Neuroendocrine and behavioral effects of high-dose anabolic

15 Pages·2003·0.08 MB·English

Psychoneuroendocrinology28 (2003)317–331
www.elsevier.com/locate/psyneuen
Neuroendocrine and behavioral effects of
high-dose anabolic steroid administration in
male normal volunteers
R.C. Daly ∗, T.-P. Su, P.J. Schmidt, M. Pagliaro, D. Pickar,
D.R. Rubinow
Behavioural EndocrinologyBranch, NationalInstitute ofMentalHealth, Building10,Room 3N238,
10Center DriveMSC1277, 20892-1277Bethesda, MD,USA
Received22October 2001;received inrevisedform21 February2002;accepted 8 March2002
Abstract
Objective: Despite widespread abuse of anabolic-androgenic steroids (AAS), the endocrine
effects of supraphysiologic doses of these compounds remain unclear. We administered the
AAS methyltestosterone (MT) to 20 normal volunteers in an in-patient setting, examined its
effectsonlevelsofpituitary-gonadal,-thyroid,and-adrenalhormones,andexaminedpotential
relationships between endocrine changes and MT-induced psychological symptoms. Method:
Subjects received MT (three days of 40 mg/day, then three days of 240 mg/day) or placebo
in a fixed sequence with neither subjects nor raters aware of order. Sampleswere obtained at
theendsofthebaseline,high-doseMTandwithdrawalphases.Potentialrelationshipsbetween
hormonal changes and visual analog scale measured mood changes were examined. Results:
Significantdecreasesinplasmalevelsofgonadotropins,gonadalsteroids,sexhormonebinding
globulin,freeT3andT4,andthyroidbindingglobulin(Bonferronit,p(cid:1)0.01foreach)were
seenduringhigh-doseMT;freethyroxineandTSHincreasedduringhigh-doseMT,withTSH
increases reaching significance during withdrawal. No significant changes in pituitary-adrenal
hormones were observed. Changes in free thyroxine significantly correlated with changes in
aggressiveness (anger, violent feelings, irritability) (r(cid:2)0.5,p(cid:2)0.02) and changes in total
testosteronecorrelatedsignificantlywithchangesincognitiveclustersymptoms(forgetfulness,
distractibility) (r(cid:2)0.52,p(cid:2)0.02). Hormonal changesdid not correlatewith plasma MT lev-
els.Conclusions:Acutehigh-doseMTadministrationacutelysuppressesthereproductiveaxis
and significantly impacts thyroid axis balance without a consistent effect on pituitary-adrenal
∗ Corresponding author.Tel.:[phone]; fax:[phone].
E-mailaddress: [email protected] (R.C. Daly).
0306-4530/03/$-seefrontmatterPublishedbyElsevierScienceLtd.
doi:10.1016/S0306-4530(02)00025-2
318 R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331
hormones.MoodandbehavioraleffectsobservedduringAASusemayinpartreflectsecondary
hormonal changes.
Published by Elsevier Science Ltd.
Keywords:Methyltestosterone;Anabolicsteroids;Aggression;Thyroid; Mood
1. Introduction
Anabolic-androgenicsteroid(AAS)abusecanbeaccompaniedbyarangeofmood
and behavioral disturbances, including irritability and aggression (Bahrke et al.,
1990) and hypomania (Pope et al., 2000) and may represent a significant unrecog-
nized public health problem (Pope et al., 2000). Despite an extensive literature on
the psychotoxic effects of AAS, the mechanisms underlying these effects remain
unknown.Methodologiclimitationsofpreviousstudiesexamininghormonalchanges
during AAS use may have restricted their interpretation and generalization. These
limitationsincludethecommonemploymentofoutpatientstudysettings(withresult-
antpotentialconfoundingbypoorcompliance,exercise,orco-morbidsubstanceuse),
administration of comparatively low doses of AAS, subject choice (e.g. seriously
medically ill subjects), and lack of placebo controls. The widespread abuse of AAS
(Yesalis et al., 1993) plus their recent emergence as a potential therapy in such
conditions as HIV-related hypogonadism (Rabkin et al., 2000) dictate that we better
understand the physiologic consequences of supraphysiologic doses of AAS. Such
understanding would also potentially contribute to our knowledge of the biological
mechanisms underlying behavioral disturbances accompanying AAS abuse.
