Shorter Anogenital Distance Predicts Poorer Semen Quality in Young Men in Rochester, New York

Department of Obstetrics and Gynecology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA.
Environmental Health Perspectives (Impact Factor: 7.98). 03/2011; 119(7):958-63. DOI: 10.1289/ehp.1103421
Source: PubMed

ABSTRACT In male rodents, anogenital distance (AGD) provides a sensitive and continuous correlate of androgen exposure in the intrauterine environment and predicts later reproductive success. Some endocrine-disrupting chemicals can alter male reproductive tract development, including shortening AGD, in both rodents and humans. Whether AGD is related to semen quality in human is unknown.
We examined associations between AGD and semen parameters in adult males.
We used multiple regression analyses to model the relationships between sperm parameters and two alternative measures of AGD [from the anus to the posterior base of the scrotum (AGD(AS)) and to the cephalad insertion of the penis (AGD(AP))] in 126 volunteers in Rochester, New York.
AGD(AS), but not AGD(AP), was associated with sperm concentration, motility, morphology, total sperm count, and total motile count (p-values, 0.002-0.048). Men with AGD(AS) below (vs. above) the median were 7.3 times more likely (95% confidence interval, 2.5-21.6) to have a low sperm concentration (< 20 × 10⁶/mL). For a typical study participant, sperm concentrations were 34.7 × 10⁶/mL and 51.6 × 10⁶/mL at the 25th and 75th percentiles of (adjusted) AGD(AS).
In our population, AGD(AS) was a strong correlate of all semen parameters and a predictor of low sperm concentration. In animals, male AGD at birth reflects androgen levels during the masculinization programming window and predicts adult AGD and reproductive function. Our results suggest, therefore, that the androgenic environment during early fetal life exerts a fundamental influence on both AGD and adult sperm counts in humans, as demonstrated in rodents.

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Available from: Niels Jørgensen, Sep 27, 2015
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    • "In males, children with hypospadias and cryptorchidism have significantly shorter AGD than controls (Hsieh et al., 2008, 2012; Thankamony et al., 2013). In male adults, shorter AGD predicts poorer semen quality (Eisenberg et al., 2011; Mendiola et al., 2011) and reduced testosterone and testicular volume (Eisenberg et al., 2012). Among men seen in an infertility clinic, AGD was longer in fathers than in infertile men (Eisenberg et al., 2011). "
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    ABSTRACT: Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010-2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was <13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N = 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N = 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant's age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center. Three metabolites of DEHP were significantly and inversely associated with both measures of boys' AGD. Associations (β, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: -1.12 (-2.16, -0.07) for mono-2-ethylhexyl phthalate (MEHP), -1.43, (-2.49, -0.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and -1.28 (-2.29, -0.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical. Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4. The authors report no conflict of interest. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
    Human Reproduction 02/2015; 30(4). DOI:10.1093/humrep/deu363 · 4.57 Impact Factor
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    • "While long-term studies of perinatal exposure to BPA and adult reproductive health are lacking, prenatal BPA exposure has been correlated with reduced anogenital distance (AGD) in babies (Li et al., 2011). Importantly, AGD is positively associated with semen quality in adulthood, which suggests that developmental exposure to BPA in humans may result in decreased semen quality in adulthood (Mendiola et al., 2011). "
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    ABSTRACT: Endocrine disrupting chemicals (EDCs), including the mass-produced component of plastics, bisphenol A (BPA) are widely prevalent in aquatic and terrestrial habitats. Many aquatic species, including fish, amphibians, aquatic reptiles and mammals, are exposed daily to high concentrations of BPA and ethinyl estradiol (EE2), estrogen in birth control pills. In this review, we will predominantly focus on BPA and EE2, well-described estrogenic EDCs. First, the evidence that BPA and EE2 are detectable in almost all bodies of water will be discussed. We will then predominantly consider how BPA affects sexual and neural development in these species, as these effects have been the best characterized across taxa. For instance, such chemicals have been in many cases reported to cause sex-reversal of males to females. Even if these chemicals do not overtly alter the gonadal sex, there are indications that several EDCs might demasculinize male-specific behaviors that are essential for attracting a mate. In so doing, these chemicals may reduce the likelihood that these males reproduce. If exposed males do reproduce, the concern is that they will then be passing on compromised genetic fitness to their offspring and transmitting potential transgenerational effects through their sperm epigenome. We will thus consider how diverse epigenetic changes might be a unifying mechanism of how BPA and EE2 disrupt several processes across species. Such changes might also serve as universal species diagnostic biomarkers of BPA and other EDCs exposure. Lastly, the evidence that estrogenic EDCs-induced effects in aquatic species might translate to humans will be considered.
    General and Comparative Endocrinology 09/2014; 214. DOI:10.1016/j.ygcen.2014.09.014 · 2.47 Impact Factor
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    • "Most of these studies measured AGD to the posterior of the scrotum and reported correlations with semen quality (Eisenberg et al. 2011, 2012b, Mendiola et al. 2011b). Importantly, when AGD was measured both to the base of the scrotum and to the top of the penis, an association with semen quality was only found with the fi rst method (Mendiola et al. 2011b), whereas mean diff erences between boys with normal genitals and with hypospadias were of greater magnitude when using AGD measured to the base of the scrotum (26.5%; P Ͻ 0.01) versus (vs.) the bottom of the penis (22.5%; "
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    ABSTRACT: Phthalate diesters are a diverse group of chemicals used to make plastics flexible and are found in personal care products, medical equipment, and medication capsules. Ubiquitous in the environment, human exposure to phthalates is unavoidable; however, the clinical relevance of low concentrations in human tissues remains uncertain. The epidemiological literature was inadequate for prior reviews to conclusively evaluate the effects of phthalates on male reproductive tract development and function, but recent studies have expanded the literature. Therefore, we conducted a systematic review of the literature focused on the effects of phthalate exposure on the developing male reproductive tract, puberty, semen quality, fertility, and reproductive hormones. We conclude that although the epidemiological evidence for an association between phthalate exposure and most adverse outcomes in the reproductive system, at concentrations to which general human populations are exposed, is minimal to weak, the evidence for effects on semen quality is moderate. Results of animal studies reveal that, although DEHP was the most potent, different phthalates have similar effects and can adversely affect development of the male reproductive tract with semen quality being the most sensitive outcome. We also note that developmental exposure in humans was within an order of magnitude of the adverse effects documented in several animal studies. While the mechanisms underlying phthalate toxicity remain unclear, the animal literature suggests that mice are less sensitive than rats and potentially more relevant to estimating effects in humans. Potential for chemical interactions and effects across generations highlights the need for continued study.
    Critical Reviews in Toxicology 07/2014; 44(6):467-498. DOI:10.3109/10408444.2013.875983 · 5.10 Impact Factor
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