Library of Excerpts

Testosterone, Estrogen, Related Hormones and Heterochronic Patterns: Part 3

[from abstract] "Clinically apparent prostate cancer occurs more commonly among Caucasians living in Western countries than in Chinese in the Far East. Prior studies demonstrated diminished facial and body hair and lower levels of plasma 3 alpha-androstanediol glucuronide and androsterone glucuronide in Chinese than in Caucasian men. Based upon these findings, investigators postulated that Chinese men could have diminished 5 alpha-reductase activity with a resultant decrease in prostate tissue dihydrotestosterone levels and clinically apparent prostate cancer. An alternative hypothesis suggests that decreased 3 alpha-androstanediol glucuronide and androsterone glucuronide levels might reflect reduced production of androgenic ketosteroid precursors as a result of genetic or environmental factors. The present study examined 5 alpha-reductase activity, androgenic ketosteroid precursors, and the influence of genetic and environmental/dietary factors in groups of Chinese and Caucasian men. We found no significant differences in the ratios of 5 beta-:5 alpha-reduced urinary steroids (a marker of 5 alpha-reductase activity) between Chinese subjects living in Beijing, China, and Caucasians living in Pennsylvania. To enhance the sensitivity of detection, we used an isotopic kinetic method to directly measure 5 alpha-reductase activity and found no difference in testosterone to dihydrotestosterone conversion ratios between groups. Then, addressing the alternative hypothesis, we found that the Caucasian subjects excreted significantly higher levels of individual and total androgenic ketosteroids than did their Chinese counterparts. To distinguish genetic from environmental/dietary factors as a cause of these differences, we compared Chinese men living in Pennsylvania and a similar group living in Beijing, China. We detected a reduction in testosterone production rates and total plasma testosterone and sex hormone-binding levels, but not in testosterone MCRs in Beijing Chinese as a opposed to those living in Pennsylvania. Comparing Pennsylvania Chinese with their Caucasian counterparts, we detected no significant differences in total testosterone, free and weakly bound testosterone, sex hormone-binding globulin levels, and testosterone production rates. Taken together, these studies suggest that environmental/dietary, but not genetic, factors influence androgen production and explain the differences between Caucasian and Chinese men." (Santner SJ, Albertson B, Zhang GY, Zhang GH, Santulli M, Wang C, Demers LM, Shackleton C, Santen RJ (1998) Comparative rates of androgen production and metabolism in Caucasian and Chinese subjects. J Clin Endocrinol Metab 83(6):2104-2109)

"OBJECTIVE: To test predictions that basal salivary testosterone and cortisol are related to antisocial and internalizing behaviors, respectively, and that cortisol moderates the testosterone-aggression relationship. METHOD: Saliva samples were assayed to determine testosterone and cortisol levels in 40 clinic-referred disruptive children (aged 7 through 14 years) who were rated on aggression, inattention/overactivity, and internalizing behavior by parents, teachers, and clinic staff members. RESULTS: Results indicated significant positive relationships between testosterone and staff-rated aggression and between cortisol and parent-rated internalizing behavior. A significant negative relationship was found between cortisol and staff-rated inattention/overactivity. No interactions between testosterone and cortisol were found. These results were maintained regardless of age, racial background, height, weight, diagnosis, or medication status. CONCLUSIONS: Results suggest moderate relationships between testosterone and observed aggression, and between cortisol and emotional behaviors, in a group of disruptive children. Cortisol did not moderate the testosterone-aggression relationship in this population." (Scerbo AS, Kolko DJ (1994) Salivary testosterone and cortisol in disruptive children: relationship to aggressive, hyperactive, and internalizing behaviors. J Am Acad Child Adolesc Psychiatry 33(8):1174-1184)

