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Abstract Context The anogenital distance (AGD) is considered a postnatal readout of early fetal androgen action. Little is known of prenatal AGD and how it correlates with AGD postnatally. Objective We present longitudinal measurements of fetal and infant AGD. We evaluate the impact of testosterone and dihydrotestosterone at minipuberty on AGD and penile size. Methods We performed secondary analyses of an observational, prospective pregnancy and birth cohort, COPANA (2020-2022), at Copenhagen University Hospital—Rigshospitalet, enrolling 685 healthy, singleton pregnant women, of whom 657 attended third trimester ultrasound and 589 infants completed follow-up. Fetal AGD was measured at third semester ultrasound (gestational week 29-34), and infant AGD, penile width, stretched penile length, and circulating testosterone and dihydrotestosterone (LC-MS/MS) were assessed at the minipuberty clinical examination (approximately 3.5 months postpartum): Results AGD was available in 650/657 fetuses (310 boys) and 588/589 infants (287 boys). Boys had longer fetal and infant AGD than girls; fetal AGDas: mean (SD) 21.4 mm (±3.5), fetal AGDaf: 12.8 mm (±2.3), P < .001, infant AGDas: 32.0 mm (±5.6) and infant AGDaf: 15.8 (±3.3), P < .001. Fetal AGD correlated with infant AGD in boys and girls (Spearman r = .275, P < .001 and r = .189, P = .001 respectively), but not with circulating testosterone or dihydrotestosterone at minipuberty. Penile size correlated positively with circulating androgen levels at minipuberty: stretched penile length vs testosterone: r = .235, P < .001. Conclusion AGD is sexually dimorphic already in the third trimester. Fetal and infant AGD correlate. AGD is associated with body size but not circulating androgen levels at minipuberty. These findings suggest that fetal and infant AGD reflect androgen action during early fetal development.

Abstract Context Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. Objectives To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). Design, Setting A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. Patients and Methods EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0–12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0–24 months) and 181 preterm babies, and 111 babies with atypical genitalia. Results The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6–11.5); in males 28–32 weeks 11.5 (9.2–12); in males 33–36 weeks 11.5 (10.5–12) and in full-term males 12 (10.5–12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. Conclusions EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research.

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 new-born 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.

Abstract Context The use of anogenital distance (AGD) in clinical and epidemiological settings is increasing; however, sex-specific reference data on AGD and data on longitudinal changes in AGD in children is scarce. Objective To create age-, sex-, and method-related reference ranges of AGD in healthy boys and girls aged 0–24 months, to assess the age-related changes in AGD and to evaluate the 2 predominantly used methods of AGD measurement. Design The International AGD consortium comprising 4 centers compiled data from 1 cross-sectional and 3 longitudinal cohort studies (clinicaltrials.gov [NCT02497209]). Setting All data were collected from population-based studies, recruiting from 4 maternity or obstetric centers (United States, Cambridge [United Kingdom], Odense, and Copenhagen [Denmark]). Subjects This study included a total of 3705 healthy, mainly Caucasian children aged 0–24 months on whom 7295 measurements were recorded. Main Outcome Measures AGDAS (ano-scrotal), AGDAF (ano-fourchette), AGDAP (ano-penile), AGDAC (ano-clitoral), AGD body size indices (weight, body mass index [BMI], body surface area, and length), and intra- and interobserver biases. Results We created age-specific reference ranges by centers. We found that AGD increased from birth to 6 months of age and thereafter reached a plateau. Changes in AGD/BMI during the first year of life were minor (0–6% and 0–11% in boys and girls, respectively). Conclusions Reference ranges for AGD can be used in future epidemiological research and may be utilized clinically to evaluate prenatal androgen action in differences-in-sex-development patients. The increase in AGD during the first year of life was age-related, while AGD/BMI was fairly stable. The TIDES and Cambridge methods were equally reproducible.

