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STUDY QUESTION: Does anogenital distance (AGD) - distance from the anus to the genitals - correlate from infancy (3 months) to the age of 9 years in boys and girls? SUMMARY ANSWER: In boys, AGD correlated from infancy to 9 years of age, whereas in girls, correlations were weaker, especially between infancy and later childhood. WHAT IS KNOWN ALREADY: AGD is considered a marker for prenatal androgen action. In males, reduced AGD is associated with testicular cancer, infertility, and lower sperm count. In females, AGD is associated with endometriosis and polycystic ovary syndrome. STUDY DESIGN SIZE DURATION: In the Odense Child Cohort, a prospective population-based birth cohort, pregnant women were enrolled in early pregnancy. AGD and BMI were measured repeatedly in children at ages 3 and 18 months, as well as at 3, 5, 7, and 9 years. PARTICIPANTS/MATERIALS SETTING METHODS: AGD was measured from the anus to the scrotum (AGDas) and to the penis (AGDap) in 1022 boys, and to the posterior fourchette and the clitoris in 887 girls repeatedly between the age of 3 months to 9 years. In total, 7706 assessments were made. AGD was adjusted for body weight, and SD scores (the difference between individual AGD and the mean of AGD in the population divided by SD of AGD) were calculated for each child. Pearson correlation coefficient (r) of each measurement was performed to investigate whether individual AGD was stable during childhood. Short predictive values at 3 months (20th percentile) to 9 years were investigated using the AUC produced by the receiver operating characteristic curve. MAIN RESULTS AND THE ROLE OF CHANCE: In boys, AGD/body size-index SD score correlated significantly between infancy and 9 years, strongest for AGDas (r = 0.540 P > 0.001). In girls, weaker significant correlation coefficients were found between AGD at infancy and 9 years; higher correlation coefficients were found between AGD from 3 to 9 years (P > 0.001). Short AGDas in infancy predicted short AGDas in boys aged 9 years (AUC: 0.767, sensitivity 0.71, specificity 0.71). The predictive values of short infant AGDap, penile width (in boys), and AGD (in girls) concerning short outcomes at 9 years were low. LIMITATIONS REASONS FOR CAUTION: The AGD measurements are less precisely measurable in girls compared to boys, especially in infancy, resulting in less reproducible measurements. Additionally, because AGD is shorter in girls, the same absolute measurement error is relatively more significant, potentially contributing to greater variability and lower reproducibility in girls. This may contribute to the weaker correlations in girls compared to boys. WIDER IMPLICATIONS OF THE FINDINGS: In boys, AGDas, relative to body size, correlated from infancy to 9 years, suggesting that AGD in infancy can be considered a non-invasive marker of later reproductive health. Further follow-up studies are needed to evaluate long-term individual tracking of AGD as well as assessment of childhood AGD as early marker of adult reproductive health. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Odense University Hospital, Denmark, the Region of Southern Denmark, the Municipality of Odense, Denmark, the University of Southern Denmark, Odense Patient data Exploratory Network (OPEN), Denmark, the Danish Research Council (4004-00352B_FSS), Novo Nordisk Foundation, Denmark (grant no. NNF19OC0058266 and NNF17OC0029404), Sygeforsikring Danmark (journalnr. 2021-0173), the Collaborative Foundation between Odense University Hospital and Rigshospitalet, and Helsefonden. There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported. TRIAL REGISTRATION NUMBER: N/A.

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BACKGROUND: Early identification of fetal gender is crucial for managing gender-linked genetic disorders. This study aimed to evaluate the predictive performance of anogenital distance (AGD) and genital tubercle angle (GTA) for fetal sex determination during the first trimester. METHODS: A multicenter retrospective cohort study was conducted on 312 fetal cases between 11 and 13 + 6 weeks of gestation from two tertiary hospitals. AGD and GTA measurements were taken from midsagittal plane images using ultrasound, with intra- and inter-reader reproducibility assessed. Binomial logistic regression and ROC curve analysis were employed to determine the diagnostic performance and optimal cutoff points. RESULTS: AGD had a mean of 7.16 mm in male fetuses and 4.42 mm in female fetuses, with a sensitivity of 88.8%, specificity of 94.4%, and an area under the ROC curve (AUC) of 0.931 (95% CI: 0.899-0.962) using 5.74 mm as a cutoff point. For GTA, the mean was 35.90 degrees in males and 21.57 degrees in females, with a sensitivity of 92%, specificity of 84.7%, and an AUC of 0.932 (95% CI: 0.904-0.961) using 28.32 degrees as a cutoff point. The reproducibility results were excellent for AGD (intra-operator ICC = 0.938, inter-operator ICC = 0.871) and moderate for GTA (intra-operator ICC = 0.895, inter-operator ICC = 0.695). CONCLUSIONS: The findings suggest that AGD and GTA are reliable markers for early fetal sex determination, with AGD showing higher reproducibility. The findings highlight the feasibility and accuracy of these non-invasive sonographic markers and their potential usefulness in guiding timely interventions and enhancing the management of gender-linked genetic conditions.