While the endocrine effects of androgens are well described, the hormonal effects of
the massive doses of anabolic steroids taken by abusers are not clearly defined, and the
needforfurtherinvestigationsemployingmoresophisticatedbatteriesofneuroendocrine
measures has recently been emphasized (Pope et al., 2000). AAS use impacts upon
severalhormonalsystems,mostnotablythehypothalamic-pituitary-adrenal(HPA),hypo-
thalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes
(Clericoetal.,1981;Ale´netal.,1985,1987;DeyssigandWeissel,1993).Perturbations
in these hormonal axes in association with affective and behavioral changes in other
psychiatric conditions are well documented and presumed to be pathophysiologically
relevant. Thus, changes in endocrine function secondary to AAS administration could
potentially contribute to AAS-induced psychiatric changes. For example, some authors
havesuggestedthatAAS-inducedadversebehavioralresponsesmayarisepartlythrough
theireffectsonglucocorticoidreceptors(BonsallandMichael,1989;AhimaandHarlan,
1992) or estrogen levels (Bahrke et al., 1996).
In an effort to more clearly define the hormonal changes that occur during high-
dose AAS use and to explore possible mechanisms underlying the accompanying
adverse behavioral changes, we carried out a comprehensive battery of neuroendoc-
rine hormone measures during MT administration in our previously described (Su
et al., 1993) study group. We studied hormonal axes that are known to potentially
R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331 319
influencemoodandbehaviorandthathavealsobeenpreviouslyreportedaschanging
during AAS use.
Two specific questions were posed in this study. First, what are the acute effects
of supraphysiologic doses of MT on circulating levels of HPA, HPT and HPG axes
hormones when administeredunder carefully controlled conditions tohealthy volun-
teers?Second,areMT-inducedhormonalchangesassociatedwiththebehavioraland
mood symptoms observed?
2. Methods
2.1. Subjects
Subjectselectionandprotocolareaspreviouslydescribed(Suetal.,1993)andare
summarized as follows: 23 medication-free male volunteers aged 18–42 underwent
extensive medical screening, including urine testing for illicit drugs; three were
excluded due to medical problems or a positive drug screen. The remaining 20 sub-
jects had no significant current or past history of psychiatric disorder or AAS use
andwerefreeofanycurrentorrecent(pasttwoyears)historyofalcoholorsubstance
abuse, confirmed with a standardized psychiatric interview, the Schedule for Affect-
ive Disorders and Schizophrenia—Lifetime (Spitzer and Endicott, 1979), adminis-
tered by a psychiatrist (TPS). After complete description of the study, written infor-
med consent was obtained. The protocol was approved by the NIMH Institutional
Review Board. Subjects were paid for their participation according to the schedule
of payment issued by the National Institutes of Health Normal Volunteer Office.
Followingatwo-dayacclimatizationperiodonanNIMHinpatientunit,allsubjects
received MT or placebo, administered as three capsules t.i.d. These were adminis-
tered in a fixed sequence, with neither subjects nor raters aware of the order of the
administration of active drug and placebo. The following sequential schedule was
used for each subject: three days of placebo (‘baseline’ phase), three days of MT
40 mg/day (‘low dose’ phase), three days of MT 240 mg/day (‘high-dose’ phase),
and three days of placebo (‘withdrawal’ phase). Subjects were informed that the
purposeofthestudywas tounderstandpossible behavioralactionsofAASandwere
toldtheywouldbeaskedquestionregardingtheirmoodandthinkingonadailybasis.
