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Therapies
Sous presse. Epreuves corrigées par l'auteur. Disponible en ligne depuis le mardi 3 décembre 2019
Doi : 10.1016/j.therap.2019.10.004
Received : 11 Mars 2019 ;  accepted : 22 October 2019
Genital tract and reproductive characteristics in daughters of women and men prenatally exposed to diethylstilbestrol (DES)
 

Anne Wautier a, , Michel Tournaire b, c, Emmanuel Devouche c, d, Sylvie Epelboin e, f, Jean-Luc Pouly g, Anne Levadou a
a Association réseau DES France, 1052, rue de la Ferme du Carboué, 40000 Mont-de-Marsan, France 
b AP–HP, 75004 Paris, France 
c Descartes University, 75006 Paris, France 
d Laboratoire psychopathologie et processus de santé, Research Unit 4057, 92100 Boulogne-Billancourt, France 
e Hôpital Bichat-Claude-Bernard, AP–HP, 75018 Paris, France 
f Paris 7 Diderot University, 75013 Paris, France 
g Hôpital Estaing de Clermont Ferrand, Clermont-Auvergne University, 63000 Clermont-Ferrand, France 

Corresponding author.
Summary
Objective

Prenatal exposure of women to diethylstilbestrol (DES) has been associated with reproductive tract anomalies, menstrual irregularity, infertility and pregnancy complications. In prenatally exposed men, adverse effects included genital anomalies and possible risk of infertility. In children of prenatally exposed women, i.e the third generation, an increased incidence of genital defects was observed in sons (hypospadias), but not in daughters. In daughters of prenatally exposed men, the incidence of genital anomalies was in the normal range. Experimental studies in mice evidenced an increased incidence of reproductive tract anomalies in the female descendants of females and males prenatally exposed to DES, indicative of transgenerational transmission of DES defects. The aim of this study is to assess genital tract defects, fertility and pregnancy outcome, in daughters of women and men prenatally exposed to DES.

Methods

In a retrospective observational analysis, 759 daughters of prenatally exposed women and men reported their genital and reproductive characteristics that were compared with those of: 1) general population in France; 2) two cohorts of daughters of exposed women reported in previous publications; 3) women prenatally exposed to DES.

Results

An increased incidence of uterine defects was observed, with both doubling of uterus and bicornuate and aplastic uterus which constitutes the Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS). No specific anomalies described in prenatally exposed women such as T-shape or hypoplastic uterus were reported. Infertility appeared to be in the normal range. Pregnancy outcomes of our 121 pregnancies of women born to DES exposed mothers and two other published cohorts presented inconsistent results for ectopic pregnancy, miscarriage and preterm delivery. Early and late miscarriages were higher than expected in general population in our cohort but not in the two others.

Conclusion

These results must be considered as preliminary, due to the small numbers of patients, limited follow-up duration after birth due to young age of the studied population, and observational methods. An important point is that the high risk of reproductive dysfunction of women prenatally exposed to DES was not observed in their daughters. There is a signal on the high incidence of uterine defects, especially aplastic uterus, and its possible link with DES exposure through epigenetic effects is discussed in our findings. Inconsistent findings regarding pregnancy outcomes in the third generation are worthy of further examination.

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Keywords : Diethylstilbestrol, Epigenetic repression, Endocrine disruptors, Prenatal exposure delayed effects, Maternal exposure, Uterine anomalies




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