PHQ-9 scores did not statistically correlate with any testosterone laboratory measures (TT, FT, or SHBG). At baseline, 17.3% (132/762) of the population had moderately severe to severe depression symptoms (score ≥15), 52% (396/762) had mild to moderate symptoms (score [5][6][7][8][9][10][11][12][13][14], and 31% (234/762) had minimal to no symptoms (score <5). The percentages of patients with moderately severe to severe depression symptoms was significantly higher in subcohorts defined by antidepressant or opioid use, self-reported depression history, age <60 years, TT levels <250 ng/dl (<8.68 nmol/l), and HIV/AIDS ( Figure 2), but not obesity (data not shown). ...
... Maximum benefit was seen at 12 months following TRT with a mean PHQ-9 score decrease of 5.62 ± 6.24 points, representing a clinical improvement (≥5 points [18]) in depression symptoms. After initiation of TRT, the percentage of patients with no or minimal depression symptoms (score <5) increased whereas the percentages of patients with mild to moderate (score [5][6][7][8][9][10][11][12][13][14] and moderately severe to severe (score 15-27) depression symptoms decreased ( Figure 4). Maximum benefit was seen at 12 months, when the percentage of patients with no or minimal symptoms increased significantly (p < 0.0001) from 31% (234/762) at baseline to 60% (140/233), and the percentage of patients with moderately severe to severe depression decreased significantly (p < 0.0001) from 17% (132/762) at baseline to 2% (5/233). ...
Article
Full-text available
To determine the effect of long-term testosterone replacement therapy (TRT) on depression symptoms in hypogonadal men. Data were from TRiUS, a multicenter, 12-month observational registry (N = 849) of hypogonadal men prescribed 1% testosterone gel. Measures including total testosterone (TT) were assessed at baseline and months 3, 6, and 12. Depression symptoms were measured with Patient Health Questionnaire-9 (PHQ-9), a validated self-report questionnaire. A PHQ-9 score decrease of ≥5 represents clinical improvement. PHQ-9 scores were available for 762/849 TRiUS participants at baseline. Overall, 92.4% (704/762) demonstrated some level of depressive symptoms, with 17.3% (132/762) having moderately severe (score 15-19) to severe (score 20-27) symptoms. Subcohorts with significantly (p ≤ 0.03) more moderately severe to severe symptoms were: <60 years old, TT levels <250 ng/dl (<8.68 nmol/l), HIV/AIDS-positive, or used antidepressants or opioids. TT levels and PHQ-9 scores improved significantly (p < 0.01) by 3 months of TRT. At 12 months PHQ-9 scores showed a clinically meaningful mean improvement of 5.62 points, patients with moderately severe to severe symptoms decreased from 17.3% to 2.1% (5/233), and subcohorts, including those defined by age (<60 years) and antidepressant use, had improved PHQ-9 scores ≥5. TRT may reduce depression symptoms in hypogonadal men, including middle-aged men and those using antidepressants.
... Neuroactive steroid hormones (progesterone, testosterone, and estradiol) may have excitatory and inhibitory effects in the brain (Rupprecht and Holsboer, 1999a, b; Zinder and Dar, 1999; Rupprecht, 2003). There is increasing evidence that the neuroactive steroid hormones may attenuate anxiety and depression (Su et al, 1993; Pope and Brower, 2000; Rupprecht, 2003; Kanayama et al, 2007; Rupprecht et al, 2009), and these conditions often are associated with cocaine abuse and propensity for relapse after cessation of use (Gold, 1997; Mello and Mendelson, 2010). An emerging literature suggests that the neuroactive steroid hormones may enhance or diminish cocaine's reinforcing effects (see for a review, Lynch et al, 2002; Mello and Mendelson, 2002, 2009; Carroll et al, 2004; Evans, 2007; Anker and Carroll, 2010; Evans and Foltin, 2010). ...
... Progesterone is often associated with dysphoric mood, fatigue, and sedation in normally cycling and post-menopausal women (Freeman et al, 1992; Schechter, 1999; Andreen et al, 2006). Although testosterone does not have acute intoxicating effects (Fingerhood et al, 1997; Kanayama et al, 2009), during chronic treatment, it has mood-enhancing effects in oophorectomized women (Shifren et al, 2000) and in men with and without a history of steroid abuse (Kanayama et al, 2007Kanayama et al, , 2009). These clinical data suggest that if testosterone and progesterone had similar effects on the abuse-related effects of cocaine, testosterone's mood-enhancing effects might make it more acceptable to patients. ...
... The clinical profile of testosterone is very different from that of progesterone. Testosterone is often self-administered by body builders (Kanayama et al, 2009; Pope and Brower, 2000) and is effective in reducing depression, and increasing general feelings of well-being and libido in oophorectomized women (Shifren et al, 2000) and elderly men ( Kanayama et al, 2007). In contrast to our findings in non-human primates, testosterone is a weak reinforcer in rats and hamsters (see for a review, Wood, 2004). ...
Article
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The neuroactive steroid hormone progesterone attenuates cocaine's abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose-effect curves in female rhesus monkeys. Cocaine self-administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose-effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032-0.32 mg/kg, i.m.) and testosterone (0.001-0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose-effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse.
... By generating a large set of TSC-strength configurations adapted to SSRI and each of 74 different chronic drug/hormone combinations in a computational model of the male MSS system, we identified candidate combinations that could potentially provide symptomatic relief to a larger proportion of depressed male patients than the current first-line approach. Additionally, our modeling results support preliminary clinical findings that augmentation of SSRI action with testosterone can provide depression relief in a larger proportion of male depressives ( Kanayama et al., 2007 ). ...
... It shows that certain combinations of antidepressants and the hormone testosterone could be more effective than SSRI by itself as a treatment for depression in men. Preliminary clinical studies suggest that testosterone supplementation can enhance the antidepressant response ( Kanayama et al., 2007 ;Miclea et al., 2018 ;Orengo et al., 2005 ). The combinations that included an SSRI, another drug that targeted the monoamines, and testosterone were in the upper range of the Fig. 6 heatmap close to the therapeutic reference vector. ...
Article
Second-line depression treatment involves augmentation with one (rarely two) additional drugs, of chronic administration of a selective serotonin reuptake inhibitor (SSRI), which is the first-line depression treatment. Unfortunately, many depressed patients still fail to respond even after months to years of searching to find an effective combination. To aid in the identification of potentially effective antidepressant combinations, we created a computational model of the monoaminergic neurotransmitter (serotonin, norepinephrine, and dopamine), stress-hormone (cortisol), and male sex hormone (testosterone) systems. The model was trained via machine learning to represent a broad range of empirical observations. Neuroadaptation to chronic drug administration was simulated through incremental adjustments in model parameters that corresponded to key regulatory components of the neurotransmitter and neurohormone systems. Analysis revealed that neuroadaptation in the model depended on all of the regulatory components in complicated ways, and did not reveal any one or a few specific components that could be targeted in the design of antidepressant treatments. We used large sets of neuroadapted states of the model to screen 74 different drug and hormone combinations and identified several combinations that could potentially be therapeutic for a higher proportion of male patients than SSRIs by themselves.
... By generating a large set of TSC-strength configurations adapted to SSRI and each of 74 different chronic drug/hormone combinations in a computational model of the male MSS system, we identified candidate combinations that could potentially provide symptomatic relief to a larger proportion of depressed male patients than the current first-line approach. Additionally, our modeling results support preliminary clinical findings that augmentation of SSRI action with Testosterone can provide depression relief in a larger proportion of male depressives (Kanayama et al., 2007;Scantamburlo et al., 2015). ...
... It shows that certain combinations of antidepressants and the hormone testosterone could be more effective than SSRI by itself as a treatment for depression in men. Preliminary clinical studies suggest that Testosterone supplementation can enhance the antidepressant response (Kanayama et al., 2007;Miclea et al., 2018;Orengo et al., 2005). The combinations that included an SSRI, another drug that targeted the monoamines, and Testosterone were in the upper range of the Figure 6 heatmap close to the therapeutic reference vector. ...
Preprint
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Second-line depression treatment involves augmentation with one (rarely two) additional drugs, of chronic administration of a selective serotonin reuptake inhibitor (SSRI), which is the first-line depression treatment. Unfortunately, many depressed patients still fail to respond even after months to years of searching to find an effective combination. To aid in the identification of potentially affective antidepressant combinations, we created a computational model of the monoaminergic neurotransmitter (serotonin, norepinephrine, and dopamine), stress-hormone (cortisol), and male sex-hormone (testosterone) systems. The model was trained via machine learning to represent a broad set of empirical observations. Neuroadaptation to chronic drug administration was simulated through incremental adjustments in model parameters that corresponded to key regulatory components of the neurotransmitter and neurohormone systems. Analysis revealed that neuroadaptation in the model depended on all of the regulatory components in complicated ways, and did not reveal any one or a few specific components that could be targeted in the design of combination antidepressant treatment. We used large sets of neuroadapted states of the model to screen 74 different drug and hormone combinations and identified several combinations that could potentially be therapeutic for a higher proportion of male patients than SSRIs by themselves.
... It has been shown that a low testosterone level in hypogonadal men is associated with numerous non-specific symptoms including depression and anxiety (Alkamel et al., 2014;Khera, 2013). Among them, testosterone-replacement therapy has been shown to greatly improve mood, alleviate anxiety and mitigate symptoms of depression (Kanayama et al., 2007;Zarrouf et al., 2009). Jovanovic et al. also showed that testosterone modulates serotoninergic transmission playing a crucial role in the development of depression (Jovanovic et al., 2015). ...
... Studies investigating the effect of the testosterone-replacement therapy are also inconsistent. Some studies have shown testosterone therapy to improve mood and mitigate symptoms of depression in hypogonadal men (Kanayama et al., 2007;Pope et al., 2003). Additionally, frail older men with low testosterone levels might benefit from testosterone therapy, as it appears to improve quality of life and physical function. ...
Article
Background: Several studies have shown a positive association between depression and obesity; however the underlying mechanisms are not fully understood. It is not known if this association is driven by altered sex hormone levels in men due to increased BMI. Patients and methods: Data were obtained from the LIFE-Adult-Study, a population-based cohort study. A total of 3925 men (2244<60years and 1681>60years) were included into analyses. Associations between BMI, sex hormones and depressive symptomatology according to CES-D score were evaluated. Results: Obese men had compared to normal weight controls lower total testosterone (12.6±4.7 vs 19.4±5.5 nmol/L, p<0.001 in <60years, and 13.8±6.9 vs 18.3±5.9 nmol/L, p<0.001 in >60years group) and free testosterone (249.0±73.9 vs 337.2±82.0pmol/L, p<0.001, and 217.8±71.2 vs 263.4±72.2pmol/L, p<0.001), and increased estradiol in older group only (97.3±43.0 vs 82.3±34.2pmol/L, p<0.001 in obese). Men <60years old with depressive symptomatology had higher estradiol levels compared to those without depressive symptomatology (96.3±40.7 vs 84.4±36.6pmol/L, p<0.001), however no association with BMI was observed. Conclusions: Selected sex hormone parameters were significantly different in overweight and obese compared to normal weight males and certain differences could be seen between younger and older males. Depressive symptomatology was associated with increased estradiol levels in younger men, regardless of BMI.
... Androgen increases dopamine production in the mesencephalic limbic system, which can prevent the decrease of dopamine activity in the brain and the associated depression-induced loss of pleasure [9,10]. A study of male subjects suffering from hypogonadism has shown that decreased testosterone (T) increases the prevalence of depression in patients with hypogonadism [11] and that T supplementation was able to significantly improve their depression and anxiety symptoms [12,13]. However, in a different study, T replacement therapy showed no significant improvement in depressive symptoms in androgen deficient men compared to placebo-treated controls [14]. ...
