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Drug and Alcohol Dependence 128 (2013) 250– 254

Contents lists available at SciVerse ScienceDirect

Drug and Alcohol Dependence

j ourna l ho me pag e: www.elsev ier .com/ locate /drugalcdep

hort communication

elationship between sex hormones and cognitive performancen men with substance use

ihail F. Zilberminta, Amy B. Wisniewskib, Xiaoqiang Xuc, Ola A. Selnesd, Adrian S. Dobse,∗

Program on Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building0/CRC 1-3140, 10 Center Drive, Bethesda, MD 20892-1109, USADepartment of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L. Young Boulevard, WP 3150, Oklahoma City, OK 73104, USADepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USADepartment of Neurology, Cognitive Neuroscience Division, Johns Hopkins University School of Medicine, Reed Hall East, Suite 2206, 1620 McElderry Street, Baltimore, MD 21287,SAJohns Hopkins Clinical Research Network, The Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, 1830 Monument Street, Suite 328, Baltimore,D 21287, USA

r t i c l e i n f o

rticle history:eceived 11 March 2012eceived in revised form 17 July 2012ccepted 20 August 2012vailable online 26 September 2012

eywords:estosteronestradiolex hormonesognitive function

llicit drug usersubstance use

a b s t r a c t

Background: Hypogonadism is common with opiate-like drug use and may contribute to cognitive abnor-malities. With the increasing epidemic of HIV and substance use (SU) worldwide, it is important tounderstand the impact of these conditions on cognition, which may affect quality of life and possi-bly decrease adherence to treatment. We hypothesized that men with SU, by virtue of hypogonadismsecondary to HIV and/or SU, may demonstrate impaired cognition.Methods: We recruited men aged 18–50 from a population of low income, inner-city individuals. Detailsof HIV and SU status, serum blood levels of total testosterone (TT), free testosterone (FT) and estradiol(E2) were assessed. All subjects were administered ten neuropsychological tests.Results: Our sample consisted of 68 men (mean age: 43.2 years (SD 5.8), African Americans: 86.6%). Therecruited population was primarily from low socioeconomic status and unemployed. The mean level ofTT was 553.9 ng/dL (SD 262.0), the mean level of FT was 69.5 pg/mL (SD 34.8), mean E2 was 3.2 pg/mL (SD4.4). We found that 30.9% were hypogonadal and it was associated with higher SU. We observed some

relationships between sex hormones and cognitive domains, however, after adjustment for age, drug usecategory, education, depression, HIV, there was no statistically significant correlation between cognitiveperformance and sex hormone levels.Conclusions: In this cross-sectional study of men with a high prevalence of SU and hypogonadism, endoge-nous levels of TT, FT or E2 were not related to cognitive performance. Other factors need to be identifiedwhich may contribute to poor cognitive function in the setting of SU.

. Introduction

The effects of sex hormones on brain function are unclear. It isnown that sex hormones, mainly testosterone, may influence cog-ition; substance use (SU) and HIV infection may alter the functionf hypothalamic-pituitary-gonadal (HPG) axis. With the increasingpidemic of HIV and SU worldwide, it is important to understandhe possible impact of these conditions on cognitive function, which

ay affect quality of life, and possibly decrease adherence to treat-

ent.Substantial impairment of executive control has been recog-

ized in a variety of dependent drug using groups (Hoff et al., 1996;

∗ Corresponding author. Tel.: +1 410 955 2130; fax: +1 410 955 8172.E-mail address: adobs@jhmi.edu (A.S. Dobs).

376-8716/$ – see front matter. Published by Elsevier Ireland Ltd.ttp://dx.doi.org/10.1016/j.drugalcdep.2012.08.024

Published by Elsevier Ireland Ltd.

Bolla et al., 1999; Simon et al., 2000; Rosselli et al., 2001; Fillmoreand Rush, 2002; Goldstein et al., 2004; Lundqvist, 2005; McHaleand Hunt, 2008). An association between executive control deficitsand dysfunction in prefrontal, orbitofrontal and anterior cingulateregions has been identified using neuroimaging studies (Bolla et al.,2000, 2003). A number of neuropsychological studies suggested theworking memory is impaired in chronic cannabis users (Lundqvist,2005). Chronic cocaine and heroin users may exhibit neuropsychol-ogical deficits (Grant et al., 1977; Hill et al., 1979; O’Malley et al.,1992; Holman et al., 1993).