2.2. Outcome measures
2.2.1. Plasma hormones
Blood samples were collected at 8:00 a.m. on the final day of the baseline, high-
dose,andwithdrawalconditions.(Bloodsampleswerenotuniformlyobtainedduring
the low dose condition and are, therefore, not considered further.) Blood was drawn
viavenipunctureintopre-chilledheparinorEDTAcontainingtubesoniceandcentri-
fuged at 3000 rpm for 15 min. Samples were then promptly frozen at (cid:3)70 °C; the
specimens were stored for a maximum of one year and the assays performed in one
batch as soon as the study was completed.
320 R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331
2.2.2. Urinary cortisol
Twoconsecutive24hurinesampleswerecollectedforurinaryfreecortisol(UFC)
on the final two days of the baseline, high-dose, and withdrawal conditions.
Asdescribedpreviously(Suetal.,1993)visualanaloguescale(VAS)ratingswere
completed daily at 10:00 a.m., 6:00 p.m., and 10:00 p.m. for a range of subjective
mood and behavioral measures. The reliability and validity of such analogue scales
in rating subjective feelings has been established (Canat et al., 1992). The highest
of the three ratings recorded each day was selected and then averaged for the three
days of that particular drug condition, i.e. baseline, high-dose and withdrawal con-
ditions. Mood and behavioral ratings were measured during all four phases of the
study (baseline, low dose, high-dose and withdrawal). As reported in our previous
study(Suetal.,1993),behavioralratingsduringthehigh-doseandwithdrawalphases
werecomparedwiththe baselinephaseusingposthoc pairedt-testswhere permitted
byresultsofanalysisofvariancewithrepeatedmeasures(ANOVA-R).Sevensymp-
toms showed substantial change from the baseline to the high-dose phase (p(cid:4)0.1)
(Table 1), while sexual arousal was the only symptom that significantly increased
during withdrawal. These symptoms fellwithin our three previously observed (Su et
al., 1993)behavioral symptomclusters:‘activation’ symptomcluster(energy, sexual
arousal,diminishedsleep),‘aggressiveness’symptomcluster(anger,violentfeelings,
irritability),and‘cognitive’symptomcluster(distractibility).Clusterscoreswerecal-
culated by averaging the means from each contributory symptom. Cluster score
changes, and not individual symptom score changes, were correlated with hormonal
changes in order to decrease the number of comparisons made. To diminish the
likelihood that a significant correlation would represent the effect of a single symp-
tom, the symptom of memory was also included (p (cid:2) 0.13) to constitute the cogni-
tive cluster.
2.3. Assays
Assays were performed by Smith Kline Beecham Clinical Laboratories
(testosterone, sex hormone binding globulin (SHBG), and UFC), Hazelton Labora-
tories (adrenocorticotropic hormone (ACTH), cortisol, β-endorphin, dehydroepiand-
rosterone (DHEA), dihydrotestosterone (DHT), and estradiol), and NIH Clinical
CenterLaboratories(thyroxine(T4),freethyroxine(FT4),thyroxinebindingglobulin
(TBG), thyroidstimulating hormone(TSH),albumin,luteinizing hormone(LH), and
follicle stimulating hormone (FSH)). Free testosterone levels were calculated by a
formula using testosterone, SHBG, and albumin (Sodergard et al., 1982). Free MT
levels were kindly measured by Dr Christine Ayotte employing gas
chromatography/mass spectroscopy (Ayotte, 1994). (For description of assay
methods and characteristics, see Table 2.)