Article
Full-text available
The interaction between the endocrine system and inflammation is crucial pathogenesis of depression. Our study aimed at exploring the possible relationship between sex hormones and growth differentiation factor-15 (GDF-15), a common indicator of inflammation in male patients with major depressive disorder (MDD). Methods: GDF-15 levels of 121 male MDD patients were compared with 105 healthy subjects with the help of a Cobas 8000 automatic chemiluminescence immunoanalyzer. Results: (1) MDD patients showed higher GDF-15 levels, a lower testosterone (T) level and testosterone/estradiol ratio (T/E2 ratio) than healthy subjects (all p < 0.05). (2) Serum T levels and the T/E2 ratio were inversely associated with GDF-15 serum levels (all p < 0.05). (3) HAMD-24 scores were positively correlated with the levels of GDF-15 (p < 0.01), but not with T levels, estradiol (E2) levels, and the T/E2 ratio (all p > 0.05). Conclusion: The high level of GDF-15 was correlated with a low T/E2 ratio and T deficiency in male MDD patients. The above results demonstrate that up-regulation of serum GDF-15 and down-regulation of T and T/E2 ratio may be correlated with the occurrence and severity of depression. So, changing the level of GDF-15 by regulating the proportion of sex hormones may play a key role in the prognosis and treatment of depression.
... 4 Further, the association between hypogonadism and depression is seen among both middle aged 89,97 and older men. 86,95 While the underlying pathophysiologic link between low testosterone and depression is supported by existing evidence in general, relatively few studies have assessed the potential effects of TRT on depression in middle aged and older hypogonadal men 6,15,23,24,28,29,31,98,99 Majority of current evidence is based on studies of small samples of men, specific subpopulations of hypogonadal men or correlations between testosterone levels (i.e. not clinically defined hypogonadism) and depression. ...
Thesis
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Hypogonadism is posited as a risk factor for depression. Limited evidence from randomized controlled trials (RCTs) suggests that testosterone replacement therapy (TRT) may improve depressive symptoms in hypogonadal men. However, evidence from real world, population-based studies is lacking. Moreover, TRT prescription increased by over three-fold for middle aged and older men in the past decade; however little is known about TRT prescribing patterns in men with depression. To the best of our knowledge, this is the first large-scale, real-world, nationally representative study of middle aged and older men to examine: a) TRT prescribing patterns, by depression status b) the association between untreated hypogonadism and incident depression and c) the risk of depression in hypogonadal men exposed to TRT. This dissertation used data from Clinformatics Data Mart-one of the nation’s largest commercial health insurance programs. The association between hypogonadism and depression was tested using a case-control study design. The effects of TRT on risk of depression were assessed using nested case control and retrospective cohort study designs. In order to examine TRT prescribing patterns, annual incident TRT use was calculated for each year from 2002-2016 and stratified by age and hypogonadal status. Separate conditional logistic regression models tested whether a) hypogonadism is associated with increased odds of incident depression and b) exposure to TRT in hypogonadal men is associated with reduced odds of incident depression. Cox proportional hazards regression analyses assessed whether exposure to TRT in hypogonadal men is associated with reduced risk of depression. For each given calendar year from 2002-2016, TRT prescription rates were higher among depressed men, compared to their counterparts; the overall increase was similar for the two groups. After adjusting for relevant covariates, we did not find a consistent association between hypogonadism and depression. No association was observed between TRT and depression. This dissertation will add significantly to current knowledge of TRT prescription patterns in depressed men. Contrary to our hypothesis, we did not find an association between TRT and depression. Our results will improve current knowledge regarding the link between hypogonadism, TRT and depression, and inform future research in light of methodological challenges discussed herein.
... Males with hypogonadism, which leads to a decrease in testosterone levels, have significantly higher rates of anxiety and depression (Shores et al., 2004;Zarrouf et al., 2009;Wainwright et al., 2011;Aydogan et al., 2012). Furthermore, hormone replacement therapy in men with a testosterone deficiency prevents or alleviates anxiety and depression (Wang et al., 1996;Seidman and Rabkin, 1998;Seidman et al., 2001;Pope et al., 2003;Kanayama et al., 2007;Zarrouf et al., 2009;Jung and Shin, 2016). Similarly, gonadectomized male rodents exhibit increased anxiety and depressive-like behavior, which is reversed following testosterone replacement treatment (Frye and Seliga, 2001;Edinger and Frye, 2005;Carrier and Kabbaj, 2012;Carrier et al., 2015). ...
Article
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The early life environment markedly influences brain and behavioral development, with adverse experiences associated with increased risk of anxiety and depressive phenotypes, particularly in females. Indeed, early life adversity (ELA) in humans (i.e., caregiver deprivation, maltreatment) and rodents (i.e., maternal separation, resource scarcity) is associated with sex-specific emergence of anxious and depressive behaviors. Although these disorders show clear sex differences in humans, little attention has been paid toward evaluating sex as a biological variable in models of affective dysfunction; however, recent rodent work suggests sex-specific effects. Two widely used rodent models of ELA approximate caregiver deprivation (i.e., maternal separation) and resource scarcity (i.e., limited bedding). While these approaches model aspects of ELA experienced in humans, they span different portions of the pre-weaning developmental period and may therefore differentially contribute to underlying mechanistic risk. This is borne out in the literature, where evidence suggests differences in trajectories of behavior depending on the type of ELA and/or sex; however, the neural underpinning of these differences is not well understood. Because anxiety and depression are thought to involve dysregulation in the balance of excitatory and inhibitory signaling in ELA-vulnerable brain regions (e.g., prefrontal cortex, amygdala, hippocampus), outcomes are likely driven by alterations in local and/or circuit-specific inhibitory activity. The most abundant GABAergic subtypes in the brain, accounting for approximately 40% of inhibitory neurons, contain the calcium-binding protein Parvalbumin (PV). As PV-expressing neurons have perisomatic and proximal dendritic targets on pyramidal neurons, they are well-positioned to regulate excitatory/inhibitory balance. Recent evidence suggests that PV outcomes following ELA are sex, age, and region-specific and may be influenced by the type and timing of ELA. Here, we suggest the possibility of a combined role of PV and sex hormones driving differences in behavioral outcomes associated with affective dysfunction following ELA. This review evaluates the literature across models of ELA to characterize neural (PV) and behavioral (anxiety- and depressive-like) outcomes as a function of sex and age. Additionally, we detail a putative mechanistic role of PV on ELA-related outcomes and discuss evidence suggesting hormone influences on PV expression/function which may help to explain sex differences in ELA outcomes.
... Hypogonadism is a clinical condition defined by serum testosterone concentrations of <250-300 ng/dL in men [20], and studies have shown a significant relationship between hypogonadism and depression in men [21]. Males undergoing androgen-depleting therapy for prostate cancer treatment also display a greater risk of developing MDD [22], while testosterone therapy appears to be effective in alleviating symptoms of depression in older hypogonadal men [10,[23][24][25][26]. Furthermore, an increase in circulating levels of testosterone along with low levels of sex-hormone-binding globulin (SHBG) is associated with cardiovascular disease, insulin resistance, and visceral obesity [27], while cardiovascular morbidity and mortality may be correlated with major depression [28]. ...
Article
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Testosterone’s role in female depression is not well understood, with studies reporting conflicting results. Here, we use meta-analytical and Mendelian randomization techniques to determine whether serum testosterone levels differ between depressed and healthy women and whether such a relationship is casual. Our meta-analysis shows a significant association between absolute serum testosterone levels and female depression, which remains true for the premenopausal group while achieving borderline significance in the postmenopausal group. The results from our Mendelian randomization analysis failed to show any causal relationship between testosterone and depression. Our results show that women with depression do indeed display significantly different serum levels of testosterone. However, the directions of the effect of this relationship are conflicting and may be due to menopausal status. Since our Mendelian randomization analysis was insignificant, the difference in testosterone levels between healthy and depressed women is most likely a manifestation of the disease itself. Further studies could be carried out to leverage this newfound insight into better diagnostic capabilities culminating in early intervention in female depression.
... Depression: Testosterone's long-known mood elevating properties, which led to its patenting as an anti-depressant in 1948 prior to the modern anti-depressant era (209), have recently resurfaced with recognition of testosterone's psychoactive, mood elevating effects (210,211). These produce pleasurable mood and sensations that may explain its modest efficacy as an adjuvant antidepressant for mild depression (212,213). ...
Article
Androgens are potent drugs requiring prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit non-medical application for performance or image enhancement. Following discovery and first clinical application of testosterone in the 1930s, commercialisation of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for anti-ageing, sexual dysfunction and/or obesity, where efficacy and safety remains unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, body-builders and others for image-oriented, cosmetic or occupational reasons.
... At times, the administration of testosterone actually improves male emotional state toward compassion and consideration of others depending on ones intrinsic temperament and permissive situational factors. In fact, at times testosterone can diminish aggression and other -negative' emotions while relieving aspects of general depression and fatigue (Kanayama and Seidman, 2007). An intriguing paper published some years ago focused on examination of two personality characteristics (dominance and anger) and their relationship to hormone level in over 1700 naturally aging males. ...
Chapter
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There has been a perennial debate about whether aggression is learned or innate. The power of extreme arguments in this area has diminished as all are beginning to recognize that both evolution and learning contribute much to our tendency to be aggressive in various distinct ways, including impulsive anger, premeditated predatory behavior in its many forms, as well as our seeking of dominance as exemplified best in inter-male jousting. Here we will be almost exclusively concerned with the biological roots of the type of impulsive aggression that arises from our genetically prescribed capacity for anger, and affective state that we label the RAGE circuitry of the brain.
... The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis caused by stress is related to the pathogenesis of depression (Kawabata et al., 2010), accompanied by the dysfunction of hypothalamic-pituitary-gonadal (HPG) axis (Mou et al., 2017). HPG axis was weakened in depressed individuals (Jin et al., 2019) and testosterone can improve depression mood in clinical therapy (Kanayama et al., 2007). HPA axis is the biological system responsible for stress response. ...
Article
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Ginseng (Panax ginseng Meyer), a famous traditional medicinal herb, has been widely used for many centuries. Numerous studies have shown that ginseng has a positive effect on the prevention and treatment of neurological disorders. In this review, we summarized the effects of ginseng in treating neurological diseases, particularly the anti-depressant effects of ginseng. Furthermore, its potential mechanism was also outlined. Therefore, this review may provide new insight into the treatment of ginseng on neurological diseases.
... In men, lower concentrations of androgens due to hypogonadism, androgen depletion therapy or related conditions were associated with anxiety and depressive symptoms and disorders ( DiBlasio et al., 2008;Dinh et al., 2017;Shores et al., 2004;Zarrouf et al., 2009). Consistently, androgen replacement therapy was associated with beneficial effects on anxiety and depression (Aydogan et al., 2012;Kanayama et al., 2007;Pope et al., 2003;Wang et al., 1996;Zarrouf et al., 2009). In women, periods of increased hormonal flux (e.g., the premenstrual, peripartum or menopausal period) ( Lambrinoudaki et al., 2015;Martini et al., 2015;Wittchen et al., 2002) and medical conditions associated with altered androgen concentrations (e.g., polycystic ovary syndrome, PCOS) ( Cooney et al., 2017;Dokras et al., 2012) were related to anxiety and depressive symptoms and disorders. ...
... Beginning a new life as one's desired sex may also have positive effects on mood among GD individuals (Costantino et al., 2013); further, some clinical evidence suggests that testosterone has antidepressant effects (McHenry, Carrier, Hull, & Kabbaj, 2014). Depressive symptoms, fatigue, and irritability have been found to be greatly reduced during testosterone replacement therapy (Kanayama, Amiaz, Seidman, & Pope, 2007;Pope, Cohane, Kanayama, Siegel, & Hudson, 2003;Wang et al., 1996). In our cohort, testosterone may have acted as an antidepressant by reducing general psychopathological symptoms. ...