Higher T males, at this point in our evolution, evidenced increasingly asymmetrical brain lateralization. Geschwind and Galaburda (1987) hypothesize that testosterone is the primary agent responsible for variations in cerebral lateralization. The timing of the relative levels of T is vitally important to understanding variations in language facility. The absence of light has an effect on the pineal gland which results in a diminution of T production (Geschwind & Galaburda, 1987). Most people in temperate zones have lowered T in winter and raised T in summer. It is hypothesized that this pattern was established in equatorial regions according to the diurnal cycle (Geschwind & Galaburda, 1987). Changes in migration patterns away from equatorial regions, perhaps to southern Africa or into the Eurasian continent, could have placed humans at a latitude where symmetrical brains became more lateralized as a result of the changes in light and its influence on the pineal gland which regulates testosterone. Seasonal fluctuations in light hypothetically also caused asymmetrical cerebral lateralization at conception and during gestation (zygote & uterine selection) if male T is high at the point of sperm production or if female T is low during the phase of gestation when developmental rates for the fetus are set. The evolution of language from symbol to sign was occurring during the same period. The increased lateralization made further dissociation more likely which made possible the transition into sign, and the split consciousness we identify as "thought". Other potential triggers to increased lateralization could have included dietary changes or ceremonial natural inebriants. (Lehman A & Bernsten M (1999) Evolution and the Structure of Health and Disease. web link)

[from abstract] "The possible effect of dietary fat content and the ratio of polyunsaturated to saturated fatty acids (P/S-ratio) on serum sex hormones was studied in 30 healthy male volunteers. The customary diet of the subjects, which supplied 40% of energy as fat (mainly from animal sources, P/S-ratio 0.15) was replaced for a 6 weeks period by a practically isocaloric experimental diet containing significantly less fat (25% of energy) with a higher P/S-ratio (1.22) and other environmental factors were stabilized. Serum testosterone and 4-androstenedione decreased from 22.7 +/- 1.1 nmol/l to 19.3 +/- 1.2 nmol/l, (SEM, P less than 0.001) and from 4.6 +/- 0.2 nmol/l to 4.3 +/- 0.2 nmol/l (SEM, P less than 0.01), respectively. These changes were paralleled by a reduction in serum free (non-protein bound) testosterone (P less than 0.01) suggesting a possible change in biological activity. During the low fat period a significant negative correlation between serum prolactin and androgens was observed. All the changes in androgen levels were reversible. With the exception of a small but non-significant decrease in serum estradiol-17 beta, the other hormone parameters were practically unaffected by the dietary manipulation. Our results indicate that in men a decrease in dietary fat content and an increase in the degree of unsaturation of fatty acids reduces the serum concentrations of androstenedione, testosterone and free testosterone. The mechanism and importance of this phenomenon is discussed in the light of epidemiological and experimental data." (Hamalainen E, Adlercreutz H, Puska P, Pietinen P (1984) Diet and serum sex hormones in healthy men. J Steroid Biochem 20(1):459-464)

"Tan (1990a, b, c, 1991a, b, c) has investigated the relation between serum testosterone levels and hand performance extensively. In a 1990 (1990c) study, he reported that serum testosterone levels correlated with right-hand skill on a modified version of the Annett pegboard: right-handed men showed a positive correlation between serum testosterone level and right-hand skill, while right-handed women showed a negative correlation. This would suggest that high testosterone levels are associated with increased right-hand skill in men, but with decreased right-hand skill in women. In a further study, Tan (1990b) found that right-hand superiority on the Tapley and Bryden (1985) dot-filling task increased with increasing serum testosterone level in males, but was unaffected by testosterone in women. Next, Tan (1991a) showed that high testosterone levels in right-handed women were assoicated with poorer peg-moving performance and less improvement with practice, generally replicating his 1990 (1990a) study. Subsequently, Tan (1991b) found the reverse pattern in male subjects. These findings generally show that increased serum testosterone is associated with increased right-handed performance in men, but not in women. However, Tan (1991c) has also reported that testosterone levels are significantly higher in both women with AD than in those with standard dominance, when the AD group includes left-handers, weak right-handers, and right-handers with a history of familial sinistrality. This latter finding is in general agreement with Tan's (1990a) report that degree of hand preference in negatively correlated with testosterone level in right-handed women and in right-handed men without a history of familial sinistrality. However, Tan's studies of hand skill (1990b,c, 1991a,b) suggest that increased levels of testosterone are associated with stronger right-handedness, at least in men. Given the relatively small sample sizes employed in these studies (usually about 45 men and 20 women), the large number of potential confounding factors (eye dominance, footedness, and intellectual ability, to name a few), and the apparent inconsistencies in the effects on preference and on skill, it is unclear how best to interpret these data." (Bryden MP, McManus IC, Bulman-Fleming, MB (1994) Evaluating the Empirical Support for the Geschwind-Behan-Balaburda Model of Cerebral Lateralization. Brain and Cognition 26: pp. 151)

