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Original Article |

Monoamines and Neurosteroids in Sexual Function During Induced Hypogonadism in Healthy Men FREE

Miki Bloch, MD; David R. Rubinow, MD; Kate Berlin, BA; Karl R. Kevala, MSC; Hee-Yong Kim, MD; Peter J. Schmidt, MD
[+] Author Affiliations

Author Affiliations: Behavioral Endocrinology Branch, National Institute of Mental Health (Drs Bloch, Rubinow, and Schmidt and Ms Berlin), and National Institute of Alcohol Abuse and Alcoholism (Mr Kevala and Dr Kim), National Institutes of Health, Bethesda, Md.


Arch Gen Psychiatry. 2006;63(4):450-456. doi:10.1001/archpsyc.63.4.450.
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Context  Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans.

Objective  To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism.

Design  Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design.

Setting  National Institutes of Health, Bethesda, Md.

Participants  Twelve healthy male volunteers.

Interventions  We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month.

Main Outcome Measures  Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites.

Results  The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = −0.76 and −0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = −0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure.

Conclusion  These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Recently, there has been considerable interest in the behavioral effects of androgenic anabolic steroids, in large part due to the extent and consequences of androgenic anabolic steroid abuse among young men, the potential impact on mood and behavior of the age-related decline in androgen secretion, and the potential therapeutic use of androgen replacement in symptomatic aging men. Both increased and decreased androgen secretion have been observed to induce clinically significant mood and behavioral changes in some men.19 However, the effects observed are not uniform, and factors have not been identified that will predict which individuals will develop androgen-induced mood and behavioral disorders. Additionally, despite the well-described relationship between hypogonadism and loss of sexual function,1013 the hormonal mediators of the reported loss of libido are not well described.

Several physiologic systems could mediate changes in mood associated with a change in androgen secretion, including the γ-aminobutyric acid (GABA) and serotonin systems, both of which are involved in the control of mood and behavior and are regulated by androgens. The animal literature has clearly documented the important regulatory effects on these systems of both increases and decreases in androgen secretion.14,15 Concerted changes in androgen and serotonin may underlie behavioral disorders in humans as well. For example, Virkkunen et al16 reported both lower 5-hydroxyindoleacetic acid (5-HIAA) and higher testosterone levels in the cerebrospinal fluid (CSF) of alcoholic, impulsive offenders with antisocial personality disorders compared with controls. In this study, although levels of both 5-HIAA (lower) and testosterone (higher) differed from controls in the group as a whole, higher CSF testosterone levels were associated with aggressive behavior, whereas lower 5-HIAA levels were associated with impulsive behavior. More recently, Daly et al17 observed that the androgenic anabolic steroid methyltestosterone increased CSF 5-HIAA levels and that levels of CSF 5-HIAA were correlated with observed androgenic anabolic steroid–induced behavioral changes but not with CSF levels of methyltestosterone. Androgens such as testosterone and dehydroepiandrosterone (DHEA) may also influence behavior through conversion into several GABAA receptor–modulating neuroactive steroids such as androsterone, low levels of which may cause abnormalities in GABAA receptor function and mood symptoms.18

Although the serotonin system is implicated in the behavioral effects of high-dose androgen administration, those systems that mediate the effects of androgen withdrawal are less well studied. Several studies6,1930 have suggested the relevance of both declining and deficient androgen secretion and androgen withdrawal in depression that occurs in men. To identify systems that could mediate mood disturbances, behavioral symptoms related to mood (eg, sleep, appetite, energy, and impulsivity), and changes in sexual function secondary to androgen withdrawal, we examined CSF monoamine metabolites and hormone levels in healthy volunteers with no current or past psychiatric illness during gonadotropin-releasing hormone agonist (leuprolide acetate)–induced hypogonadism and testosterone replacement. Additionally, given prior findings, including those of Daly et al,17 we examined correlations between observed changes in ratings of mood, behavior, and sexual function during leuprolide-induced hypogonadism and measures of CSF monoamine and hormone levels.

PARTICIPANT SELECTION

This study was a component of a larger study that examined the effects on mood and behavior of gonadotropin-releasing hormone agonist–induced hypogonadism and testosterone replacement in healthy male volunteers.6 Study participants were men aged 18 to 45 years (mean ± SD age, 30.1 ± 4.1 years) recruited through advertisements and referred from the National Institutes of Health Normal Volunteer Office. All were medication free, had no significant medical illness (current or in the past 2 years), and had normal laboratory results. Specifically, complete blood cell counts, blood chemistry test results (including electrolytes, liver, and kidney function tests), thyroid function test results (thyrotropin and free thyroxine), and prostate-specific antigen levels were within normal limits. Plasma total testosterone levels at baseline (mean ± SD, 575.2 ± 246.6 ng/dL [19.96 ± 8.56 nmol/L]) ranged from 355 to 992 ng/dL (12.32-34.42 nmol/L) (reference range, 300-1200 ng/dL [10.41-41.64 nmol/L]) (National Institutes of Health Clinical Center, Bethesda, Md). Plasma prolactin levels were within normal limits (1-16 μg/L), and the mean ± SD body mass index (calculated as weight in kilograms divided by the square of height in meters) was 25.9 ± 2.3. The absence of current or past psychiatric illness was confirmed by a structured psychiatric diagnostic interview31 and daily symptom self-ratings consisting of a visual analog scale32,33 and the Daily Rating Form (DRF).34 Participants were excluded from this study if they had a past or present psychiatric illness or evidence of persistent (>3-5 days) clinically significant mood and behavioral symptoms of moderate severity on the DRF during their 2-month screening phase. The protocol was reviewed and approved by the National Institute of Mental Health Intramural Research Board, and oral and written informed consent documents were obtained from all participants. Each of the men in the larger study was approached, and 12 agreed to participate in the lumbar puncture (LP) portion of the study. All of the men were paid for their participation in this protocol according to the guidelines of the National Institutes of Health Normal Volunteer Office.

