The effects of pharmacologically induced hypogonadism on mood in healthy men

BACKGROUND: The effects of declining androgen secretion on mood regulation and the potential psychotropic efficacy of androgen replacement in men are largely undetermined. OBJECTIVE: To examine the effects on mood of the acute suppression of testosterone secretion. DESIGN: A double-blind, placebo-controlled, crossover (self-as-own-control) study. SETTING: An ambulatory care clinic in a research hospital. PARTICIPANTS: Thirty-one healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuse. INTERVENTIONS: Men received depot leuprolide acetate (Lupron, 7.5 mg intramuscularly) every 4 weeks for 3 months. After the first month of Lupron alone, all men received (in addition to Lupron) testosterone enanthate (200 mg intramuscular) or placebo (sesame oil as color-matched vehicle) every 2 weeks for 1 month each in a crossover design. The order of administration of testosterone and placebo was randomly assigned and counterbalanced. MAIN OUTCOME MEASURES: Mood and behavior rating scores (self-report and rater administered). RESULTS: With the exceptions of hot flushes, libido, and the feeling of being emotionally charged, none of the symptoms measured showed a significant difference across eugonadal, Lupron plus placebo, and Lupron plus testosterone conditions. Despite the absence of a uniform effect of Lupron plus placebo on mood, 3 men experienced clinically relevant mood symptoms during this induced hypogonadal condition. High baseline levels of sexual functioning predicted the greatest decline in sexual function during Lupron plus placebo. CONCLUSIONS: These data, the first to describe the effects on mood of induced hypogonadism in healthy young men, suggest that short-term hypogonadism is sufficient to precipitate depressive symptoms in only a small minority of younger men. The predictors of this susceptibility remain to be determined.     

CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that was followed by replacement with placebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and 5-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.     

Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial

BACKGROUND: Symptoms of male hypogonadism include low libido, fatigue, and dysphoria and are alleviated with testosterone replacement. The prevalence of major depressive disorder (MDD) in hypogonadal men is not known, nor is the antidepressant efficacy of testosterone replacement in depressed, hypogonadal men. METHOD: A 6-week double-blind, placebo-controlled clinical trial was conducted in 32 men with DSM-IV MDD and a low testosterone level, defined as total serum testosterone < or = 350 ng/dL. Patients were randomly assigned to receive weekly 1-mL intramuscular injections of either testosterone enanthate, 200 mg, or sesame seed oil (placebo). The primary outcome measure was the 24-item Hamilton Rating Scale for Depression (HAM-D). RESULTS: Thirty patients were randomly assigned to an intervention; 13 received testosterone, and 17 received placebo. Mean +/- SD age was 52+/-10 years, mean testosterone level was 266.1+/-50.6 ng/dL, and mean baseline HAM-D score was 21+/-8. All patients who received testosterone achieved normalization of their testosterone levels. The HAM-D scores decreased in both testosterone and placebo groups, and there were no significant between-group differences: reduction in group mean HAM-D score from baseline to endpoint was 10.1 in patients who received testosterone and 10.5 in those who received placebo. Response rate, defined as a 50% or greater reduction in HAM-D score, was 38.5% (5/13) for patients who received testosterone and 41.2% (7/17) for patients who received placebo. Patients receiving testosterone had a marginal but statistically significant improvement in sexual function (p = .02). CONCLUSION: In this clinical trial with depressed, hypogonadal men, antidepressant effects of testosterone replacement could not be differentiated from those of placebo.     

Cerebrospinal fluid and behavioral changes after methyltestosterone administration: preliminary findings

BACKGROUND: 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. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Increased incidence of diagnosed depressive illness in hypogonadal older men

CONTEXT: 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. OBJECTIVE: To determine if hypogonadal men have an increased incidence of depressive illness compared with eugonadal men. DESIGN: Historical cohort study using computerized medical records, followed by a manual medical record review. SETTING: Veterans Affairs Puget Sound Health Care System. PARTICIPANTS: 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. MAIN OUTCOME MEASURES: Incidence of, and time to, a depression diagnosis. RESULTS: 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). CONCLUSIONS: 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.     