Evolutionary and comparative approaches can yield novel insights into human adaptation and disease. Endometriosis and polycystic ovary syndrome (PCOS) each affect up to 10% of women and significantly reduce the health, fertility, and quality of life of those affected. PCOS and endometriosis have yet to be considered as related to one another, although both conditions involve alterations to prenatal testosterone levels and atypical functioning of the hypothalamic–pituitary–gonadal (HPG) axis. Here, we propose and evaluate the novel hypothesis that endometriosis and PCOS represent extreme and diametric (opposite) outcomes of variation in HPG axis development and activity, with endometriosis mediated in notable part by low prenatal and postnatal testosterone, while PCOS is mediated by high prenatal testosterone. This diametric disorder hypothesis predicts that, for characteristics shaped by the HPG axis, including hormonal profiles, reproductive physiology, life‐history traits, and body morphology, women with PCOS and women with endometriosis will manifest opposite phenotypes. To evaluate these predictions, we review and synthesize existing evidence from developmental biology, endocrinology, physiology, life history, and epidemiology. The hypothesis of diametric phenotypes between endometriosis and PCOS is strongly supported across these diverse fields of research. Furthermore, the contrasts between endometriosis and PCOS in humans parallel differences among nonhuman animals in effects of low versus high prenatal testosterone on female reproductive traits. These findings suggest that PCOS and endometriosis represent maladaptive extremes of both female life‐history variation and expression of sexually dimorphic female reproductive traits. The diametric disorder hypothesis for endometriosis and PCOS provides novel, unifying, proximate, and evolutionary explanations for endometriosis risk, synthesizes diverse lines of research concerning the two most common female reproductive disorders, and generates future avenues of research for improving the quality of life and health of women.

Abstract Context Soy formula feeding is common in infancy and is a source of high exposure to phytoestrogens, documented to influence vaginal cytology in female infants. Its influence on minipuberty in males has not been established. Objective To assess the association between infant feeding practice and longitudinally measured reproductive hormones and hormone-responsive tissues in infant boys. Methods The Infant Feeding and Early Development study was a prospective cohort of maternal–infant dyads requiring exclusive soy formula, cow milk formula, or breast milk feeding during study follow-up. In the 147 infant boy participants, serum testosterone, luteinizing hormone, stretched penile length, anogenital distance, and testis volume were longitudinally assessed from birth to 28 weeks. We examined feeding-group differences in age trajectories for these outcomes using mixed-effects regression splines. Results Median serum testosterone was at pubertal levels at 2 weeks (176 ng/dL [quartiles: 124, 232]) and remained in this range until 12 weeks in all feeding groups. We did not observe differences in trajectories of hormone concentrations or anatomical measures between boys fed soy formula (n = 55) and boys fed cow milk formula (n = 54). Compared with breastfed boys (n = 38), soy formula–fed boys had a more rapid increase in penile length (P = .004) and slower initial lengthening of anogenital distance (P = .03), but no differences in hormone trajectories. Conclusion Reproductive hormone concentrations and anatomical responses followed similar trajectories in soy and cow milk formula–fed infant boys. Our findings suggest that these measures of early male reproductive development do not respond to phytoestrogen exposure during infancy.