Article
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Body dissatisfaction plays an important role in the development of psychiatric problems such as eating disorders as well as gender dysphoria (GD). Cross-sex hormonal treatment (CHT) alleviates the dissatisfaction by making various changes in the body. We examined the alteration of body uneasiness, eating attitudes and behaviors, and psychological symptoms longitudinally in Turkish participants with female-to-male gender dysphoria (FtM GD) after CHT. Thirty-seven participants with FtM GD and 40 female controls were asked to complete the Body Uneasiness Test to explore different areas of body-related psychopathology, the Eating Attitudes Test to assess eating disturbances, and the Symptom Checklist-90 Revised to measure psychological state, both before CHT and after 6 months of CHT administration. The baseline mean body weight, BMI scores, body uneasiness scores, and general psychopathological symptoms of participants with FtM GD were significantly higher than female controls, whereas baseline eating attitudes and behaviors were not significantly different. Over time, FtM GD participants’ mean body weight and BMI scores increased, body uneasiness and general psychopathological symptoms decreased, and eating attitudes and behaviors had not changed at 24th weeks following CHT administration compared to baseline. CHT may have a positive impact on body uneasiness and general psychopathological symptoms in participants with FtM GD. However, CHT does not have an impact on eating attitudes and behaviors.
... Hypogonadal men with low testosterone have an increased risk for developing anxiety-and stress-related disorders (DiBlasio et al., 2008;Shores et al., 2004;Zarrouf, Artz, Griffith, Sirbu, & Kommor, 2009). The risk of developing pathological anxiety can also be reversed with testosterone administration, improving affect and reducing anxiety and depression (Kanayama, Amiaz, Seidman, & Pope, 2007;Pope, Cohane, Kanayama, Siegel, & Hudson, 2003;Wang et al., 1996;Zarrouf et al., 2009). Moreover, testosterone replacement in castrated male rodents ameliorates anxiety behaviors (Hodosy et al., 2012;Khakpai, 2014). ...
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This article is part of a Special Issue "SBN 2014". Women are more vulnerable to stress- and fear-based disorders, such as anxiety and post-traumatic stress disorder. Despite the growing literature on this topic, the neural basis of these sex differences remains unclear, and the findings appear inconsistent. The neurobiological mechanisms of fear and stress in learning and memory processes have been extensively studied, and the crosstalk between these systems is beginning to explain the disproportionate incidence and differences in symptomatology and remission within these psychopathologies. In this review, we discuss the intersect between stress and fear mechanisms and their modulation by gonadal hormones and discuss the relevance of this information to sex differences in anxiety and fear-based disorders. Understanding these converging influences is imperative to the development of more effective, individualized treatments that take sex and hormones into account. Copyright © 2015. Published by Elsevier Inc.
... For further reading on how additional factors may influence gender differences in depression see, for example,Mendlewicz & Fleiss, 1974;Goldin & Gershon, 1983;Ehrhardt, 1985;Sevy, Mendlewicz & Mendelbaum, 1995;Seeman 1997; Winokur, 1997;Cyranowski et al., 2000;Perry et al., 2002;Seidman, 2006;Staley et al., 2006;Kanayama, 2007;Gooren, 2007;Vermeersch et al., 2008. ...
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A vast amount of work on depression exists and, according to Leader (2008), comments on depression can be found everywhere: on films and television, in GP’s referral letters, in magazine articles and celebrities’ interviews. It is of no surprise then that depression is considered by some as ‘the common cold of mental health’ (Harvard Mental Health Letter, 2006, p.1). Rowe (2003) argues that depression is an experience that more or less everyone has felt at times. Terms such as ‘being down in the dumps’, ‘having a low mood’, ‘being fed up’, ‘feeling down’ or simply, as ‘having the blues’ are commonplace. In this review, views on the nature and definition of depression, gender differences in depression, and the unique nature of male depression are critically discussed.
... Moreover, hypogonadal men with human immunodeficiency virus are more likely to experience depressive moods, an effect reversed by testosterone administration (Rabkin et al., 2000). Collectively, several reports suggest that testosterone-replacement therapy in hypogonadal men greatly improves mood, alleviates anxiety, and mitigates symptoms of depression (Wang et al., 1996;Pope et al., 2003;Kanayama et al., 2007;Zarrouf et al., 2009). However, this is not the case in all clinical studies. ...
... As a result of these decreased pituitary hormone concentrations , the testosterone plasma level declines [30] . Mc- Intyre et al. [31] found that depressed men had lower mean bioavailable and total testosterone levels; likewise, several lines of evidence suggest that testosterone might be effective for the treatment of depression [32,33]. In several studies, it was established that opiate addicts were significantly more depressed than normal controls [8] and even slightly more depressed than psychiatric patients [34] . ...
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Opium use in diabetic populations is associated with major depressive disorder (MDD). This study was designed to investigate the relationship between opium use and severity of depression in Iranian diabetic patients. In this case-control study, 642 type 2 diabetic patients were recruited from those presenting at two outpatient clinics at the Akhavan Hospital in Kashan, Iran; of them, 600 diabetic patients were included in the study and divided into two groups: opium-abusers (150 patients) and non-opium-abusers (450 patients). Clinical and demographic information was obtained through a detailed questionnaire. Depression symptomalogy and severity were assessed with the Beck Depression Inventory (BDI), and a corresponding diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders-IV, Text Revision, 2000 (DSM-IV TR) criteria. The mean depression score was higher in the opium abuse group than in the non-abuser group (29.27±1.44 vs. 18.29±1.31, P<0.001). In general, a significant association was found between opium abuse and depression among patients (odds ratio [OR], 4.54; 95% confidence interval [CI], 2.87 to 7.44; P=0.001). No significant relationship was found between dysthymia and opium abuse (OR, 0.68; 95% CI, 0.18 to 1.192; P=0.155), while MDD was significantly higher in the opium abuser group (OR, 7.32; 95% CI, 5.20 to 12.01; P<0.001). Depression is more frequent in opium-dependent diabetic patients, and its severity is also greater. Given these findings, opium-dependent diabetic patients should be advised about the increased risks of depression and related comorbidities.
... Affective disorders are twice as likely to occur in women as in men (1-4) implicating a critical role for gonadal hormones in their etiology. In particular, testosterone has moodenhancing properties and antidepressant effects in men (5). In fact, increased incidence of hypogonadism occurs in men with major depressive disorder (MDD) (6, 7)= and testosterone replacement effectively improves mood (7)(8)(9). ...
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Human and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression. The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal neurogenesis and gene expression of stress-related molecules. Through the use of viral vectors, we pursued the antidepressant molecular mechanism(s) of testosterone in mediating anhedonia and manipulated extracellular signal-regulated kinase 2 (ERK2) expression in the dentate gyrus in gonadectomized rats with testosterone replacements. Testosterone had antidepressant effects, likely mediated by aromatization to estrogen metabolites, in the sucrose preference and forced swim tests despite having no effects on hippocampal cell proliferation or survival. We found a testosterone-dependent regulation of hippocampal ERK2 expression. Functionally, reducing ERK2 activity within the dentate gyrus induced anhedonia in gonadectomized rats receiving testosterone supplementation, whereas the overexpression of ERK2 rescued this behavior in gonadectomized rats. These results implicate a role for ERK2 signaling within the dentate gyrus area of the hippocampus as a key mediator of the antidepressant effects of testosterone.
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Gonadal hormone deficiency is associated with the development of depression, but what mediates this association is unclear. To test the possibility that it reflects neuroimmune and neuroinflammatory processes, we analyzed how gonadal hormone deficiency and replacement affect microglial activation and inflammatory response during the development of depressive symptomatology in gonadectomized male mice. Testosterone level and the ratio of testosterone to estradiol in the serum and brain tissue of mice exposed to 3–35 days of chronic unpredictable stress were much lower than in control animals. Gonadal hormone sustained deficiency in gonadectomized mice and subsequent led to acute inflammation at day 7 following castration. Activating microglia in mice exposed to 7 days of castration subsequently suppressed the proliferation of microglia, such that their numbers in hippocampus and cortex were lower than the numbers in sham-operated mice after 30 days of castration. Here, we showed that gonadal hormone deficiency induces Traf6-mediated microglia activation, a type of inflammatory mediator. Microglia treated in this way for long time showed down-regulation of activation markers, abnormal morphology and depressive-like behaviors. Restoration and maintenance of a fixed ratio of testosterone to estradiol significantly suppressed microglial activation, neuronal necroptosis, dramatically inducing hippocampal neurogenesis and reducing depressive behaviors via the suppression of Traf6/TAK1 pathway. These findings suggest that activated or immunoreactive microglia contribute to gonadal hormone deficiency-induced depression, as well as testosterone and estradiol exert synergistic anti-depressant effects via suppressing microglial activaton in gonadectomized male mice, possibly through Traf6 signaling.
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Backgrounds: Gonadal hormone deficiency is associated with the development of depression, but what mediates this association is unclear. To test the possibility that it reflects neuroimmune and neuroinflammatory processes, we analyzed how gonadal hormone deficiency and replacement affect microglial activation and inflammatory response during the development of depressive symptomatology in gonadectomized male mice. Methods: Adult male ICR mice received gonadectomy. Gonadal hormone levels, neuroinflammation, mciroglial activation and depressive behaviors were evaluated 7 days, 14 days, and 30 days later. Furthermore, the neuroprotective mechanism of treatment with testosterone and estradiol on depressive symptomatology were also observed. Results: Testosterone level and the ratio of testosterone to estradiol in the serum and brain tissue of mice exposed to 3-35 days of chronic unpredictable stress were much lower than in control animals. Gonadal hormone sustained deficiency in gonadectomized mice and subsequent led to acute inflammation at day 7 following castration. Activating microglia in mice exposed to 7 days of castration subsequently suppressed the proliferation of microglia, such that their numbers in hippocampus and cortex were lower than the numbers in sham-operated mice after 30 days of castration. Here, we showed that gonadal hormone deficiency induces Traf6-mediated microglia activation, a type of inflammatory mediator. Microglia treated in this way for long time showed down-regulation of activation markers, abnormal morphology and depressive-like behaviors. Restoration and maintenance of a fixed ratio of testosterone to estradiol significantly suppressed microglial activation, neuronal necroptosis, dramatically inducing hippocampal neurogenesis and reducing depressive behaviors via the suppression of Traf6/TAK1 pathway. Conclusions: These findings suggest that activated or immunoreactive microglia contribute to gonadal hormone deficiency-induced depression, as well as testosterone and estradiol exert synergistic anti-depressant effects via suppressing microglial activaton in gonadectomized male mice, possibly through Traf6 signaling.
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Depression and related mood disorders constitute an enormous burden on health, quality of life, and the global economy, and women have roughly twice the lifetime risk of men for experiencing depression. Here, we review sex differences in human brain physiology that may be connected to the increased susceptibility of women to major depressive disorder (MDD). Moreover, we summarize decades of preclinical research using animal models for the study of mood dysfunction that uncover some of the potential molecular, cellular, and circuit-level mechanisms that may underlie sex differences and disease etiology. We place particular emphasis on a series of recent studies demonstrating the central contribution of the circuit projecting from ventral hippocampus to nucleus accumbens and how inherent sex differences in the excitability of this circuit may predict and drive depression-related behaviors. The findings covered in this review underscore the continued need for studies using preclinical models and circuit-specific strategies for uncovering molecular and physiological mechanisms that could lead to potential sex-specific diagnosis, prognosis, prevention, and/or treatments for MDD and other mood disorders.
Chapter
Psychiatric disorders are often seen in the primary care setting before they are referred to a psychiatrist. In many cases, patients with mental health issues just follow up with a primary care physician and never see a psychiatrist. Many of these mental health disorders display gender differences in epidemiology and presentation. For instance, women are more likely to present with depressive, anxiety, and eating disorders than men. Women attempt more suicides than men, although more men complete the act. Women are more likely to seek help and communicate problems to providers and family, thereby facilitating earlier detection. Sex differences can also influence treatment planning and prognosis. This chapter reviews sex and gender differences in the context of three main mental health conditions: major depressive disorder, generalized anxiety disorder, and schizophrenia.
