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Cerebrospinal Fluid and Behavioral Changes After Methyltestosterone Administration
Preliminary Findings
Robert C. Daly, MB, MRCPsych, MPH;
Tung-Ping Su, MD;
Peter J. Schmidt, MD;
David Pickar, MD;
Dennis L. Murphy, MD;
David R. Rubinow, MD
Arch Gen Psychiatry. 2001;58:172-177.
ABSTRACT
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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, ß-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.
INTRODUCTION
ANABOLIC ANDROGENIC steroid (AAS) abuse poses a significant public health
problem and has been associated with a range of psychiatric symptoms, including
psychosis,1 irritability and aggression,2 and major mood syndromes.3
In a previous study of normal men,4 we demonstrated
that even short-term administration of the AAS methyltestosterone (MT) produced
significant mood and behavioral symptoms. Two subsequent blind, placebo-controlled
studies5, 6 confirmed the ability
of such steroids to induce mood and behavioral symptoms in both normal volunteers
and AAS users. The mechanisms underlying the development of AAS-induced psychiatric
symptoms remain largely undetermined.
Studies in animals and humans have implicated several neurochemical
systems in the observed effects of AAS. For example, in rodents these steroids
produce brain region–specific increases in ß-endorphin7 and vasopressin,8 up-regulate
glucorticoid receptor immunoreactivity in the hippocampus,9
and bind the benzodiazepine binding site of the  -aminobutyric acid
type A receptor10; further, AAS-induced aggression
can be modulated by manipulation of central serotonin function.11, 12
In human beings, AAS administration may be accompanied by increases in plasma
homovanillic acid (HVA). In addition, steroid abuse may be associated with
hypomania, depression, and a dependent pattern of use.5, 13
Previous studies examining cerebrospinal fluid (CSF) have yielded valuable
information about the pathophysiology of such conditions, including the potential
roles of somatotropin release–inhibiting factor (SRIF)14
and corticotropin-releasing hormone (CRH) in affective disorders15
and of endorphins in addiction.16
In an effort to further identify possible mechanisms underlying observed
behavioral changes, we performed CSF sampling in our previously described
group4 at baseline and following 6 days of MT
administration. A variety of CSF measures were obtained, including amine metabolites
that reflect the activity of neural systems presumed to underlie affect and
behavioral regulation, and neuropeptides and neurohormones that can cause
behavioral disorders related to stress and addiction.
Two questions were posed in the investigation. First, during MT administration,
are there alterations in CSF metabolites that have been observed to change
either in animal studies of AAS effects or in clinical syndromes in humans
(such as hypomania or aggression) that may be associated with AAS use? Second,
are such metabolic changes (if any) correlated with the observed behavioral
changes following AAS use?
SUBJECTS AND METHODS
Subject selection and protocol are as previously described4
and are summarized as follows. Twenty-three medication-free, healthy men between
the ages of 18 and 42 years were recruited through advertisements in the hospital
newsletter of the National Institutes of Health Clinical Center in Bethesda,
Md. Three volunteers were excluded because of medical problems or a positive
drug screen. The remaining 20 subjects had no significant history of psychiatric
illness or AAS use and were free of any recent (past 2 years) history of alcohol
or substance abuse. This was confirmed with a standardized psychiatric interview17 administered by a psychiatrist. After the subjects
received a complete description of the study, written informed consent was
obtained. The protocol was approved by the National Institute of Mental Health
(NIMH) Institutional Review Board (Bethesda, Md).
Following a 2-day acclimatization period at an NIMH inpatient unit,
all subjects received MT or placebo administered as 3 capsules, 3 times daily.
These capsules were given in a fixed sequence with neither subjects nor raters
aware of the order of administration. The following schedule was used for
each subject: 3 days of placebo (baseline phase), 3 days of MT (low-dose phase;
40 mg/d), 3 days of MT (high-dose phase; 240 mg/d), and 3 more days of placebo
(withdrawal phase). Subjects were informed that the purpose of the study was
to understand possible behavioral reactions to AAS and were told that they
would be asked questions regarding their mood and thinking on a daily basis.