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The timing of exposure to the steroid hormone, testosterone, produces activational and organizational effects in vertebrates. These activational and organizational effects are hypothesized to relate with the number of female mating partners and reproductive success in males. We tested this hypothesis by examining 151 wild degu (Octodon degus) males across a 10-year study. We quantified the association between adult serum testosterone levels (i.e., an indirect index of adult activational effects) and anogenital distance (AGD) length (i.e., a direct index of fetal organizational effects), and their interaction on the number of female mating partners and reproductive success. We found no evidence of an association between adult male serum testosterone levels and the number of female mating partners, or between adult male serum testosterone levels and reproductive success. However, male AGD was positively associated with reproductive success, but not so with the number of female mating partners. Additionally, the positive association between male AGD and male reproductive success was mediated by the number of mates. Our findings do not support major roles of activational or organizational effects of testosterone on the number of female mating partners and its consequences on male reproductive success. Instead, our results suggest that compared with individual male attributes, the female social environment plays a more important role in driving male reproductive success.

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Introduction: Assessment of genitalia is an important part of the neonatal examination. Regional, racial, and ethnic variations in phallic length have been documented. Clitoral dimensions may also show similar variations. Normal values for neonatal clitoral measurements may help the pediatrician/neonatologist to accurately diagnose clitoromegaly and underlying etiology to guide appropriate investigations. Data on clitoral measurements is limited with only one study from India (Kolkata). Hence we aimed in this study to generate south Indian data on neonatal clitoral dimensions, anogenital distance, and anogenital ratio. Two hundred and fifty two hemodynamically stable term female neonates without ambiguous genitalia/vulval masses born in a community hospital. Hospital-based cross-sectional study. 1. To measure clitoral dimensions, anogenital distance, and anogenital ratio in female neonates. 2. To correlate clitoral dimensions, anogenital distance, and ratio with anthropometric measurements, gestational age, and maternal comorbidities. Methods: Measurements were recorded using a digital vernier caliper, under strict aseptic precautions with labia majora gently separated and the baby held in a frog-leg position. Clitoral length, width, and anogenital distance were measured and anogenital ratio and clitoral index were calculated. Results: In term neonates, the mean ± SD of clitoral length (CL), clitoral width (CW), anogenital ratio (AGR) were 6.34 ± 1.75 mm, 6.39 ± 1.27 mm and 0.39 ± 0.05, respectively. The 3rd and 97th centiles for mean clitoral length were 3.55 and 9.93 mm, for mean clitoral width were 3.37 and 8.35 mm, and for AGR were 0.28 and 0.48, respectively. These clitoral dimensions in south Indian neonates were higher than those from East India (Kolkata), lower than Nigerian babies, and similar to Israeli neonates. Mean CL and CW had no statistical correlation with birth weight, gestational age, head circumference, or length in term neonates. A significant correlation was noted between pregnancy-induced hypertension and mean clitoral width, and between gestational diabetes and AGR. Conclusion: Normative values for clitoral dimensions (length and width) and AGR for south Indian term female neonates have been established. 97th centiles of 9.93 mm (CL) and 8.35 mm (CW) and 0.48 mm (AGR) may be used as practical cut-offs to diagnose clitoromegaly and virilization. Clitoral measurements had no statistical correlation with birth weight, gestational age, or anthropometry. Clitoral measurements exhibit ethnic and racial differences, thus emphasizing the importance of regional cut-offs and need for more studies from different parts of India on CL.

