Androgen–Behavior Correlations in Hypogonadal Men and Eugonadal Men

Hormones and Behavior 33, 85–94 (1998) Article No. HB981439

Androgen–Behavior Correlations in Hypogonadal Men and Eugonadal Men II. Cognitive Abilities1 Gerianne M. Alexander,*,2 Ronald S. Swerdloff,† Christina Wang,† Tina Davidson,† Veronica McDonald,† Barbara Steiner,† and Melissa Hines‡ *Department of Psychology, University of New Orleans, New Orleans, Louisiana 70148; †Division of Endocrinology, Department of Medicine, Harbor–UCLA Medical Center, Torrance, California 90509; ‡Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, California 90024, and Department of Psychology, City University, London, United Kingdom Received August 15, 1997; revised December 19, 1997; accepted January 13, 1998

Sex-typed cognitive abilities were assessed in 33 hypogonadal men receiving testosterone replacement therapy, 10 eugonadal men receiving testosterone in a male contraceptive clinical trial, and 19 eugonadal men not administered testosterone. Prior to and following hormone administration, men completed four tests measuring visuospatial ability, three tests measuring verbal fluency, two tests measuring perceptual speed, and a measure of verbal memory. Group differences in testosterone levels were unrelated to performance on most cognitive measures, including visuospatial ability. Relative to other men, hypogonadal men were impaired in their verbal fluency and showed improved verbal fluency following treatment with testosterone. These data suggest that testosterone may enhance verbal fluency in hypogonadal men and support the general hypothesis that current levels of testosterone may influence some aspects of cognitive function. © 1998 Academic Press

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Supported by National Institutes of Health Grants HD07596 (G.M.A.), HD24542 (M.H.), M01-RR00425 to the General Clinical Research Center at Harbor-UCLA Medical Center, CSA-91-085 by the CONRAD Program, Eastern Virginia Medical School under a cooperative agreement with USAID CCP-3044-A-2011-00 (R.S.S.), and a grant from BioTechnology General Corp. (R.S.S., C.W.). The views expressed by the authors do not necessarily reflect the views of USAID and CONRAD. The authors thank Mark G. Packard for comments on an earlier version of the manuscript. 2 To whom correspondence should be addressed. E-mail: [email protected]. 0018-506X/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.

It is generally hypothesized that perinatal exposure to sex steroids may organize brain structures controlling a sex-typed behavior that may be later activated by the presence of critical amounts of hormones in older individuals (i.e., after puberty). Evidence exists for early hormonal control of sex-typed cognitive abilities in rodents (e.g., Roof and Ravens, 1992; Williams and Meck, 1993) and in nonhuman primates (e.g., Clark and Goldman-Rakic, 1989). In humans, cognitive abilities also vary according to sex. Men generally outperform women on visuospatial tasks and women generally outperform men on verbal fluency tasks, measures of perceptual speed (Ekstrom, French, and Harman, 1976; Halpern, 1992; Linn and Petersen, 1985; Maccoby and Jacklin, 1974), and perhaps spatial memory, defined as memory for object locations (Silverman and Eals, 1994). Cognitive abilities in individuals with a variety of endocrine disorders (for review, see Collaer and Hines, 1995) and in very young children (e.g., Overman et al., 1996) support the hypothesis that gonadal steroid levels during critical periods of perinatal development contribute to sex differences in human cognitive abilities. However, not all sex-typed behaviors organized by hormones in early development depend on steroid levels in later life (e.g., rough and tumble play) (for reviews, see Beatty, 1984; Meaney, 1989). Therefore, activational effects of testosterone (T) on cognitive abilities cannot be assumed on the basis of evidence of organizational effects of T on cognitive abilities.