CSF MEASURES
All subjects adhered to a low-monoamine diet beginning 2 days before
the first lumbar puncture. Before the procedure, subjects fasted for at least
9 hours and had had continuous bed rest for a minimum of 1 hour, except for
getting up once to void. Lumbar punctures were conducted between 9 AM and
10:30 AM on the final mornings of the baseline and high-dose phases. They
were performed in the L4-5 interspace with the patient in the lateral decubitus
position, using a sterile technique. Seventeen of the 20 subjects underwent
successful CSF sampling in both phases. From each subject, 21 mL of CSF were
collected. The first 3 mL were used for standard clinical studies, and the
next 18 mL were drawn in 3 aliquots (12 mL, 3 mL, 3 mL). The first aliquot
was subdivided into 1-mL subaliquots; the samples were placed on ice and stored
at -70°C until assayed. The following CSF assays were performed:
3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA),
HVA, norepinephrine, dopamine, ß-endorphin, prolactin, adrenocorticotropic
hormone (ACTH), cortisol, CRH, SRIF, and arginine vasopressin (AVP). Cerebrospinal
fluid measures and serum MT level assays were also performed on samples obtained
during the high-dose phase.
BEHAVIORAL MEASURES
Visual analog scale ratings were completed 3 times per day (10 AM, 6
PM, and 10 PM) for a range of subjective behavioral measures. The reliability
and validity of such analog scales in rating subjective feelings has been
established.18 The highest rating recorded each
day was selected and then averaged for the 3 days of that particular phase
(ie, baseline or high-dose phase). The use of highest daily rating scores
was chosen for several reasons. The low doses of AAS used in this study (compared
with doses abused) gave rise to relatively modest mood changes. Additionally,
mood symptoms occurring in response to AAS tend to be episodic. Consequently,
the use of highest daily scores enhanced our ability to detect symptoms precipitated
during the course of the study. Mood and behavioral ratings were measured
during all 4 phases of the study (baseline, low-dose, high-dose, and withdrawal)
and were reported in our previous article.4
The Bonferroni t test comparison of the withdrawal
phase with the baseline phase demonstrated only 1 symptom, sexual arousal,
to be significantly increased during withdrawal; in this article we confined
our analysis to symptoms showing significant change during the high-dose phase.
Use of this approach (examining the difference between baseline and high-dose
scores) yielded 7 symptoms that changed during the high-dose phase (P .1; Table 1). These symptoms fell within 3 previously observed4
behavioral symptom clusters: "activation" (energy, sexual arousal, and diminished
sleep), "aggressiveness" (anger, violent feelings, and irritability), and
"cognitive" (distractibility). Cluster scores were calculated by averaging
the means from each contributory symptom. Cluster score changes, not individual
symptom score variations, were correlated with CSF changes (to decrease the
number of comparisons made). To reduce the possibility that a significant
correlation would represent the effect of a single symptom, the symptom of
forgetfulness was added to distractibility to create a cognitive cluster.
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Table 1. Effect of Methyltestosterone on Symptom Cluster Scores Between
Baseline and High-Dose Phases*
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ASSAYS
The following assays were performed by the methods previously described:
ACTH,19 CRH,20
and ß-endorphin21 were measured at Hazelton
Laboratories in Vienna, Va, by radioimmunoassay, with intra-assay and interassay
coefficients of variation of 9.4% (18.6%), 5.6% (12.7%), and 9.3% (6.7%),
respectively. Cortisol and AVP22, 23
were also measured by radioimmunoassay. Intra-assay and interassay coefficients
of variation were 1.8% (7.2%) and 9.8% (19.4%), respectively. Cerebrospinal
fluid and serum MT measurements24 were performed
by Christiane Ayotte, PhD, at the Institute National de la Recherche Scientifique-Santé
in Quebec City, Quebec, using gas chromatography and mass spectrometry. Cerebrospinal
fluid SRIF assays25 with modifications26 were performed by the Behavioral Endocrinology Laboratory
at the NIMH using radioimmunoassay. Catecholamine and monoamine metabolite
measures were performed by the Laboratory of Clinical Science at the NIMH.
Norepinephrine and dopamine were initially extracted by acid hydrolysis.27 The metabolites 5-HIAA, MHPG, and HVA, and the extracted
catecholamines, were measured using high-performance liquid chromatograpy
with electrochemical detection.28, 29
Assays for 5-HIAA, MHPG, HVA, dopamine, and norepinephrine were performed
in 1 batch, with 4% to 6% intra-assay variation.
