З. Стоянов, И. Пашалиева, П. Николова СООТНОШЕНИЕ ДЛИН ВТОРОГО И ЧЕТВЕРТОГО ПАЛЬЦА У ЛЕВОРУКИХ И ПРАВОРУКИХ ЖЕНЩИН: ДОКАЗАТЕЛЬСТВО В ПОЛЬЗУ ГИПОТЕЗЫ ГЕШВИНДА И ГАЛАБУРДЫ (С. 20-25)


З. Стоянов, И. Пашалиева, П. Николова

СООТНОШЕНИЕ ДЛИН ВТОРОГО И ЧЕТВЕРТОГО ПАЛЬЦА У ЛЕВОРУКИХ И ПРАВОРУКИХ ЖЕНЩИН: ДОКАЗАТЕЛЬСТВО В ПОЛЬЗУ ГИПОТЕЗЫ ГЕШВИНДА И ГАЛАБУРДЫ

Медицинский университет «Профессора П. Стоянова», отделение физиологии и патофизиологии, Варна, Болгария

FINGER LENGTH RATIO (2D:4D) IN LEFT- AND RIGHT-HANDED FEMALES: EVIDENCE SUPPORTING GESCHWIND AND GALABURDA HYPOTHESIS
Z. Stoyanov, I. Pashalieva, P. Nikolova
The finger length ratio (2D:4D) is a biomarker for the prenatal levels of testosterone. The prenatal effects of testosterone on the brain are considered as a key factor in the etiology of left-handedness. In our previous study we established that handedness-related peculiarities in 2D:4D exist in males. In the present study right hand 2D:4D, left hand 2D:4D, average 2D:4D and the difference between right and left 2D:4D (Dr–l) were compared between left- and right-handed females. The results obtained replicated the observed in males: significant differences in Dr–l and reverse pattern of asymmetry in 2D:4D. Dr–l in left-handed was significantly lower than Dr–l in right-handed. The pattern of asymmetry in 2D:4D in left-handed was presented as a significantly higher left hand 2D:4D. These results suggest that left-handed females have been exposed to higher levels of testosterone in utero. Our data are in concordance with Geschwind and Galaburda hypothesis that high intrauterine levels of testosterone determine left-handedness.
Keywords: finger length ratio (2D:4D), testosterone, handedness, left-/right-handed females.

Introduction. It is well known that during intrauterine development the sex steroids have an important organizing effect on the brain with subsequent long-term effects on the behaviour (Carlson, 2005; Voracek et al., 2006). Such hormonal influences have been assumed as etiological factors for “anomalous cerebral dominance” and left-handedness. According to the hypothesis suggested by Geschwind and Behan (1982) and further developed by Geschwind and Galaburda (1985a; 1985b) (the “GBG” hypothesis), the high intrauterine levels of testosterone impede the growth of certain regions of the left hemisphere, which leads to right hemisphere language dominance and increase in left-handedness. Left-handedness was associated with high levels of androgens also by Kelly (1993), who considered the inhibitory effect of testosterone on the ontogenetic cellular death in the left hemisphere. Slightly different is Witelson’s (1991) point of view, namely, that lower levels of testosterone in men lead to less axon elimination, a larger callosal isthmus, and reduced regressive events in the development of the temporo-parietal regions (related to functional asymmetry), and are associated with less functional asymmetry and increased left-handedness. Witelson’s hypothesis is supported by the data of Grimshaw et al. (1995): they found that females with lower levels of testosterone in the second trimester amniotic fluid are more likely to be left-handed at age 10. On the same lines are the results of Medland et al. (2005), who studied the association between handedness and the androgen receptor polymorphism. The authors concluded that the probability of left-handedness in both males and females is associated with the length of the androgen receptor, such that the risk of left-handedness increases in those individuals with variants of the androgen receptor associated with lower testosterone levels.