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Activational effects of T on cognitive behavior are typically investigated in adult males by measuring the covariation between transient steroid levels and cognitive abilities or, less frequently, by measuring the effects of T administration. Correlational research has suggested that increasing T levels enhance visuospatial ability in young healthy European men (Christiansen and Knussman, 1987) and in young healthy Bushmen (Christiansen, 1993). These data are consistent with the effects of exogenous T on older men’s performance of a block design task (Janowsky et al., 1994) and with cognitive changes following sex reassignment and associated treatment with anti-androgen and estrogen to men (Van Goozen et al., 1994, 1995). However, other correlational data suggest that visuospatial ability in men is unrelated to levels of T (Kampen and Sherwin, 1996) or that increasing levels of T in men may actually impair visuospatial ability (e.g., Gouchie and Kimura, 1991; Shute et al., 1983). The goal of the present investigation was to evaluate further the relationship between T and visuospatial ability in men by studying sex-typed cognitive behavior in two groups of men prior to and following T treatment. One group consisted of hypogonadal men scheduled to receive hormone replacement therapy. The second group consisted of eugonadal men administered testosterone enanthate (TE) in a contraceptive trial where T levels are increased several fold in order to abolish spermatogenesis (WHO, 1996). To our knowledge, no previous research has examined the effects of exogenous T administration on cognitive function in young, eugonadal men. In addition to considering whether increased T levels in men are associated with systematic changes in cognitive abilities, we also considered whether individual differences in endogenous T are associated with individual differences in cognitive abilities. Specifically, we hypothesized that evidence of a positive linear relationship between T and visuospatial ability in this research would include a positive correlation between endogenous T levels and visuospatial ability and a finding that T administration is associated with enhanced visuospatial abilities. A curvilinear (i.e., inverted U-shaped function) hypothesis of T-visuospatial ability (Nyborg, 1983; Petersen, 1976) is supported, in part, by a negative association between T and visuospatial ability in eugonadal men (Gouchie and Kimura, 1991; Kimura and Hampson, 1994; Moffat and Hampson, 1996). The curvilinear hypothesis suggests that blood levels of T in the contraceptive group would exceed a hypothetical level of T that optimizes

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men’s performance on tests of visuospatial ability. Therefore, we hypothesized that evidence of a curvilinear relationship between T and visuospatial ability in this research would include a negative correlation between endogenous T and visuospatial ability and a finding that T administration is associated with decreased visuospatial ability. The design of the study was dependent on recruitment of subjects from ongoing clinical investigations of the pharmacological effects of androgens. No placebo was included in the design of the study of the contraceptive efficacy of TE (WHO, 1996). Most of the hypogonadal men had prior treatment with T (Salehian et al., 1995; Wang et al., 1996), with symptoms of hypogonadism occurring usually 3 to 4 weeks after treatment withdrawal. For ethical reasons, these men were not assigned to a placebo group as symptoms of hypogonadism would necessitate T administration. Therefore, we also tested, as a comparison group for practice effects, a third group consisting of eugonadal men who were not administered any hormone treatment during the study.

METHOD Subjects Subjects included 33 hypogonadal men and 10 eugonadal men recruited from clinical studies of the pharmacological effects of T administration. A comparison group of 19 eugonadal men was recruited from the community of Westwood, California (see Table 1). Men in the three groups were similar in ethnicity, marital status, and a vocabulary test score (Ekstrom et al., 1976), a global measure of crystallized intelligence (i.e., acquired knowledge). The majority of men reported writing, drawing, and throwing exclusively with their right hands. Three men in the comparison group, 1 man in the contraceptive group, and 3 men in the hypogonadal group reported using their left hands for these tasks. Hypogonadal men included 12 hypogonadotropic hypogonadal men (i.e., hypogonadal as a result of pituitary tumor or disease or Kallman’s syndrome), 16 hypergonadotropic hypogonadal men (i.e., hypogonadal as a result of Klinefelter’s syndrome, testicular failure, or orchidectomy), and 3 men who did not meet the criteria for either classification.