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BACKGROUND: Measurement of rat anogenital distance (AGD) dates to at least 1912. Increased interest in endocrine disrupting chemicals and the use of AGD as a biomarker for fetal androgen effects have increased the number of studies with this endpoint in recent decades. A literature review revealed different landmarks, methods of measurement, and methods to adjust for body weight differences. AGD is often reported to hundredths of millimeters and as such, deserves precision in all these aspects. This paper presents recommendations for the measurement and analysis of rodent AGD. METHODS: Literature and regulatory guidance documents that mentioned or measured rodent AGD were reviewed. Four adjustment methods were evaluated using available online data from three rat studies each with two generations of offspring. RESULTS: Tabulation of studies reveals that species/stocks and time of data collection, but more importantly anatomical landmarks and methods of measurement have produced a variety of results which are difficult to compare. Not all studies have adjusted for test article effects on body weight (and thus size). The four adjustment methods were fairly comparable. CONCLUSION: Recommendations are as follows. A microscopic method should be used to measure AGD of late rodent fetuses and early postnatal pups. The caudal edge of the genital tubercle and the cranial edge of the anus are clear and identifiable landmarks. The simplest adjustment is to divide individual AGDs by the cube root of animals' body weight. These recommendations will help ensure data consistency and accuracy, and facilitate meaningful comparisons across laboratories and chemical classes.

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Objectives: To describe the anatomical abnormalities of hypospadias before puberty using current commonly used anthropometric index data and predict postoperative diagnostic classification. Methods: Children with hypospadias before puberty who were initially treated at Sichuan Provincial People's Hospital from April 2021 to September 2022 were selected. We recorded their preoperative penoscrotal distance, anogenital distance, 2D:4D finger ratio, and postoperative hypospadias classification. The receiver operating character curve was used for univariate analysis of the diagnostic predictive value of each index for hypospadias classification in the training set. Binary logistic regression, random forest, and support vector machine models were constructed. In addition, we also prospectively collected data from October 2022 to September 2023 as a test set to verify the constructed machine learning models. Results: This study included 389 cases, with 50 distal, 167 midshaft, and 172 proximal cases. In the validation set, the sensitivity of the binary LR, RF, and SVM was 17%, 17% and 0% for identifying the distal type, 61%, 55% and 64% for identifying the midshaft type, and 56%, 60% and 48% for identifying the proximal type, respectively. The sensitivity of the three-classification RF and SVM models was 17% and 17% for distal type, 64% and 73% for midshaft type, 60% and 60% for proximal type, respectively. In the Testing set, the sensitivity of the binary LR, RF and SVM was 6%, 0% and 0% for identifying the distal type, 64%, 55% and 66% for identifying the midshaft type, and 48%, 62% and 39% for identifying the proximal type, respectively. The sensitivity of the three-classification RF and SVM models was 12% and 0% for distal type, 57% and 77% for midshaft type, and 65% and 53% for proximal type, respectively. Compared with binary classification models, the sensitivity of the three-classification models for distal type was not improved. Conclusion: Anogenital distance and penoscrotal distance have a favorable predictive value for midshaft and proximal hypospadias, among which AGD2, with higher test efficiency and stability, is recommended as the preferred anogenital distance indicator. The 2D:4D finger ratio (RadioL, RadioR) has little predictive value for hypospadias classification.

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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. OBJECTIVES: We present longitudinal measurements of fetal- and infant AGD. We evaluate the impact of testosterone and dihydrotestosterone at minipuberty on AGD and penile size. DESIGN: Secondary analyses of an observational, prospective pregnancy and birth cohort, COPANA (2020-2022). SETTING: Copenhagen University Hospital - Rigshospitalet. PARTICIPANTS: 685 healthy, singleton pregnant women enrolled, 657 women attended 3rd trimester ultrasound, 589 infants completed follow-up. MAIN OUTCOME MEASURES: 3rd trimester ultrasound (GW29-34): Fetal AGD. Minipuberty clinical examination (app. 3.5 months postpartum): infant AGD, penile width and stretched length (SPL), circulating testosterone and dihydrotestosterone (LC-MS/MS). RESULTS: AGD was available in 650/657 fetuses (310 boys) and 588/589 infants (287 boys). Boys had longer fetal and infant AGD compared to girls; fetal AGDas: mean (SD) 21.4 mm (±3.5), fetal AGDaf: 12.8 mm (±2.3), p < 0.001, infant AGDas: 32.0 mm (±5.6) and infant AGDaf: 15.8 (±3.3), p < 0.001. Fetal AGD correlated with infant AGD in boys and girls (Spearman's r = 0.275, p < 0.001 and r = 0.189, p = 0.001 respectively), but not with circulating testosterone or dihydrotestosterone at minipuberty. Penile size correlated positively with circulating androgen levels at minipuberty, i.e.: SPL vs testosterone: r = 0.235, p < 0.001. CONCLUSIONS: AGD is sexual dimorphic already in the 3rd trimester. Fetal and infant AGD correlates. 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.