Cerebrospinal fluid and plasma monoamine metabolites and their relation to psychosis. Implications for regional brain dysfunction in schizophrenia.

The relationship between central (cerebrospinal fluid [CSF]) and peripheral (plasma) monoaminergic metabolites and psychotic symptoms was examined in 22 drug-free schizophrenic inpatients. The CSF homovanillic acid levels did not differ significantly between patients and normal controls (n = 33). The CSF homovanillic acid levels, however, were negatively correlated with ratings of psychosis and positive symptoms, and the CSF homovanillic acid and 5-hydroxyindoleacetic acid levels correlated negatively with individual deficit symptoms. Stepwise and hierarchical multiple-regression analysis revealed that among monoaminergic measures, only the CSF and plasma homovanillic acid levels contributed significantly to the total Brief Psychiatric Rating Scale and positive symptom variance with negative and positive partial correlations, respectively. Levels of CSF 3-methoxy-4-hydroxyphenylglycol, but not of CSF norepinephrine, were significantly elevated in the schizophrenic patients compared with controls, and plasma 3-methoxy-4-hydroxyphenylglycol levels were positively correlated with negative symptoms. We discuss the potential implications of these findings for a model of dopaminergic dysfunction in schizophrenia involving distinct cortical and subcortical contributions.     

Cerebrospinal fluid amine metabolites. Relationships with behavioral measurements in depressed, manic, and healthy control subjects

We studied 99 hospitalized depressed, 14 manic, and 61 healthy control subjects and evaluated relationships during a drug-free baseline period between behavioral measures (postulated to be associated with brain norepinephrine, dopamine, and serotonin function) and metabolites of these neurotransmitters sampled from lumbar cerebrospinal fluid (CSF): 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid, and 5-hydroxyindoleacetic acid. Depressed subjects with increased anxiety, agitation, somatization, and sleep disturbance were found to have significantly elevated concentrations of CSF MHPG; this relationship was not found in the healthy controls. A correlation between CSF MHPG level and an anxiety/agitation dimension measured in all subjects was statistically significant but explained a modest portion of the total variance. No consistent relationships were found between CSF MHPG and depression/retardation, hostility/interpersonal sensitivity, and global severity, nor did any of these measures correlate significantly with the levels of the other monoamine metabolites, although some trends were found. Other factors did not account for the relationships between CSF MHPG and some behavioral measures, including diagnostic subgroup, motor movement, age, sex, and premenopausal or postmenopausal status in women. Suggested relationships among drug treatment modality, eventual treatment outcome, behavioral and mood state at baseline, and these metabolite levels will require further analyses.     

CSF monoamine metabolite levels in Alzheimer's and Parkinson's disease

Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 32 patients with a clinical diagnosis of Alzheimer's disease (AD) and from 21 patients with Parkinson's disease (PD). The baseline CSF metabolite values did not differ significantly between the two groups of patients, although HVA levels were lowest in patients with PD and in the more severely demented patients with AD. Levels of all three metabolites increased significantly in both patient groups during probenecid administration, but HVA levels were significantly higher in patients with AD than in patients with PD. Within the AD group, those with the most severe dementia had the greatest rise in MHPG levels. Alterations in monoamine metabolite levels in the CSF detected during probenecid administration aid in the differential diagnosis of neurodegenerative diseases such as AD.     

5-Hydroxyindoleacetic acid and homovanillic acid in human cerebrospinal fluid below partial and complete spinal subarachnoid block

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were investigated by lumbar cerebrospinal fluid (CSF) of 21 patients with partial and total spinal subarachnoid block. HVA levels in CSF below a complete block were significantly lower and 5-HIAA levels were signigicantly higher than controls. Below a partial block, HVA levels were normal; 5-HIAA levels were higher than in patients with complete block. Possible explanations for these findings are discussed.     

