Human anogenital distance

an update on fetal smoke-exposure and integration of the perinatal literature on sex differences

Paul A. Fowler, Panagiotis Filis, Siladitya Bhattacharya, Bruno Le Bizec, Jean-Philippe Antignac, Marie-Line Morvan, Amanda J. Drake, Ugo Soffientini, Peter J. O'Shaughnessy

Research output: Contribution to journalArticle

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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.WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to cigarette smoke chemicals is known to lead to reduced fertility in men and women. Integration of our data into the perinatal human AGD literature shows that more work needs to be done to enable reliable inter-study comparisons.
Original languageEnglish
Pages (from-to)463-472
Number of pages10
JournalHuman Reproduction
Volume31
Issue number2
Early online date4 Jan 2016
DOIs
Publication statusPublished - Feb 2016

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Smoke
Sex Characteristics
Smoking
Fetus
Testosterone
Mothers
Second Pregnancy Trimester
Tobacco Products
Pregnancy
Clitoris
Hypospadias
Fetal Weight
Cryptorchidism
Penis
Gonads
Anal Canal
Androgens
Fertility
Life Style
Biomarkers

Keywords

  • anogenital distance
  • endocrine-disrupting chemicals
  • maternal cigarette smoking human
  • fetus
  • normative data
  • proliferation
  • apoptosis
  • second trimester
  • dysregulation
  • testosterone

Cite this

Human anogenital distance : an update on fetal smoke-exposure and integration of the perinatal literature on sex differences. / Fowler, Paul A.; Filis, Panagiotis; Bhattacharya, Siladitya; Le Bizec, Bruno; Antignac, Jean-Philippe; Morvan, Marie-Line; Drake, Amanda J.; Soffientini, Ugo; O'Shaughnessy, Peter J.

In: Human Reproduction, Vol. 31, No. 2, 02.2016, p. 463-472.

Research output: Contribution to journalArticle

Fowler, Paul A. ; Filis, Panagiotis ; Bhattacharya, Siladitya ; Le Bizec, Bruno ; Antignac, Jean-Philippe ; Morvan, Marie-Line ; Drake, Amanda J. ; Soffientini, Ugo ; O'Shaughnessy, Peter J. / Human anogenital distance : an update on fetal smoke-exposure and integration of the perinatal literature on sex differences. In: Human Reproduction. 2016 ; Vol. 31, No. 2. pp. 463-472.
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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.WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to cigarette smoke chemicals is known to lead to reduced fertility in men and women. Integration of our data into the perinatal human AGD literature shows that more work needs to be done to enable reliable inter-study comparisons.",
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author = "Fowler, {Paul A.} and Panagiotis Filis and Siladitya Bhattacharya and {Le Bizec}, Bruno and Jean-Philippe Antignac and Marie-Line Morvan and Drake, {Amanda J.} and Ugo Soffientini and O'Shaughnessy, {Peter J.}",
note = "Acknowledgements We thank the staff at Grampian NHS Pregnancy Counselling Service who were essential for collecting fetuses and we are grateful to Ms Margaret Fraser and Ms Samantha Flannigan for their expert assistance. Funding Support for the study was provided by 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). Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council.",
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T1 - Human anogenital distance

T2 - an update on fetal smoke-exposure and integration of the perinatal literature on sex differences

AU - Fowler, Paul A.

AU - Filis, Panagiotis

AU - Bhattacharya, Siladitya

AU - Le Bizec, Bruno

AU - Antignac, Jean-Philippe

AU - Morvan, Marie-Line

AU - Drake, Amanda J.

AU - Soffientini, Ugo

AU - O'Shaughnessy, Peter J.

N1 - Acknowledgements We thank the staff at Grampian NHS Pregnancy Counselling Service who were essential for collecting fetuses and we are grateful to Ms Margaret Fraser and Ms Samantha Flannigan for their expert assistance. Funding Support for the study was provided by 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). Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council.

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N2 - 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.WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to cigarette smoke chemicals is known to lead to reduced fertility in men and women. Integration of our data into the perinatal human AGD literature shows that more work needs to be done to enable reliable inter-study comparisons.

AB - 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.WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to cigarette smoke chemicals is known to lead to reduced fertility in men and women. Integration of our data into the perinatal human AGD literature shows that more work needs to be done to enable reliable inter-study comparisons.

KW - anogenital distance

KW - endocrine-disrupting chemicals

KW - maternal cigarette smoking human

KW - fetus

KW - normative data

KW - proliferation

KW - apoptosis

KW - second trimester

KW - dysregulation

KW - testosterone

U2 - 10.1093/humrep/dev323

DO - 10.1093/humrep/dev323

M3 - Article

VL - 31

SP - 463

EP - 472

JO - Human Reproduction

JF - Human Reproduction

SN - 0268-1161

IS - 2

ER -