Clinical studies and testosterone substitution

Evidence of a connection between sex hormones and spatial abilities came first from studies of phenotypic women with Turner's syndrome (X0 karyotype, no gonadal hormones) or testicular-feminization syndrome (XY karyotype; here the body tissues are unable to respond to normal levels of testosterone; see Chapter 2 in this volume). These patients have female external genitalia, they are raised as girls, and develop a feminine gender identity. With regard to cognitive functioning such individuals' verbal skills surpass their spatial abilities, the typical pattern of cognitive abilities in women. Moreover, on average they are also below healthy women in terms of their nonverbal performance but not of their verbal abilities (Collaer and Hines 1995; Dellantonio et al. 1984; Garron and van der Stoep 1969; Imperato-McGinley et al. 1991; Masica et al. 1969; Rovet and Netley 1979; 1982; Serra et al. 1978; Silbert et al. 1977). The strikingly poor nonverbal abilities are mainly explained by their low sex hormone levels.

Feminized prepubertal boys suffering from a kwashiorkor-induced endocrine dysfunction have been found to exhibit a more feminine cognitive style than a male control group. Dawson (1972) attributed this finding to a two-way relationship between sex hormones and socialization - because of their physical effeminateness, the boys tended to be raised into more feminine roles, including feminine cognitive behaviour.

Studies on men with idiopathic or aquired hypogonadotrophic hypogonadism appear to confirm the importance of testosterone for spatial abilities (Alexander etal. 1998; Buchsbaum and Henkin 1980; Hier and Crowley 1982; O'Connor etal. 2001). A group of men with idiopathic hypogonadotrophic hypogonadism, and presumably a lifelong testosterone deficiency, performed significantly poorer than a group of men with late onset of pathologically reduced testosterone levels or normal controls on a number of spatial tests, but not on verbal tests. As short-term androgen therapy did not restore spatial function, these findings suggest that pre-and perinatal hormonal environments have lifelong effects on intellectual function in humans.

Although controversial, data from children with congenital adrenal hyperplasia (CAH) more or less support this hypothesis. Beginning in the third month of gestation, these patients are exposed to high levels of fetal androgens as a result of an enzymatic defect of the adrenal cortex. As a result, androgen production is greatly and continuously increased until treatment is initiated sometime in early postnatal life (Lauritzen 1987). While Lewis et al. (1968), Baker and Ehrhardt (1974), and McGuire et al. (1975) could not ascertain any effect of the prenatal exposure to higher-than-normal levels of androgens in CAH-children, Perlman (1973), Resnick etal. (1986), and Berenbaum etal. (1995) found that CAH-girls were superior to their siblings or normal controls in spatial tasks. However, in boys

Table 4.5 Androgen treatment and cognitive functioning in men and women

Study

Sample

Cognitive task

Simonson etal. 1941

castrates, eunuchoids

critical flicker frequency ▲

Simonson etal. 1944

older men

critical flicker frequency ▲

Duker 1957

men in a state of mental

Arithmetical problem solving ▲

exhaustion

Klaiber et al. 1971

college students

verbal and nonverbal repetitive tasks ▲

Stenn et al. 1972

poorly androgenized male

verbal repetitive tasks ▲

adolescents

Sherwin 1988

oophorectomized women

short-term memory ▲

abstract reasoning ▲ perceptual speed ▲

van Goozen et al. 1994b

female-to-male transsexuals

visual-spatial skills ▲

verbal fluency ▼

Janowsky etal. 1994

older men

visual-spatial ability ▲

Alexander et al. 1998

hypogonadal men

word fluency ▲

Slabbekoorn et al. 1999

female-to-male transsexuals

visual-spatial skills ▲

Janowsky et al. 2000

elderly men

verbal and spatial memory ▲

Cherrier et al. 2001

elderly men

verbal and spatial memory ▲

▲ significant increase ▼ significant decrease

▲ significant increase ▼ significant decrease with CAH the prenatal increase of androgens did not significantly influence their visual-spatial abilities (Hampson et al. 1998; Resnick et al. 1986; Trautmann et al. 1995). This lack of androgen influence on cognition in boys is consistent with two studies measuring fetal or neonatal androgens. Neither Jacklin et al. (1988), who measured testosterone in umbilical cord blood obtained at birth, nor Finegan et al. (1992), who measured testosterone in second trimester amniotic fluid obtained via amniocentesis, detected a significant relationship to cognitive skills of boys at age six or age four.

