Anogenital distance as a marker of androgen exposure in humans

Abstract

SUMMARYAbnormal foetal testis development has been proposed to underlie common disorders of the male reproductive system such as cryptorchidism, hypospadias, reduced semen quality and testicular germ cell tumour, which are regarded as components of a 'testicular dysgenesis syndrome'. The increasing trends and geographical variation in their incidence have been suggested to result from in utero exposure to environmental chemicals acting as endocrine disruptors. In rodents, the anogenital distance (AGD), measured from the anus to the base of genital tubercle, is a sensitive biomarker of androgen exposure during a critical embryonic window of testis development. In humans, several epidemiological studies have shown alterations in AGD associated with prenatal exposure to several chemicals with potential endocrine disrupting activity. However, the link between AGD and androgen exposure in humans is not well-defined. This review focuses on the current evidence for such a relationship. As in rodents, a clear gender difference is detected during foetal development of the AGD in humans which is maintained thereafter. Reduced AGD in association with clinically relevant outcomes of potential environmental exposures, such as cryptorchidism or hypospadias, is in keeping with AGD as a marker of foetal testicular function. Furthermore, AGD may reflect variations in prenatal androgen exposure in healthy children as shorter AGD at birth is associated with reduced masculine play behaviour in preschool boys. Several studies provide evidence linking shorter AGD with lower fertility, semen quality and testosterone levels in selected groups of adults attending andrology clinics. Overall, the observational data in humans are consistent with experimental studies in animals and support the use of AGD as a biomarker of foetal androgen exposure. Future studies evaluating AGD in relation to reproductive hormones in both infants and adults, and to gene polymorphisms, will help to further delineate the effect of prenatal and postnatal androgen exposures on AGD.

Testicular Dysgenesis Syndrome and Long-Lasting Epigenetic Silencing of Mouse Sperm Genes Involved in the Reproductive System after Prenatal Exposure to DEHP

“…Recently, an in silico approach revealed that the DEHP molecule may compete with DHT and/or testosterone for SHBG [6]. AGD is a biomarker of androgen exposure during the fetal testis development period in rodents as well as in humans [21], whereas sperm concentration and motility are the most significant predictor of human fertility [22]. …”

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

“…Hence, AGD could be measured at any postnatal age in rats and used to retrospectively decipher the level of fetal androgen exposure during the MPW (11,21). In human males, AGD shows similar male-female differences as in rats (11,(24)(25)(26), and lower AGD has been related to the occurrence of TDS disorders evident at birth (27)(28)(29)(30)(31)(32)(33) and, in a majority of studies, to lower sperm counts (34)(35)(36)(37) and hormone levels (38,39) in adult men, similar to rats (reviewed in ref. 11).…”

“…As there is already a substantial body of similar association data in human males (Table 1), it is reasonable to propose that an MPW exists in humans, so that studies to identify potential causes of TDS disorders should focus on the presumptive MPW (~8-14 weeks' gestation). While such studies have several inherent limitations, the measurement of AGD in newborn offspring, as an indicator of androgen exposure within the presumptive MPW, will play an important role, even if interindividual variation may restrict its usefulness to population-based studies (11,25,36).…”

Sex-Specific Effects of Combined Exposure to Chemical and Non-chemical Stressors on Neuroendocrine Development: a Review of Recent Findings and Putative Mechanisms

“…In humans, prenatal exposure to phthalates has been associated with altered sex steroid levels [34–36] and de-masculinized phenotypes among boys, including reduced anogenital distance [37]. In turn, anogenital distance is considered a sensitive marker of androgen activity in early gestation [38] and correlates with sex-specific neurobehaviors [39]. Dibutyl phthalate (DBP) is a plasticizer that has been used extensively in toys and personal care products [40].…”