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TABLE 1 Characteristics of Men in the Comparison Group (n 5 19), Contraceptive Group (n 5 10), and Hypogonadal Group (n 5 33) Group Variablea Ethnicity White African American Hispanic Asian Native American Marital Status Married Divorced/separated Cohabiting Single Age in years (range) Vocabulary score

Comparison

Contraceptive

Hypogonadal

17 0 0 1 1

8 0 0 1 1

21 3 3 2 1

5 1 1 12 32.7 (19–48) 34.0 (15.7)

5 0 5 0 33.4 (21–44) 38.5 (11.1)

16 8 1 6 41.1 (20–59)b 34.2 (15.2)

a

Not all subjects provided complete questionnaire data. Men in the hypogonadal group were significantly older than men in the other two groups [F(2, 59) 5 6.0, P , 0.01]. However, using age as a covariate does not influence the direction or significance of the results we report. b

Testosterone Measures

Levels of T in hypogonadal men treated with sublingual T cyclodextrin (SLT) or TE and men in the contraceptive group treated with TE were measured according to the schedules of the clinical studies (Salehian et al., 1995; Wang et al., 1996; WHO, 1996). For men in the contraceptive and hypogonadal groups, multiple blood samples were drawn on the first day scheduled for behavioral testing. Multiple blood samples were also drawn from hypogonadal men on the second test session and from eugonadal men within a week of the second test session. For men in the comparison group, one blood sample was drawn from all subjects at a single session when no behavioral testing occurred. For each group, serum T was measured by sensitive and specific RIA using reagents obtained from ICN Pharmaceuticals (Costa Mesa, CA) (see Table 2). Briefly, hypogonadal men were treated with 200 mg TE every 20 days or either 2.5 or 5.0 mg SLT three times daily. Other data from these same subjects showed that all regimens resulted in improved mood and sexual functioning (Alexander et al., 1997; Salehian et al., 1995; Wang et al., 1996). For the contraceptive studies, eugonadal young men were treated with 200 mg TE every week.

Cognitive Behavior Measures

Table 3 summarizes the sex-typed cognitive behavior measures. A questionnaire battery contained paper and pencil measures of three classes of cognitive abilities: (1) tests of visuospatial ability that typically favor men, (2) tests of verbal-associational fluency (referred to in this research as verbal ability) that typically favor women, and (3) tests of perceptual speed that typically favor women. Measures were selected for use because they are reliable and show consistent sex differences (Ekstrom et al., 1976; Hyde and Linn, 1988; Linn and Petersen, 1985; Voyer, Voyer, and Bryden, 1995), albeit of variable size. Typically, effect sizes for sex differences in visuospatial ability, verbal-associational flu-

TABLE 2 Average Serum Testosterone Levels (ng/dL) for Men in Each of the Three Groups Session

Comparison group Contraceptive group Hypogonadal group

Prior to T treatmenta

After T treatment

512.5 (49.9) 440.2 (33.9) 53.7 (10.8)

— 1251.1 (141.3) 220.1 (17.3)

Note. Data are given as means (SEM). a Normal male range: 288 – 892 ng/dL.

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TABLE 3 A Description of Cognitive Measures Administered to the Three Groups of Men at Each of the Two Test Sessions

Task requirement/item Visuospatial ability 1. Mental Rotations (Shepard and Metzler, 1971) 2. Surface Development (Ekstrom et al., 1976) 3. Paper Folding (Ekstrom et al., 1976) 4. Hidden Patterns (Ekstrom et al., 1976) Verbal ability 1. Controlled Associates (Ekstrom et al., 1976) 2. Making Sentences (Ekstrom et al., 1976) 3. Word Fluency (Thurstone, 1962)

Identify two of four figures as being rotated examples of item Correctly match five edges of an unfolded version of a figure with the edges of a folded version of the same figure Correctly match a folded paper that has a hole punched through its folds with the correct unfolded representation Indicate whether or not an item contains an embedded target figure Write down words that have the same meaning as a given word Create a sentence of a specified word length, using words beginning with specified letters Write down words beginning with a specified letter