2.4. Statistical analysis
Data were examined in the following ways: hormone levels were examined by
ANOVA-R,withtreatmentconditionasthewithinsubjectsvariable,forthebaseline,
R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331 321
1
0.03(cid:2)0.13(cid:2)0.010.001(cid:2)0.04(cid:2)0.00(cid:2)0.080.01(cid:2)0.07(cid:2)0.06(cid:2)0.04
(cid:2) (cid:2) (cid:2)
pp ppp ppp
3,p56,69,2,p24,09,83,8,p93,00,25,
2.1.2.4.2.4.1.2.1.2.2.
bp (cid:2)(cid:2)(cid:2)(cid:2)(cid:2)(cid:2)(cid:2)(cid:2)(cid:2)(cid:2)(cid:2)
t, ttttttttttt
s
e
s
a
ph ng
se ati
andhigh-do HighdoserMean(SD) 9.3(8.8)7.2(9.8)11.4(12.4)31.5(16.9)42.0(28.5)35.3(31.1)17.2(16.8)18.5(12.3)7.4(11.6)27.1(20.3)20.9(19.8)
e
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et
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20) ng
(cid:2)scores(n BaselineratiMean(SD) 4.6(4.7)3.8(4.6)5.4(6.9)24.8(20.7)37.5(30.8)27.3(29.8)9.5(11.4)14.6(9.9)5.4(8.9)23.9(18.4)14.6(12.5)
er
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mpto mpto er uesc
Table1EffectofMTonbehavioralsy aBehavioralsymptomsandsy CognitivesymptomclusterForgetfulnessDistractibilityActivationsymptomclusterEnergySexualarousalDisturbedsleepAggressivenesssymptomclustAngerViolentfeelingsIrritability aMeasuredbyvisualanalog(cid:2)bPairedt-test,df19.
322 R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331
Table 2
Assaycharacteristics
Assay CV Sensitivity limit Normal range
Intraassay (%) Inter assay(%)
ACTH(Nicholson etal., 9 19 5–10pg/ml 5–80pg/ml
1984)
Albumina (Rodkey, 3 3 (cid:1)0.1g/l 3.7–4.7 g/l
1965)
β-Endorphin(Healyet 9 17 25–50pg/ml 52–64pg/ml
al.,1983)
Cortisol(Abrahametal., 2 7 0.7ug/dl 8–18ug/dl
1972b)
Cortisol, urinaryfreeb 3 6 5 meq/l 9–95ug/24 h
(Ruderetal.,1972)
DHEA(Busterand 11 12 12.5–25ng/dl 160–1200ng/dl
Abraham,1972)
DHT(Abraham,1973) 6 13 10ng/dl 30–90ng/dl
Estradiol(Abrahamet 6 12 5–12pg/ml (cid:1)10–58pg/ml
al.,1972a)
FSHc 2 5 1.0mIU/ml 1–8mIU/ml
LHc 3 5 2.5mIU/ml 2–12mIU/ml
SHBG(Khanetal., 4 8 6 nmol/l 8–49nmol/l
1982)
T3d 3 8 15ng/dl 88–162 ng/dl
T4e 3 4 1.05 ug/dl 5–10ug/dl
FT4f 5 9 0.08 ng/dl 1.0–1.9 ng/dl
TBGg 5 6 1.0ug/ml 12–28ug/ml
Testosterone,freeh 1 pg/ml 80–280 pg/ml
Testosterone,total 5 10 20ng/dl 225–900 ng/dl
(Abraham,1973)
TSHi 3 7 0.03 uIU/ml 0.4–4.6 uIU/ml
a Spectrophotometricdetermination.
bHPLC.
c Microparticleenzymeimmunoassay.
dQuanticoat, KallestadDiagnostics,Chaska, MN.
e Fluorescent polarizationimmunoassay(AXSYM,AbbottLaboratories, AbbottPark,IL).
f GammaCoat, INCSTAR,Stillwater,MN.
gIRMA, (Immophase,CorningMedical, Medford,MA).
hCalculated—see Sodergardetal.,1982.
iIRMA (MAIAClone, CIBACorningDiagnostics, E.Walpole, MA).
