Hypospadias in DES Sons

Latrogenic legacy from diethylstilbestrol exposure

2002 Study Abstract

Hypospadias, characterised by the emergence of the urethral orifice on the ventral surface of the penis or on the perineum rather than at the tip of the glans, is one of the most common birth defects in boys. Although there is no increased mortality associated with hypospadias, there is substantial morbidity, including surgical operations and the psychosocial consequences of having a genital abnormality.

Little is known about the causes of hypospadias. However, since fusion of the urethral groove is mainly under the control of androgens originating in the fetal testis, it has been suggested that agents with antiandrogenic or oestrogenic activities might increase the risk.

Diethylstilbestrol also seems to affect sons exposed in utero, leading to higher risks of structural urogenital anomalies, including cryptorchidism, testicular hypoplasia, microphallus, abnormalities of the penile urethra, hypospadias, and epididymal cysts. Similar disorders were induced in mice exposed to diethylstilbestrol in utero.

In males, fusion of the urethral folds brings the urogenital meatus from the perineal region to the tip of the phallus between the 8th and 14th week of gestation, and genital malformations were more frequent among males exposed to diethylstilbestrol before the 11th week than among those exposed later.

Sources

  • Latrogenic legacy from diethylstilbestrol exposure, NCBI PubMed PMID: 11943252, 2002 Mar.
  • Featured image credit mcgill.ca.
DES DIETHYLSTILBESTROL RESOURCES

Characterization of DES-induced hypospadias in female mice

DES influence on urogenital sinus morphogenesis and hypospadias formation

2002 Study Abstract

The urethral duct and vagina are formed from the urogenital sinus (UGS) during the early neonatal period in mice. Neonatal estrogen exposure results in hypospadias, or the malpositioning of vaginal and urethral openings, with wide cleft clitoris.

We sought to characterize diethylstilbestrol (DES) influence on UGS morphogenesis and hypospadias formation.

Newborn (day 0) and 1-4-day-old female mice (ICR/Jcl) were given (s.c.) oil or 3.0 microg DES. Animals were killed 24 hr later; then hypospadias formation and epithelial apoptosis and proliferation within the developing UGS were assessed.

DES did not alter normal UGS morphogenesis by day 1, in comparison with controls. However, hypospadias formation was observed in DES-treated mice by day 3. In these mice, the distal dorsal urethral duct appeared to fuse with and open into the lower vaginal solid cord region. Further, DES treatment produced a gradual significant increase in dorsal urethral epithelial apoptosis (P < 0.05) just prior to and during fusion and hypospadias formation. DES-induced urethral epithelial and sinus cord proliferation appeared significantly increased (P < 0.05) and unchanged, respectively, just prior to fusion. By day 5, DES-treated mice exhibited wide cleft clitoris. In addition, if DES was given on day 3 or 5, a gradual, distinct caudal shift in the vaginal-urethral junction was observed compared to mice treated on days 0-2. Although hypospadias was not induced when neonates were given DES on day 7, these mice continued to display early vaginal opening. Dose-response analysis indicated that 0.03 microg DES for 5 days is the lowest known critical dose for hypospadias induction.

We have shown for the first time that DES-induced hypospadias onset may primarily be the result of changes in developing dorsal urethral epithelial cell apoptotic and proliferative activity, and that the location of DES-induced hypospadias formation is dependent on age at time of exposure.

Sources

  • Characterization of diethylstilbestrol-induced hypospadias in female mice, NCBI PubMed PMID: 11748570, 2002 Jan 1.
  • Featured image credit mcgill.ca.
DES DIETHYLSTILBESTROL RESOURCES

How DES prescribed during gestation can alter foetal sex differentiation in men

Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation

2001 Study Abstract

The effects of diethylstilbestrol (DES) provide an unfortunate model of how a potent estrogenic chemical prescribed during gestation can alter foetal sex differentiation in human. The occurrence of genital abnormalities in the sons of women exposed to DES during pregnancy is noteworthy:

  • 20.8% of the males exposed to DES in utero had epididymal cysts (vs 4.9% in controls),
  • 4.4% had hypospadias (vs 1.1% in controls),
  • 11.4% presented with cryptorchidism and hypoplastic testes (vs 2.1% in controls),
  • and 1.5% had micropenis (vs 0% in controls).

This set of data emphasizes the sensitivity of foetal external genitalia to excess synthetic estrogen exposure.

The adverse effects of DES have been extensively studied in experimental animals. After DES exposure in pregnant mice, male offspring exhibited micropenis, hypospadias, and cryptorchidism along with underdevelopment of the vas deferens, epididymis, and seminal vesicles.

