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      Testosterone measured from amniotic fluid and maternal plasma shows no significant association with directional asymmetry in newborn digit ratio (2D:4D)

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          Abstract

          Foetal sex hormones can have powerful and far-reaching effects on later phenotype. However, obtaining accurate measurements is difficult for ethical reasons, and researchers often employ proxy variables to examine their effects. The relative length of the second and fourth fingers (digit ratio or 2D:4D) is frequently used for this purpose, as it is hypothesized to index variance in prenatal androgen and oestrogen exposure. Most studies employing this method examine digit ratio for the right hand (R2D:4D) and/or left hand (L2D:4D), though the mean value (M2D:4D) (i.e., the average of R2D:4D and L2D:4D) and directional asymmetry (D [R–L]) (i.e., R2D:4D minus L2D:4D) are also commonly used. As no published studies have examined M2D:4D or D [R-L] in relation to testosterone measured from amniotic fluid, we conducted a secondary analysis of data published by Ventura et al. The sample comprises 106 mothers from Portugal who underwent amniocentesis during the second trimester and their neonates. Newborn M2D:4D was negatively correlated with amniotic testosterone in females ( P<0.05) but not in males; no significant association was observed between amniotic testosterone and D [R–L] in either sex. In addition, we examined testosterone measured from maternal circulation during the second trimester, and found that it was not a significant predictor of M2D:4D or D [R–L] in male or female infants. Further research should aim to measure the ratio of testosterone to oestradiol present in amniotic fluid and maternal plasma, to examine whether either is a predictor of digit ratio variables at different stages of postnatal development.

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          The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen

          The differentiation of the urinogenital system and the appendicular skeleton in vertebrates is under the control of Hox genes. The common control of digit and gonad differentiation raises the possibility that patterns of digit formation may relate to spermatogenesis and hormonal concentrations. This work was concerned with the ratio between the length of the 2nd and 4th digit (2D:4D) in humans. We showed that (i) 2D:4D in right and left hands has a sexually dimorphic pattern; in males mean 2D:4D = 0.98, i.e. the 4th digit tended to be longer than the 2nd and in females mean 2D:4D = 1.00, i.e. the 2nd and 4th digits tended to be of equal length. The dimorphism is present from at least age 2 years and 2D:4D is probably established in utero; (ii) high 2D:4D ratio in right hands was associated with germ cell failure in men (P = 0.04); (iii) sperm number was negatively related to 2D:4D in the right hand (P = 0.004); (iv) in men testosterone concentrations were negatively related to right hand 2D:4D and in women and men LH (right hand), oestrogen (right and left hands) and prolactin (right hand) concentrations were positively correlated with 2D:4D ratio and (v) 2D:4D ratio in right hands remained positively related to luteinizing hormone and oestrogen after controlling for sex, age, height and weight.
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            2nd to 4th digit ratios, fetal testosterone and estradiol.

            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. To investigate the relationships between 2D:4D ratios and FT and FE from amniotic fluid. Cohort study. 33 children. 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. A significant negative association between right 2D:4D ratio and FT/FE ratio, which was independent of sex. 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.
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              Developmental basis of sexually dimorphic digit ratios.

              Males and females generally have different finger proportions. In males, digit 2 is shorter than digit 4, but in females digit 2 is the same length or longer than digit 4. The second- to fourth-digit (2D:4D) ratio correlates with numerous sexually dimorphic behavioral and physiological conditions. Although correlational studies suggest that digit ratios reflect prenatal exposure to androgen, the developmental mechanism underlying sexually dimorphic digit development remains unknown. Here we report that the 2D:4D ratio in mice is controlled by the balance of androgen to estrogen signaling during a narrow window of digit development. Androgen receptor (AR) and estrogen receptor α (ER-α) activity is higher in digit 4 than in digit 2. Inactivation of AR decreases growth of digit 4, which causes a higher 2D:4D ratio, whereas inactivation of ER-α increases growth of digit 4, which leads to a lower 2D:4D ratio. We also show that addition of androgen has the same effect as inactivation of ER and that addition of estrogen mimics the reduction of AR. Androgen and estrogen differentially regulate the network of genes that controls chondrocyte proliferation, leading to differential growth of digit 4 in males and females. These studies identify previously undescribed molecular dimorphisms between male and female limb buds and provide experimental evidence that the digit ratio is a lifelong signature of prenatal hormonal exposure. Our results also suggest that the 2D:4D ratio can serve as an indicator of disrupted endocrine signaling during early development, which may aid in the identification of fetal origins of adult diseases.
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                Author and article information

                Journal
                Journal of Developmental Origins of Health and Disease
                J Dev Orig Health Dis
                Cambridge University Press (CUP)
                2040-1744
                2040-1752
                June 2019
                October 31 2018
                June 2019
                : 10
                : 3
                : 362-367
                Article
                10.1017/S2040174418000752
                30376903
                1c9030a0-993d-4095-9ddb-f18e61f279b7
                © 2019

                https://www.cambridge.org/core/terms

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