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Objective GnRH (gonadotropin releasing hormone) is a crucial hormone for sexual development, puberty, and fertility, and its deficiency leads to hypogonadotropic hypogonadism (HH), which causes abnormal secondary sexual development and infertility. The combination of the lack of sense of smell, i.e., anosmia, and HH is a type of GnRH deficiency known as Kallmann syndrome, which affects both men and women. The impact of Kallmann syndrome can be very severe and causes a variety of psychological problems in patients. The aim of the present study was to investigate psychopathology, sexuality, and personality characteristics in patients with GnRH deficiency under hormonal replacement therapy. Design A total of 38 patients with GnRH deficiency aged 30.6 ± 10.44 years and 38 healthy matched for age individuals participated in the study and completed a series of questionnaires concerning sexual functioning, ego defense mechanisms, quality of life, personality characteristics, as well as anxiety and depression. Results After adjustment for anxiety and depression, no difference in sexuality parameters were reported between men with and without GnRH deficiency, while women with GnRH deficiency had significantly lower sexual desire compared to controls. Concerning quality of life, satisfaction with general health was significantly lower in patients compared to controls, even after adjusting for sex. Furthermore, patients with GnRH deficiency indicated markedly less anxiety and a trend for less depression compared to controls. Finally, defense styles, ego-strength, and hostility did not differ between GnRH deficiency patients and controls. Conclusions Our study is the first to investigate psychological and sexual functioning impacts in patients with GnRH deficiency under hormonal replacement therapy. However, larger studies are needed so as to add further empirical evidence.
Chapter
Increasing evidence supports the influence of sex hormones on the central nervous system’s (CNS) plasticity and mental state. Indeed, gender differences have been described in proneness to many psychiatric and neurological diseases, among which differences in incidence between men and women have been reported. In addition, biological aspects can affect the clinical presentation of some mental diseases. In fact, changes in hormonal levels across the life span may also affect mental illness expression.
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Depression is the leading cause of disability worldwide, and its prevalence is 2 times higher in women than in men. There is, however, a lack of data on sex-specific pathophysiology of this disorder. The purpose of this systematic review is to identify the biological sex differences found in major depressive disorder (MDD) in studies published in the last 10 years. We conducted a literature search using the Medline, PsycInfo, PubMed, and Web of Science databases, selecting English-language studies that included physiological measures compared by sex in addition to MDD. We identified 20 relevant studies, which consisted primarily of mixed methodology and samples. The reported physiological measures comprised a variety of serum biomarkers, gene mRNA expression, and brain activity. Findings suggest different biological patterns in those with MDD depending on sex. Specifically, women presented higher levels of inflammatory, neurotrophic, and serotonergic markers and a stronger correlation between levels of some inflammatory and neurotrophic factors and the severity of symptoms. This review provides information about possible different biological patterns for women and men with depressive disorder and may have important implications for treatment. Future research should include homogeneous samples; make comparisons based on sex, control sex hormone fluctuations and pharmacological treatment; and use consistent criteria for evaluating psychobiological changes in MDD.
Chapter
Androgens are potent pharmacological drugs requiring legal prescription for valid medical indications but are also misused for invalid or unproven off-label medical reasons as well as used illicitly as a form of drug abuse. Understanding these distinctions and applications requires a knowledge of androgen physiology, pharmacology, and toxicology which is discussed in historical as well as present clinical practice terms. The present epidemic of testosterone misuse mainly involves using testosterone as an antiaging and/or sexual dysfunction tonic for middle-aged or older men for which the efficacy and safety are unproven, and there is concern that such treatment may be unsafe. Androgen abuse originated during the Cold War as an epidemic among elite athletes as ergogenic agents but in the 1980s transitioned to become an endemic in most communities with sufficient affluence to support an illicit drug industry geared toward body sculpting of hypermasculine body image for occupational or recreational reasons.
Article
Background: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is a well-established pathological feature of major depression, accompanied by the persistent increase of glucocorticoid level and the dysfunction of hypothalamic-pituitary-gonadal (HPG) axis. Ginsenoside Rg1 (Rg1) is one of the most active ingredients of Panax ginseng, which has various biological activity. Objective: This study aimed to investigate the antidepressive effects of Rg1 and elucidate its impact on neuroendocrine system. Methods: The antidepressive effects of Rg1 were first analysed in mice, and was further identified in the chronic-unpredictable-mild-stress (CUMS) model and the gonadectomized (GDX) model. The effects of Rg1 on depression-like behaviour were analysed by the forced swimming test (FST), tail suspension test (TST), sucrose preference test, and measurement of pentobarbital-induced sleep. The serum corticosterone and testosterone levels were detected by ELISA. The protein levels of glucocorticoid receptor (GR) and androgen receptor (AR) were analysed by western blot and immunohistochemistry analysis. Results: Rg1 significantly decreased the immobility time of mice in FST and TST. Furthermore, Rg1 alleviated anhedonia and hopelessness, decreased serum corticosterone level, and increased serum testosterone level, and the GR protein level in the PFC and hippocampus of the CUMS-treated rats. Moreover, Rg1 improved sleep disruption, down-regulated the serum corticosterone level, and increased AR protein level in the PFC of the GDX-treated mice. Conclusion: Together, these studies suggest that Rg1 displayed antidepressant activity through the modulation of the HPA and the HPG axis. These findings provide new mechanism involved in the antidepressive effects of Rg1 and propose theoretical clues for clinical therapies.
Article
Leuprolide acetate (LEU), also known as Lupron, is commonly used to treat prostate cancer in men. As a gonadotropin-releasing hormone (GnRH) receptor agonist, it initially stimulates the release of gonadal hormones, testosterone (T) and estradiol. This surge eventually suppresses these hormones, preventing the further growth and spread of cancer cells. Individuals receiving this treatment often report anxiety and cognitive changes, but LEU’s effects on the neural mechanisms that are involved in anxiety during the trajectory of treatment are not well known. In this study, we examined the acute effects of LEU on fear extinction, hypothesizing that increased T levels following a single administration of LEU will facilitate extinction recall by altering neuronal activity within the fear extinction circuitry. Two groups of naïve adult male rats underwent a 3-day fear conditioning, extinction, and recall experiment. The delayed group (n = 15) received a single injection of vehicle or LEU (1.2 mg/kg) 3 weeks before behavioral testing. The acute group (n = 25) received an injection one day after fear conditioning, 30 min prior to extinction training. Following recall, the brains for all animals were collected for c-fos immunohistochemistry. Blood samples were also collected and assayed for T levels. Acute administration of LEU increased serum T levels during extinction training and enhanced extinction recall 24 h later. This enhanced extinction memory was correlated with increased c-fos activity within the infralimbic cortex and amygdala, which was not observed in the delayed group. These results suggest that the elevation in T induced by acute administration of LEU can influence extinction memory consolidation, perhaps through modification of neuronal activity within the infralimbic cortex and amygdala. This may be an important consideration in clinical applications of LEU and its effects on anxiety and cognition.
Chapter
Androgens are potent pharmacological drugs requiring legal prescription for valid medical indications but are also misused for invalid or unproven off-label medical reasons as well as used illicitly as a form of drug abuse. Understanding these distinctions and applications requires a knowledge of androgen physiology, pharmacology, and toxicology which is discussed in historical as well as present clinical practice terms. The present epidemic of testosterone misuse mainly involves using testosterone as an antiaging and/or sexual dysfunction tonic for middle-aged or older men for which the efficacy and safety are unproven, and there is concern that such treatment may be unsafe. Androgen abuse originated during the Cold War as an epidemic among elite athletes as ergogenic agents but in the 1980s transitioned to become an endemic in most communities with sufficient affluence to support an illicit drug industry geared toward body sculpting of hypermasculine body image for occupational or recreational reasons.
Article
Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80-95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300 μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300 μg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood.
Chapter
Anabolic-androgenic steroids include the male hormone, testosterone and its synthetic derivatives. They are Schedule III Controlled Substances with legitimate therapeutic indications, but they are also used non-medically to enhance physical appearance and athletic performance. Patterns of illicit, non-medical use include combining several anabolic-androgenic steroids, including both injection and oral preparations (“stacking”) as well as both human and veterinary preparations; using 10–100 times therapeutic doses; increasing doses of anabolic-androgenic steroids to a peak and then tapering over time (“stacking the pyramid”); and alternating periods of use with non-use (“cycling”). Although used non-medically for their physical effects, anabolic-androgenic steroids have adverse psychiatric effects including hypomania or mania (especially during periods of use), depression and suicidality (especially between periods of use), psychosis, and marked aggression. Adverse medical consequences of illicit use are manifested predominantly in the endocrine, hepatic, and cardiovascular systems, with some deaths reported. In addition to their abuse potential, anabolic-androgenic steroids can lead to withdrawal symptoms and addiction with both similarities to and differences from so-called classical addictive drugs such as opioids. Addiction appears limited to illicit, non-medical users, and has not been documented among those treated therapeutically for legitimate medical purposes. Approximately one-third of 426 non-medical anabolic-androgenic steroid users that were recruited from convenience samples across five different studies met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for anabolic steroid dependence, although the true prevalence is unknown. Both abuse and addiction generally occur in the context of intensive training with weights, combined with strict dietary regimens, in order to optimize bodybuilding effects. Screening questions for anabolic-androgenic steroid use are suggested; and knowledge of the psychiatric, physical, and laboratory findings aids detection. The level of evidence for treating anabolic-androgenic steroid dependence is currently based on case reports and series as well as expert opinion.
Chapter
Studies have documented sex differences in psychiatric illness from diagnosis to treatment. In particular, there is a profound disparity in the prevalence of stress- and fear-based disorders, such as anxiety and posttraumatic stress disorder, in which women are more vulnerable. Fear processes have been extensively studied, and their relevance to anxiety and stress-related disorders is being increasingly examined. The mechanisms for fear learning and its subsequent extinction may provide a framework for understanding how gonadal hormones might contribute to the disproportionate incidence of these psychopathologies. Here, we discuss the influence of gonadal hormones in fear regulation processes and their contributions to the sex differences observed in the pathophysiology, neurobiology, and treatment of anxiety disorders. A better understanding of these interactions may contribute to the development of more effective, personalized treatments that take hormonal status into account.
Chapter
The anabolic–androgenic steroids (AAS) are a family of hormones that includes the natural male hormone, testosterone, together with a group of synthetic derivatives of testosterone. These drugs are widely abused by men (and rarely, women) to gain muscle mass and lose body fat. Prior to about 1980, abuse of AAS was confined largely to elite competitive athletes, but in recent decades, AAS abuse has broken out of the athletic community and into the general population. Many modern AAS users have no specific athletic aspirations at all, but simply want to become bigger and more muscular. About 2–6% of men in many Western industrialized countries have used AAS, but AAS use is rare in Asian societies. Individuals with body image concerns, such as “muscle dysmorphia,” appear more prone to abuse AAS. Male muscularity is more strongly emphasized and rewarded in industrialized Western cultures than in Asia, and this difference likely explains the geographic distribution of AAS abuse. AAS cause few serious short-term medical effects, but over the long term may cause suppression of hypothalamic–pituitary–gonadal function, adverse effects on serum lipids, and cardiomyopathy. The most common psychiatric effects of AAS are mood disorders (typically hypomanic or manic syndromes during AAS exposure and depressive symptoms during AAS withdrawal); these are idiosyncratic, affecting a minority of AAS users, but are occasionally severe. A growing literature describes syndromes of AAS dependence, where individuals use AAS almost continuously despite adverse medical or psychiatric effects. Individuals displaying AAS abuse or dependence may also exhibit other forms of substance dependence. Unfortunately, AAS users rarely seek treatment, but this situation may change as the first large wave of illicit AAS users—those who first began AAS as youths in the 1980s—now reaches middle age and enters the age of risk for long-term cardiac, neuroendocrine, and psychiatric complications from these drugs.