These defects are similar to those of DES-exposed human male foetus.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Effects in Men of Intra-Uterine Exposure to DES

1998 Study Abstract

The reasons for increased incidence of cryptorchidism, hypospadias and testicular cancer are unknown, but experimental data demonstrating the important role of sex steroids in the physiology of testicular descent and urethral development point to the possibility that environmental factors could cause the problem by interfering with the sex steroids. The best example of such an influence is diethylstilbestrol (DES), which has been studied extensively in both humans and experimental animals.

Millions of pregnant women in the USA and Europe were treated with DES between the late 1940s and early 1970s to prevent abortion, pre-eclampsia and other complications of pregnancy. Doubleblind, placebo-controlled trials had already demonstrated in the 1950s that the treatment was not efficacious, but despite that it was used until the 1970s when the US Food and Drug Administration banned its use during pregnancy after it had become evident that the daughters of DES-treated women had an increased risk of developing clear cell adenocarcinoma of the vagina.

Thereafter, several studies on the effects of DES on the children of exposed mothers were published. Many of the papers are based on the socalled Dieckmann cohort comprising more than 1600 pregnant women who were treated with increasing doses of DES or placebo from gestational weeks 7-20 to week 35 . The use of the medication was verified by a dye indicator in the urine. Children from these pregnancies have been followed since the 1970s, and a large number of structural and functional abnormalities in their reproductive organs have been found. For example, 20.8% of 308 men exposed to DES in utero had epididymal cysts, compared with 4.9% of 307 placebo-exposed controls. There were other structural anomalies in reproductive organs that were more frequent in DES-exposed male subjects than in controls, for example meatal stenosis (12.9% versus 1.8%), hypospadias (4.4% versus 0%), testicular abnormalities, including hypoplastic testis, cryptorchidism and capsular induration (11.4% versus 2.9%), and microphallus (4 cases versus 0 cases). The frequency of anomalies was dependent on the timing of exposure, so that the men who were exposed to DES before week 11 of gestation had a significantly higher prevalence of anomalies than those who were exposed only later, emphasizing the sensitivity of organogenesis to external disturbance. In these cohort studies, cryptorchidism was significantly more frequent in DES-exposed men than in controls, but in retrospective case-control studies, maternal oestrogen exposure was not associated with an increased incidence of cryptorchidism in the offspring. The strength of a retrospective case-control study, however, is not as good as that of a prospective cohort study, and DES can therefore be considered to be a risk factor for cryptorchidism. In a metaanalysis of 14 studies, no association was found between first-trimester exposure to sex hormones other than DES, and external genital abnormalities.

Several reports have demonstrated that the semen quality of men exposed to DES in utero is significantly worse than in placebo-exposed controls. However, the sperm concentrations of most of the DES-exposed men were well above the limit at which subfertility occurs, and it is therefore not surprising that the fertility of these men was reported to be normal.

The risk of testicular cancer among men exposed to DES in utero has been a controversial issue, and one can often read in the literature claims that the risk is not increased. This does not seem to be true. On the basis of a meta-analysis of six case-control studies, Mantel-Haenszel estimate of the odds ratio was 2.6, with 95% confidence limits of 1.1-6.1. However, more direct evidence would be necessary to assess the risk. Thus far, no data have been available for testicular cancer in the known DES-exposed cohorts.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Estrogen fetal exposure and male reproductive health alterations

Do environmental estrogens contribute to the decline in male reproductive health?

1995 Study Abstract

Several observations suggest that male reproductive health has been declining since World War II in many countries.

The incidence of testicular cancer, hypospadias, and cryptorchidism has been increasing and semen quality has been decreasing, and these may have a common etiology.

Treatment of several million pregnant women with the synthetic estrogen diethylstilbestrol led to an increase in these conditions among the sons of these women. These abnormalities probably arise during fetal development.

The similarity between these effects and the adverse change in male reproductive development and function raised the question of whether the adverse changes are attributable to altered exposures to estrogenic and other endocrine-disrupting agents during fetal development.

We speculate that alteration in exposure to estrogen in the past half-century may have caused the changes in male reproductive health.

Sources

  • Do environmental estrogens contribute to the decline in male reproductive health?, NCBI PubMed PMID: 7497651, 1995 Dec.
  • Featured image credit John Jason.
DES DIETHYLSTILBESTROL RESOURCES

Fertility disorders attributable to the use of diethylstilbestrol during intrauterine life

Women treated with distilbene during pregnancy : it seems that the increased number of miscarriages, extra-uterine pregnancies and perinatal deaths are probably due to the maternal treatment which is also responsible for semen abnormalities

1984 Study Abstract

In the early 1970s, the elevated rate of abnormalities in children of the 2-3 million US women and 260,000 French women treated with diethylstilbestrol (DES) during pregnancy began to be recognized.