"Hassler (1991) has reported decreased levels of salivary testosterone in male musical composers and increased levels of testosterone in female musical composers, suggesting a minimization of sex differences in creative musicians. Similar effects were not found with musical performers or artistic painters." (Bryden MP, McManus IC, Bulman-Fleming, MB (1994) Evaluating the Empirical Support for the Geschwind-Behan-Balaburda Model of Cerebral Lateralization. Brain and Cognition 26: pp.

"However, Moffat and Hampson (1993) have found that salivary testosterone levels are significantly lower in left-handers than in right-handers. While circulating testosterone levels in adults may not correlate well with fetal exposure to testosterone, these data provide suggestive evidence against the Geschwind hypothesis --- one would expect higher, rather than lower, levels of testosterone in left-handers." (Bryden MP, McManus IC, Bulman-Fleming, MB (1994) Evaluating the Empirical Support for the Geschwind-Behan-Balaburda Model of Cerebral Lateralization. Brain and Cognition 26: pp. 151)

"In a follow-up study, using more reliable measures of laterality, Grimshaw, Bryden, and Finegan (1993) found that increased prenatal testosterone levels were associated with stronger right-handedness and stronger right-ear effects on the dichotic listening test in girls. Both these findings are contrary to the predictions of the GBG model. [was than embryos T level or the mom's?] (Bryden MP, McManus IC, Bulman-Fleming, MB (1994) Evaluating the Empirical Support for the Geschwind-Behan-Balaburda Model of Cerebral Lateralization. Brain and Cognition 26: pp. 52)

"The GBG model is essentially a theory of sex-related differences because prenatal testosterone levels is the pivotal concept. If there is little or no prenatal testosterone available during the gestational stage when the genitals are being formed, the fetus will develop as a female, even if the chromosomal pattern is male. Thus, the effect of prenatal testosterone will depend on the amount available at different gestational ages and the sexual status of the fetus. Males necessarily are exposed to more prenatal testosterone than females because this hormone is produced by their own developing testes. The mother also provides smaller quantitites of masculinizing hormones via her adrenals and ovaries and from other structures such as body fat. Smoking and extreme stress can also increase testosterone production in pregnant women, which in turn increases the probability of left-handedness in offspring (Bakan, 1991). As predicted by the GBG model, males have a higher rate of left-handedness, superior visual-spatial skills, much higher incidences of dyslexia and stuttering, and a sex -differentiated pattern of immune disorders. (These data are reviewed in Coren & Halpern, 1991; Halpern & Coren, 1993; and Halpern, 1992.) (Halpern, D.F. (1994) Evaluating support for the Geschwind-Behan-Galaburda model: with a rubber ruler and a thumb on the scale. Brain and Cognition 26 (2): 186)

"Nevertheless, their review of the twin studies on handedness gave figures which allow some doubt: the rate of handedness-discordance in monozygotic twins (2900 pairs) is 21.7% and the rate of handedness discordance in dizygotic twins (2589 pairs) is 22.6% (p. 121). The suggestion that there is almost no empirical support for the specific "testosterone hypothesis" is convincing; it should not lead to rejection of all prenatal non-genetic models of cerebral lateralization." (Dellatolas, G. (1994) Birth order and month of birth are not related with handedness in a sample of 9370 young men. Cortex 27 (1): 196)