STUDY QUESTIONCould anogenital distance (AGD) be a non-invasive marker of endometriosis and correlated to the American Society for Reproductive Medicine revised score (r-ASRM) and ENZIAN classifications?SUMMARY ANSWERSurgically and histologically proven endometriosis is associated with a short AGD in women of reproductive age but not correlated either to the severity or to the location of the disease.WHAT IS KNOWN ALREADYAGD is a marker of intrauterine androgen exposure and exposure to oestrogen-like chemicals such as phthalates. Moreover, exposure to endocrine disruptors, such as organochlorine chemicals, is associated with endometriosis. It has been suggested that a short AGD in women is associated with an increased risk of endometriosis based on clinical and ultrasound exams.STUDY DESIGN, SIZE, DURATIONA prospective cohort study was conducted from January 2018 to June 2019 in a tertiary-care centre including 168 adult women undergoing pelvic surgery.PARTICIPANTS/MATERIALS, SETTING, METHODSOf the 168 women included, 98 patients had endometriosis (endometriosis group) and 70 did not (non-endometriosis group). An operator (not the surgeon) measured the distance from the clitoral surface to the anus (AGD-AC) and from the posterior fourchette to the anus (AGD-AF) before surgery using a millimetre accuracy ruler. Endometriosis was diagnosed on exploration of the abdominopelvic cavity, and the r-ASRM and ENZIAN scores were calculated. All removed tissues underwent pathological examination.MAIN RESULTS AND THE ROLE OF CHANCEMean (±SD) AGD-AF measurements were 21.5 mm (±6.4) and 32.3 mm (±8.1), and average AGD-AC measurements were 100.9 mm (±20.6) and 83.8 mm (±12.9) in the endometriosis and non-endometriosis groups (P < 0.001), respectively. Mean AGD-AF and AGD-AC measurements were not related to r-ASRM stage (P = 0.73 and 0.80, respectively) or ENZIAN score (P = 0.62 and 0.21, respectively). AGD-AF had a better predictive value than AGD-AC for discriminating the presence of endometriosis (AUC = 0.840 (95% CI 0.782–0.898) and 0.756 (95% CI 0.684–0.828)), respectively. For AGD-AF, an optimal cut-off of 20 mm had a specificity of 0.986 (95% CI 0.923–0.999), sensitivity of 0.306 (95% CI 26.1–31.6) and positive predictive value of 0.969 (95% CI 0.826–0.998). In multivariable analysis, the diagnosis of endometriosis was the only variable independently associated with the AGD-AF (β = −9.66 mm 95% CI −12.20–−7.12), P < 0.001).LIMITATIONS, REASONS FOR CAUTIONThe sample size was relatively small with a high proportion of patients with colorectal endometriosis reflecting the activity of an expert centre. Furthermore, we did not include adolescents and the AGD-AF measurement could be particularly relevant in this population.WIDER IMPLICATIONS OF THE FINDINGSThe measurement of AGD could be a useful non-invasive tool to predict endometriosis. This could be especially relevant for adolescents and virgin women to avoid diagnostic laparoscopy and empiric treatment.STUDY FUNDING/COMPETING INTEREST(S)None.

Anti-androgenic endocrine-disrupting chemicals (EDCs) can cross the placenta to modify early offspring sexual dimorphic markers. These changes are linked to anogenital distance (AGD), which is an androgen-sensitive anthropometric parameter used as a biomarker of perineal growth and caudal migration of the genital tubercle. This review aimed to summarize strength of evidence for associations of in utero exposure to EDCs with AGD and to identify gaps and limitations in the literature so as to inform future research. We performed an electronic search of English literature in September 2019 in medical literature analysis and retrieval system online (MEDLINE), Web of Science and Toxline. We included epidemiological studies that examined in utero exposure to persistent and nonpersistent EDCs and considered AGD in offspring as an outcome. Our review contained 16 investigations examining exposure to persistent EDCs (nine studies) and nonpersistent EDCs (seven studies). Some individual studies reported an inverse association between exposure to bisphenol A (BPA), dioxins, perfluoroalkyl substances, and organochlorides and AGD in both male and female offspring. Meta-analysis of three studies found a small reduction of AGD in female offspring exposed to BPA. The number of studies per chemical is small, and number of subjects examined is limited; so, replication of these results is needed. To achieve more specificity and better replication of results, future studies should establish the association of nonpersistent EDCs using multiple urine samples, evaluate the cumulative impact of exposure to a mixture of anti-androgenic chemicals, and offer adequate consideration of more maternal- and children-related confounding factors. Summary sentence Early-life exposure to anti-androgenic endocrine disrupting chemicals provide inconsistent findings demonstrating an inverse association between higher maternal levels of some chemicals and anogenital distance, the effect being more common in male offspring.