PROCEDURE

This was a double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design. After a 2-month screening phase, men received leuprolide acetate (7.5 mg intramuscularly) (Lupron; TAP Pharmaceuticals, Chicago, Ill) every 4 weeks for 3 months. Leuprolide alone was administered for the first 4 weeks. Once a consistent state of hypogonadism was achieved, participants continued to take leuprolide for an additional 8 weeks and received replacement therapy under double-blind, placebo-controlled conditions. Thus, all participants received, in addition to leuprolide, testosterone enanthate (200 mg intramuscularly every 2 weeks) or placebo (sesame oil, 1.5 mL intramuscularly every 2 weeks as color-matched vehicle) for 1 month (ie, 2 consecutive injections of each compound) and then crossed over to the other replacement. The order of replacement was randomly assigned and counterbalanced. Both subjects and raters were blind to the order of replacement. Blood samples were obtained at the time of the LP. Blood samples were centrifuged, aliquoted, and stored at −70°C until time of assay.

CSF MEASURES

All participants consumed a low-monoamine diet for 2 days before LP. The participants remained fasting from midnight. All LPs were conducted between 9:00 am and 10:30 am at the end of both the testosterone replacement and placebo phases. The LPs were performed with a sterile technique in the L4-L5 interspace with the participant in the lateral decubitus position. A total of 21 mL of CSF was collected from each participant. The first 3 mL collected was used for standard clinical studies. The next 18 mL was drawn in 3 aliquots (12, 3, and 3 mL). The first aliquot was subdivided into six 1-mL subaliquots and two 3-mL aliquots, to which 20 μL of 20% formic acid was added. The samples were placed on ice and stored at −70°C until assayed.

ASSAYS

The following CSF assays were performed: 5-HIAA, homovanillic acid (HVA), testosterone, dihydrotestosterone, androsterone, DHEA, and pregnenolone. The CSF steroids and neurosteroids were analyzed by gas chromatography/electronic capture negative chemical ionization mass spectrometry, as described previously.35 The metabolites 5-HIAA and HVA were measured using high-performance liquid chromatography with electrochemical detection.36,37 Assays for 5-HIAA and HVA were performed in 1 batch, with 4% and 6% intra-assay variation, respectively.

Blood levels of testosterone, estradiol, and dihydrotestosterone were measured by radioimmunoassay as described previously,3842 and free testosterone was measured by equilibrium dialysis43 (Quest Diagnostics, Baltimore, Md).

SYMPTOM RATINGS

To assess the severity of mood symptoms, the DRF was completed at baseline and during each hormonal condition. The DRF, a 6-point Likert-type scale, was modified to include the symptoms measured in this study34 and was completed nightly to represent a composite rating for the previous 12 hours; scores range from 1 (symptom not present) to 6 (symptom present in the extreme). The symptoms measured included the following: avoidance of social activity; loss of enjoyment or interest; impaired function at work or at home; irritability or anger; impaired concentration or distractibility; mood swings; feeling depressed, sad, low, or blue; anxiety or nervousness; decreased eating; increased eating; more sleep, naps, or lying in bed; low energy; loneliness or feeling rejected; being physically restless or agitated; feeling powerful, emotionally charged, or pumped up; increased sexual interest; decreased sexual interest; disturbed sleep; drinking of alcohol or use of nonprescribed drugs; impulse to hurt self; impulse to hurt someone else; acting on impulse to hurt someone; daytime hot flushes; and nighttime hot flushes. The mean DRF rating for the last 7 days of each hormonal condition was calculated for each symptom. Finally, during each biweekly clinic visit, the Beck Depression Inventory (BDI), a standardized measure of depression severity,44 was completed.

STATISTICAL ANALYSIS

Levels of both blood and CSF androgens and BDI and DRF symptom ratings were not normally distributed (ie, the standard deviation approximated the mean for several measures, and no values were negative numbers)45; consequently, all measures were compared across hormone conditions (hypogonadal vs testosterone replacement) by the Wilcoxon signed rank test.

Spearman correlation coefficients were used as a conservative measure because of the nonparametric nature of mood ratings and the skewed distribution of CSF measures. Correlations performed were those between CSF measures of steroids and monoamine metabolites and those between selected mood and behavioral symptoms and CSF measures. Spearman correlations were performed on the values for measures obtained during both the hypogonadal and testosterone-replaced conditions and on the difference in measures between these conditions. However, the latter correlations were limited to only those measures (either biological or behavioral) that significantly changed across hormone conditions (as demonstrated by the Wilcoxon signed rank test). Finally, Spearman correlation coefficients were calculated between levels of free and total testosterone in the blood and levels of testosterone in the CSF.