high-dose and withdrawal phases. Where justified by the ANOVA, paired compari-
sons were performed with post hoc Bonferroni t-tests. Spearman rank correlation
coefficients were calculated both between behavioral cluster score changes and hor-
monalmeasuresshowingsignificantchanges(betweenbaselineandhigh-dosephases
on paired t-test (Bonferroni corrected p (cid:4) 0.05), and also between MT levels and
hormonal changes. Additionally, subjects were divided into groups (n (cid:2) 7) showing
R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331 323
the greatest and least change from baseline to high-dose condition in the activation,
aggressiveness and cognitive symptom clusters. Hormone changes from baseline to
high-dose condition were then compared between high symptom and low symptom
groups using Student’s t-tests. The α-level of significance was p(cid:4)0.05 for analyses
unless otherwise specified. Two-tailed t-tests were used. Data are presented as mean
± standard deviation (SD).
3. Results
3.1. Neuroendocrine effects
3.1.1. HPG axis (Table 3)
Significant suppression of plasma levels of reproductive axis hormones was seen
duringbothhigh-doseMTandwithdrawalconditionscomparedwithbaseline.Levels
of gonadotropins also fell significantly during the high-dose condition, but returned
to baseline values during the withdrawal condition.
3.1.2. HPT axis (Table 3)
SignificantdecreasesinthelevelsofT3,T4andTBGwereseenduringbothhigh-
dose and withdrawal conditions compared with baseline, while significant increases
were seen in FT4 and TSH during the high-dose condition compared with baseline,
Table 3
EffectsofMTon gonadaland thyroidaxishormones
Hormones B(Mean±SD) HD (Mean±SD) W(Mean±SD) F p df
Gonadalaxis
Totaltestosterone 748.8(246.0) 290.4 (251.7)∗∗ 398.5(181.4)∗∗ 50.4 0.001 2,38
(ng/dl)
Freetestosterone 203.6(57.3) 98.0 (87.8)∗∗ 132.2(52.7)∗∗ 23.8 0.001 2,38
(pg/ml)
DHT(ng/dl) 139.2 (72.6) 54.5 (33.0)∗∗ 71.5(35.0)∗∗ 24.6 0.001 2,38
Estradiol(pg/ml) 41.8 (15.1) 25.8 (14.4)∗∗ 30.3(16.3)∗∗ 10.5 0.001 2,38
SHBG(nmol/l) 30.6 (9.6) 17.2 (6.4)∗∗ 16.8(6.8)∗∗ 53.7 0.001 2,38
FSH(mIU/ml) 8.8(1.1) 7.3(0.7)∗∗ 8.7(2.0) 9.7 0.001 2,38
LH(mIU/ml) 8.4(1.9) 5.4(1.6)∗∗ 9.2(2.5) 27.6 0.001 2,38
Thyroidaxis
Triiodothyroxine 131.6 (17.9) 96.0 (9.6)∗∗ 107.4(11.3)∗∗ 83.6 0.001 2,38
(ng/dl)
T4(ug/dl) 6.5(0.8) 5.8(1.0)∗∗ 6.0(1.0)∗ 7.6 0.005 2,38
TBG(ug/ml) 18.2 (2.9) 13.2 (3.5)∗∗ 14.2(3.2)∗∗ 48.0 0.001 2,38
TSH(uIU/ml) 1.9(1.0) 2.3(1.4)∗ 3.2(2.0)∗∗ 18.6 0.001 2,38
FT4(ng/dl) 1.2(0.2) 1.4(0.2)∗∗ 1.3(0.2)∗ 8.1 0.005 2,38
B,baseline;HD,high-dose;W,withdrawal;ANOVA-R,analysisofvariancewithrepeatedmeasures.
AllBonferroni t-testp-valuesrepresent comparisonswith baseline(∗∗p(cid:1)0.01,∗p(cid:1)0.05).
324 R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331
with FT4 levels returning to baseline and TSH levels further increasing during the
withdrawal condition.