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Dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP), two common types of phthalates, are known to cause reproductive and developmental toxicity in animals and humans. The reference doses (RfD) of DBP and DEHP should be determined by sensitive endpoints. We here aimed to identify sensitive endpoints for DBP- and DEHP-induced such toxicity using published literatures. By examining the impacts of maternal exposure to DBP or DEHP on anogenital distance (AGD) and semen quality of offspring, we discovered that DBP or DEHP caused AGD decline in boys but increase in girls with DBP being more potent and the first 14weeks of pregnancy being more susceptible, suggesting a chemical- and time-dependent phenomenon. We also identified AGD shortening and total sperm count reduction as two sensitive endpoints for DBP- or DEHP-induced reproductive and developmental toxicity, respectively. Based upon these two endpoints and the employment of the Bayesian benchmark dose approach with an uncertainty factor of 3,000, we estimated the RfD values of DBP and DEHP were 15 µg/kg/day and 36 µg/kg/day, respectively. Thus, we uncover previously unrecognized phenomena of DBP- or DEHP-induced reproductive and developmental toxicity and establish new and comparable or more conservative RfDs for the risk assessment of phthalates exposure in humans.

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OBJECTIVE: To investigate the anogenital distance from the upper verge of the anus to the posterior fourchette (AGDAF), FASL, and BCL2 combination as a reliable and non-invasive tool for the diagnosis of endometriosis. METHODS: This study included 100 women with endometriosis and 50 women without endometriosis as the control group. All cases underwent history taking, body mass index (BMI) measurement, AGD measurement, and FASL and BCL2 immunohistochemical staining of the eutopic endometrial tissue. RESULTS: This study included 150 women divided into endometriosis and control groups. Endometriosis cases significantly had shorter AGDAF, 22.9 ± 2.6 mm, compared with the control group, 27.3 ± 3.5 mm (P < 0.001). Lower FASL and higher BCL2 expression were associated with endometriosis (P < 0.001). The combined measurement of AGDAF (cut-off point 24.55 mm) with FASL and BCL2 was associated with endometriosis (P < 0.001). The combined diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of AGDAF, FASL, and BCL2 were 83%, 78%, 87.3%, and 69.6%, respectively. The area under the curve was greater for AGDAF, FASL, and BCL2 in combination than for individual measurements. CONCLUSION: Combining short AGDAF with high BCL2 and low FASL is a highly sensitive, non-invasive diagnostic tool for endometriosis.

