Human anogenital distance: an update on fetal smoke-exposure and integration of the perinatal literature on sex differences

Fowler, P. A., Filis, P., Bhattacharya, S., le Bizec, B., Antignac, J.-P., Morvan, M.-L., Drake, A. J., Soffientini, U. and O'Shaughnessy, P. (2016) Human anogenital distance: an update on fetal smoke-exposure and integration of the perinatal literature on sex differences. Human Reproduction, 31(2), pp. 463-472. (doi: 10.1093/humrep/dev323) (PMID:26732622) (PMCID:PMC4716811)

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Abstract

study question: Do sex and maternal smoking effects on human fetal anogenital distance (AGD) persist in a larger study and how do these data integrate with the wider literature on perinatal human AGD, especially with respect to sex differences? summary answer: Second trimester sex differences in AGD are broadly consistent with neonatal and infant measures of AGD and maternal cigarette smoking is associated with a temporary increase in male AGD in the absence of changes in circulating testosterone. what is known already: AGD is a biomarker of fetal androgen exposure, a reduced AGD in males being associated with cryptorchidism, hypospadias and reduced penile length. Normative fetal AGD data remain partial and windows of sensitivity of human fetal AGD to disruption are not known. study design, size, duration: The effects of fetal sex and maternal cigarette smoking on the second trimester (11 –21 weeks of gestation) human fetal AGD were studied, along with measurement of testosterone and testicular transcripts associated with apoptosis and proliferation. participants/materials, setting methods: AGD, measured from the centre of the anus to the posterior/caudal root of penis/clitoris (AGDapp) was determined in 56 female and 70 male morphologically normal fetuses. These data were integrated with current literature on perinatal AGD in humans. main results and the role of chance: At 11 – 13 weeks of gestation male fetal AGDapp was 61% (P , 0.001) longer than in females, increasing to 70% at 17 – 21 weeks. This sexual dimorphism was independent of growth characteristics (fetal weight, length, gonad weight). We confirmed that at 14 – 16 weeks of gestation male fetal AGDapp was increased 28% (P , 0.05) by in utero cigarette smoke exposure. Testosterone levels were not affected by smoking. To develop normative data, our findings have been integrated with available data from in vivo ultrasound scans and neonatal studies. Inter-study variations in male/female AGD differences lead to the conclusion that normalization and standardization approaches should be developed to enable confidence in comparing data from different perinatal AGD studies. limitations, reasons for caution: Sex differences, and a smoking-dependent increase in male fetal AGD at 14 – 16 weeks, identified in a preliminary study, were confirmed with a larger number of fetuses. However, human fetal AGD should, be re-assessed once much larger numbers of fetuses have been studied and this should be integrated with more detailed analysis of maternal lifestyle. Direct study of human fetal genital tissues is required for further mechanistic insights.

Item Type:Articles
Additional Information:The study was supported by grants from the Chief Scientist Office (Scottish Executive, CZG/1/109 & CZG/4/742), NHS Grampian Endowments (08/02), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 and the Medical Research Council, UK (MR/L010011/1).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:O'Shaughnessy, Professor Peter and Soffientini, Mr Ugo
Authors: Fowler, P. A., Filis, P., Bhattacharya, S., le Bizec, B., Antignac, J.-P., Morvan, M.-L., Drake, A. J., Soffientini, U., and O'Shaughnessy, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Human Reproduction
Publisher:Oxford University Press
ISSN:0268-1161
ISSN (Online):1460-2350
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Human Reproduction 31(2):463-472
Publisher Policy:Reproduced under a creative commons license

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