Plasma hormone levels (Table 1) showed significant changes between testosterone-replaced and hypogonadal conditions, with the hypogonadal state associated with significantly lower levels of total testosterone, free testosterone, dihydrotestosterone, and estradiol. Comparisons of the BDI scores and the DRF symptom scores across hormone conditions showed a significant increase (more symptomatic) in the following symptoms during the hypogonadal state compared with the testosterone-replaced condition: BDI scores (z = 2.4; P = .02), daytime hot flushes (z = 2.2; P = .03), nighttime hot flushes (z = 2.2; P = .03), and decreased sexual interest (z = 2.6; P=.009) (the symptom of increased sexual interest changed [decreased] but only at a trend level of significance [z = −2.0; P = .05]). The BDI scores during hypogonadism ranged from 0 to 14, but only 2 men had BDI scores of 7 or greater (values of 9 and 14). No other symptom rating scores significantly changed across hormone conditions. A similar pattern of symptom change was observed in a larger study of men participating in this protocol6 (many of whom did not undergo LP).

Table Graphic Jump LocationTable 1. Blood Hormone Levels in 12 Men During Leuprolide Acetate–Induced Hypogonadal and Testosterone-Replaced Conditions*

The CSF monoamine and neurosteroid levels are presented in Table 2. Significantly lower CSF levels of testosterone, androsterone, and dihydrotestosterone but not DHEA or pregnenolone were observed during hypogonadism compared with the testosterone-replaced condition. No significant differences in CSF measures of 5-HIAA or HVA were observed across hormonal conditions.

Table Graphic Jump LocationTable 2. Cerebrospinal Fluid Measures of Monoamine Metabolites and Neurosteroids in 12 Men During Leuprolide Acetate–Induced Hypogonadism and After Testosterone Replacement*
CORRELATIONS BETWEEN SYMPTOMS AND CSF MEASURES

The CSF levels of androsterone were correlated with the severity of decreased sexual interest during both hypogonadal and testosterone-replaced conditions (r = −0.76, P<.01; and r = −0.81, P<.001, respectively) (Table 3). Additionally, the change in CSF androsterone levels was correlated with the change in the severity of decreased sexual interest between testosterone-replaced and hypogonadal conditions (r = −0.68; P<.05). Only a few additional symptom correlations were significant. During the hypogonadal state, values of CSF testosterone significantly correlated with BDI scores (r = −0.72; P = .01), as well as with both daytime and nighttime hot flushes (r = −0.72 and −0.83, respectively; P<.01). No other significant correlations were observed between those symptoms selected for showing a significant difference across hormone conditions and measures of CSF monoamines or neurosteroid levels.

Table Graphic Jump LocationTable 3. Spearman Correlation Coefficients Between Cerebrospinal Fluid Measures of Neurosteroids and Symptom Ratings
CORRELATIONS BETWEEN BLOOD HORMONE LEVELS AND CSF MEASURES

The change in serum levels of free testosterone but not total testosterone correlated with the change in CSF testosterone (r = 0.6; P<.05); no significant correlations were observed, however, between these measures during either the hypogonadal or testosterone-replaced conditions.

CORRELATIONS BETWEEN INDIVIDUAL CSF MEASURES

The CSF measures of 5-HIAA and HVA were significantly correlated during both the leuprolide-induced hypogonadism (r = 0.85; P<.01) and testosterone-replaced conditions (r = 0.87; P = .001). Additionally, during the hypogonadal state, CSF measures of androsterone were correlated with both CSF 5-HIAA (r = −0.60; P = .05) and CSF DHEA (r = 0.66; P<.05). During testosterone replacement, there were no significant correlations other than that between 5-HIAA and HVA. However, across hormone conditions, a significant correlation was present between changes in CSF dihydrotestosterone and androsterone (r = 0.67; P<.05).

This study yielded 2 main findings. First, the symptom of decreased sexual interest correlated significantly with CSF measures of androsterone. Thus, this novel hormone, whose affinity is low for the androgen receptor (AR) but high for the GABAA receptor, could mediate the effects of androgen on male sexual function. Second, during hypogonadism, changes in mood, sexual interest, and hot flushes were not correlated with CSF 5-HIAA or HVA. In contrast to previous studies in both animals and humans, levels of these monoamine metabolites did not significantly change during hypogonadism compared with testosterone replacement.

