A Context Dependent Interpretation of Inconsistencies in 2D:4D Findings: The Moderating Role of Status Relevance

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.

Our aims are, first, to describe the sex difference in the length ratio of the second and fourth digits (2D:4D), which likely reflects prenatal testosterone levels in humans. Second, to infer the loss of reliability observed in 2D:4D based on self-measured finger lengths. We used random-effects meta-analysis of 2D:4D based on expert-measured finger lengths (116 samples with 13,260 females and 11,789 males). We find a moderate sex difference (with lower 2D:4D for males), which shows substantial heterogeneity (which is unrelated to age). The sex difference is moderated by the type of finger length measurement and by hand. Measurement involving the distortion of soft tissue leads to a significantly larger sex difference than finger length measurement avoiding this. The sex difference in 2D:4D is larger in the right hand than in the left. The reliability of self-measured 2D:4D in the BBC internet study, by far the largest study on 2D:4D, is estimated to be 46% of that of expert-measured 2D:4D. Right-hand 2D:4D might be a better indicator of prenatal androgenisation than left-hand 2D:4D. The view that 2D:4D has allometric properties (Kratochvil L, Flegr J. 2009. Differences in 2nd to 4th digit length ratio in humans reflect shifts along the common allometric line. Biol Lett 5:643-646.) is not supported. Bone lengths contribute to the sex difference in 2D:4D. In addition, there might be a sex difference in fingers' soft tissue, which should be investigated. Because of measurement unreliability, correlations between 2D:4D and variables of interest are about one-third smaller in the BBC internet study than in studies in which 2D:4D is based on expert-measured finger lengths. (c) 2010 Wiley-Liss, Inc.