Does the anogenital distance change across pregnancy?

Highlights

• In crude analyses, AGD_AC length increased during pregnancy while AGD_AF did not.

• After adjustment for BMI, AGD_AC and AGD_AF were not associated with pregnancy trimester.

• AGD_AF in pregnant women may be used as a prenatal biomarker of their in-utero hormone exposure.

Abstract

Research question

Does the length of the anogenital distance (AGD), an anthropometric biomarker of fetal androgen exposure, change across pregnancy? It has been suggested that AGD remains stable during adulthood with no changes across the menstrual cycle. No studies, however, have been carried out during pregnancy, during which women are exposed to important hormonal and anthropometric variations.

Design

A cohort study of 186 singleton pregnant women recruited in the first trimester of pregnancy. Measurements from the anterior clitoral surface to the upper verge of the anus (AGD_AC), and from the posterior fourchette to the upper verge of the anus (AGD_AF) and body mass index (BMI) were obtained in each trimester. Generalized linear model for repeated measures was carried out to assess differences in AGDs and BMI across the three trimesters of the pregnancy.

Results

In crude analyses, AGD_AC was progressively and significantly longer as the pregnancy developed (first trimester: 87.69 ± 13.14mm; second trimester: 89.69 ± 13.47mm; third trimester: 91.95 ± 13.25 mm; P < 0.001), whereas AGD_AF did not significantly change throughout pregnancy (first trimester: 28.37 ± 6.94 mm; second trimester: 28.09 ± 7.66 mm; third trimester: 28.94 ± 6.7 mm). In the multivariable mixed-effect models for fixed effect (trimester) and time-covariate (BMI), AGDs did not show significant associations with trimesters of pregnancy when BMI was included in the model.

Conclusions

Our results suggest that AGD_AF and AGD_AC, when adjusted by BMI, do not change throughout gestation despite maternal anthropometric variations during pregnancy. AGD_AF may be a meaningful measurement at any time during pregnancy without considering BMI. Therefore, maternal AGD_AF may be used as a prenatal biomarker of the mother's in-uteru hormonal exposure even during pregnancy.

Introduction

Anogenital distance (AGD) is a measure of sexual dimorphism in genital development determined by intrauterine hormonal influence, especially androgen action during the ‘masculinization programming window’ (before 11–13 weeks of gestation) (Dean et al., 2012; Dean and Sharpe, 2013). Growing evidence shows that AGD measurement correlates with adult reproductive ailments in men (Eisenberg et al., 2012a; 2012b; Mendiola et al., 2012) and with some hormone-dependent diseases in women (Mendiola et al., 2012; 2016; Sánchez-Ferrer et al., 2017).

In humans, sex differences in AGD are evident at 13–14 weeks of gestation, reaching its normal difference (around twice as large in men than women) by 17–20 weeks. That difference is also evident and clearly established in children from birth onwards (Salazar-Martinez et al., 2004; Sathyanarayana et al., 2010; Domenici et al., 2018). Anogenital distance is an anthropometric measurement highly correlated with body weight (Lee et al., 2015; Singal and Jain, 2016). Studies of repeated measurements during childhood suggest that AGD adjusted for body weight is a relatively stable phenotypic trait (Papadopoulou et al., 2013; Priskorn et al., 2018). Information on adult AGD measurements, is, however, limited. Eisenberg et al. (2013) reported that, in men of different ages, the AGD–ano–scrotum distance remains stable during adult life. All available information, however, comes from cross-sectional studies, as no studies have followed up a population of men or women with repeated AGD measurements throughout life.

In women, information on the reproducibility of AGD measurements is limited, especially whether hormonal changes modify the distances, e.g. hormone treatments or physiological changes such as pregnancy or even menopause. Genital anatomy shows cyclic variation (Morotti et al., 2013), and adult circulating hormones used for contraception might be associated with shorter AGD (Mendiola et al., 2012). Nonetheless, in a cohort of fertile adult women, no significant change of AGD was observed during the menstrual cycle (Barrett et al., 2015). In animal studies, Mitchell et al. (2015) suggested a certain degree of plasticity in adult rats. Other animals studies, however, indicate that AGD is a stable anatomical landmark, even though it may be slightly responsive to changes in the androgen environment after pubertal exposure in some cases (van den Driesche et al., 2011; Kita et al., 2016).

A potential limitation for the use of AGD as a biomarker of hormonal prenatal exposure and reproductive outcome in women is the potential variation during pregnancy owing to changes in reproductive hormones. This measurement is considered stable during adulthood, and even during the different stages of the woman's menstrual cycle. It has not, however, been analysed during the period of greatest hormonal variation in women, which is during pregnancy. To the best of our knowledge, no studies on the reliability of AGD measurements across pregnancy have been published. Therefore, our objective was to compare measurements of AGD in the three trimesters of pregnancy in a cohort of pregnant women.