Direct manipulation of steroid hormones supports the conclusion that androgens play a role in cognition. Studies on the effects of hormone treatment on cognitive functioning in adult males date back to 1941 and 1944 when Simonson and his co-workers published their experiments using methyl testosterone (Table 4.5). Administration of testosterone to castrated human males, eunuchoids, and older men improved their ability to perceive flicker (critical flicker frequency), a measure of attention and alertness, as long as the androgen treatment lasted. Duker (1957) using either testosterone, estradiol, or a combination of testosterone and estradiol produced a significant rise in concentration and speed solving simple arithmetical problems in a group of men with severe mental exhaustion. Similar results were reported by Stenn et al. (1972) who treated three poorly androgenized male adolescents. Intramuscular injections of testosterone enhanced their concentration and performance in a verbal fluency task. However, testosterone replacement therapy in hypogonadal men does not necessarily enhance cognitive speed and memory functions. While Alexander etal. (1998) obtained significant improvements in their subjects with either hyper- or hypogonadotropic hypogonadism, Sih et al. (1997) did not find such positive effect on word fluency or memory in older hypogonadal men.

A double-blind, cross-over, placebo-controlled study on substitution of sex steroids in oophorectomized women also demonstrated a causal link between testosterone and cognition (Sherwin 1988). Patients treated after surgery with either testosterone enanthate or a combination of testosterone enanthate, estra-diol dienanthate, and estradiol benzoate showed stability both in sex hormone concentrations and in aspects of cognitive performance which are typically the most prominent deficits in menopausal women, short- and long-term memory and perceptual speed. Similar improvements of verbal and spatial memory were found in healthy elderly males under testosterone substitution (Cherrier etal. 2001; Janowsky etal. 2000). When normal, aging men were given testosterone to enhance sexual functioning, as a side-effect they showed improved performance on a visual-spatial task, relative to a placebo group (Janowsky et al. 1994). Zitzmann et al. (2001) investigated whether cerebral structures previously described to be involved in mental rotation (Gur et al. 2000) are influenced by testosterone substitution in hypogonadal males who reached eugonadal levels during the treatment. Using a positron emission tomography (PET) during a mental rotation task before and after testosterone substitution they could demonstrate in four out of six males between ages 20 to 63 years distinct changes in cerebral glucose metabolism in specific areas, however, with marked interindividual variability. Two men who did not improve their spatial ability score showed no change in cerebral glucose metabolism.

Direct effects of sex steroids on spatial performance could not be ascertained in 35 boys with delayed puberty (Liben etal. 2002). In a placebo-controlled study the adolescent boys (mean age 13.7 years) did not show an improvement of visual-spatial abilities under testosterone supplementation used to approximate the normal hormone environments of early, middle and late puberty, as the spatial performance of the adolescents did not vary with levels of actively circulating sex steroids.

Androgen treatment was also given to female-to- male transsexuals who received high doses of testosterone esters intramuscularly in preparation for sex therapy. Their spatial skills improved dramatically and their verbal fluency skills declined considerably within three months (van Goozen et al. 1994b). A more recent study (Slabbekoorn et al. 1999) involving 16 female-to- male and 14 male-to-female transsexuals before, during and after cross-sex hormone therapy confirmed the earlier findings. Testosterone treatment showed an enhancing, slowly reversible effect on spatial performance in adult female-to male transsexuals, but no deteriorating effect on their verbal fluency. In contrast, anti-androgen treatment of male-to-female transsexuals in combination with estrogen therapy had no declining effect on spatial ability, nor an enhancing one on verbal fluency. For ethical reasons, today manipulation of gonadal hormones is restricted to patients in clinical studies. Thus, it is over 25 years ago that Klaiber etal. (1971) tested effects of infused testosterone on mental performance in healthy male college students. After a 4-hour infusion of testosterone or a saline infusion in the control group, performance of the control group on a repetitive mental task showed a significantly greater decline than the testosterone-infused group. The result indicates that testosterone acted to prevent the typical decline from morning to afternoon in the performance of simple repetitive verbal or number tasks.

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