Number of items

Time constraint

10

5 min

6

6 min

10

3 min

Number of correct matches

200

2 min

Number correct

4

3 min

Number of words

10

2

1 2

min

Number of words

10

2 min

Number of correctly circled words Number of pairs correct

Paired associate learning (Wechsler, 1945)

Recall the second word of a list of word pairs

10

—

Vocabulary (Ekstrom et al., 1976)

Circle the correct meaning of words

60

4 min

Subjects were scheduled for testing on two occasions, Session 1 and Session 2. For hypogonadal

Number of completed sentences

2 min

Circle 5 words in a list of 41 words that contain the letter ‘‘A’’ Indicate by circling whether a number pair is identical or different

Procedures

Number of correct matches Number of correct matches

1

Perceptual speed 1. Finding A’s (Ekstrom et al., 1976) 2. Number Comparison (Ekstrom et al., 1976)

ency (i.e., verbal ability), and perceptual speed are large, moderate, and moderate, respectively (Collaer and Hines, 1995). Verbal measures also included a measure of associate learning, the Verbal Paired-Associate Task (Immediate Recall) subtest of the Wechsler Memory Scale–Revised (Stone, Girdner, and Albrecht, 1946; Wechsler, 1945), as prior studies suggest that sex hormone administration may facilitate that form of memory in women (e.g., Kampen and Sherwin, 1994; Phillips and Sherwin, 1992). Two forms of the test battery (Form A and Form B) were constructed to allow repeated assessment of all subjects. Form A and Form B were presented in test booklets, along with an audiotape of task instructions in order to facilitate test administration.

Scoring method

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1

1 2

min

Number of correct recalled words Number correct

men and eugonadal men treated with T, Session 1 corresponded to a time immediately prior to T administration and Session 2 corresponded to a time following T administration. An intertrial interval of a minimum of 6 weeks was selected because activational effects of T on other aspects of behavior (i.e., mood and sexual behavior) are well established at that point in time (e.g., Bancroft and Wu, 1983; Wang et al., 1996). The majority of men (over 90% in each group) were tested between 10:00 AM and 2:00 PM. For each test session, men were taken to a quiet room and presented with the cognitive battery. The order of the form of the cognitive battery (Form A and Form B) was counterbalanced across the test sessions. Test instructions were presented to men on an audiocassette. An experimenter was present during the cognitive battery to clarify any instructions and to ensure that men conformed to the time constraints of the testing procedures.

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Data Analyses Scores on tests of visuospatial ability, on tests of verbal ability, and on tests of perceptual speed were each analyzed using MANOVA with Group (Comparison, Eugonadal, Hypogonadal) as the grouping factor and Time (Session 1 vs Session 2) as a repeated-measures factor. The results of the analyses of individual test scores were also compared to the analyses of cognitive ability based on conversion of the test scores to z scores and averaged across tests of each cognitive ability. This method was used by previous researchers (Hampson, 1990; Gouchie and Kimura, 1991), who argued that individual test results may be too variable to detect hormone– behavior relations. If a MANOVA was significant, then univariate tests were considered and post hoc comparisons (Newman–Keuls) used where appropriate. Pearson product moment correlations between blood levels of T and cognitive abilities were calculated as a measure of within-subject hormone– behavior relations. Unless otherwise specified, two-tailed tests were used. Estimates of effect size for changes in cognitive ability using the statistic d, where 0.2, 0.5, and 0.8 are considered small, moderate, and large, respectively (Cohen, 1988), were also calculated as a measure of the magnitude of cognitive change across the two sessions.