The data of Grimshaw et al. (1995) and Medland et al. (2005) are an argument in confirmation of the critics and opponents of the “GBG” hypothesis (see Bryden et al., 1994; Berenbaum and Denburg, 1995). Nevertheless, the apologists of the “GBG” theory continue to search evidence supporting the suggestion that higher prenatal levels of testosterone determine left-handedness. In this context as a useful methodological tool can be applied the ratio between the lengths of the 2nd and 4th fingers of the hand (2D:4D), established during the last years as a reliable biomarker for the prenatal levels of testosterone and for the effects of the sex steroids (Manning et al., 1998; Putz et al., 2004; McIntyre, 2006; Hönekopp et al., 2007). The high prenatal levels of androgens (or the high ratio of testosterone/estrogens) determine lower values (male type) of 2D:4D, and, vice versa, the lower relative levels of testosterone (low testosterone/estrogens ratio) are associated with higher values (female type) of 2D:4D (Manning et al., 1998; Lutchmaya et al., 2004). To date, several publications reported on association between 2D:4D and handedness. Some of them are concentrated mainly on hand skills. Manning et al. (2000) examined the relationship between lateralized hand performance and 2D:4D and established that low 2D:4D ratio in the right hand is associated with a reduction in rightward performance asymmetry. Similar are the data of Fink et al. (2004), who report that in right-handed children the high 2D:4D correlates with improved right-hand skill, and low 2D:4D correlates with enhanced left-hand skill. In other studies comparisons of 2D:4D values in left-handers and right-handers have been made. According to the data of Choudhary et al. (2005) 2D:4D values do not correspond with the type of handedness (left or right). Studying children with dyslexia Boets et al. (2007) observed higher incidence of left-handedness in the dyslexic group but did not find differences between the 2D:4D values (left hand, right hand, dominant hand) in left-handers and right-handers. Voracek et al. (2006), however, reported on such differences in a study on the sports skills in fencers. They found that right hand 2D:4D is significantly lower in left-handed compared to right-handed fencers. In the study of Nicholls et al. (2008) non-dextrals showed a more masculine pattern of 2D:4D ratio (lower index/ring ratio), whereas dextrals showed a more feminine pattern of finger ratio. Manning and Peters (2009), using the preferred for writing hand as an indicator of handedness, found two significant correlations: between right hand 2D:4D and writing hand preference (low right hand 2D:4D is associated with left hand preference) and between writing hand preference and the difference between right and left hand 2D:4D (designated as Dr–l – low Dr–l is associated with left hand preference). In a recent study Beaton et al. (2011) also found that the difference between the digit ratios of the right and left hands (Dr–l) is a significant predictor of handedness.

In our previous research we studied only males and found out a constellation of 2D:4D measures suggesting the existence of handedness-related peculiarities in the 2D:4D ratio (Stoyanov et al., 2009). The main finding was that the difference between right and left 2D:4D (Dr–l) in left-handers was significantly lower than Dr–l in right-handers. We concluded that left-handers were subjected to higher levels of testosterone in utero, because low value of Dr–l testifies for relatively higher prenatal levels of testosterone. In the present study we set ourselves the aim to check: (1.) whether handedness-related peculiarities in the 2D:4D ratio exist in females too and (2.) if exist, whether the pattern of handedness-related 2D:4D peculiarities in females is similar to the pattern observed in males. We suspected sex effect because in males Hox genes (Hoxa, Hoxd) control the development of the fingers and the testes (with subsequent increase of foetal testosterone production) (Manning et al., 1998), and a question arise regarding the sources of testosterone in female foetuses.

Methods. Subjects were 30 right-handed and 15 left-handed female volunteers – students of medicine, aged between 20 and 25 years. The volunteers were recruited from participants in a more general research project entitled “Left-handedness: biological foundations and concomitant psychophysiological phenomena” (approved by local ethical committee). Written informed consent was obtained from subjects after the experimental procedure had been explained.