The short-term suppression of androgen secretion is associated with decreased libido and the development of hot flushes in most men and with changes in mood, energy level, and cognition in only some men.6,12,46 In a relatively small sample of men with leuprolide-induced hypogonadism, we observed that hypogonadism was associated with a significant decrease in sexual interest and an increase in both hot flushes (daytime and nighttime) and BDI scores (depression). These data are consistent with observations from the larger cohort of men, from which the men in this study were recruited.6 The symptom of decreased sexual interest did not correlate with CSF measures of testosterone, dihydrotestosterone, or DHEA, all of which are reported to increase sexual interest when administered to hypogonadal men.10,11,47 However, we observed that decreased sexual interest significantly correlated with CSF measures of androsterone. The correlations with CSF androsterone were observed during both the hypogonadal and testosterone-replaced conditions; in addition, the magnitude of the decrease in sexual interest correlated with the magnitude of the decrease in CSF androsterone levels across conditions. Thus, regardless of the hormonal state, the association between decreased sexual interest and CSF androsterone levels (but not other androgens measured) remained significant. Our findings, then, suggest that CSF androsterone contributes to the regulation of sexual interest in men.

The neurobiologic characteristics of sexual behavior are complex, involving multiple neuroanatomical regions (eg, limbic and prefrontal reward areas), neuroregulatory systems (eg, serotonin, dopamine, and nitric oxide), and the influence of numerous contextual variables (eg, past experience and environmental cues).4850 Gonadal steroids are well-established neuromodulators and play an integral regulatory role in several aspects of sexual behavior. For example, in male sexual behavior, the AR and estrogen receptors α and β are implicated; however, the mechanisms involved are not fully documented.49,51,52 Additionally, sexual regulation in female rodents appears to involve neurosteroid metabolites of both progesterone and androgens, potentially acting through modulation of ligand-gated ion channels, mediating several important aspects of sexual behavior (eg, receptivity).49,53

Our findings with androsterone in men are not without precedent in studies of animal sexual behavior. Although less is known about the behavioral relevance of androsterone compared with other androgens, androsterone administration reverses castration-induced decreases in the sexual behavior of male zebra finches.54 However, these effects of androsterone are not observed in other species of birds55,56 or rodents.57 Finally, androsterone reduces anxiety in male mice during sexual encounters58 and therefore may indirectly modulate aspects of sexual behavior.

Androsterone (3α-hydroxy-5α-androstane-17-one) is a 17-ketosteroid metabolite of 5α-dihydrotestosterone, and like other gonadal steroids, androsterone may exert its effects on the central nervous system through several possible mechanisms. It is a weak androgen with a lower affinity for the AR than either of its precursors, dihydrotestosterone or testosterone. Androsterone and its sulfate are also both potent neurosteroids59 and modulate activity at the GABAA receptor complex with an affinity comparable to the neurosteroid allopregnanolone.60 Androsterone increases GABA-activated chloride influx, with brain region–specific potentiation in the amygdala and hippocampus.61 Finally, androsterone may serve as a precursor for the production of 3α- and 3β-androstanediol, the latter compound being an active ligand at the estrogen receptor β receptor.62,63 Thus, androsterone has neuroregulatory potential and could regulate sexual function by its actions at the AR, the estrogen receptor, or the GABAA receptor complex. Recent studies of both estrogen receptor β and aromatase knockout mice have identified regulatory roles for both estradiol and its receptors in male sexual function.6467 Two observations in this study suggest that androsterone's effects on sexual function are more likely mediated through estrogen receptor than either AR or GABAA receptors. First, the lack of association between changes in sexual function and either testosterone or dihydrotestosterone is not consistent with an AR-mediated effect. Both testosterone and dihydrotestosterone are more potent agonists at the AR than androsterone, and if the effects on sexual function involved the AR, one would expect to observe greater effects on sexual function with changes in these more potent AR ligands. Second, no significant changes in anxiety accompanied the hypogonadism-related changes in either libido or androsterone levels, and therefore a role for GABAA action is unlikely.

The second finding of this study was the absence of evidence in humans that short-term induction of hypogonadism alters CSF monoamine activity. No significant changes in CSF monoamine levels were observed during hypogonadism compared with testosterone replacement, and no significant correlations were observed between CSF 5-HIAA and either CSF testosterone levels or behavioral symptoms. In fact, with the exception of a significant negative correlation between CSF androsterone and 5-HIAA, no significant correlations were observed between CSF levels of monoamines and those of testosterone, DHT, DHEA, or pregnenolone. Although CSF androgen levels significantly decreased during hypogonadism, we observed no decrease in 5-HIAA levels. The significant correlation between 5-HIAA and androsterone levels during hypogonadism was negative, in a direction consistent with the observations of Virkkunen et al.16 As a caveat, it is difficult to attribute physiologic significance to the correlations between CSF measures of androsterone and 5-HIAA or DHEA, since levels of neither 5-HIAA nor DHEA changed across hormonal conditions despite significant changes in androsterone. In contrast to the reported association of anabolic steroid–induced mood and behavioral symptoms (activation) with increased CSF 5-HIAA levels,17 we observed no correlation between androgen withdrawal–related behavioral symptoms and measures of CSF 5-HIAA or HVA. There are several possible reasons for our inability to detect significant changes in CSF monoamine activity during induced hypogonadism. First, androgen withdrawal–related behavioral symptoms may be mediated by systems distinct from those implicated in the behavioral activation secondary to androgen excess (ie, serotonergic). Alternatively, CSF measures of monoamine metabolites, which represent integrated measures of central monoamine activity, may not be sufficiently sensitive to brain region–specific changes in monoamines occurring after a short-term change in endocrine state or behavior. For example, in male rats gonadectomy alters brain monoamine metabolism in a brain region–specific manner, increasing levels of HVA in the hypothalamus and brainstem and levels of 5-HIAA in the hypothalamus and striatum.68 Finally, it is possible that our failure to observe significant correlations between CSF 5-HIAA and sexual behavior was due to the relatively low levels of behavioral symptoms that were observed in our sample.