A low serum testosterone level may contribute to cognitivedecline in men as they age (Moffat, 2005). Even though the rela-

tionship between various sex hormone levels and several cognitivedomains has been studied, the results are inconsistent (Nelsonet al., 2008; Ulubaev et al., 2009). Most of the studies mea-sured total testosterone (TT), free testosterone (FT), estradiol (E2),

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nd administered batteries of cognitive tests in aging popula-ions. Some authors reported a curvilinear correlation (U-shaped)etween testosterone and cognition (Moffat and Hampson, 1996;arrett-Connor et al., 1999); others acknowledged a positive linearelationship (Silverman et al., 1999; Janowsky, 2006; Thilers et al.,006; Fukai et al., 2009), yet others report an inverse relationshipGouchie and Kimura, 1991; Yeap et al., 2008). Interestingly, someesearchers found no statistically significant correlation betweenarious sex hormone levels and cognitive domains (Fonda et al.,005; Martin et al., 2008; Young et al., 2010; Anonymous, 2010;dvani, 2011). In fact, Martin et al. (2007b) reported that higherT and FT are associated with poorer executive function and verbalemory.One can speculate that the reports were inconsistent due to

mall sample sizes (Sherwin, 2003), different ages of subjects, dis-imilar research methodologies (Martin et al., 2007a), timing of sexteroid measurements (LeBlanc et al., 2010), and “practice” effectsSalminen et al., 2004).

Hormonal changes in patients with SU are well recognizedLafisca et al., 1985; Rasheed and Tareen, 1995; Rajagopal et al.,004; Kalyani et al., 2007), including decreased FT and TT. This maye due to direct and indirect effects of illicit drugs on the HPG axisde la Rosa and Hennessey, 1996).

HIV infection, often a comorbidity of SU, is shown to resultn central nervous system impairment and altered cognitive per-ormance: decreased attention, poor memory and psychomotorlowing (Egan et al., 1992; McArthur et al., 1993; Silberstein et al.,993). In contrast, Selnes et al. (1997) observed no associationetween HIV infection and the progression of cognitive symp-oms in SU. Equally important, endocrine abnormalities, especiallyypogonadism, were reported in HIV-infected men and womenGrinspoon et al., 1997; Rabkin et al., 1997, 2000; Dobs, 1998). Its unclear if endocrine abnormalities relate to HIV-infected indi-iduals independently of SU.

We hypothesized that males with SU, by virtue of hypogonadismecondary to HIV and/or SU, may exhibit impaired cognition. Thiseport presents a cross-sectional investigation of the effects ofndocrine health on mental performance of men using drugs, in atudy entitled CHIEF (Cognitive Health in Endocrine Function; Dobsnd Wisniewski, 2004).

. Methods

.1. Participants

161 men, 18–50 years old, from Baltimore, MD were enrolled in the studyetween 2004 and 2008. For the cross-sectional analysis, subjects were classified

nto four categories: non-users (no drug use in the past three years), occasional userscocaine and/or heroin use less than three times per week), heavy users/methadone

aintenance (methadone, cocaine and/or heroin use more than three times pereek or methadone maintenance). Complete hormonal and cognitive performanceata was available in 68 individuals. We excluded subjects with a known gonadal

mpairment, chronic neurological and psychiatric disorders (see full exclusion crite-ia in Supplementary Material Item 1).

After signing the informed consent, participants were interviewed. Informationbout substance use, sociodemographic status, medical history, use of medicationsnd highly active antiretroviral therapy was obtained. Depressive symptoms weressessed by the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff,977; Golub et al., 2004). The Johns Hopkins University Medicine Institutionaleview Boards approved the study.

.2. Hormone measurements

Blood samples were collected before 10:00 h for measurement of TT, FT, sex hor-one binding globulin (SHBG), and E2 concentrations. TT was measured by liquid

hromatography tandem mass spectrometry (LC–MS/MS) (Singh, 2008). SHBG waseasured by radioimmunoassay (RIA). FT was measured via tracer equilibrium dial-

sis calculation. E2 was measured by LC–MS/MS. Normal testosterone range is stillot clearly defined (Wheeler and Barnes, 2008). We used commonly accepted levelso define male hypogonadism in adults (serum TT < 300 ng/dL or FT < 50 pg/mL).

Dependence 128 (2013) 250– 254 251

2.3. Cognitive tests

Participants were administered ten standardized neuropsychological tests withestablished reliability and validity (Lezak et al., 2004) to evaluate working mem-ory, verbal learning and memory, verbal fluency, and visuospatial, graphomotorand psychomotor abilities (Table 1).

2.4. Statistical analysis

Analysis of covariance (ANCOVA) models were constructed to compare sex hor-mone levels, including TT, FT, and E2, among the three drug use groups. Age wasincluded in the model as a covariate, since it is a strong factor affecting the hormonelevels. If a cross-group significance is observed, then pair-wise comparisons wereperformed.

The primary objective was to test the correlation between TT, FT, and E2 withcognitive tests. First, we treated the hormones as continuous variables. Multi-linearregression models were constructed with cognitive test scores as dependent vari-ables and hormones as the independent variables. Other covariates were drug usecategory, education, depression, HIV status, since they show effect on cognitive testresults. An adaptive step-up Bonferroni method was used for multiple compari-son correction across the cognitive tests (Hochberg and Benjamini, 1990). Thenthe cognitive test results were compared using ANCOVA models between hypog-onadal and normogondal men, with age, depression, HIV status, education and druguse category as covariates. Two-sided P values < 0.05 were considered statisticallysignificant.

3. Results

3.1. Demographics

Our sample consisted of 68 men (mean age: 43.2 years (SD 5.8),African Americans: 86.6%). The population was primarily unem-ployed, not married, and heavy substance users. The mean levelof TT was 553.9 ng/dL (SD 262.0), median 507 ng/dL, the meanlevel of FT was 69.5 pg/mL (SD 34.8), median 70.5 pg/mL, mean E2was 3.2 pg/mL (SD 4.4), median 2.1 pg/mL. We found that 30.9%were hypogonadal. Socio-demographic characteristics of subjectsare listed in Table 2.

3.2. Relationship between substance use and sex hormone levels

Sex hormone levels across the substance use groups were eval-uated (Supplementary Material Item 2). Heavy users/methadonemaintenance group had a statistically significant lower FT(p = 0.014). After using the pair-wise comparison, this group hada lower FT, as compared to occasional substance users (p = 0.004).

3.3. Relationship between cognitive performance and sexhormone levels

After adjustment for age, education, drug use category, depres-sion, and HIV, we observed that higher TT level predictedbetter performance in the copying of Rey-Osterrieth complexfigure (coeff. = 0.0081, p = 0.022), as well as higher levels of E2(coeff. = 0.4383, p = 0.033). Higher E2 predicted better performancein the scoring of identical pictures (coeff. = 0.4234, p = 0.013). TTand E2 predicted a better performance for non-dominant handuse in the Grooved Pegboard test (TT coeff. = −0.0206, p = 0.019;E2 coeff. = −1.0788, p = 0.035). Only higher E2 predicted a bet-ter performance for the dominant hand in the Grooved Pegboardtest (coeff. = −1.1165, p = 0.008). Higher E2 levels predicted betterperformance in the forward span length with sequence errors inWechsler Digit Span Test (coeff. = 0.0851, p = 0.042) and in the back-ward span length with sequence errors (coeff. = 0.1080, p = 0.015).Higher TT and FT were positively correlated with the total recallscoring in the Hopkins Verbal Learning Test (TT coeff. = 0.0051,

p = 0.054; FT coeff. = 0.4, p = 0.054). Similarly, higher TT and FT pre-dicted better performance in the learning index of the HopkinsVerbal Learning Test (TT coeff. = 0.003, p = 0.036; FT coeff. = 0.0231,p = 0.038).

252 M.F. Zilbermint et al. / Drug and Alcohol Dependence 128 (2013) 250– 254

Table 1Cognitive tests.

Cognitive domain Test Description

Baseline cognition Adapted Mini-Mental Examination (Folstein et al., 1975) Participants are required to provide a vocal response that coversorientation, memory, and attention. They are then being tested forthe ability to name, follow written and verbal commands, andcopy a complex picture.

Working memory Wechsler Digit Span Test (Wechsler, 1981) The examiner verbally presents digits at a rate of one per second.The “forward test” required the subject to repeat the digitsverbatim. The “backward test” obliged the subject to say again thedigits in reverse order. The number of digits increases by one untilthe subject consecutively fails to repeat the numbers twice, in thesame digit span length.

Letter Number Sequencing Test (WAIS-III) (Wechsler,1997)

Participants are asked to recall combinations of numbers andletters, numbers in ascending order, and then letters inalphabetical order.

Verbal learning and memory The Hopkins Verbal Learning Test (Brandt and Benedict,2001; Hogervorst et al., 2002)

Participants are required to recall a list of words immediately afterpresentation and following a 20 min delay. In addition,participants are asked to recognize which words were originallypresented to them from a list of target and distracter words.

Verbal fluency FAS Verbal Fluency Test (Benton and Hamsher, 1976) Participants are required to generate lexical words that begin withgiven letters (F, A, and S).

Visuomotor andvisuoconstruction abilities

Rey-Osterrieth Complex Figure (copy, immediate anddelayed recall) (Rey, 1964)

Participants are asked to copy a complex two-dimensionaldrawing, and then the original figure was removed from view, andthe subject was asked to reproduce the figure from memory20 min later (delayed recall).

Visuospatial abilities Card Rotation Test (Ekstrom et al., 1976) Participants are required to mentally rotate a 2-dimensional objectin their mind and match the rotated figure to one of a series ofpossible answers.

Hidden Figures Test (Weckowicz, 1960; EducationalTesting Service, 1962)

Participants are required to decide which piece of a figure isembedded in a more complex figure from five response options.

Graphomotor andpsychomotor speed,executive function, anddivided attention

Trail Making Tests (Parts A and B) (Reitan, 1955, 1958) Participants are required to connect consecutively numberedcircles with a line (Part A). Additionally to connect consecutivelynumbered and lettered circles in sequence, alternating betweennumbers and letters (Part B).

Psychomotor and fine motorperformance

Identical Pictures Test (Ekstrom et al., 1976) Participants are required to match a test item to an identicalpicture. Participants are required to identify a picture amongst agroup of similar-appearing distracting images.

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Nevertheless, with the use of Bonferroni correction, results wereost. Overall, we did not observe statistically significant correla-ion between cognitive performance and sex hormone levels (seeupplementary Material Item 3).

.4. Comparison of cognitive performance of normogonadal andypogonadal men

Hypogonadal participants scored better on the Adapted Mini-ental Status Exam (p = 0.042), and had a superior total recall score

n the Hopkins Verbal Learning Test (p = 0.045). These results wereost after Bonferroni correction. Cognitive performance showed aoteworthy overlap in scores, irrespective of hypogonadal statesee Supplementary Material Item 4).

. Discussion

In this cross-sectional study of men with SU versus group con-rols, we investigated whether TT, FT and E2 levels were associatedith cognitive performance, based on standardized cognitive test-

ng. We found a high prevalence of male hypogonadism (30.9%),onsistent with other studies (Brambilla et al., 1977; Celani et al.,984; Brown et al., 2006), and this was associated with higherU. The mechanism is likely multifactorial: due to an opiate-elated suppression gonadotropin releasing hormone, and possibly

cytokine-mediated inhibition of steroidogenesis in the testis. Weuggest screening for hypogonadism in this high-risk population forhe possibility that treatment with sex steroids might be beneficialor androgen deficiency syndromes.

Participants are required to place 25-keyed pegs into an array of25 slotted holes as quickly as possible. The dominant andnon-dominant hands are tested separately.

Our data suggested that low levels of serum FT and TT didnot predict lower cognitive performance in men with SU, inde-pendently of age, education, depression, HIV status, and drug usecategory. Hence, we rejected our hypothesis that low FT and TTwere related to cognitive impairment in our cohort.

4.1. Testosterone effects on the brain

Even though clinical and animal data suggested that sex steroidsinfluence cognition (Leranth et al., 2003; Almeida et al., 2004;Schoning et al., 2007), clinical studies are conflicting. A curvilinearrelationship between endogenous testosterone and visuospatialabilities has been reported where subjects with intermediate levelsperformed better than those who had higher and lower testos-terone levels (Shute et al., 1983; Gouchie and Kimura, 1991; Moffatand Hampson, 1996; Thilers et al., 2006). Memory and processingcapacity and speed performance had a similar relationship (Mulleret al., 2005). Silverman et al. (1999) observed a positive correlationbetween testosterone and visuospatial abilities and Thilers et al.(2006) found a similar association between FT and better visuospa-tial abilities. Moreover, subjects with higher FT had better semanticmemory and episodic memory (Thilers et al., 2006). Yeap et al.(2008) observed higher FT was associated with better performanceon the Standardized Mini-Mental State Examination (SMMSE) in alarge cohort of older men. A similar positive association was seen

in general cognitive performance in other groups (Barrett-Connoret al., 1999; Yaffe et al., 2002). Contrarily, others report no suchrelationships (Fonda et al., 2005; Martin et al., 2008). Overall, lowendogenous testosterone may be associated with some cognitive

M.F. Zilbermint et al. / Drug and Alcohol

Table 2Socio-demographic characteristics of patients.

n = 68 n (%)

Age <40 16 (23.5%)40–50 52 (76.5%)

Race African Americans 58 (86.6%)Other 9 (13.4%)

Income per year <$5000 15 (29.4%)$5001–10,000 36 (70.6%)

Education <12 years 29 (42.6%)≥12 years 39 (57.4%)

HIV status Not infected 32 (47.1%)Infected 36 (52.9%)

Drug use status Non-users 20 (29.4%)Occasional users 14 (20.6%)Heavy users/methadonemaintenance

34 (50%)

Gonadal status Hypogonadal 21 (30.9%)Normogonadal 47 (69.1%)

Marital status Not married 60 (89.6%)Married 7 (10.4%)

Public assistance? No 38 (56.7%)Yes 29 (43.3%)

In the past year receivedpublic assistance

No 39 (59.1%)Yes 27 (40.9%)

In the past year beenhomeless

No 48 (72.7%)Yes 18 (27.3%)

Currently employed No 59 (86.8%)Yes 9 (13.2%)

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mpairment in older adults; however, we did not find this relation-hip in our cohort of men with SU. Size of the study, ability to controlor multiple confounders may account for some of the differencesrom previous reports.

.2. The limitations and strengths

We studied men with SU, from a lower socioeconomic back-round, and with high prevalence of hypogonadism. Thus resultshould be extrapolated to other settings with prudence. The infor-ation of age at exposure to HIV is not available. However, the

trengths of this study are well-validated assays and extensive cog-itive testing.

. Conclusion

We found a high prevalence of hypogonadism (30.9%) in ourtudy population of men from low socioeconomic status and highrevalence of SU, which has been previously reported. However,ndogenous levels of total testosterone, free testosterone or estra-iol were not associated with cognitive performance.

We suggest future studies should look into the value of screeningor hypogonadism in this high-risk population to examine whetherdjunctive therapy with sex steroids might be beneficial for andro-en deficiency syndromes.

ole of funding source

This research was supported in part by the Johns Hopkins Uni-ersity and by the National Institute on Drug Abuse, National Insti-utes of Health (grants: 1R01DA014098-01A2, 5R01DA014098-2, 3R01DA014098-03S1, 5R01DA014098-03, 5R01DA014098-04,R01DA014098-05). These organizations had no further role in

tudy design; in the collection, analysis and interpretation of data;n the writing of the report; and in the decision to submit the paperor publication. ClinicalTrials.gov identifier: NCT00245531.

Dependence 128 (2013) 250– 254 253

Contributors

Author Mihail F. Zilbermint wrote the manuscript. Authors AmyB. Wisniewski and Ola A. Selnes contributed to the design the study.Author Xiaoqiang Xu undertook the statistical analysis. AuthorAdrian S. Dobs designed the study, received the grant, and assistedin writing and proofreading the final manuscript. All authors con-tributed to and approved the final manuscript.

Conflict of interest

The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials discussed inthe manuscript.

Acknowledgements

We gratefully acknowledge the assistance of Ann V. Munsonwith data collection. We thank Maya Nadison and Jeffrey Nadi-son who assisted with proof-reading the manuscript. We especiallythank all participants of the Effects of Endocrine Health on MentalPerformance of Men and Women Using Drugs study.

Appendix A. Supplementary data

Supplementary data associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.drugalcdep.2012.08.024.

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