The evaluation of handedness was based on: (1.) a handedness questionnaire, which was adapted for Bulgarian compilation from the questionnaires of Annett (the 12-item version) and of Oldfield (the 10-item version) (Stoyanov, 1998); and (2.) a set of manipulative tests (Bragina and Dobrohotova, 1988). A handedness quotient was computed on the basis of the handedness questionnaire (Fedoruk and Dobrohotova, 1980). The handedness quotient varied between –100% (strong left-handers) and +100% (strong right-handers). The group of left-handers included persons with handedness quotient between –100% and –30%. All subjects in the right-handers’ group were with handedness quotient between +30% and +100%.

Photocopies of the ventral surface of the hands were obtained for measurement of the fingers’ length (Putz et al., 2004; Lutchmaya et al., 2004; Fink et al., 2004). Before photocopying, the flexion creases in the bases (closest to the palm) of the 2nd and 4th fingers were marked with a fine stylo pen. Using a vernier calliper with precision of up to 0.05 mm, the distance between the middle of the marker line to the tip of the finger was measured. Right hand 2D:4D, left hand 2D:4D, average 2D:4D, and the difference between right and left 2D:4D (Dr–l = 2D:4D right hand – 2D:4D left hand) were calculated and compared between the two subject groups.

The statistical significance of the differences in the values of 2D:4D of the two groups was estimated by an unpaired two-tailed t-test (GraphPAD Prism 4 software). A probability of p < 0.05 was considered statistically significant.

Results. As it is visible in Table 1, the mean values for average 2D:4D in right-handed (0.979) and left-handed females (0.978) are almost identical. Insignificant, but better pronounced are the between-group differences in right hand 2D:4D and left hand 2D:4D: the right hand 2D:4D is lower in left-handers (0.970 against 0.980 in right-handers), but left hand 2D:4D in left-handers (0.986) is higher than in right-handers (0.978).

Table 1. Measures of 2D:4D in left- and right-handed females.

Right-handers Left-handers
Measures of 2D:4D M ± SD M ± SD
Right hand 2D:4D 0.980 ± 0.024 0.970 ± 0.024
Left hand 2D:4D 0.978 ± 0.026 0.986 ± 0.016
Average 2D:4D 0.979 ± 0.021 0.978 ± 0.014
Dr–l 0.002 ± 0.024 –0.016 ± 0.030

The different pattern of asymmetry of 2D:4D in right-handed and left-handed females deserves attention. In right-handers the mean value of right hand 2D:4D (0.980) is higher (insignificant) than the value of left hand 2D:4D (0.978). The pattern of asymmetry is reverse in left-handers: higher mean value of 2D:4D in the left hand (0.986) as compared to 2D:4D in the right hand (0.970) – t = 2.148, p < 0.05. The different pattern of asymmetry is reflected in the mean values of Dr–l: this measure of 2D:4D has a positive value in right-handed females (0.002) and a negative value in left-handed (–0.016), and the difference is significant (t = 2.209, p < 0.05).

Discussion. The initial questions in our study were whether handedness-related peculiarities in the 2D:4D ratio exist in females and, if exist, whether the pattern of these handedness-related 2D:4D peculiarities is similar to the pattern observed in males. Our answer is yes. The results obtained in females replicated the observed in males: there are significant differences in Dr–l and reverse pattern of asymmetry in the digits formula (2D:4D) in left-handers as compared to right-handers. Moreover, the reverse pattern of asymmetry of 2D:4D in left-handed females is presented as a significant difference between left hand 2D:4D and right hand 2D:4D – that has not been observed as a significant finding in left-handed males in our previous study. Our data are identical to the data reported by Manning and Peters (2009): they found significantly larger left hand 2D:4D (than right hand 2D:4D) in females with left hand preference. Although insignificant, the differences we established in the values of right hand 2D:4D in right-handers and left-handers are in agreement with the finding of Voracek et al. (2006): the right hand 2D:4D is lower in left-handers compared to right-handers.