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STUDY QUESTION: Do different boys with different types of cryptorchidism exhibit different anogenital distances (AGDs)? SUMMARY ANSWER: Length of AGD seemed to differ in different groups of patients with cryptorchidism. WHAT IS KNOWN ALREADY: AGD, which is used as an indicator of prenatal androgen action, tends to be shorter in boys with cryptorchidism compared to unaffected boys. Shorter AGDs have also been reported in boys with hypospadias, in men with poor semen quality, and in men with testicular cancer. STUDY DESIGN, SIZE, DURATION: A prospective descriptive cohort study was performed using data from consecutively selected boys with cryptorchidism (n = 169) operated in a single center over a period of 3 years (September 2019 to October 2022). PARTICIPANTS/MATERIALS, SETTING, METHODS: AGD was measured in 169 infant boys, at 3 to 26 months of age, during anesthesia with a vernier caliper measuring the distance from the anus to the base of the scrotum (AGDAS) and from the anus to the anterior base of the penis (AGDAP) in two body positions according to the methods by 'The Infant Development and the Environment Study' (TIDES) and 'Cambridge Baby Growth Study', resulting in four mean values per patient (TIDES AGDAS/AP and Cambridge AGDAS/AP). Normal values for AGD by age were set by our hospital Department of Growth and Reproduction based on a large cohort of healthy infant boys (n = 1940). Testicular biopsies were performed at orchidopexy as a clinical routine. The germ cell number (G/T) and type Ad spermatogonia number (AdS/T) per cross-sectional tubule of at least 100 and 250 tubules, respectively were measured and related to normal samples. Blood samples were obtained by venipuncture for measuring serum LH, FSH, and inhibin B. They were analyzed in our hospital Department of Growth and Reproduction where the normal reference was also established. Correlations between the four mean AGD measurements for each boy were evaluated by Spearman rank correlation analyses. The AGD measurement of every boy was transferred to the multiple of the median (MoM) of the normal AGD for age and named MoM AGD. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 boysoperated for unilateral, and 47 boys operated for bilateral, undescended testes, whereas 18 boys had vanished testis including one boy with bilateral vanished testes. Only 6% of cases with vanished testes had a MoM AGD higher than the normal median compared to 32% with undescended testes (P < 0.05). MoM AGD increased with the age at surgery for boys with vanished testis (Spearman r = 0.44), but not for boys with undescended testes (Spearman r = 0.14). Boys with bilateral cryptorchidism had longer AGDs and more often had hypogonadotropic hypogonadism than boys with unilateral cryptorchidism (P < 0.005) and (P < 0.000001). LIMITATIONS, REASONS FOR CAUTION: Although being the largest published material of AGD measurements of infant boys with cryptorchidism, one limitation of this study covers the quite small number of patients in the different groups, which may decrease the statistical power. Another limitation involves the sparse normal reference material on G/T and AdS/T. Finally, there are currently no longitudinal studies evaluating AGD from birth to adulthood and evaluating childhood AGD in relation to fertility outcome. Our study is hypothesis generating and therefore the interpretation of the results should be regarded as exploratory rather than reaching definite conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The study findings are in agreement with literature as the total included group of boys with cryptorchidism exhibited shorter than normal AGDs. However, new insights were demonstrated. Boys with vanished testis had shorter AGDs compared to unaffected boys and to boys with undescended testes. This finding challenges the current concept of AGD being determined in 'the masculinization programming window' in Week 8 to 14 of gestation. Furthermore, boys with bilateral cryptorchidism had longer AGDs and more often had hypogonadotropic hypogonadism than boys with unilateral cryptorchidism, suggesting that the lack of fetal androgen in hypogonadotropic hypogonadism is not that significant. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and no competing interests are declared. TRIAL REGISTRATION NUMBER: The trial was not registered in an ICMJE-recognized trial registry.

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In vertebrates, male testosterone levels vary across the year being generally higher during the mating season relative to the offspring rearing season. However, male testosterone levels may also be associated with male anogenital distance (AGD) length (a proxy of prenatal androgen exposition), and influenced by the social group environment. In social species, it has been proposed that high levels of testosterone could be incompatible with the development of an amicable social environment. Thus, in these species, it is predicted that males have relatively low levels of testosterone. Our goal was to examine the potential association between male serum testosterone levels, season, male AGD length, and the social environment in the rodent Octodon degus under natural conditions. We quantified male serum testosterone levels during the mating and offspring rearing seasons, and we determined the number of females and males in each social group, as well as the composition of groups, in terms of the AGD length of the female and male group mates, from 2009 to 2019. Our results revealed that male testosterone levels covary with season, being highest during the offspring rearing season. Additionally, male testosterone levels vary with male AGD length, and female and male social group environments. More importantly, male degus exhibit low levels of testosterone that are indistinguishable from female levels during offspring rearing season. Similar to other highly social mammals, where males and females live together year-round, male amicable behavior could be the best male mating strategy, thus leading to a reduction in circulating testosterone levels.

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Testosterone is known as a "male" hormone; however, females also synthetize testosterone, which influences female sexual and aggressive behavior. In female vertebrates, as in males, testosterone levels can vary seasonally. However, female testosterone levels may also be related with female anogenital distance (AGD) length phenotype (a proxy of prenatal androgen exposure), and the social group environment. We used data from a long-term rodent study (2009-2019) in a natural population of degus (Octodon degus) to examine the potential associations between female serum testosterone levels, season, female AGD phenotype, and social group composition. We quantified female serum testosterone levels during the mating and offspring rearing seasons, and we determined the number of females and males in social groups, as well the composition of groups, in terms of the AGD of the female and male group mates. Our results indicate that female testosterone levels vary with season, being highest during the offspring rearing season. Additionally, female testosterone levels were associated with the number of male group-members and the AGD of male group-members but were not associated with female social environment and focal female AGD phenotype. Together, our results suggest that female testosterone levels are sensitive to intersexual interactions. Our results also reveal that female and male testosterone levels do not differ between the sexes, a finding previously reported only in rock hyraxes. We discuss how the complex social system of degus could be driving this physiological similarity between the sexes.