Although not significantly correlated with sexual interest, CSF levels of testosterone correlated with both hot flush severity and BDI scores during the hypogonadal state, when men were symptomatic. Hot flush severity accounted for approximately 60% of the variance in BDI scores in a stepwise linear regression; therefore, BDI scores probably reflected hot flush–related symptoms of disturbed sleep or fatigue. The correlation between hot flushes and testosterone suggests that testosterone may be a direct thermoregulator or, alternatively, that testosterone levels reflect the amount of precursor available for aromatization to estrogen.

Our data suggest that the effects of testosterone on some aspects of sexual function are mediated by the neurosteroid metabolite of dihydrotestosterone, androsterone. In contrast to the other androgens measured in this study, CSF levels of androsterone alone correlated with decreased libido during both hypogonadism and testosterone replacement; in addition, the change in androsterone levels across hormone conditions was correlated with the corresponding decrease in sexual interest. The self-report rating scale that we used does not permit discrimination of changes in sexual behavior from changes in cognition or perception. As a caveat, had we studied a larger sample of men, it is possible that some of the correlations between additional CSF measures and symptoms would have met statistical significance. Future studies using larger samples of men, a more comprehensive measure of the components of sexual function, and possibly measures of performance may identify a more specific role of androsterone or its metabolites in male sexual function. Finally, the failure to measure androsterone may help explain the discrepant findings in the literature regarding the role of testosterone in sexual function in men.

Correspondence: Peter J. Schmidt, MD, National Institute of Mental Health, Building 10-CRC, Room 65340 (SE), 10 Center Dr MSC 1276, Bethesda, MD 20892-1276 (peterschmidt@mail.nih.gov).

Submitted for Publication: May 20, 2005; final revision received September 28, 2005; accepted September 29, 2005.

Funding/Support: This study was supported by the Intramural Research Programs of the National Institutes of Health, National Institute of Mental Health, and National Institute of Alcohol Abuse and Alcoholism, Bethesda, Md.

Acknowledgment: We acknowledge Markku Linnoila, MD, PhD (in memoriam), for the monoamine metabolite assays; Carolyn Gibson, BSc, for assistance with data analysis; and Merry Danaceau, RN, MSNCS, for clinical assistance.