RESULTS Preliminary Analyses Testing the Assumption of Relations Among SexTyped Cognitive Measures To investigate whether the cognitive tasks used in this research did indeed represent two dimensions of abilities (described as male-typical vs female-typical), men’s scores on the nine sex-typed cognitive measures were factor analyzed using the method of Principal Components Analysis followed by varimax rotation. These analyses showed that two factors with eigenvalues of 4.33 and 1.26, respectively, accounted for 62.1% of the variance in test performance. Varimax-rotated factor loadings (Table 4) generally support the categorization of the tasks used in the present study into two different abilities. Testing the Assumption of Similar Cognitive Abilities Across Subgroups of Hypogonadal Men Before comparing the group of hypogonadal men to the other groups of men on cognitive measures,

TABLE 4 Varimax-Rotated Factor Loadings for the Nine Measures of Sex-Typed Cognitive Abilities

Masculine cognitive abilities Mental Rotations Surface Development Paper Folding Hidden Patterns Feminine cognitive abilities Controlled Associates Making Sentences Word Fluency Finding A’s Number comparisons

Female-typical

Male-typical

0.17 0.23 0.25 0.25

0.83 0.83 0.81 0.49

0.62 0.71 0.88 0.69 0.82

0.24 0.26 0.15 0.23 0.27

we considered whether the different treatment regimens or the different classifications of hypogonadism influenced cognitive performance. A comparison of cognitive abilities in hypogonadal men administered 2.5 mg SLT (n 5 12) or 5.0 mg SLT (n 5 9) or TE (200 mg/every 20 days) (n 5 12) found no differential treatment regimen effects on test performance. These results are consistent with other data showing that the different treatment regimens produce similar effects on sexual behavior and on mood (Alexander et al., 1997; Salehian et al., 1996; Wang et al., 1996). We also found no association between test performances at Session 1 (prior to T treatment) and the length of the washout period. In addition, the length of T treatment (i.e., the intertrial interval) was also not associated with changes in men’s cognitive abilities.3 We found no differences in the cognitive behavior of hypogonadotropic hypogonadal men (n 5 12) and hypergonadotropic hypogonadal men (n 5 18).3 Men with Klinefelter’s syndrome may show deficits in verbal ability (e.g., Mandoki, Sumner, Hoffman, and Riconda, 1991; Money, 1994). Therefore, we also compared the verbal ability scores of hypogonadal men with and without a diagnosis of Klinefelter’s syndrome using one-tailed t tests. That analysis indicated that hypogonadal men with Klinefelter’s syndrome (n 5 7) scored lower than did other hypogonadal men on the Controlled Associates task, t(30) 5 1.90, P , 0.05.

3

These data are available from the authors upon request.

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Testing the Hypotheses of Positive or Negative Relations between Testosterone and Visuospatial Ability

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TABLE 5 A Summary of Men’s Performance on the Sex-Typed Cognitive Tasks across the Two Test Times

Measures of Testosterone and Cognitive Abilities For the two groups (hypogonadal and contraceptive) who provided measures of T and cognitive abilities at Session 1 (prior to T treatment), we calculated correlations between the measures of baseline T levels and men’s scores on the cognitive tests. No association between T and visuospatial ability or perceptual speed was supported by these analyses. A positive relationship between T levels and the composite verbal ability score at Session 1 was found for men in the contraceptive group [r(10) 5 .68, P , 0.05]. Analyses of Group Differences: Visuospatial Ability Table 5 shows the average scores at Session 1 (prior to T treatment) and Session 2 (after T treatment) and the associated effect sizes for the three groups of men on tests of visuospatial ability. For all groups, test performance improved across sessions, Multivariate F(4, 56) 5 6.57, P , 0.01. Univariate analyses showed improved test scores at Session 2 relative to Session 1 on Hidden Patterns, F(1, 59) 5 8.7, P , 0.01, and Surface Development, F(1, 59) 5 11.2, P , 0.01, consistent with practice effects on test performances. Analyses of z scores were consistent with the analyses of raw scores, showing no interaction effects, no group differences, and no time effects on visuospatial ability. Analyses of Group Differences: Verbal Ability Table 5 shows the average scores at Session 1 and Session 2 and the associated effect sizes for the three groups of men on tests of verbal ability. For all groups, performance on verbal tests improved across test sessions, Multivariate F(3, 57) 5 2.82, P , 0.05. Univariate analysis showed improved test scores at Session 2 relative to Session 1 on Making Sentences, F(1, 59) 5 6.12, P , 0.05, consistent with practice effects on test performance. Overall, the three groups differed on measures of verbal ability, Multivariate F(6, 116) 5 3.48, P , 0.01. Univariate analyses for group differences were significant for Making Sentences, F(2, 59) 5 7.99, P , 0.05, and for Controlled Associations, F(2, 59) 5 4.11, P , 0.05. Post hoc comparisons of men’s performances on the two tests of verbal ability showed that hypogo-