ANALYSIS OF DATA
All analyses were computed using the Systat 8.0 (Statistical Product
and Service Solutions, Chicago, Ill) statistical package. Differences in CSF
laboratory parameters between baseline and high-dose phases were analyzed
using paired t tests; P
values for paired t test scores examining differences
in CSF measures were adjusted using the Bonferroni adjustment for multiple
comparisons. Spearman rank correlation coefficients were calculated between
behavioral cluster scores, CSF measures showing changes (Bonferroni adjustment, P.1) during MT administration, CSF MT levels, and plasma
MT levels. The  level of significance was P.05
for analyses unless otherwise specified. Two-tailed t
tests were used; data are presented as mean ± SD.
RESULTS
Following MT administration, CSF MT levels ranged from 65 to 898 nmol/L
(mean ± SD, 232.7 ± 210.9 nmol/L). Serum MT levels ranged from
3 to 102 nmol/L (mean ± SD, 20.5 ± 24.0 nmol/L). After MT administration,
there was a significant increase (compared with baseline) in CSF levels of
5-HIAA (t16 = 3.3, P = .005) (Figure 1) and a
significant decrease in MHPG levels (t16
= 3.0, P = .009) (Figure 2). After the Bonferroni adjustment, P values for changes in CSF 5-HIAA and MHPG remained significant or
near significant at P.05 and P.1, respectively. Other CSF measures did not change significantly
between the baseline and high-dose phases (Table 2). Changes in CSF 5-HIAA were not significantly correlated
with changes in CSF MHPG (r = 0.21, P = .40). Changes in CSF 5-HIAA were significantly correlated with
changes in activation cluster scores (r = 0.55, P = .02) (Figure 3);
changes in aggressiveness (r = -0.30, P = .21) and cognitive (r = 0.18, P = .49) cluster scores did not correlate significantly
with changes in CSF 5-HIAA. Changes in MHPG did not significantly correlate
with activation (r = -0.09, P = .72), aggressiveness (r = 0.03, P = .91), or cognitive (r = 0.31, P = .22) cluster score changes.
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Figure 1. Methyltestosterone-induced changes
in cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations
(n = 17). Treatment conditions resulted in a significant increase in CSF 5-HIAA
(t16 = 3.3, P= .005).
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Figure 2. Methyltestosterone-induced changes
in cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (CSF MHPG) concentrations
(n = 17). Treatment conditions resulted in a significant decrease in CSF MHPG
(t16 = 3.0, P= .009).
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Table 2. Effect of Methyltestosterone on Cerebrospinal Fluid Neuropeptide
and Neurotransmitter Metabolite Levels*
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Figure 3. Correlation of changes in activation
symptom cluster scores with changes in cerebrospinal fluid 5-hydroxyindoleacetic
acid (CSF 5-HIAA) following methyltestosterone administration (r=
0.55, P= .02). Activation symptom cluster includes energy, sexual
arousal, and diminished sleep.
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Cerebrospinal fluid and serum MT levels were significantly correlated
(r = 0.77, P<.01). Cerebrospinal
fluid MT levels did not significantly correlate with aggressiveness (r = -0.19, P = .47), activation (r = 0.14, P = .61), or cognitive
(r = -0.03, P = .91)
cluster score changes, nor did they correlate with changes in CSF 5-HIAA (r = -0.12, P = .65) or CSF
MHPG (r = 0.08, P = .76).
In addition, plasma MT levels did not correlate significantly with aggressiveness
(r = -0.02, P = .93),
activation (r = -0.07, P = .78), or cognitive (r = 0.35, P = .18) cluster score changes, nor did they correlate with changes
in CSF 5-HIAA (r = 0.08, P
= .76) or CSF MHPG (r = 0.16, P = .55 levels).
COMMENT
To our knowledge, this is the first reported study examining CSF changes
following AAS administration in human subjects and suggests a possible mechanism
underlying AAS-induced alterations of mood and behavior. Most notably, CSF
5-HIAA increased and MHPG levels decreased following MT administration, and
the changes observed in CSF 5-HIAA were significantly correlated with the
changes seen in activation symptom cluster scores.
After oral MT administration, MT was present in both plasma and CSF,
and levels were significantly correlated. A high CSF-to-plasma concentration
gradient was observed; relative differences between CSF and plasma in amounts
of binding proteins and solubility of MT may possibly have contributed to
this gradient. The absence of correlation between CSF or plasma MT levels
and either behavioral changes or CSF measure changes suggests that biological
and behavioral responses to MT do not show a linear dose-response relationship.