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Increased longevity and population aging will increase the number of men with late onset hypogonadism. It is a common condition, but often underdiagnosed and undertreated. The indication of testosterone-replacement therapy (TRT) treatment requires the presence of low testosterone level, and symptoms and signs of hypogonadism. Although controversy remains regarding indications for testosterone supplementation in aging men due to lack of large-scale, long-term studies assessing the benefits and risks of testosterone-replacement therapy in men, reports indicate that TRT may produce a wide range of benefits for men with hypogonadism that include improvement in libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life and cardiovascular disease. Perhaps the most controversial area is the issue of risk, especially possible stimulation of prostate cancer by testosterone, even though no evidence to support this risk exists. Other possible risks include worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea or severe heart failure. Despite this controversy, testosterone supplementation in the United States has increased substantially over the past several years. The physician should discuss with the patient the potential benefits and risks of TRT. The purpose of this review is to discuss what is known and not known regarding the benefits and risks of TRT.
Article
Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disrupter. The present study investigated the effect of DEHP on emotional behavior of mice following perinatal exposure (10, 50, and 200mgkg(-1)d(-1)) from gestation day 7 through postnatal day 21. The results showed that, in pubertal males (6-w-old), DEHP decreased the time spent in the open arms and the number of entries into them in elevated plus maze and decreased the time in the mirrored chamber and in the light-box; in pubertal females, DEHP decreased the time spent in the open arms and the number of entries into them, suggesting that DEHP exposure made a anxiogenic effect in pubertal offspring regardless of sex. While DEHP effect on anxiety of adult (12-w-old) displayed sex differences, with decreased time spent in the open arms in the adult females. Perinatal exposure to DEPH significantly extended the time of immobility in forced swim task of pubertal offspring and adulthood regardless of sex. Furthermore, DEHP down-regulated the expressions of androgen receptor (AR) in pubertal male hippocampus and of estrogen receptor (ER) β in pubertal female and adult hippocampus of both sexes and inhibited the phosphorylation of ERK1/2 of hippocampus in pubertal mice and adult males. These results suggest that exposure to DEHP early in life affected the anxiety- and depressive-like behaviors of pubertal offspring and even adult. The disruption of gonadal hormones' modulation of behaviors due to down-regulation of AR or ERβ in the hippocampus may be associated with the aggravated anxiety- and depression-like status induced by DEHP. Copyright © 2014 Elsevier Ltd. All rights reserved.
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There has been a perennial debate about whether aggression is learned or innate. The power of extreme arguments in this area has diminished as all are beginning to recognize that both evolution and learning contribute much to our tendency to be aggressive in various distinct ways, including impulsive anger, premeditated predatory behavior in its many forms, as well as our seeking of dominance as exemplified best in inter-male jousting. Here we will be almost exclusively concerned with the biological roots of the type of impulsive aggression that arises from our genetically prescribed capacity for anger, and affective state that we label the RAGE circuitry of the brain.
Article
Humans are routinely exposed to low levels of bisphenol A (BPA), an environmental endocrine disruptor, which is widely used in the production of polycarbonate plastics. The effects of perinatal exposure to BPA have been shown to affect various aspects of social behaviors such as anxiety and depression in adult offspring. Because sex hormones play a critical role in neurobehavior in adulthood, it is possible that long-term exposure to BPA has widespread effects on these emotional behaviors in adulthood. In the present study, adult mice were exposed to BPA at dosages of 0.04, 0.4, 4, 40mgkg(-1)d(-1) for 12weeks. A behavioral assay was performed using the open field test (OFT), mirrored maze, the elevated plus maze (EPM), and the forced swim task. The results showed that, after exposure to BPA at 0.4-40mgkg(-1)d(-1), the number of open arm entries and the time spent in them in the elevated plus maze task were reduced in males but increased in females, and thus eliminating or reversing sex differences in these behaviors. BPA at 0.04-40mgkg(-1)d(-1) increased the immobility of male mice in the forced swimming test. Furthermore, BPA (0.4-40mgkg(-1)d(-1)) significantly decreased brain level of testosterone in males, but no significant influence was found in serum and the brain levels of estradiol in females. Western blot analysis further indicated that BPA at 0.4, 4, or 40mgkg(-1)d(-1) significantly down-regulated the protein level of estrogen receptor β (ERβ) in the hippocampus of the adult males but not females, and inhibited the protein level of GABA(A)α2 receptor in hippocampus of males but promoted that of females. These results suggest that long-term exposure to BPA sex specifically affects anxiety- and depression-like behaviors in adult mice. Changes in the levels of GABA(A)α2 receptor and ERβ proteins of hippocampus might be associated with BPA-induced changes in these emotional behaviors.
Article
Psychiatric adverse effects associated with the use of clomiphene are relatively uncommon. Though case reports link mood swings to be associated with clomiphene, it is not known to be associated with a syndromal affective episode. Being a selective oestrogen receptor modulator, clomiphene affects the hypothalamus-pituitary-gonadal axis and can have potential neuropsychiatric effects in vulnerable persons. Herein we report a case of clomiphene induced manic episode in a known bipolar male patient.
Article
Objective: This study assessed the efficacy and safety of testosterone replacement therapy (TRT) in aging Japanese men with late-onset hypogonadism (LOH). Methods: This study included 50 (median age: 57.7 years) Japanese men with LOH, who were consecutively enrolled and treated with TRT for at least six months at our institution. We evaluated the following measurements before and after six months of treatment with TRT as follows: blood tests, prostate volume, residual urine volume, self-ratings for International Index of Erectile Function 5 (IIEF-5), International Prostate Symptom Score (IPSS), Self-Rating Depression Scale (SDS), Aging Male Symptom (AMS) and the Medical Outcomes Study 8-item Short-Form health survey (SF-8). Results: Following six months of TRT, the levels of testosterone, red blood cells, hemoglobin and hematocrit were significantly increased from baseline, while total cholesterol level was significantly decreased from baseline. Furthermore, TRT led to a significant increase in IIEF-5 score and a significant decrease in IPSS score. Of 30 men who were diagnosed with depression at baseline, only 11 men (36.7%) were still suffering from depression after TRT, and SDS scores were significantly decreased from baseline at month six. Treatment with TRT led to a significant decrease in all scores of the AMS scale as well as a significant improvement in all scores of the SF-8 survey, with the exception of the bodily pain score. Conclusion: These findings suggest that TRT is an effective and safe treatment for aging Japanese men with LOH. TRT improved depressive symptoms as well as health-related quality of life.
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Male hypogonadism is a condition that is receiving increasing medical scrutiny, resulting in research producing results favorable to the consideration of maintaining physiological levels of testosterone. As healthcare professionals interested in the health and welfare of a significant portion of the population, surely compounding pharmacists are interested in what can be done for men with this condition to help these patients improve their quality of life and long-term health. This article discussed the various ways that men's testosterone levels can be raised and provides insight into the importance of androgen-estrogen balance.
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Male hypogonadism is a common condition widely associated with the aging process. Understanding of this condition is continuing to grow as new information is available. Pharmacists are in a very unique position to work with patients and physicians in achieving better diagnosis and treatment plans for the hundreds of thousands of men in the U.S. who are hypogonadal. This article discusses various methods that can be employed to restore testosterone in men and the varying expectations associated with each treatment methods.
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Epidemiological studies have demonstrated a close relationship between depression and cardiovascular disease (CVD). Although it is known that the central nervous system (CNS) contributes to this relationship, the detailed mechanisms involved in this process remain unclear. Recent studies suggest that the endoplasmic reticulum (ER) molecular chaperone sigma-1 receptor and brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of CVD and depression. Several meta-analysis studies have showed that levels of BDNF in the blood of patients with major depressive disorder (MDD) are lower than normal controls, indicating that blood BDNF might be a biomarker for depression. Furthermore, blood levels of BDNF in patients with CVD are also lower than normal controls. A recent study using conditional BDNF knock-out mice in animal models of myocardial infarction highlighted the role of CNS-mediated mechanisms in the cardioprotective effects of BDNF. In addition, a recent study shows that decreased levels of sigma-1 receptor in the mouse brain contribute to the association between heart failure and depression. Moreover, sigma-1 receptor agonists, including the endogenous neurosteroid dehydroepiandosterone (DHEA) and the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, show potent cardioprotective and antidepressive effects in rodents, via sigma-1 receptor stimulation. Interestingly, agonist activation of sigma-1 receptors increased the secretion of mature BDNF from its precursor proBDNF via chaperone activity in the ER. Given the role of ER stress in the pathophysiology of CVD and MDD, the author will discuss the potential link between sigma-1 receptors and BDNF-TrkB pathway in the pathophysiology of these two diseases. Finally, the author will make a case for potent sigma-1 receptor agonists and TrkB agonists as new potential therapeutic drugs for depressive patients with CVD.
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The prevalence of depression in chronic obstructive pulmonary disease (COPD) is greater than in the general population, but the mechanism is unknown. Depression has been linked mechanistically to testosterone deficiency, and testosterone deficiency (hypogonadism) affects many men with COPD. Accordingly, we hypothesized that significant depressive symptoms would be associated with hypogonadism in men with COPD. The hypothesis was tested in a prospective cross-sectional investigation of 104 men (FEV1 = 43 ± 1% predicted (± SE)), 36 of whom had significant depressive symptoms (Geriatric Depression Scale score or GDS ≥ 11). Hypogonadism was present in 14 patients with GDS ≥ 11 (39%) and in 21 with GDS < 11 (31%; p = 0.41). The independent association between depressive symptoms and gonadal state was evaluated after adjusting for potential confounders: combined severity of lung disease and functional impairment (BODE-index), co-morbidities (Charlson co-morbidity-Index), age, active smoking, education, and marital status. After controlling for confounding variables, multivariable logistic-regression analysis revealed that only BODE-index (odds ratio 1.40; p = 0.003), lack of companion (2.73; p = 0.045) and younger age (0.93; p = 0.021) were independently associated with depressive symptoms. In a secondary analysis, patients were stratified into those with severe depressive symptoms (GDS ≥ 19) and those with mild depressive symptoms (GDS 11-18). Prevalence of hypogonadism was greater in first group than in the second (62% vs. 26%; p = 0.036). After controlling for confounders, however, gonadal state was not associated with severe depressive symptoms. Similarly, gonadal state was not associated with mood and motivation subscale scores of the GDS. In conclusion, presence of significant depressive symptoms was not associated with hypogonadism in men with COPD.
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Disturbances in some endocrine hormones have been implicated in the pathophysiology of depression. Some of these hormones (and drugs that affect hormone function) have been used as therapeutic agents for the treatment of depression, especially adrenal, thyroid, and gonadal axis hormones. Open-label and controlled studies of various drugs that directly suppress or inhibit adrenal axis function have shown some benefit for the treatment of major depression, including treatment-resistant depression. Thyroid hormone augmentation is effective for nonresponders to antidepressant agents, although it has not been studied extensively. Estrogen may improve mild mood symptoms in perimenopausal women but may not be effective alone for major depression. Evidence of the antidepressant effects of testosterone in men is inconsistent, with mixed results from controlled studies. The adrenal steroid hormone dehydroepiandrosterone has an important role in mood regulation and may have significant antidepressant effects.
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Depressive disorders are highly prevalent and are a leading cause of disability, morbidity, and mortality worldwide; however, they often remain undertreated or untreated. This article provides a broad overview of the many strategies for treating depression. More than 24 antidepressant medications and depression-focused psychotherapies are available as first-choice options for treating depression. When patients have not had a satisfactory treatment response, the 2 main strategies are switching to an alternative antidepressant therapy or adding a second antidepressant therapy. A large number of medication combinations have been reported in the literature, and some have been shown to be effective in controlled studies. Nonstandard alternatives to conventional antidepressant treatments include exercise, light therapy, sleep deprivation, and various complementary and alternative therapies. For more chronic and refractory forms of depression, various neuromodulation therapies are available or are being investigated. Because depressive disorders are common in primary care and other medical settings, medical practitioners should be aware of the therapeutic armamentarium available for treating depression.