On the background of the mentioned handedness-related peculiarities in the digits ratio (2D:4D) we can speculate that prenatal testosterone plays a role in the etiology of handedness. In both of our studies (in males and in females) we found that the right hand 2D:4D ratio is lower (suggesting higher levels of prenatal testosterone) in left-handers compared to right-handers. Despite of lack of statistically significant difference, the finding is important, because many authors share the point of view that the relationship between 2D:4D and testosterone is expressed more strongly in the right hand (Manning et al., 1998; Fink et al., 2004; Lindová et al., 2008). It is noteworthy the fact that the right hand digit ratio established in left-handed females (0.970) is equal to the male type of 2D:4D observed by us in right-handed males (0.971) (Stoyanov et al., 2009).

In the same context Dr–l attracts attention. According to interpretations known from the literature, the low value of Dr–l testifies for relatively higher prenatal levels of testosterone, and it is considered that men with low right hand 2D:4D in relation to left hand 2D:4D are likely to have been exposed in utero to the influence of high levels of testosterone (Manning et al., 2000; Fink et al., 2004; Manning et al., 2004). Analyzed against this background, the negative values of Dr–l we observed in left-handed females seem to support the “GBG” hypothesis where the high intrauterine levels of testosterone determine left-handedness (Geschwind and Behan, 1982; Geschwind and Galaburda, 1985a; 1985b). It is also pointed out that men with negative values of Dr–l are more sensitive to testosterone than men with positive values of Dr–l (Manning et al., 2004). Our comparison showed that Dr–l in left-handed females (–0.016) is lower than Dr–l established in left-handed males (–0.005) (Stoyanov et al., 2009). The post-hoc analysis however did not reveal a statistical significance of the observed difference (t = 1.346, p = 0.188), and we can not conclude that female foetuses with genetic potential for left-handedness are more sensitive to testosterone than male foetuses with genetic potential for left-handedness.

As we already mentioned above, Hox genes (Hoxa, Hoxd) in males control the development of the fingers and the testes, with subsequent increase of foetal testosterone production (Manning et al., 1998), and a question arise regarding the sources of higher testosterone in female foetuses with genetic potential for left-handedness. Discussing on the same problem Geschwind and Galaburda (1985b) pointed out that androgens are produced not only by foetal testes and the placenta, but also by the maternal ovaries and adrenals. Hence, the foetuses (and the development of the foetal brain respectively) can be influenced by increased maternal testosterone – it is known that testosterone may cross the placental barrier (Talarovičová et al., 2009; van de Beek et al., 2009). Searching for causes of the enhanced influences of maternal testosterone on the foetuses, it can be speculated also on the activity of placental enzyme aromatase which normally buffers high levels of testosterone (Cohen-Bendahan et al., 2005).

Although direct analogy with animal data should carefully be made, a recent study on field voles suggested an alternative explanation of the relationship between the intrauterine hormonal environment and 2D:4D. The results of Lilley et al. (2010) provided no evidence for 2D:4D being associated with prenatal exposure to testosterone but indicated a significant interaction between the levels of maternal corticosterone and 2D:4D: in the right paw high maternal corticosterone is related to a lower 2D:4D. Thus, an additional issue of discussion can be introduced – the effect of maternal stress on the development of the foetuses.

In conclusion, the results obtained confirm the existence of handedness-related peculiarities in the 2D:4D ratio in both sexes. The pattern of handedness-related 2D:4D peculiarities in females is similar to the pattern observed in males. In right-handers as a whole the values of right hand 2D:4D ratio are higher than the values of left hand 2D:4D ratio. In left-handers the pattern of asymmetry is opposite: lower values of right hand 2D:4D ratio as compared to left hand 2D:4D ratio and to right hand 2D:4D ratio in right-handers. The values of the indicator Dr–l (2D:4D right hand – 2D:4D left hand) in left-handers as a whole are negative and can be interpreted as proof that those persons were exposed to high levels of testosterone in utero. Despite the possible alternative explanations, the data obtained are in accord with the “GBG” hypothesis which claims that high intrauterine levels of testosterone determine left-handedness.

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Information about author:
Zlatislav Stoyanov, Department of Physiology and Pathophysiology, Medical University “Prof. Paraskev Stoyanov”, zsd@mu-varna.bg
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