2nd to 4th digit ratios, fetal testosterone and estradiol

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Abstract

Background: The ratio of 2nd to 4th digit length (2D:4D) is sexually dimorphic (mean 2D:4D is lower in males than females) and is thought to be fixed early in development. 2D:4D has been reported to be related to fetal growth, hand preference, autism, Asperger's syndrome, sperm counts, family size, age at myocardial infarction in men and breast cancer in women. There is indirect evidence that 2D:4D is established in utero and is negatively related to prenatal testosterone and positively with prenatal estradiol. However, there are no studies which show direct relationships between fetal testosterone (FT), fetal estradiol (FE) and 2D:4D. Aims: To investigate the relationships between 2D:4D ratios and FT and FE from amniotic fluid. Study design: Cohort study. Subjects: 33 children. Outcome measures: Radioimmunoassays of FT and FE obtained from routine amniocentesis; 2D:4D ratios calculated from 2nd and 4th digit length of the right and left hands at age 2 years. Results: A significant negative association between right 2D:4D ratio and FT/FE ratio, which was independent of sex. Conclusions: These preliminary findings lend support to an association between low 2D:4D and high levels of FT relative to FE, and high 2D:4D with low FT relative to FE.

Introduction

The Homeobox genes Hox a and d control (a) the differentiation of the urinogenital system, and may therefore indirectly influence the prenatal production of testicular androgen and (b) the development of the digits [1], [2]. This observation has led to the suggestion that patterns of digit formation may relate to gonad function [3]. One likely candidate for such a link is the ratio between the length of the 2nd (the “index” finger) and 4th (the “ring” finger) digit (2D:4D). The 2D:4D ratio is a sexually dimorphic trait which is lower in men than women [3], [4], relative digit length is established as early as the 14th week [5], and the sex difference appears by two years and perhaps before birth [3].

2D:4D is associated with measures of size at birth in males [6], sperm counts [3], family size [7], age at breast cancer presentation [8] and age at myocardial infarction [9]. It is therefore important to understand the factors which lead to 2D:4D formation. There is indirect evidence that the sex difference in 2D:4D is causally related to relative concentrations of testosterone and oestrogen. Thus, (a) the waist/hip ratio of mothers, a positive correlate of testosterone and a negative correlate of estradiol, is negatively related to the 2D:4D ratio of their male and female children [10]; (b) some behavioural traits with an excess of males have been shown to be associated with low values of 2D:4D, e.g. left hand preference [11], good visual-spatial ability [12], autism and Asperger's syndrome [13]; (c) males and females with congenital adrenal hyperplasia, a trait associated with high prenatal testosterone, have low values of 2D:4D compared to controls [14], [15]; and (c) traits which show an excess of females, e.g. high verbal fluency [16] and high levels of emotional behaviour [17], are associated with high 2D:4D. However, these and similar observations may result from interactions between 2D:4D and sex-related factors other than prenatal androgen and estradiol. The purpose of this work was to examine the association between 2D:4D and relative concentrations of fetal testosterone (FT) and estradiol (FE).

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Subjects and methods

FT and FE may be obtained from amniocentesis [18]. This test is offered to mothers in the second trimester of their pregnancy when there is an elevated risk of a fetus with a chromosomal abnormality. The mothers in this study had undergone routine amniocentesis in the Cambridge area in 1996 and 1997, and had all given birth to healthy singleton infants. The protocol was agreed by the local Ethics Committees and informed consent was obtained from the mothers.

The amniotic fluid was analysed in

Results

There were 33 children, 18 males and 15 females, in the sample. Means for hormonal concentrations were FT=0.72±0.46 nmol/l, FE=1013±379.05 pmol/l and FT/FE ratio 0.001±0.001. Male children had significantly higher levels of FT than females (males 0.91±0.31, females 0.52±0.53, t=2.62, p=0.01). There were no significant differences in FE between the sexes (males 979.77±372.30, females 1058.73±407.02, t=0.57, p=0.57). FT/FE ratios showed significantly higher values for males compared to females

Discussion

We have found that low 2D:4D ratios are associated with high FT in relation to FE levels, and high values of 2D:4D with low FT and high FE. The relationship is likely to reflect testosterone produced by the fetal gonads and adrenals as the fetus is isolated from maternal androgen by its conversion to estradiol within the placenta by the enzyme aromatase [20]. It may be noteworthy that all relationships between 2D:4D and fetal sex steroids were stronger in the right hand than the left. Traits

Acknowledgements

This work was submitted in part fulfillment of the degree of PhD by SL to the University of Cambridge. SBC and SL were supported by the MRC during the period of this work. RK was supported by an Overseas Research Studentship, Cambridge Overseas Trust, and Gonville and Caius College. We are grateful to the Gatsby Foundation for supporting the costs of biochemistry analysis.

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