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Malone  DA  JrDimeff  RJLombardo  JASample  RHB Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sport Med 1995;525- 31
PubMed Link to Article
Thiblin  IRuneson  BRajs  J Anabolic androgenic steroids and suicide. Ann Clin Psychiatry 1999;11223- 231
PubMed Link to Article
Brower  KJBlow  FCEliopulos  GABeresford  TP Anabolic androgenic steroids and suicide [letter to the editor]. Am J Psychiatry 1989;1461075
PubMed
Spitzer  RLWilliams  JBGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R, Patient Edition.  New York Biometrics Research Dept, New York State Psychiatric Institute1990;
Miller  MDFerris  DG Research methodology: measurement of subjective phenomena in primary care research: the visual analogue scale. Fam Pract Res J 1993;1315- 24
PubMed
Luria  RE The validity and reliability of the visual analogue mood scale. J Psychiatr Res 1975;1251- 57
PubMed Link to Article
Endicott  JNee  JCohen  JHalbreich  U Premenstrual changes: patterns and correlates of daily ratings. J Affect Disord 1986;10127- 135
PubMed Link to Article
Kim  YSZhang  HKim  HY Profiling neurosteroids in cerebrospinal fluids and plasma by gas chromatography/electron capture negative chemical ionization mass spectrometry. Anal Biochem 2000;277187- 195
PubMed Link to Article
Scheinin  MChang  WHKirk  KLLinnoila  M Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection. Anal Biochem 1983;131246- 253
PubMed Link to Article
Molchan  SELawlor  BAHill  JLMartinez  RADavis  CLMellow  AMRubinow  DRSunderland  T CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression. Biol Psychiatry 1991;291110- 1118
PubMed Link to Article
Furuyama  SMayes  DMNugent  CA A radioimmunoassay for plasma testosterone. Steroids 1970;16415- 428
PubMed Link to Article
Abraham  GE Radioimmunoassay of plasma steroid hormones. In:Heftman  Eed.Modern Methods of Steroid Analysis. New York, NY Academic Press1973;451- 470
Abraham  GEBuster  JDLucas  LACorrales  PCTeller  RC Chromatographic separation of steroid hormones for use in radioimmunoassay. Anal Lett 1972;5509- 517
Link to Article
Jiang  N-SRyan  PJ Radioimmunoassay for estrogens: a preliminary communication. Mayo Clin Proc 1969;44461- 465
PubMed
Ito  THorton  R Dihydrotestosterone in human peripheral plasma. J Clin Endocrinol Metab 1970;31362- 368
PubMed Link to Article
Vermeulen  AStoica  TVerdonck  L The apparent free testosterone concentration, an index of androgenicity. J Clin Endocrinol Metab 1971;33759- 767
PubMed Link to Article
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed Link to Article
Glantz  SA Primer of Biostatistics. 5th New York, NY McGraw-Hill2001;
Cherrier  MMRose  ALHigano  C The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol 2003;1701808- 1811
PubMed Link to Article
Rabkin  JGFerrando  SJWagner  GJRabkin  R DHEA treatment for HIV+ patients: effects on mood, androgenic and anabolic parameters. Psychoneuroendocrinology 2000;2553- 68
PubMed Link to Article
Pfaus  JGKippin  TECenteno  S Conditioning and sexual behavior: a review. Horm Behav 2001;40291- 321
PubMed Link to Article
Pfaus  JG Neurobiology of sexual behavior. Curr Opin Neurobiol 1999;9751- 758
PubMed Link to Article
Bancroft  J Central inhibition of sexual response in the male: a theoretical perspective. Neurosci Biobehav Rev 1999;23763- 784
PubMed Link to Article
Ogawa  SChester  AECurtis Hewitt  SWalker  VRGustafsson  J-ASmithies  OKorach  KSPfaff  DW Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO). Proc Natl Acad Sci U S A 2000;9714737- 14741
PubMed Link to Article
O'Donnell  LRobertson  KMJones  MESimpson  ER Estrogen and spermatogenesis. Endocr Rev 2001;22289- 318
PubMed Link to Article
Frye  CA The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Res Brain Res Rev 2001;37201- 222
PubMed Link to Article
Harding  CFSheridan  KWalters  MJ Hormonal specificity and activation of sexual behavior in male zebra finches. Horm Behav 1983;17111- 133
PubMed Link to Article
Adkins  EK Effects of diverse androgens on the sexual behavior and morphology of castrated male quail. Horm Behav 1977;8201- 207
PubMed Link to Article
Pietras  RJWenzel  BM Effects of androgens on body weight, feeding, and courtship behavior in the pigeon. Horm Behav 1974;5289- 302
PubMed Link to Article
Parrott  RF Aromatizable and 5α-reduced androgens: differentiation between central and peripheral effects on male rat sexual behavior. Horm Behav 1975;699- 108
PubMed Link to Article
Aikey  JLNyby  JGAnmuth  DMJames  PJ Testosterone rapidly reduces anxiety in male house mice (Mus musculus). Horm Behav 2002;42448- 460
PubMed Link to Article
Majewska  MD Neurosteroids: endogenous bimodal modulators of the GABAA receptor: mechanism of action and physiological significance. Prog Neurobiol 1992;38379- 395
PubMed Link to Article
Park-Chung  MMalayev  APurdy  RHGibbs  TTFarb  DH Sulfated and unsulfated steroids modulate γ-aminobutyric acidA receptor function through distinct sites. Brain Res 1999;83072- 87
PubMed Link to Article
Wilson  MABiscardi  R Influence of gender and brain region on neurosteroid modulation of GABA responses in rats. Life Sci 1997;601679- 1691
PubMed Link to Article
Weihua  ZLathe  RWarner  MGustafsson  J-A An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β, 17β-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A 2002;9913589- 13594
PubMed Link to Article
Pak  TRChung  WCJLund  TDHinds  LRClay  CMHanda  RJ The androgen metabolite, 5α-androstane-3β, 17β-diol, is a potent modulator of estrogen receptor-β1 mediated gene transcription in neuronal cells. Endocrinology 2005;146147- 155
PubMed Link to Article
Bakker  JHonda  SHarada  NBalthazart  J Restoration of male sexual behavior by adult exogenous estrogens in male aromatase knockout mice. Horm Behav 2004;461- 10
PubMed Link to Article
Temple  JLScordalakes  EMBodo  CGustafsson  J-ARissman  EF Lack of functional estrogen receptor β gene disrupts pubertal male sexual behavior. Horm Behav 2003;44427- 434
PubMed Link to Article
Carani  CQin  KSimoni  MFaustini-Fustini  MSerpente  SBoyd  JKorach  KSSimpson  ER Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;33791- 95
PubMed Link to Article
Carani  CGranata  ARMRochira  VCaffagni  GAranda  CAntunez  PMaffei  LE Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism. Psychoneuroendocrinology 2005;30413- 417
PubMed Link to Article
Bitar  MSOta  MLinnoila  MShapiro  BH Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats. Psychoneuroendocrinology 1991;16547- 557
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Blood Hormone Levels in 12 Men During Leuprolide Acetate–Induced Hypogonadal and Testosterone-Replaced Conditions*
Table Graphic Jump LocationTable 2. Cerebrospinal Fluid Measures of Monoamine Metabolites and Neurosteroids in 12 Men During Leuprolide Acetate–Induced Hypogonadism and After Testosterone Replacement*
Table Graphic Jump LocationTable 3. Spearman Correlation Coefficients Between Cerebrospinal Fluid Measures of Neurosteroids and Symptom Ratings

