Does finger fat produce sex differences in second to fourth digit ratios

The year 2009 marks the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young’s (1959) landmark study in Endocrinology (1). This study provided the basis for the Organizational Hypothesis, the notion that exposure to hormones, thought to be androgens, during sensitive periods permanently altered the structure and function of the nervous system (2). The 50 yr since its publication have produced overwhelming support for the Organizational Hypothesis, and it is now a cornerstone of our understanding of how behavioral sex differences differentiate during development. Although the organizing actions of hormones on the nervous system can produce behavioral changes, they may not leave external physical markers of their actions, such as altered genital anatomy. This lackof externalphysical evidencehas resulted ingreat interest in discovering easily observed physical proxies for exposure to differing levels of organizing hormones, particularly androgens, during development. One of the most attractive candidate proxies has been the ratio of the lengths of the index (2D) and ring fingers (4D), known as the 2D:4D digit ratio, or simply digit ratio (3). This ratio, which typically is significantly smaller in men than in women, has been argued to decrease with higher and increase with lower levels of prenatal androgen. In fact, with little supporting evidence (4), digit ratios are often referred to as “a biomarker for prenatal levels of testosterone” (5), reflecting the view that variations in prenatal testosterone produce variation in digit ratios. Definitive evidencethatdigit ratiosreflectprenatalexposuretoandrogens has not been presented. Thus, the study by Berenbaum and colleagues (4) in this issue is of particular significance. They investigated digit ratios in 46 XY individuals lacking functional androgen receptors [complete androgen insensitivity (CAIS)] (6), providing the first opportunity to unequivocally demonstrate that differences in androgen action result in differences in digit ratios. 46 XY CAIS individuals are women who, because they lack androgen receptors, are unable to respond to the endogenous prenatal androgens produced by their functional testes. As a consequence, 46 XY CAIS women develop a completely feminine phenotype, including female genital anatomy and psychology (6). Thus, CAIS women provide a remarkable opportunity to assess the role that androgens play in the formation of digit ratios. The findings of Berenbaum et al. (4) providesupport forbothsidesof thecurrentdebateabout the ontogeny of the sex difference in digit ratios. In support of prenatal androgen affecting digit ratios, the average digit ratios of CAIS women were significantly larger than those of 46 XY males with functional androgen receptors. By contrast, and arguing against prenatal androgen affecting digit ratios, CAIS women’s digit ratios were not larger than those of 46 XX women who, like 46 XY men, do have functioning androgen receptors. The 46 XX women would be expected to have smaller digit ratios than would CAIS women because 46 XX women are exposed to significant maternal levels of prenatal androgens. Previous studies have argued that sexually dimorphic phenotypic characteristics, such as sexual orientation, are related to digit ratios and therefore reflect differences in prenatal androgen exposure (7). Thus, the lack of a difference between CAIS women and 46 XX women in digit ratios argues against digit ratios serving as a marker for prenatal androgen exposure. More troubling to the notion that differences in digit ratios reflectdifferences in exposure toprenatal androgens is the finding of Berenbaum et al. (4) that variability in