Hence, variability in the expression of adverse behavioral symptoms is not
attributable simply to differences in dose of MT or to plasma levels achieved.
The finding of lowered CSF MHPG (albeit at a trend level of significance when
the Bonferroni adjustment was used) may reflect a decrease in norepinephrine
clearance, a speculation consistent with the increase (however insignificant)
in CSF norepinephrine and supported by data showing decreased metabolism of
norepinephrine by monoamine oxidase and catechol-O-methyltransferase in rat
adrenal glands after AAS administration.30 Nevertheless,
the absence of significant correlations between changes in MHPG and behavioral
changes suggests a minimal role for noradrenergic changes in the development
of behavioral symptoms.
Hypomanic symptoms have been widely reported as occurring during AAS
use,1, 5, 6 and the activation
cluster, which comprised diminished sleep, increased energy, and increased
sexual feelings, samples symptoms of hypomania. Our finding of a correlation
between increases in CSF 5-HIAA and the development of activation symptoms
is consistent with 2 studies, one showing higher levels of 5-HIAA in women
with mania compared with controls,31 and another
showing increased levels of CSF 5-HIAA during mania compared with recovery.32 However, other reports have shown CSF 5-HIAA to be
decreased33, 34 in patients with
mania compared with control subjects, and to date no consistent abnormalities
of CSF monoamine levels have been demonstrated in mania.
A large body of research has demonstrated an association between changes
in serotonergic function and both aggressive feelings and behavior. Although
not reaching statistical significance (perhaps because of a type II error),
the direction of the relationship we observed (an association between lower
5-HIAA levels following AAS administration and aggressive feelings) is in
keeping with most of these findings. Nevertheless, at least 5 studies have
not shown an inverse relationship between CSF 5-HIAA and aggression: 3 reported
no correlation between CSF 5-HIAA and aggressive feelings,35, 36, 37
and 2 showed a positive correlation.38, 39
The exact nature of the relationship between aggression and serotonergic function
remains undetermined.
This study has several limitations, including small sample size, absence
of a true placebo group, and possible confounding by stress associated with
the lumbar puncture and hospital confinement. The return of most symptoms
to baseline by the end of the withdrawal period, however, suggests that they
are not a result of prolonged hospitalization. Treatment limitations are notable;
although the doses of steroids we administered may be comparable with those
abused (63% of users in one study reported taking steroid doses of 1000 mg/wk
or less3), many abusers use higher doses, and
the duration of treatment we employed was short (cycles of steroid abuse commonly
last 4-12 weeks40). Additionally, the steroid-abusing
athlete may constitute a different biological or biosocial group than healthy
volunteers who have never used androgens. The effects of MT on 5-HIAA may
be different in such groups compared with men who exhibit aggressive behavior.
Cerebrospinal fluid studies can provide neither identification nor neuroanatomical
localization of neural subsystems underlying the changes in CSF monoamine
metabolites observed in this study. Similarly, correlational studies cannot
establish a causal relationship between the observed CSF and behavioral changes.
However, short-term AAS use does have effects on brain metabolism that are
reflected in CSF changes, including an increase in 5-HIAA and a decrease in
MHPG. The effects of MT on CSF 5-HIAA are related to the behavioral changes
observed but are unrelated to dose of MT or to CSF or plasma MT levels. These
preliminary findings suggest that serotonergic function is altered with MT
administration and that this change may be associated with some of the behavioral
effects accompanying the use of AAS.
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
Presented at the 52nd Annual Meeting of the Society of Biological Psychiatry,
Washington, DC, May 14, 1999.
From the Behavioral Endocrinology Branch (Drs Daly, Schmidt, and Rubinow),
the Experimental Therapeutics Branch (Dr Pickar), and the Laboratory of Clinical
Sciences (Dr Murphy), National Institute of Mental Health, Bethesda, Md; and
the Division of Psychiatry, National Yang-Ming University, and the Department
of Psychiatry, Veteran's General Hospital, Taipei, Taiwan (Dr Su).
Corresponding author and reprints: Robert C. Daly, MB, MRCPsych,
MPH, Behavioral Endocrinology Branch, National Institute of Mental Health,
Bldg 10, Room 3N242, 10 Center Dr, MSC 1277, Bethesda, MD 20892-1277 (e-mail: dalyr{at}intra.nimh.nih.gov).
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