"Although it is not entirely understood how the gonadal hormones affect the development of the CNS, we know that the morphological and structural repercussions of perinatal exposure to these steroids are at the level of the cell body, axons, dendrites, and synapses. The consequences of this exposure on growth of neurites, as shown by the majority of studies, are largely facilitory or enhancing. A few studies have, however, reported inhibitory effects of testosterone. For example, in the male rat, the thickness of the cerebral cortex is apparently greater on the right side than on the left and removal of the testes at birth alters this cortical laterality. Furthermore, in the neonate male rat, concentration of estrogen receptors is greater in the left than in the right cortex (Diamond, 1991). Testosterone has also been implicated in influencing the size of specific areas of the corpus callosum (Fitch, Berrebi, Cowell, Schrott, & Denenberg, 1990). More recently, Witelson (1991) has shown that lower levels of androgens lead to less axon elimination in specific areas of the brain, apparently resulting in specific patterns of functional asymmetry. She found that left-handed men had a larger isthmus of the corpus callosum than right-handed men." (Forget, H. & Cohen, H. (1994) Life after Birth: The Influence of Steroid Hormones on Cerebral Structure and Function is Not Fixed Prenatally. Brain and Cognition 26: 244)

"In a study comparing pre- and postmenstrual dichotic performance in a large sample of women, the right ear advantage (REA) for auditory language-related stimuli was significantly more pronounced in the postmenstrual phase of the cycle (Altemus, Wexler, & Boulis, 1989). Changes over the menstrual cycle were also observed on visual cerebral asymmetries in lexical dicision and line orientation tasks (Chiarello, McMahon, & Schaefer, 1989). Moreover, shift of functional cerebral asymmetry in face perception was also associated with variations in the mentrual cycle (Heister, Landis, Regard, & Schroeder-Heister, 1989)." (Forget, H. & Cohen, H. (1994) Life after Birth: The Influence of Steroid Hormones on Cerebral Structure and Function is Not Fixed Prenatally. Brain and Cognition 26: 246) [T?]

"Cohen and Forget (submitted for publication) compared right-handed men, women, and genetic male transexuals on verbal and nonverbal dichotic tasks to investigate relations between hormone therapy and auditory cerebral specialization of speech and non-speech stimuli in adults. In verbal tasks, the usual REA obtained for all subject groups; in nonverbal tasks, results revealed a left ear advantage in the processing of nonverbal information for men only; women and transsexuals exhibited similar performances in nonverbal tasks. Cautious interpretation of the data is some possible hormonal involvement, in adults, in the modulation of right hemispheric cognitive processing. In light of the inherent difficulties of isolating the early influence of testosterone, the studies that effectively submit a test of the GBG hypothesis are those of Grimshaw, Bryden, and Finegan (1993), and Grimshaw, Niccols, and Finegan (1990) who attempting to determine whether dichotic listening performance and frequency of occurance of left-handedness were correlated with levels of testosterone measured prenatally, during amniocentesis, in populations of children. These two studies do not support GBG's claim that higher levels of testosterone are associated with reduced left hemisphere dominance. If anything, the reverse appeared to be true." (Forget, H. & Cohen, H. (1994) Life after Birth: The Influence of Steroid Hormones on Cerebral Structure and Function is Not Fixed Prenatally. Brain and Cognition 26: 247)

"Bryden mentions only studies in his review of research directly linking T and cognitive abilities, namely, a study by Hassler (1991) reporting decreased levels of salivary T in male musical composers and increased levels of T in female musical composers, and a study by Christiansen and Knussman (1987) showing that, in college-age men, T levels correlated positively with spatial relations and negatively with performance on verbal-sequential tasks. The latter study is unusual in that there have been several studies showing better spatial performance in higher-androgen young women and lower-androgen young men, compared to their same sex counterparts (Gouchie & Kimura, 1991; Mofat & Hamson, in preparation; Shute et al., 1983). One interpretation of these findings is that, across sexes, there may be a nonmonotonic relationship between T (or its metabolites, which have not been measured directly in any of these studies) and spatial performance, with optimal performance occurring in the middle range of T values, closer to the lower end of the normal range of T for young adult males." (Hampson, E. & Moffat, S.D. (1994) Is testosterone related to spatial cognition and hand preference in humans? Brain and Cognition 26: 257)