Visuospatial ability Mental rotations Comparison group Contraceptive group Hypogonadal group Surface developmenta Comparison group Contraceptive group Hypogonadal group Paper folding Comparison group Contraceptive group Hypogonadal group Hidden patternsa Comparison group Contraceptive group Hypogonadal group Verbal abilityb Controlled associates Comparison group Contraceptive group Hypogonadal groupc Making sentences Comparison group Contraceptive group Hypogonadal groupd Word fluency Comparison group Contraceptive group Hypogonadal group Perceptual speed Finding Asa Comparison group Contraceptive group Hypogonadal group Number comparisons Comparison group Contraceptive group Hypogonadal group

Session 1

Session 2

d (effect size)

14.16 (0.73) 14.80 (0.90) 12.49 (0.50)

14.53 (0.92) 16.30 (0.88) 12.97 (0.71)

0.11 0.65 0.15

15.53 (1.99) 19.20 (1.78) 15.77 (1.38)

18.47 (1.92) 21.50 (2.09) 18.33 (1.27)

0.35 0.44 0.33

5.32 (0.54) 6.90 (0.59) 5.14 (0.42)

5.79 (0.62) 6.70 (0.52) 5.91 (0.39)

0.00 0.14 0.33

69.79 (4.11) 75.60 (4.52) 72.49 (6.74)

84.63 (4.91) 81.70 (7.14) 77.70 (4.83)

0.79 0.38 0.15

16.89 (1.41) 15.70 (1.73) 11.97 (0.97)

15.53 (1.11) 18.50 (2.14) 12.48 (1.28)

0.26 0.51 0.09

6.47 (0.47) 5.30 (0.60) 4.57 (0.97)

7.00 (0.45) 5.80 (0.84) 5.76 (0.47)

0.30 0.26 0.55

23.05 (1.44) 21.70 (1.37) 20.91 (1.53)

24.42 (1.60) 21.20 (1.97) 25.15 (2.00)

0.21 0.12 0.42

31.68 (2.30) 28.40 (2.16) 29.00 (1.48)

34.32 (3.45) 31.80 (3.50) 35.42 (2.43)

0.21 0.43 0.60

26.26 (1.61) 24.50 (2.40) 24.00 (0.94)

27.21 (1.42) 24.00 (1.98) 26.33 (1.41)

0.15 0.07 0.36

Note. Data are given as means (SEM). a All groups show significant improvement in test scores across the two trials. b Analysis of z scores show hypogonadal men score significantly lower than other groups at Session 1. c Hypogonadal men score significantly lower than men in other two groups. d Hypogonadal men score significantly lower than men in the comparison group.

nadal men scored lower than other men on the Controlled Associations test (P , 0.05) and lower than men in the comparison group on the Making Sen-

