Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome

H. E. Peters, B. N. Johnson, E. A. Ehli, D. Micha, M. O. Verhoeven, G. E. Davies, J. J.M.L. Dekker, A. Overbeek, M. H.van den Berg, E. van Dulmen-den Broeder, F. E.van Leeuwen, V. Mijatovic, D. I. Boomsma, C. B. Lambalk

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives?

SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.

WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.

STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.

PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.

MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.

LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.

WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.

STUDY FUNDING/COMPETING INTEREST(S): None.

TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

Original languageEnglish
Pages (from-to)1117-1125
Number of pages9
JournalHuman Reproduction
Volume34
Issue number6
Early online date21 May 2019
DOIs
Publication statusPublished - 4 Jun 2019

Fingerprint

Chimerism
Hormones
Freemartinism
Control Groups
Siblings
Phlebotomy

Bibliographical note

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Keywords

  • etiology
  • freemartinism
  • Mayer–Rokitansky–Küster–Hauser syndrome
  • microchimerism
  • Müllerian aplasia

Cite this

Peters, H. E., Johnson, B. N., Ehli, E. A., Micha, D., Verhoeven, M. O., Davies, G. E., ... Lambalk, C. B. (2019). Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome. Human Reproduction, 34(6), 1117-1125. https://doi.org/10.1093/humrep/dez044
Peters, H. E. ; Johnson, B. N. ; Ehli, E. A. ; Micha, D. ; Verhoeven, M. O. ; Davies, G. E. ; Dekker, J. J.M.L. ; Overbeek, A. ; Berg, M. H.van den ; Dulmen-den Broeder, E. van ; Leeuwen, F. E.van ; Mijatovic, V. ; Boomsma, D. I. ; Lambalk, C. B. / Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome. In: Human Reproduction. 2019 ; Vol. 34, No. 6. pp. 1117-1125.
@article{d76f61eea5ff47d5b7b0481322a0e10a,
title = "Low prevalence of male microchimerism in women with Mayer-Rokitansky-K{\"u}ster-Hauser syndrome",
abstract = "STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-K{\"u}ster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-M{\"u}llerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the M{\"u}llerian duct derivatives?SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that M{\"u}llerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8{\%}) were identified as having typical MRKH syndrome, and 41 women (43.2{\%}) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2{\%} versus 5.3{\%}, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6{\%} versus 4.9{\%}, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3{\%} of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2{\%}). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.STUDY FUNDING/COMPETING INTEREST(S): None.TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.",
keywords = "etiology, freemartinism, Mayer–Rokitansky–K{\"u}ster–Hauser syndrome, microchimerism, M{\"u}llerian aplasia",
author = "Peters, {H. E.} and Johnson, {B. N.} and Ehli, {E. A.} and D. Micha and Verhoeven, {M. O.} and Davies, {G. E.} and Dekker, {J. J.M.L.} and A. Overbeek and Berg, {M. H.van den} and {Dulmen-den Broeder}, {E. van} and Leeuwen, {F. E.van} and V. Mijatovic and Boomsma, {D. I.} and Lambalk, {C. B.}",
note = "{\circledC} The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
year = "2019",
month = "6",
day = "4",
doi = "10.1093/humrep/dez044",
language = "English",
volume = "34",
pages = "1117--1125",
journal = "Human Reproduction",
issn = "0268-1161",
publisher = "Oxford University Press",
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}

Peters, HE, Johnson, BN, Ehli, EA, Micha, D, Verhoeven, MO, Davies, GE, Dekker, JJML, Overbeek, A, Berg, MHVD, Dulmen-den Broeder, EV, Leeuwen, FEV, Mijatovic, V, Boomsma, DI & Lambalk, CB 2019, 'Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome' Human Reproduction, vol. 34, no. 6, pp. 1117-1125. https://doi.org/10.1093/humrep/dez044

Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome. / Peters, H. E.; Johnson, B. N.; Ehli, E. A.; Micha, D.; Verhoeven, M. O.; Davies, G. E.; Dekker, J. J.M.L.; Overbeek, A.; Berg, M. H.van den; Dulmen-den Broeder, E. van; Leeuwen, F. E.van; Mijatovic, V.; Boomsma, D. I.; Lambalk, C. B.

In: Human Reproduction, Vol. 34, No. 6, 04.06.2019, p. 1117-1125.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome

AU - Peters, H. E.

AU - Johnson, B. N.

AU - Ehli, E. A.

AU - Micha, D.

AU - Verhoeven, M. O.

AU - Davies, G. E.

AU - Dekker, J. J.M.L.

AU - Overbeek, A.

AU - Berg, M. H.van den

AU - Dulmen-den Broeder, E. van

AU - Leeuwen, F. E.van

AU - Mijatovic, V.

AU - Boomsma, D. I.

AU - Lambalk, C. B.

N1 - © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2019/6/4

Y1 - 2019/6/4

N2 - STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives?SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.STUDY FUNDING/COMPETING INTEREST(S): None.TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

AB - STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives?SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism.WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences.STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant.PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data.MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse.LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection.WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells.STUDY FUNDING/COMPETING INTEREST(S): None.TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

KW - etiology

KW - freemartinism

KW - Mayer–Rokitansky–Küster–Hauser syndrome

KW - microchimerism

KW - Müllerian aplasia

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U2 - 10.1093/humrep/dez044

DO - 10.1093/humrep/dez044

M3 - Article

VL - 34

SP - 1117

EP - 1125

JO - Human Reproduction

JF - Human Reproduction

SN - 0268-1161

IS - 6

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