Isoniazid effects on choreiform movement and on GABA, HVA and 5-HIAA in CSF

Isoniazid was administered in 4-week open trial in patients with choreiform movement. Gamma-aminobutyric acid (GABA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in CSF were measured before and after treatment. Isoniazid did not improve choreiform movement. CSF GABA levels were significantly increased after treatment, but HVA and 5-HIAA levels were not significantly altered. The findings suggest that isoniazid influenced brain GABA metabolism but did not influence dopamine and serotonin metabolism in patients with chorieform movement.     

Family psychiatric history, cerebrospinal fluid monoamine metabolites, and temperament in infants.

BACKGROUND: Variations in cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, and homovanillic acid have been associated with behavioral abnormalities in nonhuman primates, and with psychopathology in studies of children and adults. METHODS: We assayed monoamine metabolites in "left-over" spinal fluid from 167 neurologically normal newborn infants (0-3 months of age), and later (at age 18-21 months of age) obtained their family psychiatric histories and assessed their temperament using the Colorado Childhood Temperament Inventory (CCTI). RESULTS: Family history of antisocial personality disorder predicted significantly lower scores for soothability (p = .003) at 18-21 months. There were no statistically significant associations between newborn monoamine metabolite levels and any aspect of temperament on the CCTI. CONCLUSIONS: These findings suggest complex relationships between genetic liability for psychiatric disorders and CSF monoamine metabolite levels; those relationships do not seem to be mediated by infant temperament. It appears likely that interindividual differences in monoamine metabolite levels change over the course of development in humans.     

Use of cerebrospinal fluid drawn at pneumoencephalography in the study of monoamine metabolism in man

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in CSF obtained after injection of air during pneumoencephalography (PEG) than in lumbar CSF, as drawn before the injection. There was a high correlation between levels in the `mixed' and lumbar samples of CSF in the case of each of the two acids. The concentration of lumbar HVA, but not that of 5-HIAA, was negatively correlated with CSF pressure. 5-HIAA levels were low in both samples of CSF in a group of epileptics, by comparison with controls. In two patients with Kufs disease and in one with Niemann-Pick disease, the concentration of HVA was very low in the lumbar sample. The application of a standardized PEG technique in the study of monoamine metabolism in man is suggested.     

Cerebrospinal fluid monoamine metabolites in alcoholic patients who attempt suicide.

Reduced cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid have been reported to be commonly associated with suicidal behaviour. Alcoholics are known to often manifest suicidal behaviour. Therefore, we compared cerebrospinal fluid levels of monoamine metabolites in alcoholics who had (n = 20) and had not (n = 108) attempted suicide and healthy volunteers (n = 30). There were no significant differences among the 3 groups for CSF levels of either 5-hydroxyindoleacetic acid, the dopamine metabolite homovanillic acid, norepinephrine, or the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol.     

Seasonal variations of human lumbar CSF neurotransmitter metabolite concentrations

While circadian rhythms of many biological processes have been well characterized in humans, variations throughout the year have been little studied. Lumbar cerebrospinal fluid (CSF) neurotransmitter metabolite levels for homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) were determined in patients with schizophrenia and Alzheimer's disease. Samples from both groups taken during October through March had significantly higher levels of HVA and 5-HIAA, but not MHPG, than samples from April through September.     

Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression

Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.     

Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects

Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid, and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol were measured in CSF before and after three weeks' treatment of severe obsessive-compulsive disorder with clomipramine hydrochloride. Patients who responded to clomipramine treatment had significantly higher CSF levels of 5-HIAA before treatment. The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomipramine. Reduction of CSF concentrations of 5-HIAA, which probably reflects drug action on central serotonin neurons, was maximal at a plasma clomipramine concentration of about 300 nmole/L. At higher levels, the reduction of CSF levels of 5-HIAA was smaller. The antiobsessive effect of clomipramine may be connected to its capacity to inhibit serotonin uptake.     