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The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause. Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone. The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly. In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.
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A decline in hypothalamic-pituitary-gonadal (HPG) axis function is often seen in elderly men, and dysthymic disorder is common. Symptoms of both HPG axis hypofunction and dysthymic disorder include dysphoria, fatigue, and low libido. The authors compared total testosterone levels in three groups of elderly men. Total testosterone levels were measured in subjects who met DSM-IV criteria for major depressive disorder (N=13) or dysthymic disorder (N=32) and a comparison group (N=175) who had participated in an epidemiological study of male aging and had scored below the median on the Center for Epidemiologic Studies Depression Scale, a well-validated, self-report depression symptom inventory. There were no differences among the three groups in measured demographic variables, including age and weight. Median testosterone levels varied for those with dysthymic disorder (295 ng/dl), major depressive disorder (425 ng/dl), and no depression (423 ng/dl). A test for differences in central tendency showed a statistically significant difference among the three groups. Post hoc pairwise comparisons revealed statistically significant differences between those with dysthymic disorder and those with major depressive disorder and no depression. Total testosterone levels were lower in elderly men with dysthymic disorder than in men with major depressive disorder and men without depressive symptoms. Dysthymic disorder in elderly men may be related to HPG axis hypofunction.
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The relationships between testosterone dose and its effects on sexual function, mood, and visuospatial cognition are poorly understood. To elucidate testosterone dose-response relationships in older men, we examined the effects of graded testosterone doses on sexual function, mood, and visuospatial cognition in healthy, older men (age, 60-75 yr). This study was performed at the General Clinical Research Center. INTERVENTION/METHODS: Subjects each received a long-acting GnRH agonist to suppress endogenous testosterone production and were randomized to receive one of five doses (25, 50, 125, 300, and 600 mg) of testosterone enanthate weekly for 20 wk. Questionnaires were used to evaluate sexual function. Scores for overall sexual function as well as subcomponents of sexual function (libido, sexual activity, and erectile function) were calculated. Changes in overall sexual function (P = 0.003) and waking erections (P = 0.024) differed by dose. An interaction between libido and being sexually active was observed, such that libido changed by testosterone dose only among men who reported being sexually active at the beginning of the study (P = 0.009). Men's log-transformed free testosterone levels during treatment were positively correlated with overall sexual function (P = 0.001), waking erections (P = 0.040), spontaneous erections (P = 0.047), and libido (P = 0.027), but not with intercourse frequency (P = 0.428) or masturbation frequency (P = 0.814). No effects of testosterone dose were observed on two measures of mood: Hamilton's Depression Inventory (P = 0.359) and Young's Mania Scale (P = 0.851). The number of trials completed on a computer-based test of visuospatial cognition differed by dose (P = 0.042), but the number of squares correctly completed on this task did not differ by dose (P = 0.159). Different aspects of male behavior respond differently to testosterone. When considered together with previous data from young men, these data indicate that testosterone dose-response relationships for sexual function and visuospatial cognition differ in older and young men.
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Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).
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The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospective medication trials. Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly assigned to receive open-label treatment with either tranylcypromine (N=58) or extended-release venlafaxine plus mirtazapine (N=51). The primary outcome measure was whether patients achieved remission, which was defined as a score < or =7 at exit on the 17-item Hamilton Depression Rating Scale (HAM-D). The HAM-D was administered by telephone by raters to whom treatment was masked. Remission rates were not significantly different between the two treatment groups (6.9% for the tranylcypromine group and 13.7% for the venlafaxine plus mirtazapine group). The mean daily dose at exit for tranylcypromine was 36.9 mg (SD=18.5); for venlafaxine, 210.3 mg (SD=95.2); and for mirtazapine, 35.7 mg (SD=17.6). Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance. Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups. The lower side effect burden, lack of dietary restrictions, and ease of use of venlafaxine and mirtazapine suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments.
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More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine (T(3)) augmentation as a third-step treatment for patients with major depressive disorder. A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 mg/day; N=69) or with T(3) (up to 50 mug/day; N=73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score < or =7 on the 17-item Hamilton Depression Rating Scale. After a mean of 9.6 weeks (SD=5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T(3) augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p=0.027). Remission rates with lithium and T(3) augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of T(3) augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.
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Elsewhere one of us (L. D.)¹ has presented evidence to show that a psychosis due to estrogen deficiency exists and responds promptly to appropriate therapy. To prove the existence of a psychosis due to androgen deficiency is more difficult because of the vagueness of the diagnostic criteria. The evidence for the existence of such a psychosis will be reviewed in the present paper, and the results of therapy in new cases will be described. For some years, numerous psychiatrists and endocrinologists have been interested in the treatment of involutional melancholia in the male with androgens. Because of the comparative rarity of the disorder and the difficulty of the diagnosis, it is not reasonable to expect a single hospital to contain a large number of patients suitable for study. It is only when the results of many investigations are pooled that figures for statistical treatment can be collected. In the
1.1. Based on the scalp-recorded and computer-analyzed electroencephalogram, in high dosages antidepressant and in low dosages “psychostimulant” properties of mesterolone, a synthetic male hormone, were predicted.2.2. Open, uncontrolled clinical trials suggest dose-related antidepressant properties of mesterolone. The higher the dosage the more therapeutic effects were established.3.3. A double-blind placebo-control study suggests that the symptoms of anxiety, lack of desire, lack of drive and impaired satisfaction may have benefit from low dosages of mesterolone.
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Reviews studies that have examined the psychiatric effects of anabolic-androgenic steriods (AASs) and offers some general impressions to assist the clinician who may encounter patients who exhibit these effect. Studies that have examined the psychiatric effects of AASs include (1) clinical studies of AASs in the treatment of psychiatric or medical disorders, (2) laboratory studies of the effects of AASs in normal volunteers, and (3) naturalistic field studies of athletes using AASs illicitly. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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1. Five cases of male involutional melancholia were treated for a period of three to four months with testosterone-propionate with no noticeable improvement in their mental condition. 2. Of these five, four failed to show even the expected physiological stimulation of the sexual function although one showed some effect in that direction. 3. It is believed that testosterone is of no value in the treatment of male involutional melancholia.
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Six male strength athletes, three illicit anabolic steroid users and three non-steroid users were monitored over several months as they underwent normal training and competition routines. Subjects completed the Profile of Mood States (POMS) questionnaire, Buss-Durke Hostility Inventory and the Rosenweig Picture Frustration Test on four occasions: two on-drug periods and two off-drug periods for the steroid users and equivalent test periods for the non-users. Steroid presence was monitored objectively by gas chromatography coupled to mass spectrometry. Whilst those drugs declared by the athletes were confirmed in the “on-drug” samples and most of the “off-drug” samples, clear steroid traces were apparent in some supposed off-drug sessions. This complicated data interpretation and may partially explain why steroid users were significantly more hostile and aggressive at all times compared to the non-users. Despite this, self-rated aggression did increase significantly in steroid users during their acknowledged on-drug periods. Multiple drug use or “stacking” in particular caused severe hostility/aggression; one steroid user also admitted to attempted murder during a previous steroid-taking phase.
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Concern has been raised that persons using anabolic-androgenic steroids (AASs) to enhance physique and performance may experience negative psychological effects. This review generates and evaluates theory-based hypotheses regarding AAS-mood and behavior associations at consumption and withdrawal. Emphasis is placed on moods and behaviors typically believed to change during these times (e.g., mood lability, irritability, euphoria, libido, aggression, self-esteem). Although some data suggest that affect and behavior differ while using and withdrawing from AASs, the nature of the relationships is unclear. Nondrug factors that may play a role in the moods and behaviors linked to AASs are identified and suggestions for future research are offered.
1.1. Depressed men and women who fail to respond to conventional antidepressant treatment show significant alleviation of depressive symptoms when treated with high doses of gonadal steroids (conjugated oral estrogen in women; mesterolone in men).2.2. Depression in men is accompanied by a high production of estradiol; and depression in women is accompanied by higher production of testosterone. Whether these findings are related to the therapeutic effects of gonadal hormones upon depression are unknown.
Article
Testosterone replacement therapy is an effective treatment of some depressive symptoms in hypogonadal men, and may be an effective augmentation treatment for SSRI-refractory major depression in such men. We treated five depressed men who had low testosterone levels and had not responded to an adequate SSRI trial with 400 mg testosterone replacement biweekly for 8 weeks. Four patients underwent single-blind placebo discontinuation. Patients were assessed at baseline and biweekly thereafter using the Hamilton Depression Rating Scale (HAM-D) and the Endicott Quality of Life Enjoyment and Satisfaction Scale (Q-LES-Q). Patients' mean age was 40 years, and mean testosterone level 277 ng/dl. All had a rapid and dramatic recovery from major depression following testosterone augmentation: mean 21-item HAM-D decreased from 19.2 to 7.2 by week 2, and to 4.0 by week 8; mean Q-LES-Q increased from 45% to 68%. Three of four subjects who underwent discontinuation of testosterone under single-blind placebo treatment began to relapse. Testosterone replacement therapy may be an effective treatment of depressive symptoms in some men, and warrants further research.
Article
To determine the relationship between increasing luteinizing hormone (LH) production and the diurnal secretion of LH and testosterone (T) in adult men, studies were performed on five men with gonadotropin insufficiency associated with prolactinoma, five eugonadal men, and five men with primary testicular failure. Blood samples were drawn every 10 to 20 minutes for 24 hours beginning at 8:00 to 8:30 AM to evaluate diurnal periodicity. Mean (+/- SEM) LH levels in the three groups were 7.67 +/- 1.46 mlU/ml, 13.9 +/- 3.2 mlU/ml, and 62.3 +/- 14.4 mlU/ml, respectively, and mean serum T levels were 8.05 +/- 1.49 nmol/L, 13.9 +/- 3.5 nmol/L, and 9.15 +/- 1.3 nmol/L, respectively. Cosinor analysis revealed that each hyperprolactinemic man had a T rhythm with a significant 24-hour periodicity; the mean acrophase was at 5:00 AM. Testosterone levels were 35.0 +/- 10.6% less at 4:00 PM than at 8:00 AM. Eugonadal men also demonstrated a significant diurnal T rhythm with an acrophase at 6:00 AM, and T levels were 15.8 +/- 5.3% less at 4:00 PM than at 8:00 AM. By contrast, there was no significant diurnal rhythm in T secretion among the men with testicular failure, although serum T levels were 11.5 +/- 3.7% less at 4:00 PM than at 8:00 AM. For LH, hyperprolactinemic men demonstrated a significant 24-hour rhythm with an acrophase at 1:30 AM, whereas no significant 24-hour periodicity was identified among either eugonadal men or men with testicular failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Serum total testosterone, total 17 beta-estradiol, LH, FSH, and PRL concentrations were measured by RIA in 59 homosexual men infected with the human immunodeficiency virus (32 clinically healthy antibody-positive men (HH+), 20 men with acquired immune deficiency syndrome (AIDS), and 7 men with AIDS-related complex (ARC). The results were compared with those of 26 antibody-negative homosexual men (HH-) who served as controls. The mean serum total testosterone concentration was significantly lower in the men with AIDS [414 +/- 230 (+/- SD) ng/dL (14.5 +/- 8.0)] than in the HH- men [550 +/- 172 ng/dL (19.0 +/- 6.0 nmol/L); P less than 0.05]. The mean serum LH level was significantly higher in the men with AIDS (26 +/- 14 vs. 14 +/- 4 IU/L in HH- men; P less than 0.01) and slightly but significantly higher in the men with ARC (19 +/- 8 IU/L; 0.10 greater than P greater than 0.05). Serum FSH also was significantly higher in the men with AIDS (P less than 0.05). Serum PRL was significantly higher in the men with ARC (10 +/- 2 micrograms/L; P less than 0.05) and AIDS (16 +/- 10 micrograms/L; P less than 0.001) than in the HH- men (8 +/- 3 micrograms/L). Serum sex hormone-binding globulin levels were similar in HH- men and men with AIDS as were serum T responses to hCG administration for 2 days. These results suggest that alterations of the hypothalamic-pituitary-gonadal axis indicative of primary hypogonadism accompany human immunodeficiency virus infection in homosexual men.
