Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life

Biostatistics and Epidemiology Division, Health Canada, Ottawa, Ontario, Canada.
Environmental Health Perspectives (Impact Factor: 7.98). 07/2008; 116(7):948-51. DOI: 10.1289/ehp.11226
Source: PubMed


An international workshop titled "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.

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    • "This is supported by several animal studies (Dean et al. 2012; van den Driesche et al. 2012). Measurement of anogenital distance (AGD) has been proposed as a quantitative biomarker of fetal endocrine disruptor exposure in humans (Arbuckle et al. 2008). AGD is a marker of perineal growth and caudal migration of the genital tubercle, and is androgen dependent in male rodents (Bowman et al. 2003). "
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    ABSTRACT: Anogenital distance (AGD) in animals is a sensitive biomarker of fetal endocrine disruption and the associated testicular dysgenesis syndrome (TDS). However, AGD in human infants with cryptorchidism and hypospadias, which are potential manifestations of TDS during childhood, is not clearly described. Our aim was to compare AGD in boys with cryptorchidism or hypospadias against normative data. Boys with isolated cryptorchidism (n = 71, age 13.4 ± 5.8 months) or hypospadias (n = 81, age 11.4 ± 6.2 months) were recruited from a tertiary centre for measurement of AGD and penile length; they were compared to 487 healthy full-term boys from a birth cohort by deriving age-specific standard deviation scores (SDS). Boys with cryptorchidism were older (p = 0.048) compared to boys with hypospadias. Boys with hypospadias had shorter mean AGD and penile length SDS than healthy boys (both p < 0.0001). Mean AGD and penile length SDS values in boys with cryptorchidism were longer than mean values in boys with hypospadias (both p < 0.01) and shorter than mean values in healthy boys (both p < 0.0001). Mean penile length SDS decreased as the severity of hypospadias increased (ptrend = 0.078). In the study population, AGD and penile length were reduced in boys with hypospadias or cryptorchidism relative to normative data derived from a longitudinal birth cohort. The findings support the use of AGD as a quantitative biomarker to examine the prenatal effects of exposure to endocrine disruptors on the development of the male reproductive tract.
    Full-text · Article · Dec 2013 · Environmental Health Perspectives
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    • "Exposure to these chemicals during critical periods of development, such as infancy, is of particular concern. However, while it is possible to measure an infant or child’s exposure to a potentially estrogenic compound, there are few feasible, well validated ways of assessing response [1]. For example, exposure to an estrogenic endocrine disruptor during infancy may alter the timing of pubertal onset, but such an outcome takes many years of follow up to observe. "
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    ABSTRACT: Exposure to estrogen-mimicking chemicals during critical periods of development, such as infancy, may have adverse effects. However, these effects can be difficult to characterize in most epidemiologic studies. For example, growth of reproductive organs may be susceptible to estrogenic chemicals, but measuring it requires skilled ultrasound examination; timing of pubertal onset may be altered, but observing it requires long-term follow up. To address the need for a simple marker of response to estrogenic exposures in infants, we propose a novel application of a classic marker of estrogen response in adult women: cytological evaluation of urogenital epithelial cells. In this cross-sectional study of 34 female and 41 male infants, we demonstrate that epithelial cells can be obtained from swabs of the vaginal introitus (females) and urethral meatus (males), as well as from spun urine, and that these cells respond to differential estrogenic conditions, as indicated by the relative abundance of the superficial epithelial cell type. To model varying estrogen exposure, we sampled from infants who were either newborn (highly exposed to maternal estrogens), or 12 weeks old (12W) (negligibly exposed to estrogen). Newborns had a higher percentage of superficial cells (%S), as compared to 12W (mean ± standard error: 8.3 ± 1.8 vs. 0.9 ± 0.2) (p < 0.01), consistent with an estrogen response. This difference in %S from newborn to 12W was observed similarly for swab (-7.6 ± 1.7) and urine (-7.3 ± 2.6) specimens and for males (-9.6 ± 2.9) and females (-5.2 ± 2.1). Examination of urogenital epithelial cells can successfully demonstrate estrogen response in both sexes, using cell specimens collected from either swab or urine sampling. In future studies, this simple, non-invasive method may be applied to assess whether estrogen-mimicking chemicals produce an estrogenic response in infants.
    Preview · Article · Oct 2013 · PLoS ONE
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    • "Cryptorchidism has been considered as a milder form of TDS while hypospadias, azoospermia and testicular germ cell cancer lie at the severe end of the spectrum (Skakkebaek et al., 2001; Sharpe and Skakkebaek, 2008; Main et al., 2009). AGD has been identified as one of the end-points in US Environmental Protection Agency guidelines for reproductive toxicity studies in animals (Arbuckle et al., 2008), and many animal studies have shown that AGD, a marker of androgenization, is significantly shorter in cryptorchid males (Welsh et al., 2008; Drake et al., 2009). "
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    ABSTRACT: Are the anogenital distance (AGD) and stretched penile length (SPL) shorter in human newborn males with cryptorchidism? AGD is significantly shorter in boys with undescended testis (UDT) and this correlation may indicate that both have a common antecedent early in gestation. Animal studies have reported a critical time period during early gestation termed the male programming window (MPW) where androgen deficiency results in reduced AGD and penile length, as well as cryptorchidism and hypospadias. Two pilot human studies have explored this association but these studies were small and heterogeneous with regard to age, race and had selection bias. A prospective descriptive study involving measurement of AGD and SPL at birth in a racially homogenous sample of 1154 consecutive newborns was performed over a period of 6 months. All measurements were taken by a single trained observer (V.J.). All consecutively born male infants at a community hospital were classified as having descended and or UDT. Testicular position in the undescended group was graded as high scrotal, inguinal or non-palpable. AGD (from the centre of anus to the junction of the smooth and rugated skin of scrotum) and SPL were measured. The AGD index (AGDi) was calculated by dividing AGD by cube root of birthweight. Of the 1154 infants examined, 624 were males and 71 had UDT. AGD was significantly shorter in infants with UDT when compared with infants with descended testis (mean ± SD; 2.21 ± 0.36 versus 2.56 ± 0.31 cm; P < 0.001). AGDi was also significantly shorter in infants with UDT (mean ± SD; 1.68 ± 0.27 versus 1.81 ± 0.20 cm/kg(-3); P < 0.001). Significance was maintained even when preterm (P < 0.001) and low birthweight boys (LBW) (P < 0.001) were excluded. SPL was also significantly shorter in infants with UDT (Mean ± SD; 3.08 ± 0.52 versus 3.31 ± 0.38 cm; P < 0.001) but the significance was not maintained when preterm (P = 0.119) and LBW boys (P = 0.666) were excluded. Birthweight, gestational age and length adjusted regression models showed significantly shorter AGD in infants with UDT, but SPL was not different. Infants with higher position of testis appeared to have a shorter AGD and SPL but the correlation did not reach statistical significance. No difference in AGD or SPL was noted between boys with unilateral and bilateral UDT. The present study did not include data pertaining to maternal or newborn health status. Also parental drug exposure or occupational exposures to endocrine-disrupting chemicals was not studied. These may possibly affect genital anthropometric measurements. The study strengthens the hypothesis of existence of MPW in humans. Shorter AGD in cryptorchid infants may reflect the effect of androgen disruption or deficiency during MPW. AGD may be a more reliable non-invasive marker of androgen action during MPW than SPL to predict reproductive outcomes in humans. Supported by Hypospadias Foundation, India. The authors have no conflict of interest to declare.
    Full-text · Article · Jul 2013 · Human Reproduction
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