Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders

Abstract

Male reproductive development is intricately dependent on fetal androgen action. Consequently, disrupted androgen action during fetal life can interfere with the development of the reproductive system resulting in adverse effects on reproductive function later in life. One biomarker used to evaluate fetal androgen action is the anogenital distance (AGD), the distance between the anus and the external genitalia. A short male AGD is strongly associated with genital malformations at birth and reproductive disorders in adulthood. AGD is therefore used as an effect readout in rodent toxicity studies aimed at testing compounds for endocrine activity and anti-androgenic properties, and in human epidemiological studies to correlate fetal exposure to endocrine disrupting chemicals to feminization of newborn boys. In this review, we have synthesized current data related to intrauterine exposure to xenobiotics and AGD measurements. We discuss the utility of AGD as a retrospective marker of in utero anti-androgenicity and as a predictive marker for male reproductive disorders, both with respect to human health and rodent toxicity studies. Finally, we highlight four areas that need addressing to fully evaluate AGD as a biomarker in both a regulatory and clinical setting.

The prostate cancer drug enzalutamide shortens anogenital distance in male rat offspring by blocking the androgen receptor

“…Fetal androgen insu ciency, caused by low androgen levels or blockage of AR signaling, can prevent the male perineum to develop properly and result in a short AGD (8). One previous report shows that enzalutamide induces shortening of male AGD in mice, although they do not state how much shorter AGD is compared to controls (27).…”

“…Exposure to anti-androgens during fetal life can therefore lead to a broad range of male reproductive disorders such as hypospadias and cryptorchidism at birth (2,3) or fertility issues in adulthood (4,5). Anti-androgens can also cause general feminization of the male fetus, which can lead to a short male anogenital distance (AGD); a marker for disrupted fetal androgen action associated with male reproductive disorders (6)(7)(8).…”

“…Because of the strong link between fetal androgen insu ciency, male AGD, and male reproductive health disorders, both in humans and animals, AGD measurements are routinely performed in tests for developmental and reproductive toxicity in chemical risk assessment (9)(10)(11)(12). However, it remains unclear to what extent AGD can be used as a reliable biomarker for chemicals with different anti-androgenic modes of action (8). To gain the necessary knowledge to characterize cause-effect relationships and thus better de ne the utility of a biomarker such as AGD, performing studies on various model compounds with known mechanism of action is of particular interest.…”

Androgens and the masculinization programming window: human–rodent differences

“…from e19.5–e21.5 in rats) has none of these adverse effects [ 6 ]. One of the pivotal findings to emerge from these studies was that AGD, which is normally about twice as long in male as in female rodents postnatally [ 9 ], provides a life-long readout of the level of androgen exposure specifically within the MPW [ 6 , 7 ]. The male–female difference in AGD has been used for decades by toxicologists as an indicator of the normality of fetal reproductive development in male rodents [ 9 ] and is how animal technicians determine sex of laboratory animals at birth.…”

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

“…Evidence for chemical triggers Many EDCs are considered anti-androgenic based on their ability to block AR action in developing male rodents (Gray et al 2006;Kortenkamp and Faust 2010;Schwartz et al 2019;Vinggaard et al 2008). Neonatal exposure to the AR antagonist flutamide delays initiation of folliculogenesis and reduces ovarian cell proliferation in pigs.…”