[abstract] Theoretical speculation in humans (S.F. Witelson, Psychoneuroendocrinology 16 (1991) 131-153) and empirical findings in animals (R.H. Fitch, P.E. Cowell, L.M. Schrott, V.H. Denenberg, Int. J. Dev. Neurosci. 9 (1991) 35-38) suggest that testosterone (T) may play a significant role in the development of the corpus callosum (CC). However, there are currently no empirical studies directly relating T concentrations to callosal morphology in humans. The purpose of the present study was to investigate the relationship between free T concentrations as determined by radioimmunoassay, and the mid-sagittal area of the corpus callosum, as determined by magnetic resonance imaging (MRI). Subjects were 68 young adult (20-35 years), neurologically normal, right-handed males. All subjects underwent MRI and provided two samples of saliva for radioimmunoassay of T and cortisol. Anatomical regions of interest included total brain volume, left and right hemisphere volume and regional areas of the CC. CC regions were defined using two different measurement techniques, each dividing the CC into six sub-sections. Anatomical measurements were performed blind with respect to the hormone levels of subjects. A significant positive correlation between T concentration and cross-sectional area of the posterior body of the CC was found. This finding was consistent across the two measurement techniques and was not attributable to individual differences in total brain volume. All correlations between cortisol and CC sub-regions were non-significant. The results of this study are consistent with the notion that T, at an earlier stage in development, may play a significant role in modulating cortical/callosal architecture in humans. (Moffat SD, Hampson E, Wickett JC, Vernon PA, Lee DH (1997) Testosterone is correlated with regional morphology of the human corpus callosum. Brain Res 767(2):297-304)

"Another group providing relevant data is males with an extra X chromosome (Klinefelter syndrome: 47, XXY). Individuals with this syndrome usually perform quite normally on tests of non-verbal ability, but typically are impaired on language tests (Netley and Rovet 1982a). Netley and Rovet (1982b) reported a rate of 24 per cent left-handedness in 33 individuals with Klinefelter syndrome, which was significantly above the frequency in age-matched controls. Similarly, Thielgaard (1981) reported that XXY males were much more likely than XYY males to be ambidextrous (although the criterion for ambidexterity was not defined). Netley and Rovet (1984) noted that there is evidence for slowed development in XXY males, both fetaly and in early childhood. They interpreted their findings in terms of delayed maturation of the left hemisphere. To this extent, the syndrome is consistent with Geschwind and Galaburda's theory. However, there is one major flaw in the hormonal explanation of these findings: Netley and Rovet (1988) reported that males with Klinefelter syndrome do not have abnormally high levels of testosterone during fetal life --- if anything, their levels are unusually low. Thus, while left-handedness and language delay may be signs of slow maturation in this sydrome, there is no evidence that fetal testosterone plays a causal role. A final piece of evidence linking non-right-handedness with immaturity comes from Coren et al. (1986), who obtained questionnaire data on handedness and retrospective reports of age at puberty form a sample of 1180 university students. There was a significant association between left-handedness and late puberty in both sexes." (Bishop, D.V.M. (1990) Handedness and Developmental Disorder. MacKeith, Manchester pp. 152)

"For example, fluctuations in spatial performance in men have been reported in association with both diurnal (Mackenberg, et al., 1974) and seasonal (Kimura & Hampson, 1994) variations in circulating T concentrations. In both cases, higher T in men was associated with relatively poorer spatial performance. A recent report by Janowsky et al., (1991) suggests that testosterone supplementation in older, androgen-deficient men results in selective enhancement in spatial-constructional abilities, but not in performance on other cognitive tasks." (Hampson, E. & Moffat, S.D. (1994) Is testosterone related to spatial cognition and hand preference in humans? Brain and Cognition 26: 258)