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Organophosphate (OP) insecticides are some of the most abundantly used insecticides, and prenatal exposures have been linked to adverse maternal and child health outcomes. Anogenital distance (AGD) has emerged as an early marker of androgen activity, and later reproductive outcomes, that is sensitive to alteration by environmental chemicals. Here, we examined associations between prenatal exposure to chlorpyrifos, an OP insecticide, with AGD. Pregnant farmworkers were enrolled in the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE; N = 104) between 2017 and 2019 in Northern Thailand. Concentrations of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of chlorpyrifos, were measured in composited urine samples obtained from each trimester of pregnancy. AGD was measured at 12 months of age. Sex-specific adjusted linear regression models were used to examine associations between average and trimester-specific TCPy levels and AGD. In adjusted models for females and males, increasing TCPy was consistently associated with a modest, non-significant reduction in AGD. Across both strata of sex, associations were greatest in magnitude for trimester 3 (females: ß = -2.17, 95 % confidence interval (CI) = -4.99, 0.66; males: ß = -3.02, 95 % CI = -6.39, 0.35). In the SAWASDEE study, prenatal chlorpyrifos exposure was not strongly associated with AGD at 12 months of age.

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Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants ubiquitous in the environment and humans. In-utero PFAS exposure is associated with numerous adverse health impacts. However, little is known about how prenatal PFAS mixture exposure affects offspring's neurobehavioral function. This study aims to determine the causal relationship between in-utero PFAS mixture exposure and neurobehavioral changes in Sprague-Dawley rat offspring. Dams were exposed via drinking water to the vehicle (control), an environmentally relevant PFAS mixture, or a high-dose PFAS mixture. The environmentally relevant mixture was formulated to resemble measured tap water levels in Pittsboro, NC, USA (10 PFAS compounds; sum PFAS =758.6 ng/L). The high-dose PFAS load was 3.8 mg/L (5000×), within the range of exposures in the experimental literature. Exposure occurred seven days before mating until birth. Following exposure to PFAS-laden water or the vehicle during fetal development, neurobehavioral toxicity was assessed in male and female offspring with a battery of motor, cognitive, and affective function tests as juveniles, adolescents, and adults. Just before weaning, the environmentally relevant exposure group had smaller anogenital distances compared to the vehicle and high-dose groups on day 17, and males in the environmentally relevant exposure group demonstrated lower weights than the high-dose group on day 21 (p < 0.05). Reflex development delays were seen in negative geotaxis acquisition for both exposure groups compared to vehicle-exposed controls (p = 0.009). Our post-weaning behavioral measures of anxiety, depression, and memory were not found to be affected by maternal PFAS exposure. In adolescence (week five) and adulthood (week eight), the high PFAS dose significantly attenuated typical sex differences in locomotor activity. Maternal exposure to an environmentally relevant PFAS mixture produced developmental delays in the domains of pup weight, anogenital distance, and reflex acquisition for rat offspring. The high-dose PFAS exposure significantly decreased typical sex differences in locomotor activity.

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Background: Phthalates are ubiquitous anti-androgenic endocrine disrupting chemicals found in personal care products, medications, and many plastics. Studies have shown a racial disparity in phthalates exposure among U.S. women, which may also impact fetal development. Methods: We conducted a prospective cohort study of gestational exposure to a phthalates mixture in a racially-diverse population to determine their association with genital development. Mid-gestation (18-22 weeks) urine was collected from 152 women who self-identified as non-Hispanic Black and 158 women who self-identified as non-Hispanic White in Charleston, South Carolina between 2011 and 2014. We measured eight phthalate monoester metabolites in urine using liquid chromatography tandem-mass spectrometry. Mid-gestational penile dimensions were measured using ultrasound and anogenital distances were measured postnatally. We used Bayesian kernel machine regression to estimate the associations among the mixture of phthalate metabolites and mid-gestation penile dimensions and postnatal anogenital distance measures among singleton male (n = 179) and female (n = 131) infants, adjusted for urinary specific gravity, maternal age, body mass index, education level, cigarette smoking, and gestational age at enrollment or birth weight z-score. Results: We found a stronger association between greater phthalates and decreased anopenile distance among infants born to women who self-identified as Black. Mono (2-ethylhexyl) phthalate (MEHP) was the driving mixture component among Black women, and monobutyl phthalate (MBP) and monoethyl phthalate (MEP) were drivers among White women. We also identified a non-linear association between phthalates and lesser ultrasound penile volume among women who self-identified as Black with monoisobutyl phthalate (MiBP) and MBP being most important. We also found an association between greater phthalates and shorter anoclitoral distance among infants born to women who self-identified as Black, with MEP and monobenzyl phthalate (MBzP) contributing most to this association. Conclusion: Our results suggest a disparity in the association between gestational exposure to a mixture of phthalates and fetal genital development among women who self-identified as Black compared to White.

