Maternal cigarette smoking and effects on androgen action in male offspring: unexpected effects on second-trimester anogenital distance

Introduction: Fertility, sperm counts, and testis weights are reduced in men whose mothers smoked in pregnancy. Animal studies suggest this could be due to impaired androgen action. Anogenital distance (AGD) provides a readout of fetal androgen exposure and is reduced by in utero exposure to harmful chemicals in rodents. This study assessed whether maternal cigarette smoking disturbs AGD in the second trimester human fetus. Materials and Methods: Morphological indices, including AGD, and circulating cotinine concentrations were measured in 83 electively terminated, normally progressing, second-trimester fetuses between 11 and 20 wk gestation. Results: A gender difference in AGD (1.4-fold longer in males) was already apparent at 11-13 wk, rising to 2.00-fold longer in males at 17-20 wk gestation. In males, AGD and AGD normalized against ponderal index (a measure of fetal leanness) were significantly increased by maternal smoking (1.19- and 1.31-fold, respectively). The difference between smoke-exposed and nonexposed male AGD was greatest at 11-13 wk (1.25-fold) but had declined to 1.01-fold by 17-20 wk gestation. AGD in females was not affected by maternal cigarette smoking. Conclusions: Androgen programming of masculinization occurs before 11-13 wk gestation in the human because AGD is already significantly longer in male fetuses by that stage. AGD reaches the 2-fold difference reported for the neonate by 17-20 wk gestation. Significantly longer AGD in smoke-exposed males was surprising and may indicate increased androgen exposure in the early programming window. Convergence of AGD by late second trimester suggests, however, that by birth, male AGD may be shorter in smoke-exposed individuals.