References

Su  T-PPagliaro  MSchmidt  PJPickar  DWolkowitz  OMRubinow  DR Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA 1993;2692760- 2764
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Pope  HG  JrKatz  DL Psychiatric and medical effects of anabolic-androgenic steroid use: a controlled study of 160 athletes. Arch Gen Psychiatry 1994;51375- 382
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Pope  HG  JrKouri  EMHudson  JI Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Arch Gen Psychiatry 2000;57133- 140
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Rabkin  JGWagner  GJRabkin  R A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry 2000;57141- 147
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Wang  CSwerdloff  RSIranmanesh  ADobs  ASnyder  PJCunningham  GMatsumoto  AMWeber  TBerman  N Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000;852839- 2853
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Steidle  CSchwartz  SJacoby  KSebree  TSmith  TBachand  RThe North American AA2500 T Gel Study Group, AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003;882673- 2681
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Franklin  MCraven  RDCowen  PJ Effect of castration and castration with hormone replacement on the plasma prolactin responses to neuroendocrine challenge with iv mCPP in the male rat following a low tryptophan diet. J Psychopharmacol 1996;10250- 253
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Virkkunen  MRawlings  RTokola  RPoland  REGuidotti  ANemeroff  CBissette  GKalogeras  KKaronen  S-LLinnoila  M CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers. Arch Gen Psychiatry 1994;5120- 27
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Daly  RCSu  T-PSchmidt  PJPickar  DMurphy  DLRubinow  DR Cerebrospinal fluid and behavioral changes after methyltestosterone administration: preliminary findings. Arch Gen Psychiatry 2001;58172- 177
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van Broekhoven  FVerkes  RJ Neurosteroids in depression: a review. Psychopharmacology (Berl) 2003;16597- 110
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Barrett-Connor  EVon Muhlen  DGKritz-Silverstein  D Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study. J Clin Endocrinol Metab 1999;84573- 577
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Seidman  SNAraujo  ABRoose  SPMcKinlay  JB Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry 2001;50371- 376
PubMed Link to Article
Seidman  SN The aging male: androgens, erectile dysfunction, and depression. J Clin Psychiatry 2003;64 ((suppl 10)) 31- 37
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Brower  KJBlow  FCBeresford  TPFuelling  C Anabolic-androgenic steroid dependence. J Clin Psychiatry 1989;5031- 33
PubMed
Tennant  FBlack  DLVoy  RO Anabolic steroid dependence with opioid-type features: letter to the editor. N Engl J Med 1988;319578
PubMed Link to Article
Malone  DA  JrDimeff  RJ The use of fluoxetine in depression associated with anabolic steroid withdrawal: a case series. J Clin Psychiatry 1992;53130- 132
PubMed
Brower  KJEliopulos  GABlow  FCCatlin  DHBeresford  TP Evidence for physical and psychological dependence on anabolic androgenic steroids in eight weight lifters. Am J Psychiatry 1990;147510- 512
PubMed
Brower  KJ Withdrawal from anabolic steroids. Curr Ther Endocrinol Metab 1997;6338- 343
PubMed
Trenton  AJCurrier  GW Behavioural manifestations of anabolic steroid use. CNS Drugs 2005;19571- 595
PubMed Link to Article
Malone  DA  JrDimeff  RJLombardo  JASample  RHB Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sport Med 1995;525- 31
PubMed Link to Article
Thiblin  IRuneson  BRajs  J Anabolic androgenic steroids and suicide. Ann Clin Psychiatry 1999;11223- 231
PubMed Link to Article
Brower  KJBlow  FCEliopulos  GABeresford  TP Anabolic androgenic steroids and suicide [letter to the editor]. Am J Psychiatry 1989;1461075
PubMed
Spitzer  RLWilliams  JBGibbon  MFirst  MB Structured Clinical Interview for DSM-III-R, Patient Edition.  New York Biometrics Research Dept, New York State Psychiatric Institute1990;
Miller  MDFerris  DG Research methodology: measurement of subjective phenomena in primary care research: the visual analogue scale. Fam Pract Res J 1993;1315- 24
PubMed
Luria  RE The validity and reliability of the visual analogue mood scale. J Psychiatr Res 1975;1251- 57
PubMed Link to Article
Endicott  JNee  JCohen  JHalbreich  U Premenstrual changes: patterns and correlates of daily ratings. J Affect Disord 1986;10127- 135
PubMed Link to Article
Kim  YSZhang  HKim  HY Profiling neurosteroids in cerebrospinal fluids and plasma by gas chromatography/electron capture negative chemical ionization mass spectrometry. Anal Biochem 2000;277187- 195
PubMed Link to Article
Scheinin  MChang  WHKirk  KLLinnoila  M Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection. Anal Biochem 1983;131246- 253
PubMed Link to Article