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We investigated whether anogenital distance (AGD) is associated with adenomyosis, endometriosis and uterine leiomyomas (UL, also called uterine fibroids). We recruited 81 women with UL, 105 with ovarian endometrioma (OE), 116 with adenomyosis, 28 with both adenomyosis and UL, and 100 control subjects with other acquired gynecological conditions but not endometriosis, adenomyosis, UL, or polycystic ovarian syndrome. Measurements from the anterior clitoral surface to the center of the anus (AGDAC), from the tip of the clitoris to the center of the anus (AGDACt), and from the posterior fourchette to the center of the anus (AGDAF) were made in all subjects. Multiple regression was performed to estimate the association between AGDs and presence of OE, adenomyosis, and UL while controlling for possible confounding factors. We found that, compared with controls, women with OE and adenomyosis, but not UL, had significantly shorter AGDAF, but not AGDAC. However, the amount of variance that could be explained by the disease status is rather moderate, suggesting that factors other than disease status, bodyweight and height were also responsible for AGD. Thus, prenatal exposure to reduced levels of androgen may increase the risk of developing endometriosis and adenomyosis. However, other factors may also contribute to the pathogenesis of endometriosis and adenomyosis.

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Per- and polyfluoroalkyl substances (PFAS) are persistent, ubiquitous pollutants, and the current epidemiological evidence regarding the impact of in utero exposure to PFAS on anogenital distance (AGD) is limited and inconclusive. The primary aim of this study was to investigate the potential associations between maternal exposure to PFAS during pregnancy and AGD in newborns. A total of 2273 mother-child pairs were recruited for this study, and both PFAS levels and AGD were measured. Multiple linear regression models were utilized to explore the relationships between individual PFAS and AGD. Additionally, quantile-based g-computation (QGC) was employed to assess the joint effects of mixtures of PFAS on AGD. Our findings showed that maternal exposure to PFOS (ß = 0.518, 95% CI: 0.093, 0.942), PFNA (ß = 0.487, 95% CI: 0.037, 0.937), PFDA (ß = 0.443, 95% CI: 0.048, 0.838), PFUA (ß = 0.434, 95% CI: 0.031, 0.838), and PFBS (ß = 0.444, 95% CI: 0.124, 0.763) during early pregnancy had a significant positive association with AGD in boys. Similarly, in girls, maternal exposure to PFOS (ß = 0.423, 95% CI: 0.006, 0.841), PFNA (ß = 0.641, 95% CI: 0.207, 1.074), PFDA (ß = 0.670, 95% CI: 0.306, 1.033), PFUA (ß = 0.895, 95% CI: 0.509, 1.281), and PFBS (ß = 0.474, 95% CI: 0.178, 0.770) had a positive association with AGD, while PFOA (ß = -1.254, 95% CI: -1.786, -0.723) had a negative association. QGC models further confirmed that PFAS mixtures were positively associated with AGD. Moreover, PFBS was the primary contributor to the joint effects of PFAS mixtures on AGD. In summary, our study has provided further corroboration for the possibility that PFAS exposure can have an impact on AGD in both boys and girls. The use of AGD as a promising biomarker for endocrine disruption highlights the significance of our findings, which may have valuable clinical implications for reproductive diseases.

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OBJECTIVES: To establish gestation-wise normative data of external genitalia measurements in North Indian term and preterm female newborns. METHODS: In this cross-sectional descriptive study, institutionally-born female neonates between 28-42 wk gestation were consecutively enrolled between 24-72 h of life. Newborns with major congenital malformations, chromosomal anomalies, multifetal gestation and birth injuries were excluded. Data on various genital measurements were collected [Clitoral length (CL), clitoral width (CW), ano-clitoral distance (AGDAC), ano-fourchette distance (AGDAF) and anogenital ratio (AGR)]. RESULTS: One hundred ninety-eight of 508 neonates (39%) were preterm and 310 (61%) were term. Mean (± SD) CL and CW were 4.6 ± 1.8 mm and 3.9 ± 1.6 mm, respectively. Mean (± SD) values for AGDAF, AGDAC and AGR were 9.3 ± 1.8 mm, 30.2 ± 3.9 mm, and 0.31 ± 0.05, respectively. According to these results, term female newborns with CL more than 7 mm and/or CW more than 6 mm (95th centile) warrant evaluation for clitoromegaly. An anogenital ratio greater than 0.45 should be considered as a sign of virilization in a female neonate. Gestation-wise percentile charts for CL, CW, AGDAF, AGDAC and AGR were generated. CONCLUSIONS: The percentile values defined in the study can serve as local normative data for accurate interpretation of genital measurements in North Indian female newborns and enable health care professionals for early identification of genital virilization.