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tences test (P , 0.05). As our preliminary analyses showed that men with Klinefelter’s syndrome scored lower on the Controlled Associations test than did other hypogonadal men, we reanalyzed for group differences in verbal ability excluding those men with Klinefelter’s syndrome. That analysis comparing hypogonadal men without Klinefelter’s syndrome (n 5 26) to other groups of eugonadal men showed a Group by Time interaction effect on the test of Word Fluency, F(2, 52) 5 3.18, P , 0.05. Whereas Word Fluency scores were similar across test sessions in both groups of eugonadal men, they improved across test sessions in the group of hypogonadal men (21.7 (9.3) vs 26.2 (12.3): t (25) 5 3.63, P , 0.05). The results suggest poorer verbal ability in hypogonadal men than in eugonadal men. The interaction effect suggests that T treatment may have improved performance of hypogonadal men without Klinefelter’s syndrome on the Word Fluency test. Analyses of z scores for eugonadal men and hypogonadal men showed a Group by Time interaction effect on men’s scores, F(2, 59) 5 3.21, P , 0.05. Subsequent analyses of simple main effects showed group differences at Session 1 (prior to T treatment), F(2, 59) 5 4.57, P , 0.05, but no group differences at Session 2 (after T treatment). Post hoc comparisons showed that hypogonadal men at Session 1 scored lower than did men in the comparison group at Session 1 (P , 0.05). Excluding men with Klinefelter’s syndrome from this analysis did not change the overall results, suggesting that T treatment for hypogonadal men may have enhanced verbal ability. Analyses of Group Differences: Perceptual Speed Table 5 shows the average scores at Session 1 (prior to T treatment) and Session 2 (after T treatment) and the associated effect sizes for the three groups of men on perceptual speed tasks. For all groups, test performance improved across sessions, Multivariate, F(2, 58) 5 5.74, P , 0.01. Univariate analyses showed improved test scores at Session 2 relative to Session 1 on Finding A’s, F(1, 59) 5 11.55, P , 0.01, consistent with the practice effects on test performance. Analyses of z scores for each group were consistent with the analyses of raw scores and showed no interaction effects, no group differences, and no time effects on perceptual speed. Paired Associate Memory Task Associate learning scores were analyzed by MANOVA with Group (hypogonadal, contraceptive,

or normal) as a grouping factor and Trial (first, second, third) and Time (Session 1 vs Session 2) as the repeated factors. There were no effects of Group or Time on test performance. All groups showed improved recall of the associate words across the three trials, F(2, 118) 5 217.1, P , 0.01. Post hoc comparisons showed that this improved performance for men in all groups occurred from Trial 1 to Trial 2 (P , 0.01) and from Trial 2 to Trial 3 (P , 0.01).

DISCUSSION Sex-typed cognitive abilities were measured in hypogonadal men and in eugonadal men treated with exogenous testosterone. In general, group differences in T levels were unrelated to sex-typed cognitive abilities in men. An exception was the unexpected finding that hypogonadal men had relative deficits in verbal fluency prior to but not following T administration. Consistent with some previous results (Gordon et al., 1986; Kampen and Sherwin, 1996; McKeever et al., 1987), endogenous T levels were unrelated to visuospatial ability in eugonadal men. However, a positive (or negative) linear relationship between T levels and visuospatial ability in men has been reported in some research. These discrepant findings appear unrelated to the age of men in the samples or to the choice of behavioral measures. One possibility is that correlations between T and visuospatial ability are influenced by other variables, such as handedness or time of day (Moffat and Hampson, 1996). However, the evidence that T–visuospatial relations are apparent in right-handed men but not in left-handed men is equivocal (McKeever et al., 1987) and would not explain our negative results for a predominantly right-handed sample. Visuospatial ability may also decrease with the known diurnal decrease in T levels (Moffat and Hampson, 1996). This research suggests, but did not demonstrate, that correlations between endogenous T and visuospatial ability may be largest when both variables are measured at the same time of day. Such a relationship between T and visuospatial ability may explain why we did not find significant correlations between measures of endogenous T that were derived from serial blood sampling and measures of visuospatial ability. However, our findings that visuospatial ability was not associated with large group differences in circulating T levels, such as those associated with hypogonadism or with the