STUDY QUESTION Could the anogenital distance (AGD) as assessed by MRI (MRI-AGD) be a diagnostic tool for endometriosis? SUMMARY ANSWER A short MRI-AGD is a strong diagnostic marker of endometriosis. WHAT IS KNOWN ALREADY A short clinically assessed AGD (C-AGD) is associated with the presence of endometriosis. STUDY DESIGN, SIZE, DURATION This study is a re-analysis of previously published data from a case–control study. PARTICIPANTS/MATERIALS, SETTING, METHODS Women undergoing pelvic surgery from January 2018 to June 2019 and who had a preoperative pelvic MRI were included. C-AGD was measured at the beginning of the surgery by a different operator who was unaware of the endometriosis status. MRI-AGD was measured retrospectively by a senior radiologist who was blinded to the final diagnosis. Two measurements were made: from the posterior wall of the clitoris to the anterior edge of the anal canal (MRI-AGD-AC), and from the posterior wall of the vagina to the anterior edge of the anal canal (MRI-AGD-AF). MAIN RESULTS AND THE ROLE OF CHANCE The study compared MRI-AGD of 67 women with endometriosis to 31 without endometriosis (controls). Average MRI-AGD-AF measurements were 13.3 mm (±3.9) and 21.2 mm (±5.4) in the endometriosis and non-endometriosis groups, respectively (P < 10−5). Average MRI-AGD-AC measurements were 40.4 mm (±7.3) and 51.1 mm (±8.6) for the endometriosis and non-endometriosis groups, respectively (P < 10−5). There was no difference of MRI-AGD in women with and without endometrioma (P = 0.21), or digestive involvement (P = 0.26). Moreover, MRI-AGD values were independent of the revised score of the American Society of Reproductive Medicine and the Enzian score. The diagnosis of endometriosis was negatively associated with both the MRI-AGD-AF (β = −7.79, 95% CI (−9.88; −5.71), P < 0.001) and MRI-AGD-AC (β = −9.51 mm, 95% CI (−12.7; 6.24), P < 0.001) in multivariable analysis. Age (β = +0.31 mm, 95% CI (0.09; 0.53), P = 0.006) and BMI (β = +0.44 mm, 95% CI (0.17; 0.72), P = 0.001) were positively associated with the MRI-AGD-AC measurements in multivariable analysis. MRI-AGD-AF had an AUC of 0.869 (95% CI (0.79; 0.95)) and outperformed C-AGD. Using an optimal cut-off of 20 mm for MRI-AGD-AF, a sensitivity of 97.01% and a specificity of 70.97% were noted. LIMITATIONS, REASONS FOR CAUTION This was a retrospective analysis and no adolescents had been included. WIDER IMPLICATIONS OF THE FINDINGS This study is consistent with previous works associating a short C-AGD with endometriosis and the absence of correlation with the disease phenotype. MRI-AGD is more accurate than C-AGD in this setting and could be evaluated in the MRI examination of patients with suspected endometriosis. STUDY FUNDING/COMPETING INTEREST(S) N/A. TRIAL REGISTRATION NUMBER The protocol was approved by the ‘Groupe Nantais d’Ethique dans le Domaine de la Santé’ and registered under reference 02651077.

The timing of exposure to testosterone produces activational and organizational effects in vertebrates. Evidence in female birds and mammals suggests that high serum testosterone levels, and the exposure to high testosterone levels during early development, are negatively associated with female fertility and sexual attractiveness to males. We tested these hypotheses by examining associations between serum testosterone levels (an indirect index of activational effects), anogenital distance (AGD, a direct index of organizational effects), the number of male mating partners attained by females, and the number of offspring weaned. We examined 160 wild degu ( Octodon degus ) females during the mating season, and 308 females during the nursing season, across an 11-year study. During the mating season, we found no association between female serum testosterone levels or AGD on the number of male mating partners, and on the number of offspring weaned. However, we found that the number of male mating partners was positively associated with the number of offspring weaned, suggesting that females attain direct fitness benefits from polyandrous mating. During the nursing season, we recorded a positive association between female AGD and the number of offspring weaned. This indicates that testosterone organizational effects positively impact female fertility. This finding is unique and adds to the theoretical framework of female phenotypical masculinization via intrauterine position phenomenon.