CSF monoamine metabolites in schizophrenic patients

The monoamine metabolites 3-methoxy-4-hydroxyphenyglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 16 psychiatrically health controls and in 28 schizophrenic patients. There was no difference in CSF MHPG and HVA levels between the group of patients and the controls. CSF levels of 5-HIAA were significantly lower in schizophrenic patients than in controls. Differential analysis of patients with and without neuroleptics revealed that these findings were not due to drug treatment. Positive correlations were found between the level of 5-HIAA and the items: hallucinatory behaviour, grandiosity, and tension as rated on the Brief Psychiatric Rating Scale. As 5-HIAA CSF data are controversial for nosological entities, the search for correlations between 5-HIAA and individual psychopathological variables could provide more specific indices for psychiatric diagnosis, treatment or prophylaxis.     

Sex hormones and biogenic amine turnover of sex offenders in relation to their temperament and character dimensions

Relationships between Cloninger's temperament and character dimensions and plasma sex hormone levels and biogenic amine turnover were studied in male prison inmates convicted of rape (n=61) or child molestation (n=24) and normal male controls (n=25). The participants completed the Temperament and Character Inventory (TCI), which includes the temperament dimensions Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence as well as the character dimensions Self-Directedness, Cooperativeness and Self-Transcendence. Plasma levels of testosterone, dihydrotestosterone, sex hormone binding globulin, luteinizing hormone (LH) and follicle-stimulating hormone were estimated in plasma samples and 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine samples. Both sex offender groups had higher Novelty, Seeking and lower Reward Dependence, Self-Directedness and Cooperativeness scores compared with the controls. Plasma levels of testosterone and dihydrotestosterone were significantly higher in rapists than in controls. Novelty Seeking scores were positively correlated with LH levels in rapists, and with testosterone levels in child molesters. Harm Avoidance scores were negatively correlated with 5-HIAA levels in rapists and with HVA levels in child molesters. In rapists, the calculated free androgen index showed a negative correlation with 5-HIAA. For the sex offender sample as a whole, the subgroup with high testosterone levels had higher Harm Avoidance scores, the subgroup with low HVA levels had lower Cooperativeness scores, and the subgroups with high 5HIAA or MHPG levels had lower Persistence scores. The results indicate that Novelty Seeking behavior in the group of rapists is associated with a hyperactive hypothalamic-pituitary-gonadal axis. In addition, low serotonin turnover and low dopamine turnover seem to be associated with a passive-avoidant behavioral style in rapists and child molesters, respectively.     

Reproductive Endocrine Considerations and Hormonal Therapy for Men with Epilepsy

Summary: Androgen deficiency is unusually common among men with epilepsy. It may contribute to reproductive and sexual dysfunction and possibly exacerbate seizure frequency. The most important androgen is testosterone. It exists in the serum in a free form or bound to albumin or sex hormone-binding globulin (SHBG). Free testosterone levels have correlated significantly with measures of potency and sexual interest. The possibility that measures of non-SHBG-bound testosterone may provide a more sensitive assessment of biologically and perhaps clinically significant androgen levels is raised for consideration. Androgen deficiency may result from increased catabolism and binding induced by antiepileptic drugs (AEDs). It is a feature of the reproductive endocrine disorders that are often associated with epilepsy: hypogonad-otropic hypogonadism, hypergonadotropic hypogonadism, and functional hyperprolactinemia. It may be a consequence of medication-induced elevations in serum estradiol. Estradiol exerts a potent inhibitory influence on luteinizing hormone secretion and may contribute to premature aging of the reproductive system, both at the level of the testes and the hypothalamus. Testosterone therapy may moderately benefit reproductive and sexual function. Despite its antiseizure effects in animal experiments, however, it has not been reported to improve seizures clinically. One possible explanation is that AEDs that induce enzyme synthesis may enhance the conversion of testosterone to estradiol by aromatase. This possibility is supported by the improved seizure control achieved with the adjunctive use of the aromatase inhibitor testolactone or the antiestrogen clomiphene.     

Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia

Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n = 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were non-suppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors.