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Published in final edited form as: Drug Alcohol Depend. 2012 Sep 26;128(3):250–254. doi: 10.1016/j.drugalcdep.2012.08.024

Relationship between sex hormones and cognitive performance in men with substance use*

Mihail F Zilbermint (1), Amy B Wisniewski (2), Xiaoqiang Xu (3), Ola A Selnes (4), Adrian S Dobs (5)**
PMCID: PMC3637021  NIHMSID: NIHMS410441  PMID: 23021515

Abstract

BACKGROUND

Hypogonadism is common with opiate-like drug use and may contribute to cognitive abnormalities. With the increasing epidemic of HIV and substance use (SU) worldwide, it is important to understand the impact of these conditions on cognition, which may affect quality of life and possibly decrease adherence to treatment. We hypothesized that men with SU, by virtue of hypogonadism secondary to HIV and/or SU, may demonstrate impaired cognition.

METHODS

We recruited men aged 18-50 from a population of low income, innercity individuals. Details of 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%). The recruited population was primarily from low socioeconomic status and unemployed. The mean level of TT 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 (SD 4.4). We found that 30.9% were hypogonadal and it was associated with higher SU.

RESULTS

We observed some relationships between sex hormones and cognitive domains, however, after adjustment for age, drug use category, education, depression, HIV, there was no statistically significant correlation between cognitive performance and sex hormone levels.

CONCLUSIONS

In this cross-sectional study of men with a high prevalence of SU and hypogonadism, endogenous levels of TT, FT or E2 were not related to cognitive performance. Other factors need to be identified which may contribute to poor cognitive function in the setting of SU.

Keywords: Testosterone, estradiol, sex hormones, cognitive function, illicit drug users, substance use

1. INTRODUCTION

The effects of sex hormones on brain function are unclear. It is known that sex hormones, mainly testosterone, may influence cognition; substance use (SU) and HIV infection may alter the function of hypothalamic-pituitary-gonadal (HPG) axis. With the increasing epidemic of HIV and SU worldwide, it is important to understand the possible impact of these conditions on cognitive function, which may affect quality of life, and possibly decrease adherence to treatment.

Substantial impairment of executive control has been recognized in a variety of dependent drug using groups (Hoff et al., 1996; Bolla et al., 1999; Simon et al., 2000; Rosselli et al., 2001; Fillmore and Rush, 2002; Goldstein et al., 2004; Lundqvist, 2005; McHale and Hunt, 2008). An association between executive control deficits and dysfunction in prefrontal, orbitofrontal and anterior cingulate regions has been identified using neuroimaging studies (Bolla et al., 2000, 2003). A number of neuropsychological studies suggested the working memory is impaired in chronic cannabis users (Lundqvist, 2005). Chronic cocaine and heroin users may exhibit neuropsychological 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 cognitive decline in men as they age (Moffat, 2005). Even though the relationship between various sex hormone levels and several cognitive domains has been studied, the results are inconsistent (Nelson et al., 2008; Ulubaev et al., 2009). Most of the studies measured total testosterone (TT), free testosterone (FT), estradiol (E2), and administered batteries of cognitive tests in aging populations. Some authors reported a curvilinear correlation (U-shaped) between testosterone and cognition (Moffat and Hampson, 1996; Barrett-Connor et al., 1999); others acknowledged a positive linear relationship (Silverman et al., 1999; Janowsky, 2006; Thilers et al., 2006; Fukai et al., 2009), yet others report an inverse relationship (Gouchie and Kimura, 1991; Yeap et al., 2008). Interestingly, some researchers found no statistically significant correlation between various sex hormone levels and cognitive domains (Fonda et al., 2005; Martin et al., 2008; Young et al., 2010; Anonymous, 2010; Advani, 2011). In fact, Martin et al. (2007b) reported that higher TT and FT are associated with poorer executive function and verbal memory.

One can speculate that the reports were inconsistent due to small sample sizes (Sherwin, 2003), different ages of subjects, dissimilar research methodologies (Martin et al., 2007a), timing of sex steroid measurements (LeBlanc et al., 2010), and “practice” effects (Salminen et al., 2004).

Hormonal changes in patients with SU are well recognized (Lafisca et al., 1985; Rasheed and Tareen, 1995; Rajagopal et al., 2004; Kalyani et al., 2007), including decreased FT and TT. This may be due to direct and indirect effects of illicit drugs on the HPG axis (de la Rosa and Hennessey, 1996).

HIV infection, often a comorbidity of SU, is shown to result in central nervous system impairment and altered cognitive performance: decreased attention, poor memory and psychomotor slowing (Egan et al., 1992; McArthur et al., 1993; Silberstein et al., 1993). In contrast, Selnes et al. (1997) observed no association between HIV infection and the progression of cognitive symptoms in SU. Equally important, endocrine abnormalities, especially hypogonadism, were reported in HIV-infected men and women (Grinspoon et al., 1997; Rabkin et al., 1997, 2000; Dobs, 1998). It is unclear if endocrine abnormalities relate to HIV-infected individuals independently of SU.

We hypothesized that males with SU, by virtue of hypogonadism secondary to HIV and/or SU, may exhibit impaired cognition. This report presents a cross-sectional investigation of the effects of endocrine health on mental performance of men using drugs, in a study entitled CHIEF (Cognitive Health in Endocrine Function; Dobs and Wisniewski, 2004).

2. METHODS

2.1. Participants

161 men, 18-50 years old, from Baltimore, Maryland were enrolled in the study between 2004 and 2008. For the cross-sectional analysis, subjects were classified into four categories: non-users (no drug use in the past three years), occasional users (cocaine and/or heroin use less than three times per week), heavy users/methadone maintenance (methadone, cocaine and/or heroin use more than three times per week or methadone maintenance). Complete hormonal and cognitive performance data was available in 68 individuals. We excluded subjects with a known gonadal impairment, chronic neurological and psychiatric disorders (see full exclusion criteria in Supplementary Material Item 11.)

After signing the informed consent, participants were interviewed. Information about substance use, sociodemographic status, medical history, use of medications and highly active antiretroviral therapy was obtained. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977; Golub et al., 2004). The Johns Hopkins University Medicine Institutional Review Boards approved the study.

2.2. Hormone measurements

Blood samples were collected before 10:00h for measurement of TT, FT, sex hormone binding globulin (SHBG), and E2 concentrations. TT was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) (Singh, 2008). SHBG was measured by radioimmunoassay (RIA). FT was measured via tracer equilibrium dialysis calculation. E2 was measured by LC-MS/MS. Normal testosterone range is still not clearly defined (Wheeler and Barnes, 2008). We used commonly accepted levels to define male hypogonadism in adults (serum TT <300 ng/dL or FT< 50 pg/mL).

2.3. Cognitive tests

Participants were administered ten standardized neuropsychological tests with established reliability and validity (Lezak et al., 2004) to evaluate working memory, verbal learning and memory, verbal fluency, and visuospatial, graphomotor and psychomotor abilities (Table 1).

Table 1.

Cognitive tests.

Cognitive
domain		 Test Description
Baseline
cognition		 Adapted Mini-
Mental
Examination
(Folstein et al., 1975)		 Participants are required to provide a vocal response that covers
orientation, memory, and attention. They are then being tested
for the ability to name, follow written and verbal commands,
and copy 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
digits verbatim. The “backward test” obliged the subject to say
again the digits in reverse order. The number of digits increases
by one until the subject consecutively fails to repeat the
numbers twice, in the same digit span length.
Letter Number
Sequencing Test
(WAIS-III)
(Wechsler, 1997)		 Participants are asked to recall combinations of numbers and
letters, numbers in ascending order, and then letters in
alphabetical 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
after presentation and following a 20 minutes delay. In
addition, participants are asked to recognize which words were
originally presented 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
with given letters (F, A, and S).
Visuomotor and
visuoconstruction
abilities		 Rey-Osterrieth
Complex Figure
(copy, immediate
and delayed recall)
(Rey, 1964)		 Participants are asked to copy a complex two-dimensional
drawing, and then the original figure was removed from view,
and the subject was asked to reproduce the figure from memory
20 minutes later (delayed recall).
Visuospatial
abilities		 Card Rotation Test
(Ekstrom et al., 1976)		 Participants are required to mentally rotate a 2-dimensional
object in their mind and match the rotated figure to one of a series
of possible answers.
Hidden Figures
Test (Weckowicz, 1960;
Educational Testing Service, 1962)		 Participants are required to decide which piece of a figure is
embedded in a more complex figure from five response options.
Graphomotor and
psychomotor
speed, executive
function, and
divided attention		 Trail Making Tests
(Parts A and B)
(Reitan, 1955;
Reitan R., 1958)		 Participants are required to connect consecutively numbered
circles with a line (Part A). Additionally to connect
consecutively numbered and lettered circles in sequence,
alternating between numbers and letters (Part B).
Psychomotor and
fine motor
performance		 Identical Pictures
Test (Ekstrom et al., 1976)		 Participants are required to match a test item to an identical
picure. Participants are required to identify a picture amongst a
group of similar-appearing distracting images.
Grooved Pegboard
Test (Klove, 1963)		 Participants are required to place 25-keyed pegs into an array of
25 slotted holes as quickly as possible. The dominant and nondominant
hands are tested separately.
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2.4. Statistical analysis

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

The primary objective was to test the correlation between TT, FT, and E2 with cognitive tests. First, we treated the hormones as continuous variables. Multi-linear regression models were constructed with cognitive test scores as dependent variables and hormones as the independent variables. Other covariates were drug use category, education, depression, HIV status, since they show effect on cognitive test results. An adaptive step-up Bonferroni method was used for multiple comparison correction across the cognitive tests (Hochberg and Benjamini, 1990). Then the cognitive test results were compared using ANCOVA models between hypogonadal and normogondal men, with age, depression, HIV status, education and drug use category as covariates. Two-sided P values < 0.05 were considered statistically significant.

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 unemployed, not married, and heavy substance users. The mean level of TT was 553.9 ng/dL (SD 262.0), median 507 ng/dL, the mean level of FT was 69.5 pg/mL (SD 34.8), median 70.5 pg/mL, mean E2 was 3.2 pg/mL (SD 4.4), median 2.1 pg/mL. We found that 30.9% were hypogonadal. Socio-demographic characteristics of subjects are listed in Table 2.

Table 2.

Socio-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 <$5,000 15 (29.4%)
$5,001-10,000 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 / methadone maintenance 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 received
public assistance		 No 39 (59.1%)
Yes 27 (40.9%)
In the past year been
homeless		 No 48 (72.7%)
Yes 18 (27.3%)
Currently employed No 59 (86.8%)
Yes 9 (13.2%)
In the past year been
unemployed		 No 18 (26.5%)
Yes 50 (73.5%)
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3.2. Relationship between substance use and sex hormone levels

Sex hormone levels across the substance use groups were evaluated (Supplementary Material Item 22). Heavy users/methadone maintenance group had a statistically significant lower FT (p=0.014). After using the pair-wise comparison, this group had a lower FT, as compared to occasional substance users (p=0.004).

3.3. Relationship between cognitive performance and sex hormone levels

After adjustment for age, education, drug use category, depression, and HIV, we observed that higher TT level predicted better performance in the copying of Rey-Osterrieth Complex Figure (coeff.=0.0081, p=0.022), as well as higher levels of E2 (coeff.=0.4383, p=0.033). Higher E2 predicted better performance in the scoring of identical pictures (coeff.=0.4234, p=0.013). TT and E2 predicted a better performance for non-dominant hand use in the Grooved Pegboard test (TT coeff. = −0.0206, p = 0.019; E2 coeff. = −1.0788, p = 0.035). Only higher E2 predicted a better performance for the dominant hand in the Grooved Pegboard test (coeff.=−1.1165, p=0.008). Higher E2 levels predicted better performance in the forward span length with sequence errors in Wechsler Digit Span Test (coeff.=0.0851, p=0.042) and in the backward span length with sequence errors (coeff.=0.1080, p=0.015). Higher TT and FT were positively correlated with the total recall scoring 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 predicted better performance in the learning index of the Hopkins Verbal Learning test (TT coeff.= 0.003, p=0.036; FT coeff.=0.0231, p=0.038).

Nevertheless, with the use of Bonferroni correction, results were lost. Overall, we did not observe statistically significant correlation between cognitive performance and sex hormone levels (see Supplementary Material Item 33).

3.4. Comparison of cognitive performance of normogonadal and hypogonadal men

Hypogonadal participants scored better on the Adapted Mini-Mental Status Exam (p=0.042), had a superior total recall score in the Hopkins Verbal Learning task (p=0.045). These results were lost after Bonferroni correction. Cognitive performance showed a noteworthy overlap in scores, irrespective of hypogonadal state (see Supplementary Material Item 44).

4. DISCUSSION

In this cross-sectional study of men with SU versus group controls, we investigated whether TT, FT and E2 levels were associated with cognitive performance, based on standardized cognitive testing. We found a high prevalence of male hypogonadism (30.9%), consistent with other studies (Brambilla et al., 1977; Celani et al., 1984; Brown et al., 2006), and this was associated with higher SU. The mechanism is likely multifactorial: due to an opiate-related suppression gonadotropin releasing hormone, and possibly a cytokine-mediated inhibition of steroidogenesis in the testis. We suggest screening for hypogonadism in this high-risk population for the possibility that treatment with sex steroids might be beneficial for androgen deficiency syndromes.

Our data suggested that low levels of serum FT and TT did not predict lower cognitive performance in men with SU, independently of age, education, depression, HIV status, and drug use category. Hence, we rejected our hypothesis that low FT and TT were related to cognitive impairment in our cohort.

4.1. Testosterone effects on the brain

Even though clinical and animal data suggested that sex steroids influence cognition (Leranth et al., 2003; Almeida et al., 2004; Schoning et al., 2007), clinical studies are conflicting. A curvilinear relationship between endogenous testosterone and visuospatial abilities has been reported where subjects with intermediate levels performed better than those who had higher and lower testosterone levels (Shute et al., 1983; Gouchie and Kimura, 1991; Moffat and Hampson, 1996; Thilers et al., 2006). Memory and processing capacity and speed performance had a similar relationship (Muller et al., 2005). Silverman et al. (1999) observed a positive correlation between testosterone and visuospatial abilities and Thilers et al. (2006) found a similar association between FT and better visuospatial abilities. Moreover, subjects with higher FT had better semantic memory and episodic memory (Thilers et al., 2006). Yeap et al. (2008) observed higher FT was associated with better performance on the Standardized Mini-Mental State Examination (SMMSE) in a large cohort of older men. A similar positive association was seen in general cognitive performance in other groups (Barrett-Connor et al., 1999; Yaffe et al., 2002). Contrarily, others report no such relationships (Fonda et al., 2005; Martin et al., 2008). Overall, low endogenous testosterone may be associated with some cognitive impairment in older adults; however, we did not find this relationship in our cohort of men with SU. Size of the study, ability to control for multiple confounders may account for some of the differences from previous reports.

4.2. The limitations and strengths

We studied men with SU, from a lower socioeconomic background, and with high prevalence of hypogonadism. Thus results should be extrapolated to other settings with prudence. The information of age at exposure to HIV is not available. However, the strengths of this study are well-validated assays and extensive cognitive testing.

5. CONCLUSION

We found a high prevalence of hypogonadism (30.9%) in our study population of men from low socioeconomic status and high prevalence of SU, which has been previously reported. However, endogenous levels of total testosterone, free testosterone or estradiol were not associated with cognitive performance.

We suggest future studies should look into the value of screening for hypogonadism in this high-risk population to examine whether adjunctive therapy with sex steroids might be beneficial for androgen deficiency syndromes.

Supplementary Material

Supplementary data-final

Acknowledgements

We gratefully acknowledge the assistance of Ann V. Munson with data collection. We thank Maya Nadison and Jeffrey Nadison who assisted with proof-reading the manuscript. We especially thank all participants of the Effects of Endocrine Health on Mental Performance of Men and Women Using Drugs study.

Role of Funding Source This research was supported in part by the Johns Hopkins University and by the National Institute on Drug Abuse, National Institutes of Health (grants: 1R01DA014098-01A2, 5R01DA014098-02, 3R01DA014098-03S1, 5R01DA014098-03, 5R01DA014098-04, 5R01DA014098-05). These organizations had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. ClinicalTrials.gov identifier: NCT00245531.

Footnotes

Conflict of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Contributors Author Mihail F. Zilbermint wrote the manuscript. Authors Amy B. Wisniewski and Ola A. Selnes contributed to the design the study. Author Xiaoqiang Xu undertook the statistical analysis. Author Adrian S. Dobs designed the study, received the grant, and assisted in writing and proofreading the final manuscript. All authors contributed to and approved the final manuscript.

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