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The anogenital distance (AGD) is considered a marker for prenatal androgen exposure and fertility in multiple species including humans. In dairy cattle, it is described as the length between the center of the anus and the clitoral base (AGDc). However, in other species, the distance from the center of the anus to the dorsal commissure of the vulva (AGDv) is also considered to be a predictor for fertility traits, as well as the anogenital ratio (AGR, defined as [AGDv/AGDc]*100). The primary aim of the present study was to assess whether AGDv and AGR can be used as an indicator for reproductive performance in dairy heifers. Additionally, the relation between AGDv and AGDc and the correlation with other body measurements were explored. Data of 656 Holstein Friesian heifers at an age of 13.5 ± 1.08 months were analyzed. Respective means of 62.9 ± 8.20 mm (AGDv) and 107.6 ± 9.27 mm (AGDc) were recorded. The mean AGR ratio was calculated as 58.6 ± 6.75%, varying from 37.3 to 79.6%. The age of the heifers was not associated with any of the AGD measurements nor the ratio. Except for a very low correlation between heart girth and AGDc (r = 0.09, P < 0.05), both AGDs were largely uncorrelated with other body measurements. Linear regression models revealed that AGDc was not associated with any of the recorded fertility parameters. However, results revealed a negative association between AGDv and AGR and reproductive performance: heifers with a short AGDv and small AGR were younger at first AI (P ≤ 0.003) and at conception (P = 0.004). Based on ROC curve analyses, AGDv was the best indicator for pregnancy to first AI, with a threshold estimated at 65.3 mm. The pregnancy rate at first AI was 72.4% in heifers with a short AGDv (<65.3 mm, n = 413) compared to 61.7% in heifers with a long AGDv (≥65.3 mm, n = 243). Hence, short-AGDv heifers had 63% higher odds to conceive at first AI compared to their long-AGDv counterparts (P = 0.004). Additionally, an AGR threshold of 59,6% was determined: heifers with a small AGR (<59.6%) had 44% higher odds to be pregnant at first AI compared to heifers with an AGR ≥59.6%. Results of the present study suggest to consider AGDv and AGR as potential indicators for reproductive performance in dairy heifers. The latter implies that it is relevant to measure both AGDc and AGDv in future studies. The absence of correlation between body- and AGD-measurements furthermore suggests that AGD sizes are rather pre-than postnatally determined.

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OBJECTIVE: Previous studies revealed that prenatal exposure to androgen excess such as polycystic ovary syndrome (PCOS) is associated with offspring's anogenital distance (AGD) length, and AGD is a biomarker of intrauterine androgen exposure. This study aims to investigate a possible relationship of fetal AGD with maternal diabetes and obesity, and to evaluate whether AGD predicts the fetal androgen exposure related to diabetes and obesity in female fetus. This study is the first to focus on the relationship between offspring's AGD and maternal diabetes and obesity. MATERIALS AND METHODS: This is a prospective study investigating 218 pregnant women (125 in control group and 93 in study group). Fetal AGD was measured from the center of anus to the posterior convergence of the fourchette by ultrasound. Multivariate linear regression analysis was applied to assess the association of the fetal AGD length with maternal diabetes and obesity. RESULTS: The control patients had significantly shorter fetal AGD (mean:10.7 mm, P < 0.001) compared to diabetic, obese and diabetic obese patients (mean: 12.6 mm, 12.8 mm and 12.9 mm, respectively). The results of regression analysis showed that both maternal diabetes and obesity were significantly correlated with longer AGD in female fetus. The results confirmed also that offspring's AGD measurement in utero by ultrasound is feasible and reliable. CONCLUSION: The study findings suggest that both maternal diabetes and obesity are associated with intrauterine androgenic milieu during pregnancy, and fetal AGD may be used as a biomarker to predict this effect. This may provide important advantages in terms of early detection of reproductive system abnormalities related to prenatal androgen exposure.

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