Article
Testosterone was administered transdermally to hypogonadal men under three protocols. In the first protocol, it was shown that peak levels of testosterone were achieved three to eight hours after scrotal application of a transdermal therapeutic system containing 5, 10, or 15 mg of testosterone, and values at 22 hours were greater than 60% of peak values. In the second protocol, patients were treated with 10-mg systems for four weeks followed by 15-mg systems for eight weeks. Serum samples were obtained three to five hours after application of the transdermal therapeutic system. Testosterone increased from a pretreatment level (mean ± SE) of 1.5 ± 0.4 nmol/L to 15.2 ±3.4 nmol/L at four weeks, 18.6 ± 3.3 nmol/L at eight weeks, and 17.3 ± 2.8 nmol/L at 12 weeks. The serum testosterone/dihydrotestosterone (DHT) ratio fell from 4.53 to 2.47 at four weeks and was similar at eight and 12 weeks, reflecting a greater rise in DHT with this route of treatment (normal testosterone/DHT ratio, 9/1 to 12/1). Eight patients were treated with the 15-mg systems for an additional year. Seven of the eight were compliant and maintained serum testosterone levels (at six time points from two to 12 months [mean ± SE]) ranging from 11.5 ±1.2 to 44.9 ±2.4 nmol/L. It was possible to achieve physiological serum levels of testosterone by transdermal administration of testosterone in two thirds of our hypogonadal men. (JAMA. 1989;261:2525-2530)
Article
This paper examines the physiologic and epidemiologic evidence for a widely discussed syndrome termed either 'mid-life crisis', 'male menopause', 'male climacteric', or increasingly, 'andropause'. The paper is divided into 2 parts: (1) a review of evidence from physiologic studies conducted over the last decade that examine endocrine function in aging males; (2) a description of the salient features of an ongoing multidisciplinary epidemiologic study (the Massachusetts Male Aging Study) of a sample of approximately 1700 men aged 40-69 yr, randomly sampled from the general population. This study is markedly different in size and content from studies conducted to date. Preliminary findings suggest that age per se may be a relatively unimportant contributor to endocrine variability and that anthropometrics and life style phenomena may be at least as important.
Article
Total and free testosterone, estradiol and cortisol were measured in 12 depressed males and 12 age-matched normal volunteers. There was no significant difference in any of the hormone levels between the patient and control group. Total testosterone was negatively correlated with age in the depressed group, but not with severity of depression.
Article
The antidepressant effects of amitriptyline and mesterolone, a synthetic androgen, were compared in a double-blind parallel treatment design. The drugs were equally effective in reducing depressive symptoms. Mesterolone produced significantly fewer adverse side effects than amitriptyline.
Article
Five men with primary unipolar depression were treated with methyltestosterone and imipramine. Four promptly showed a paranoid response that cleared rapidly when treatment with the hormone was discontinued. The shift from depression to a paranoid reaction may have resulted from an increase in aggression, which may in turn have been the result of the interplay between the hormone and the drug and the effects of this interplay on brain biogenic amine metabolism.
Article
Based on computer EEG (CEEG) profiles, in high doses, antidepressant properties of mesterolone, a synthetic androgen, were predicted. In a double-blind placebo controlled study, the clinical effects of 300-450 mg daily mesterolone were investigated in 52 relatively young (age range 26-53 years, mean 42.7 years) male depressed outpatients. During 6 weeks of mesterolone treatment, there was a significant improvement of depressive symptomatology. However, since an improvement was also established during the placebo treatment, no statistically appreciable difference in the therapeutic effects of mesterolone was established compared to placebo. Mesterolone treatment significantly decreased both plasma testosterone and protein bound testosterone levels. Patients with high testosterone levels prior to treatment seem to have had more benefit from mesterolone treatment than patients with low testosterone levels. The degree of improvement weakly correlated to the decrease of testosterone levels during mesterolone treatment.
Article
The purpose of this study was to assess the psychiatric effects of anabolic-androgenic steroid (AAS) use and assess the frequency of other psychoactive substance use in a population of AAS users compared with non-AAS-using weight-lifter controls. One hundred sixty-four subjects were administered a demographic survey, including psychiatric history, substance use history, AAS use history, and medical history. Psychiatric diagnoses were made and psychological testing was performed. User categories were determined by history and urine testing. The user categories did not differ significantly on psychological testing. Past AAS users had a higher incidence of psychiatric diagnosis than the nonuser and current user groups. Hypomania was correlated with AAS use, and major depression with AAS discontinuation. Present psychoactive substance abuse or dependence was relatively low across all user categories. AAS dependence was seen in 12.9% of current users and 15.2% of past users of AAS. In conclusion, AAS use may lead to psychiatric disorders in certain individuals. Concurrent use of psychoactive drugs other than AAS does not appear to be common in intensively training weight lifters and bodybuilders.
Article
The purpose of this study was to determine whether testosterone replacement therapy ameliorates sexual dysfunction and associated problems of mood, energy, and appetite in HIV+ men with immune suppression (CD4 < 400 cells/cu mm) and low levels of serum testosterone. Assessments at study baseline and endpoint included psychiatric evaluation using the Structured Clinical Interview for DSM-III-R, the Hamilton Rating Scale for Depression, Clinical Global Impressions Scale, the Karnofsky Performance Index, and a side-effects rating scale. Eighty-one men entered treatment and 72 completed at least 8 weeks. At study entry, 84% had an AIDS-defining condition (1993 CDC Criteria). In terms of sexual interest and function, 85% of study completers were clearcut responders at week 8. Mood response was also good: of the 44 study completers who had mood problems at baseline, 28 (64%) were rated as much improved. Mean change in CD4 cell count after treatment was not statistically significant. These findings suggest that testosterone replacement therapy should be considered for men with immune suppression and low testosterone levels who complain of diminished sexual desire and/or dysfunction. Replication with a placebo component is indicated.
Article
Medical research suggests that testosterone has positive effects on mood (thereby reducing the chances of depression), and social science research finds testosterone to be related to antisocial behavior, risk behavior, unemployment and low paying jobs, and being unmarried--factors known to be positively related to depression. Analysis of a sample of 4,393 men finds a parabolic model best fits the data. The relationship between testosterone and depression is inverse for men with below average testosterone and direct for those with above average testosterone. The relationship disappears for those with above average testosterone when controls for antisocial and risk behaviors and the absence of protective factors such as marriage and steady employment are in the equation. The relationship is unchanged for those with below average testosterone. The results help explain the difference between medical and social research findings. Mechanisms accounting for the findings are explored.
Article
The goal was to evaluate the efficacy of testosterone in alleviation of hypogonadal symptoms (diminished libido, depressed mood, low energy, and depleted muscle mass) in men with symptomatic human immunodeficiency virus illness. Seventy-four patients were enrolled in a double-blind, placebo-controlled 6-week trial with bi-weekly testosterone injections, followed by 12 weeks of open-label maintenance treatment. Major outcome measures were Clinical Global Impressions Scale ratings for libido, mood, energy, and erectile function; Hamilton Depression Rating Scale scores, and Chalder Fatigue Scale scores. Body composition changes were assessed with bioelectric impedance analysis. Seventy men completed the 6-week trial. Response rates, defined as much or very much improved libido, were 74% (28/38) for patients randomized to testosterone, and 19% (6/32) for placebo-treated patients (P<.001). Of the 62 completers with fatigue at baseline, 59% (20/34) receiving testosterone and 25% (7/28) receiving placebo reported improved energy (P<.01). Among the 26 completers with an Axis I depressive disorder at baseline, 58% of the testosterone-treated patients reported improved mood compared with 14% of placebo-treated patients (Fisher exact test = .08). With testosterone treatment, average increase in muscle mass over 12 weeks was 1.6 kg for the whole group, and 2.2 kg for the 14 men with wasting at baseline. Improvement on all parameters was maintained during subsequent open-label treatment for up to 18 weeks. Testosterone is well tolerated and effective in the short-term treatment of symptoms of clinical hypogonadism in men with symptomatic human immunodeficiency virus illness, restoring libido and energy, alleviating depressed mood, and increasing muscle mass.
Article
Field studies of illicit anabolic-androgenic steroid users suggest that some develop manic or aggressive reactions to these drugs-a potential public health problem. However, controlled laboratory evaluations of these effects remain limited. In a randomized, placebo-controlled, crossover trial, we administered testosterone cypionate for 6 weeks in doses rising to 600 mg/wk and placebo for 6 weeks, separated by 6 weeks of no treatment, to 56 men aged 20 to 50 years. Psychiatric outcome measures included the Young Mania Rating Scale (YMRS), the Point Subtraction Aggression Paradigm (a computerized provocation test of aggression), the Aggression Questionnaire of Buss and Perry, the Symptom Checklist-90-R, daily diaries of manic and depressive symptoms, and similar weekly diaries completed by a "significant other" who knew the participant well. Testosterone treatment significantly increased manic scores on the YMRS (P = .002), manic scores on daily diaries (P = .003), visual analog ratings of liking the drug effect (P = .008), and aggressive responses on the Point Subtraction Aggression Paradigm (P = .03). Drug response was highly variable: of 50 participants who received 600 mg/wk of testosterone cypionate, 42 (84%) exhibited minimal psychiatric effects (maximum YMRS score, <10), 6 (12%) became mildly hypomanic (YMRS score, 10-19), and 2 (4%) became markedly hypomanic (YMRS score, > or =20). The 8 "responders" and 42 "nonresponders" did not differ significantly on baseline demographic, psychological, laboratory, or physiological measures. Testosterone administration, 600 mg/wk increased ratings of manic symptoms in normal men. This effect, however, was not uniform across individuals; most showed little psychological change, whereas a few developed prominent effects. The mechanism of these variable reactions remains unclear.
Article
A progressive decrease in androgen production is common in males after middle age. The resulting clinical picture has been erroneously named male menopause or andropause. A more appropriate designation is androgen decline in the aging male (ADAM). The syndrome is characterized by alterations in the physical and intellectual domains that correlate with and can be corrected by manipulation of the androgen milieu. We review the epidemiological aspects of aging and endocrinological manifestations of ADAM, and provide recommendations for treatment and monitoring of these patients. We performed MEDLINE, Pubmed, Current Contents and Pharmaceutical Abstracts searches of relevant peer reviewed publications on andropause, male climacteric, adult hypogonadism and aging. In addition, conference proceedings were researched to provide a more complete review of the literature. Information was scrutinized and collated, and contributory data were reviewed and summarized. ADAM is a clinical entity characterized biochemically by a decrease not only in serum androgen, but also in other hormones, such as growth hormone, melatonin and dehydroepiandrosterone. Clinical manifestations include fatigue, depression, decreased libido, erectile dysfunction, and alterations in mood and cognition. The onset of ADAM is unpredictable and its manifestations are subtle and variable, which has led to a paucity of interest in its diagnosis and treatment. Urological practice commonly includes a large proportion of men older than 50 years. Therefore, it is important for urologists to recognize the manifestations of and be familiar with evaluations necessary to document ADAM as well as its treatment and monitoring.