3.1.3. HPA axis (Table 4)
No significant changes were observed in HPA axis-related hormones during the
high-dose condition,although therewasatrend forACTH levelsto risesignificantly
during withdrawal.
3.2. Correlations
Aggressiveness clusterscore changes correlatedsignificantly with changes in FT4
levels (r (cid:2) 0.50,p (cid:2) 0.03) (i.e., increased changes in aggression with increases in
FT4 during high-dose) (Fig. 1). Cognitive cluster score changes correlated signifi-
cantly with changes in total testosterone (r (cid:2) 0.52,p (cid:2) 0.02) and at a trend level
with changes in freetestosterone levels(r (cid:2) 0.43,p (cid:2) 0.06)(i.e. increased cognitive
symptoms with blunted decreases in testosterone and free testosterone) (Table 5).
Activation cluster score changes did not correlate significantly with changes in any
hormonal levels.
NosignificantcorrelationsbetweenplasmaMTlevelsandhormonalchangeswere
observed.Specifically,MTlevelsdidnotcorrelatesignificantlywithchangesinFSH
(r (cid:2) (cid:3)0.09, p (cid:2) 0.72), TBG (r (cid:2) 0.04, p (cid:2) 0.87), plasma cortisol (r (cid:2) (cid:3)
0.25, p (cid:2) 0.31) or urinary cortisol (r (cid:2) 0.10, p (cid:2) 0.68), LH (r (cid:2) 0.06, p (cid:2) 0.80),
ACTH (r (cid:2) 0.03, p (cid:2) 0.89), GH (r (cid:2) (cid:3)0.03, p (cid:2) 0.90), estradiol (r (cid:2) (cid:3)
0.37, p (cid:2) 0.12), DHEA (r (cid:2) (cid:3)0.09, p (cid:2) 0.71), total testosterone (r (cid:2) (cid:3)0.01, p (cid:2)
0.97) or free testosterone (r (cid:2) (cid:3)0.24, p (cid:2) 0.31), SHBG (r (cid:2) 0.36, p (cid:2) 0.14), FT4
(r (cid:2) 0.03, p (cid:2) 0.91), free T3 (r (cid:2) 0.11, p (cid:2) 0.64) or T4 (r (cid:2) 0.39, p (cid:2) 0.09).
Table 4
EffectsofMTon pituitary-adrenalhormones
Hormones B (Mean±SD) HD(Mean±SD) W(Mean±SD) ANOVA-R
F p df
Plasma (n(cid:2)20)
ACTH(pg/ml) 41.9 (21.6) 37.7 (14.9) 59.2 (51.9)∗ 3.7 (cid:1)0.05 2,38
DHEA(ng/dl) 1167(525) 962(420) 999(434) 2.4 0.1 2,38
Cortisol(ug/dl) 18.6 (4.8) 17.1 (3.7) 18.8 (4.7) NS
β-Endorphin(pg/ml) 30.1 (7.7) 31.8 (8.7) 32.9 (15.3) NS
Urine (n(cid:2)19)
24h Cortisol 78.11(30.2) 74.3 (35.7) 83.9 (37.9) NS
(ug/dl)
NS,non-significantforallthreetreatmentconditions.Bonferronit-testp-valuesrepresentcomparisons
with baseline(∗p(cid:1)0.1).
R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331 325
Fig.1. CorrelationofchangesinaggressionsymptomclusterscoreswithchangesinplasmaFT4follow-
ingMTadministration(r(cid:2)0.5,p(cid:2)0.02).Aggressionclusterincludesenergy,sexualarousal,anddimin-
ishedsleep.
Table 5
Spearmancorrelationcoefficientsofchangesinbehavioral symptomclusterscoreswith changesinhor-
monallevels duringMT administration
Aggressivenesscluster Activationcluster Cognitive cluster
Totaltestosterone 0.25 0.15 0.52∗∗
Freetestosterone 0.08 0.19 0.43∗
DHT 0.11 0.10 0.33
Estradiol 0.23 0.23 0.31
FSH 0.41 (cid:3)0.20 –0.002
LH 0.25 –0.08 –0.15
T4 0.23 0.15 0.09
FT4 0.50∗∗ 0.15 –0.02
∗p(cid:1)0.1,∗∗p(cid:1)0.05.