Molchan  SELawlor  BAHill  JLMartinez  RADavis  CLMellow  AMRubinow  DRSunderland  T CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression. Biol Psychiatry 1991;291110- 1118
PubMed Link to Article
Furuyama  SMayes  DMNugent  CA A radioimmunoassay for plasma testosterone. Steroids 1970;16415- 428
PubMed Link to Article
Abraham  GE Radioimmunoassay of plasma steroid hormones. In:Heftman  Eed.Modern Methods of Steroid Analysis. New York, NY Academic Press1973;451- 470
Abraham  GEBuster  JDLucas  LACorrales  PCTeller  RC Chromatographic separation of steroid hormones for use in radioimmunoassay. Anal Lett 1972;5509- 517
Link to Article
Jiang  N-SRyan  PJ Radioimmunoassay for estrogens: a preliminary communication. Mayo Clin Proc 1969;44461- 465
PubMed
Ito  THorton  R Dihydrotestosterone in human peripheral plasma. J Clin Endocrinol Metab 1970;31362- 368
PubMed Link to Article
Vermeulen  AStoica  TVerdonck  L The apparent free testosterone concentration, an index of androgenicity. J Clin Endocrinol Metab 1971;33759- 767
PubMed Link to Article
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed Link to Article
Glantz  SA Primer of Biostatistics. 5th New York, NY McGraw-Hill2001;
Cherrier  MMRose  ALHigano  C The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol 2003;1701808- 1811
PubMed Link to Article
Rabkin  JGFerrando  SJWagner  GJRabkin  R DHEA treatment for HIV+ patients: effects on mood, androgenic and anabolic parameters. Psychoneuroendocrinology 2000;2553- 68
PubMed Link to Article
Pfaus  JGKippin  TECenteno  S Conditioning and sexual behavior: a review. Horm Behav 2001;40291- 321
PubMed Link to Article
Pfaus  JG Neurobiology of sexual behavior. Curr Opin Neurobiol 1999;9751- 758
PubMed Link to Article
Bancroft  J Central inhibition of sexual response in the male: a theoretical perspective. Neurosci Biobehav Rev 1999;23763- 784
PubMed Link to Article
Ogawa  SChester  AECurtis Hewitt  SWalker  VRGustafsson  J-ASmithies  OKorach  KSPfaff  DW Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO). Proc Natl Acad Sci U S A 2000;9714737- 14741
PubMed Link to Article
O'Donnell  LRobertson  KMJones  MESimpson  ER Estrogen and spermatogenesis. Endocr Rev 2001;22289- 318
PubMed Link to Article
Frye  CA The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents. Brain Res Brain Res Rev 2001;37201- 222
PubMed Link to Article
Harding  CFSheridan  KWalters  MJ Hormonal specificity and activation of sexual behavior in male zebra finches. Horm Behav 1983;17111- 133
PubMed Link to Article
Adkins  EK Effects of diverse androgens on the sexual behavior and morphology of castrated male quail. Horm Behav 1977;8201- 207
PubMed Link to Article
Pietras  RJWenzel  BM Effects of androgens on body weight, feeding, and courtship behavior in the pigeon. Horm Behav 1974;5289- 302
PubMed Link to Article
Parrott  RF Aromatizable and 5α-reduced androgens: differentiation between central and peripheral effects on male rat sexual behavior. Horm Behav 1975;699- 108
PubMed Link to Article
Aikey  JLNyby  JGAnmuth  DMJames  PJ Testosterone rapidly reduces anxiety in male house mice (Mus musculus). Horm Behav 2002;42448- 460
PubMed Link to Article
Majewska  MD Neurosteroids: endogenous bimodal modulators of the GABAA receptor: mechanism of action and physiological significance. Prog Neurobiol 1992;38379- 395
PubMed Link to Article
Park-Chung  MMalayev  APurdy  RHGibbs  TTFarb  DH Sulfated and unsulfated steroids modulate γ-aminobutyric acidA receptor function through distinct sites. Brain Res 1999;83072- 87
PubMed Link to Article
Wilson  MABiscardi  R Influence of gender and brain region on neurosteroid modulation of GABA responses in rats. Life Sci 1997;601679- 1691
PubMed Link to Article
Weihua  ZLathe  RWarner  MGustafsson  J-A An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β, 17β-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A 2002;9913589- 13594
PubMed Link to Article
Pak  TRChung  WCJLund  TDHinds  LRClay  CMHanda  RJ The androgen metabolite, 5α-androstane-3β, 17β-diol, is a potent modulator of estrogen receptor-β1 mediated gene transcription in neuronal cells. Endocrinology 2005;146147- 155
PubMed Link to Article
Bakker  JHonda  SHarada  NBalthazart  J Restoration of male sexual behavior by adult exogenous estrogens in male aromatase knockout mice. Horm Behav 2004;461- 10
PubMed Link to Article
Temple  JLScordalakes  EMBodo  CGustafsson  J-ARissman  EF Lack of functional estrogen receptor β gene disrupts pubertal male sexual behavior. Horm Behav 2003;44427- 434
PubMed Link to Article
Carani  CQin  KSimoni  MFaustini-Fustini  MSerpente  SBoyd  JKorach  KSSimpson  ER Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;33791- 95
PubMed Link to Article
Carani  CGranata  ARMRochira  VCaffagni  GAranda  CAntunez  PMaffei  LE Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism. Psychoneuroendocrinology 2005;30413- 417
PubMed Link to Article
Bitar  MSOta  MLinnoila  MShapiro  BH Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats. Psychoneuroendocrinology 1991;16547- 557
PubMed Link to Article

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