Article
Anabolic androgen steroid abuse is associated with multiple psychiatric symptoms and is a significant public health problem. The biological mechanisms underlying behavioral symptom development are poorly understood. We examined levels of monoamine metabolites, neurohormones, and neuropeptides in the cerebrospinal fluid (CSF) of 17 healthy men, at baseline and following 6 days of methyltestosterone (MT) administration (3 days of 40 mg/d, then 3 days of 240 mg/d). Subjects received MT or placebo in a fixed sequence, with neither subjects nor raters aware of the order. Potential relationships were examined between CSF measures, CSF MT levels, and behavioral changes measured on a visual analog scale. Following MT administration, levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly lower (mean +/- SD, 103.8 +/- 47 vs 122.0 +/- 50.7 pmol/mL; P<.01), and 5-hydroxyindoleacetic acid (5-HIAA) levels were significantly higher (mean +/- SD, 104.7 +/- 31.3 vs 86.9 +/- 23.6 pmol/mL; P<.01). No significant MT-related changes were observed in CSF levels of corticotropin, norepinephrine, cortisol, arginine vasopressin, prolactin, corticotropin-releasing hormone, beta-endorphin, and somatotropin release-inhibiting factor. Changes in CSF 5-HIAA significantly correlated with increases in "activation" symptoms (energy, sexual arousal, and diminished sleep) (r = 0.55; P =.02). No significant correlation was observed between changes in CSF and plasma MT, CSF MHPG, and behavioral symptoms. Short-term anabolic androgenic steroid use affects brain neurochemistry, increasing CSF 5-HIAA and decreasing MHPG. Changes in 5-HIAA levels caused by anabolic androgenic steroids are related to the behavioral changes we observed. In this small sample, we did not observe a significant relationship between behavioral measures and either dose of MT or CSF and plasma levels of MT.
Article
In a sense, all depression is difficult to treat. Most depressions are episodic conditions that, not infrequently, are slow to fully remit. Most also are complicated by comorbid psychiatric and general medical disorders. However, a minority of such difficult-to-treat depressions are treatment resistant. The most common cause of initial treatment failure is not resistance but undertreatment-that is, an insufficient duration of treatment, a subtherapeutic dosage of antidepressant, and/or poor adherence to the prescribed regimen. Complicating factors such as undiagnosed hypothyroidism or substance abuse can result in apparent treatment resistance unless addressed. Challenging subtypes of illness, including psychotic and bipolar subtypes of depression, are not necessarily inherently refractory but must be met with modified treatment approaches.
Article
From the age of 30 yrs on, the (free) testosterone [(F)T] levels decrease continuously with age, mean total T level at age 70 yrs, being only 2/3rds of the mean level at age 25 yrs, whereas mean FT level is only 40% of the mean level in young adults. However, inter-individual variations are wide and whereas at least 30% of men over age 70 yrs have clearly subnormal (F)T levels, 20% have still levels in the upper range of values in young men. Aging in males is accompanied by a series of signs and symptoms, reminiscent of androgen deficiency in young adults, such as decrease in muscle mass and strength, increase in abdominal, mainly visceral, fat with insulin resistance and atherogenic lipid profile, decrease in libido and sexual hair, osteopenia, decrease in cognitive performances, insomnia, excessive sweating and decrease in general well-being, and it is tempting to relate these symptoms to the age associated decrease in androgen levels, the more that often a significant, albeit generally weak, correlation of these symptoms with the (F)T levels is observed. Moreover, the preliminary data suggest favourable effects of androgen supplementation in the elderly. The decrease in (F)T levels is, however, only one of the factors responsible for the signs and symptoms of the aging male which have a multifactorial origin. Hence, the diagnosis of androgen deficiency in elderly men should be based on both the clinical symptomatology and the biochemistry, i.e. decreased (F)T levels, the latter being defined, more or less arbitrary, as levels below the lowest 1% of levels in young healthy males.
Article
This study examined the psychological symptomatology of men diagnosed with andropause and the association between calculated free testosterone (T) and depressed mood, anxiety and quality of life. Subjects were 153 men, aged 50-70 years, who participated in a screening of andropause. Total testosterone, FSH, LH and SHBG levels were measured. Depressed mood was assessed with the Carroll Rating Scale, anxiety with the "anxiety-insomnia" dimension of the General Health Questionnaire, and quality of life with the World Health Organisation Quality of Life questionnaire. The results showed that levels of free T decreased with age, whereas FSH and LH increased. Carroll Rating Scale scores were higher among hypogonadal subjects, but the mean score was low and not pathological. A negative correlation was observed between severity of depression as assessed by the Carroll Rating Scale and free T levels. However, subjects with a significant score on this scale did not exhibit different free T levels compared to subjects with a non-significant depressive score. Anxiety and quality of life did not differ between hypogonadal and eugonadal subjects. The present study therefore suggests that andropause is not characterised by specific psychological symptoms, but may be associated with "depressive symptoms" that are not considered as pathological.
Article
Naturally occurring opiates (endorphins) diminish testosterone levels by inhibiting both hypothalamic gonadotrophin releasing hormone production and testicular testosterone synthesis. Heroin addicts treated with a single daily dose of methadone and nonaddicts receiving continuous intrathecal opioids quickly develop low luteinizing hormone and total testosterone levels. A similar pattern was sought in men consuming commonly prescribed oral opioids. Free testosterone (FT), total testosterone (TT), estradiol (E(2)), dihydrotestosterone (DHT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in 54 community-dwelling outpatient men consuming oral sustained-action dosage forms of opioids several times daily for control of nonmalignant pain. Hormone levels were related to the opioid consumed, dosage and dosage form, nonopioid medication use, and several personal characteristics and were compared with the hormone analyses of 27 similar men consuming no opioids. Hormone levels averaged much lower in opioid users than in control subjects in a dose-related pattern (P < .0001 for all comparisons). FT, TT, and E(2) levels were subnormal in 56%, 74%, and 74%, respectively, of opioid consumers. Forty-eight men (89%) exhibited subnormal levels of either FT or E(2). Either TT or E(2) level was subnormal in all 28 men consuming the equivalent of 100 mg of methadone daily and in 19 of 26 (73%) consuming smaller opioid doses. Eighty-seven percent (39 of 45) of opioid-ingesting men who reported normal erectile function before opioid use reported severe erectile dysfunction or diminished libido after beginning their opioid therapy. Commonly prescribed opioids in sustained-action dosage forms usually produce subnormal sex hormone levels, which may contribute to a diminished quality of life for many patients with painful chronic illness.
Article
To evaluate a recently published algorithm for calculation of serum "Bioavailable" Testosterone (BAT) using serum Total Testosterone (TT), Sex Steroid Binding Globulin (SSBG) [also commonly known as Sex Hormone Binding Globulin (SHBG)] and albumin concentrations as parameters, in comparison with a locally available "salting-out" BAT method. If satisfactory, this calculation could serve as a substitute for the BAT assay, which would amount to a major cost saving and faster turnaround time. During a 6-month period, 426 serum samples referred for BAT analysis to the Hospitals In-Common Laboratory of Toronto were also analyzed in-house for TT, SSBG and albumin for computation of comparison calculated BAT results. A good statistical correlation was obtained, but only after unexpectedly drastic empirical modification of the association constant values: r=0.95, Calculated %BAT=0.971 x Measured %BAT + 0.008. The endocrinologist/andrologist of our team (JB), who was the responsible physician for all patients included in this study, reviewed the tabulated and charted calculated BAT results and verified that they were clinically equivalent. Although it is feasible to calculate BAT, the algorithm is not directly portable. Before adopting such a calculation each laboratory should compare it with the locally available BAT method and consider adjusting the calculation to optimize the correlation. Future reassessment may be necessary whenever the SSBG, TT or BAT assay is changed.
Article
Age-associated hypogonadism (testosterone deficit) occurs in 30% of men after the age of 55; it is associated with decreased muscle mass, bone mineral density, and libido, and with anorexia, fatigue, and irritability. Although some of these symptoms overlap with those of depression, the association between the 2 disorders is unclear. To determine if hypogonadal men have an increased incidence of depressive illness compared with eugonadal men. Historical cohort study using computerized medical records, followed by a manual medical record review. Veterans Affairs Puget Sound Health Care System. Two hundred seventy-eight men 45 years and older, without prior diagnosed depressive illness and with consistently normal or low testosterone levels (total testosterone level < or =200 ng/dL [< or =6.94 nmol/L]; or free testosterone level < or =0.9 ng/dL [< or =0.03 nmol/L]) at baseline and during a 2-year follow-up period. Incidence of, and time to, a depression diagnosis. The 2-year incidence of diagnosed depressive illness was 21.7% in hypogonadal men vs 7.1% in others (chi2(1)=6.0, P=.01). A Kaplan-Meier survival analysis showed a significant difference between hypogonadal and eugonadal men in time to diagnosed depression (log-rank test chi2(1)=6.9, P=.008). We used Cox proportional hazards regression models to examine the association of hypogonadism and time to depression diagnosis, adjusting for age, race, number of clinic visits, alcohol use disorders, prostate cancer, and overall medical comorbidity. The unadjusted hazard ratio for depression with hypogonadism was 3.5 (95% confidence interval, 1.3-9.4) (P=.01). Controlling for all covariates, hypogonadism remained significantly associated with depression (adjusted hazard ratio, 4.2; 95% confidence interval, 1.5-12.0) (P=.008). Hypogonadal men showed an increased incidence of depressive illness and a shorter time to diagnosis of depression. Further prospective studies are needed to confirm these preliminary findings and to clarify the role of testosterone in the treatment of depressive illness in older men.
Article
While testosterone's ameliorative effects on depressive disorders and fatigue in HIV-positive patients have been suggested in the literature, no placebo-controlled trial selecting for depressive disorders and including a standard antidepressant has been conducted. Accordingly, this double-blind trial was designed to determine whether testosterone, as well as fluoxetine, is superior to placebo for depression, fatigue, or both. One hundred twenty-three men with HIV/AIDS with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition depressive disorder entered the 8-week trial and were randomized to testosterone (up to 400 mg IM testosterone cypionate biweekly), fluoxetine (up to 60 mg/d), or double placebo. Outcome variables were the Clinical Global Impressions Scale for mood and for fatigue, the Hamilton Rating Scale for Depression, and the Chalder Fatigue Scale. Ninety men completed the trial. In intention-to-treat analyses, mood response rates were 54%, 47%, and 44% for fluoxetine, testosterone, and placebo, respectively. Among completers, mood response rates were 70%, 57%, and 53%, respectively; in neither analysis were differences between treatments statistically significant. In contrast, testosterone was superior to fluoxetine and placebo for completers regarding fatigue. In intention-to-treat analysis, response rates were 39%, 56%, and 42% for fluoxetine, testosterone, and placebo, respectively, and for study completers, 41%, 63%, and 52%, respectively, (P < 0.05), While over 50% of patients treated with testosterone reported improved mood, this rate was not statistically superior to placebo. Thus, our findings do not support prescription of testosterone as a first-line treatment for depressive disorders in HIV-positive men. However, if validated in additional studies, testosterone may be a useful option for medically ill men experiencing significant fatigue as well as depression.
Article
The effects of supplemental testosterone on cognition, mood and wellbeing in ageing men are unclear. This study aimed to assess the effect of 12-months of oral testosterone supplementation on cognitive function, mood and quality of life in elderly men with low-normal gonadal status, not specifically selected for cognitive or mood defects. A standard oral dose (80 mg twice daily) of testosterone undecanoate (TU) or placebo was administered for one year to 76 healthy men 60 years or older. All men had a free testosterone index (FTI) of 0.3-0.5, which represents a value below the normal lower limit for young men (19-30 years), but remains within the overall normal male range. A neuropsychological assessment including the trail making test (part B), visuospatial (VSP) block design test, mini mental state exam (MMSE), Geriatric Depression Scale (GDS), a 5-point Likert and a 10-point visual analogue quality of life (QoL) scale, along with serum hormone measurements were obtained at baseline, 6, and 12 months. Although calculated bioavailable testosterone (cBT) and FTI were higher, and muscle mass increased after 12 months, there was no difference in scores on the trail making or VSP block tests, the MMSE, GDS or either of the QoL scales between the testosterone and placebo group. There was no relationship between baseline cBT or FTI and treatment effect for any of the outcome measures. 12-month supplementation with oral TU does not affect scores on visuospatial t