3.3. Split group comparisons
For the activation cluster, a significant difference in FT4 changes between sub-
groups was observed—the high symptom and low symptom subgroup changes were
0.19 ± 0.12ng/dl and 0.06 ± 0.05ng/dl respectively (t (cid:2) 2.56,p (cid:2) 0.02). No other
significant differences in hormonal changes between high symptom and low symp-
tom subgroups were observed (data not shown).
326 R.C.Dalyetal./Psychoneuroendocrinology28(2003)317–331
4. Discussion
Several limitations of this study are notable. The duration of treatment with AAS
was shorter and doses lower than those reported by some abusers (Porcerelli and
Sandler,1998).Steroidabusingathletesmaycompriseadifferentbiologicalorbioso-
cialgroupthanhealthyvolunteerswhohaveneverusedandrogens.Thestudydesign,
byminimizing potentialconfoundssuch asexercise,co-morbid substanceabuse,and
multiplesteroiduse,mayhavereducedtheimpactofimportantfactorsthatcontribute
to AAS-induced psychological and hormonal changes. Correlational studies cannot
establish causality, and multiple comparison analyses can lead to type 1 errors.
This study is the first comprehensive examination of hormonal changes during
and after high-dose AAS administration to drug naive normal volunteers in an in-
patient setting. Inanearlierpublication(Suet al.,1993), wereportedthat behavioral
effectsofMTwereseenevenunderthehighlycontrolledandtimelimitedconditions
of this study; we also noted an association between increases in CSF 5HIAA levels
andthedevelopmentofactivationsymptoms(Dalyetal.,2001).Inthecurrentreport,
wedemonstrateacutesuppressiveeffectsofMTonthepituitary-gonadaland-thyroid
axes. These effects were acute (occurring after only six days) and dramatic. Associ-
ations were observed between some of the MT-induced changes in hormonal levels
and the behavioral and mood symptoms observed. In the following sections, we
examine the various endocrine effects of MT administration and attempt to interpret
the associations seen between endocrine changes and psychological symptoms.
4.1. Pituitary-gonadal axis
We observed decreases in SHBG and testosterone, consistent with the expected
effects of androgen administration (Ale´n et al., 1987; Ruokonen et al., 1985; Small
et al., 1984; Holma and Adlercreutz, 1976; Jones et al., 1977). We also observed
suppression of gonadotropin levels, an effect reported in many (Clerico et al., 1981;
Ale´n et al., 1985, 1987; Small et al., 1984), but not all (Hervey et al., 1976; Remes
et al., 1977; Aakvaag and Stromme, 1974) studies.
Additionally,subjectsshoweddecreasesinestradiollevelsfollowingMTadminis-
tration, contrary to some earlier studies that reported increases in estradiol (Ale´n et
al., 1985, 1987). The most likely explanation for this apparent difference is the use
intheseearlierstudiesofandrogens(e.g.testosterone),whichmayundergoaromatiz-
ation to estrogens; MT, a 17-alkylated androgen, does not undergo such metabolism
(Dimick et al., 1961).
Changes in testosterone levels have been suggested as influencing cognitive func-
tioning through ‘activating effects’ (Hampson and Moffat, 1994; Van Goozen et al.
(2000).Fewstudieshaveexaminedintra-subjectchangesincognitionaccompanying
decreases in endogenous testosterone levels. Our findings of blunted decreases in
testosterone being associated with increases in subjectively rated forgetfulness and
distractibility (i.e. smaller decreases associated with increased symptoms) are para-
doxical but consistent with prior literature suggesting a curvilinear relationship
between one component of cognitive functioning—spatial performance—and circul-