Anogenital Distance or Digit Length Ratio as Measures of Fetal Androgen Exposure: Relationship to Male Reproductive Development and Its Disorders

Abstract

Male reproductive disorders evident at birth or in young adulthood are remarkably common. They are hypothesized to comprise a testicular dysgenesis syndrome (TDS), with a fetal origin involving mild androgen deficiency. Testing this hypothesis requires "seeing back in time." Two ways have been proposed: measurement of anogenital distance (AGD), or measurement of the 2:4 digit length ratio. This review assesses the evidence that they reflect fetal androgen exposure and might be used to provide insight into the origin of TDS disorders. Supporting evidence for AGD derives from rat experimental studies that identified a fetal masculinization programming window, within which androgen action determines adult reproductive organ size, TDS disorders, and AGD. In humans, AGD is positively correlated to testis size, sperm count/fertility, penis length, and T levels, consistent with rat experimental data. The 2:4 digit ratio also shows associations with these parameters, but inconsistently between studies; evidence that the 2:4 digit ratio accurately reflects fetal androgen exposure is also equivocal. AGD appears to provide a reliable guide to fetal androgen exposure, although available data are limited. The next steps are to: standardize AGD measurement; obtain age-specific population data; and use AGD to evaluate the importance of fetal androgens in determining reproductive disorders and variation in testis/penis size and sperm count in the normal population. These studies should identify what, if any, clinical applications of AGD measurement are feasible--for example, its ability to predict adult-onset reproductive function and disorders.