"It is undisputed that in the fetal environment, testosterone can have profound effects on neonatal brain development. In animal studies, when hormonal levels have been controlled experimentally, many developmental processes are affected by exposure to testosterone, and thus lead to anatomical differences between males and females (i.e., sexual dimorphism.). Most of these are mediated by estrogen, from which testosterone is converted by normal enzymatic operations involving aromatase, a catalytic enzyme found within the brain and expressed quite early in development (McEwen, Lieberburg, Chaptal, & Krey, 1977). Ironically, the role of the female hormone estrogen in this process occurs to a significant extent only in males and not females, since the estrogen secreted by the developing ovaries never reaches the brain. High levels of alpha fetoprotein in the neonatal serum bind these estrogens and prevent their access to the central nervous system. By contrast, estrogen has an effect on brain development in males, since conversion of testosterone to estrogen takes place within the developing brain itself." (Small S.L., Hoffman G.E. (1994) Neuroanatomical lateralization of language: sexual dimorphism and the ethology of neural computation. Brain and Cognition 26: 307-8)

"Jacklin, Wilcox, and Maccoby (1988) measured five steroid hormones, including T, in umbilical cord blood obtained at time of birth, and investigated the relationship to cognitive performance at age 6 years. Only in females did T correlate significantly with spatial ability, as measured by the Spatial Relations test from the PMA battery. But contrary to the GBG hypothesis, higher T was associated with lower, not higher spatial components scores, and no correlations were evident in boys. Similar results were reported by Finegan, Niccols, and Sitarenious (1992) who measured T in second trimester amniotic fluid obtained via amniocentesis and explored the relationship to cognitive skills at age 4. Spatial relations were assessed using a block-building task, and as in the Jacklin study, associations between T and spatial ability were significant only in girls. In girls, prenatal T does not reach the excessively high levels hypothesized by GBG to interfere with spatial development. Nevertheless, in this study, higher levels of prenatal T in girls were associated at age 4 with lower, not higher, block-building scores, contrary to the predictions of the GBG model (Finegan et al., 1992). If anything, boys showed a trend in the opposite direction. Although both studies demonstrate some significant associations between early androgen levels and later cognitive performance, the direction of the correlations is perplexing and provides little support for the GBG model. It is unknown at present how prenatal or neonatal T relates to spatial ability at later ages. A problem with both these studies is that the period of maximal brain sensitivity to androgens during human development has not been established, and in particular, we don't know the critical time frame, if one exists at all, when androgens are capabel to influencing differentiation of cortical of subcortical regions involved in lateralized functions. Thus, we have no way of knowing whether either study measured T during the critical period." (Hampson, E. & Moffat, S.D. (1994) Is testosterone related to spatial cognition and hand preference in humans? Brain and Cognition 26: 259)

"Because females with CAH [congenital adrenal hyperplasia] are exposed to levels of T within or above the normal male range (Carson et al., 1982) during most of the gestational period when the gonads are normally active in the male fetus (and beyond), they provide a crucial test of the GBG hypothesis. Contrary to findings cited above from studies of normal children, girls with CAH have been reported to show enhanced spatial abilities, compared to sibling controls (Resnick, Berenbaum, Gottesman, & Bouchard, 1986). No significant differences in spatial ability have been doculmented in males with CAH. Therefore, in this syndrome, higher prenatal T is associated with enhanced spatial ability, at least in girls. This in consistent not only with the GBG theory but also with the sexual differentiation hypothesis (see Finegan et al., 1992) and with the findings in adults showing that higher T in females, but not in males, is associated with better spatial performance." (Hampson, E. & Moffat, S.D. (1994) Is testosterone related to spatial cognition and hand preference in humans? Brain and Cognition 26: 261)

"Our findings are highly consistent with those of Grimshaw et al. (1993), who measured fetal T in midtrimester amniotic fluid. In both studies, strong right-handedness was associated with higher T levels." (Hampson, E. & Moffat, S.D. (1994) Is testosterone related to spatial cognition and hand preference in humans? Brain and Cognition 26: 262)