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administration of exogenous T, suggest that late morning decreases in visuospatial ability may be related to factors other than decreasing T levels. A second possible explanation is suggested by the variability in T levels across different samples of men. Average T levels for eugonadal men in our study were around the middle of the normal male range of values. In contrast, positive associations between T and visuospatial ability have been reported in samples of men whose average T levels are below this amount (e.g., Christiansen and Knussman, 1986; Janowsky et al., 1994). This observation suggests that inconsistent reports of T–visuospatial ability in men may reflect a threshold for the enhancing effects of T on visuospatial ability. However, this hypothesis would not explain findings of a negative relationship between T and visuospatial ability. Finally, one proposal is that T levels and visuospatial ability may correlate in adulthood because both are equally determined by perinatal hormone levels (Christiansen and Knussman, 1987). If so, variables that alter endogenous levels of T (e.g., stress, disease, or hormone administration) or variables that alter adult visuospatial abilities (e.g., training or experience) may weaken T–visuospatial ability associations. This hypothesis suggests that associations between T and cognitive behavior may be quite variable, consistent with the research results. There were too few cases of idiopathic hypogonadotropic hypogonadal men to replicate findings of visuospatial deficits in these individuals (Hier and Crowley, 1982; but see Buchsbaum and Henkin, 1980; Cappa et al., 1988) or abnormal spatial attention in a subgroup of men with Kallman’s syndrome (Kertzman et al., 1990). Therefore, our data cannot address organizational effects of T on visuospatial ability. However, we, like other researchers (e.g., Hier and Crowley, 1982; O’Carroll, 1984), found that T administration did not appear to enhance visuospatial ability in hypogonadal men. These findings also appear to contradict a causal relationship between changes in T levels and visuospatial ability in men, although the possibility that hypogonadal men and eugonadal men differ in their responsiveness to T cannot be ruled out. Previous research has documented that verbal ability is impaired in men with Klinefelter’s syndrome (for review, see Money, 1994; Liester, 1989). We found low verbal fluency in these individuals and in men with forms of hypogonadism not usually associated with early perinatal abnormalities. Although this finding may be spurious, scores on the composite measure of

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verbal fluency improved in hypogonadal men following T treatment, suggesting that transient levels of T may influence verbal fluency. Brain imaging studies indicate that verbal fluency is associated with activation of the frontal and temporal lobes (e.g., Parks et al., 1988). An effect of T on cortical areas involved in verbal fluency is consistent with the recent identification of androgen receptors in the human temporal cortex (Puy et al., 1995; Sarrieau et al., 1990). Interestingly, our data suggest that improvement in verbal fluency following T administration was less apparent in men with Klinefelter’s syndrome. Klinefelter’s syndrome is associated with impaired auditory temporal processing (e.g., difficulties remembering or reproducing the serial order of auditory stimuli) and associated learning disabilities, such as dyslexia (Tallal, 1991), which may reflect abnormal degrees of hemisphere specialization of function (for review, see Mandoki et al., 1991). It is possible that these characteristics of Klinefelter’s syndrome may limit the effects of T replacement on verbal ability. As only levels of T were considered in this research, our data do not preclude a relationship between other sex steroids (e.g., DHT, estradiol) and cognitive abilities in men. For example, posttraining intrahippocampal estradiol injections enhance spatial memory in male rats (Packard, Kohlmaier, and Alexander, 1996), and estradiol levels in men are positively associated with reproduction of designs presented visually (Kampen and Sherwin, 1996). Exogenous T may also increase T-derived estradiol in the brain (Goy and McEwen, 1980; MacLusky and Naftolin, 1981) or change androgen– estrogen ratios (e.g., Janowsky et al., 1994). Therefore, men administered T may show increases in spatial memory or visual memory, variables not assessed in this research. To our knowledge, this research is the first examination of performance on a battery of tasks measuring sex-typed cognitive abilities in healthy men and hypogonadal men administered T. A nontreated comparison group, multiple measures of sex-typed cognitive abilities, and measurement of T levels were features of this research that enhance the internal validity of our results. Current models of hormone effects on cognitive behavior suggesting that changing levels of T may influence visuospatial ability were largely unsupported by our results. Examination of potential factors underlying cognitive abilities (e.g., attention or motivation) and their relationship to T levels may be of use in this relatively recent area of hormone– behavior research.

Androgens and Behavior in Men

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