Four kinds of cervicovaginal anomalies have been observed in women exposed to DES in utero:

  1. 22-58% have been estimated to have morphologic anomalies with the timing of exposure to DES more important than the total dose
  2. a high proportion has an insufficient cervical mucus not corrected by exogenous administration of estrogen
  3. a high proportion develop cervical stenosis after cryosurgery, electrocoagulation, or conization
  4. and the increased incidence of prematurity in infants of DES-exposed mothers has been attributed to cervical incompetence.

69% of 267 women studied had hysterographically demonstrated uterotubal malformations. A characteristic aspect was a T-shaped uterus but other anomalies were noted. Hysterographic anomalies were correlated with cervico-isthmic anatomic anomalies, anomalies of the vaginal epithelium, and with the date of 1st exposure to DES in utero. The total dose of DES did not affect the frequency of genital anomalies. Possible tubal anomalies have not been well studied, although 1 author has observed short and narrow tubes and other abnormalities.

The number of extrauterine pregnancies is known to be elevated in women exposed to DES in utero. The possibility of an increased incidence of menstrual irregularity, dysmenorrhea, or oligomenorrhea in DES-exposed women has been suggested but remains controversial.

The responsibility of DES exposure in utero for later reduced fertility is also in dispute. Higher rates of spontaneous abortion, extrauterine pregnancy, prematurity, and perinatal death have been reported in DES-exposed women.

Increased incidence of stenosis of the meatus, hypospadias, epididymal cysts, testicular hypoplasia and other anomalies, cryptorchidism, microphallus, and varicocele have been reported in men exposed to DES in utero. Reduced sperm counts and anomalies in the volume of the ejaculate, percentage of sperm mobile, and sperm morphology have been reported in exposed men. Sperm anomalies may be responsible for reduced fertility in exposed men, but the exact extent is unknown.

Sources

  • Fertility disorders attributable to the use of diethylstilbestrol during intrauterine life, NCBI PubMed PMID: 6397835, 1984 Apr.
  • Featured image credit Edward Cisneros.
DES DIETHYLSTILBESTROL RESOURCES

Hypospadias in rat offspring following exposure to DES

Teratogenesis and carcinogenesis in rat offspring after transplacental and transmammary exposure to diethylstilbestrol, 1979

Study Abstract

Transplacental and transmammary exposure of tat offspring to diethylstilbestrol (DES) was studied in regard to potential teratogenesis and carcinogenesis.

Pregnant and/or lactating rats received DES in oil subcutaneously.

  • In females so exposed, abnormal development of the urogenital sinus (hypospadias and urethrovaginal cloaca formation) occurred.
  • In exposed male offspring, hypospadias, phallic hypoplasia, inhibition of growth and descent of testes, as well as abnormalities of Wolffian derivatives, were observed.
  • In 20–40 per cent of DES-exposed female offspring, vaginal adenosis, endometrial squamous metaplasia, and genital malignancy were encountered. Two DES-exposed offspring had a vaginal squamous carcinoma, one had an endometrial adenocarcinoma, and one had an ovarian adenocarcinoma. Vaginal squamous carcinomas may have originated in foci of squamous metaplastic epithelium of vaginal adenosis.
  • None of the control rats developed genital malignancy.

Sources

  • Teratogenesis and carcinogenesis in rat offspring after transplacental and transmammary exposure to diethylstilbestrol, NCBI PubMed PMID: 454458, 1976.
  • Featured image credit Taton Moïse.
DES DIETHYLSTILBESTROL RESOURCES

Urogenital tract abnormalities in DES sons

DES-exposed male offspring urogenital tract abnormalities, 1976

Study Abstract

Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices.

The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).

Remark : a DES-induced abnormality of the male urethra is embryologically consistent with DES-induced abnormalities of the vagina whether the latter are of Mullerian or urethral fold origin.

The findings suggest that more detailed historical and clinical examination of such boys is warranted.

Sources

  • Urogenital tract abnormalities in sons of women treated with diethylstilbestrol, NCBI PubMed PMID: 972792, 1976.
  • SELECTED MEDICAL HISTORIES IN DES-EXPOSED AND DES-UNEXPOSED MALES featured image credit PMID: 972792.
DES DIETHYLSTILBESTROL RESOURCES

Victimes d’effets indésirables graves de médicaments, État des lieux et Recommandations, Version 1.0

Résumé de l’état des lieux

Notes de synthèse conjointe : 1ère et 2e parties, Février 2015

  • En Europe, les victimes d’effets indésirables graves de médicaments qui souhaitent obtenir réparation des préjudices
    subis sont confrontées à un parcours d’épreuves plus insurmontables les unes que les autres.
  • Afin d’obtenir réparation, les victimes doivent :
    • agir avant que leur action ne soit plus recevable ;
    • démontrer le lien de causalité entre une prise de médicament et la survenue de l’effet indésirable à l’origine
      du dommage (alias imputabilité) ;
    • rechercher une responsabilité.
  • Depuis l’application d’une directive européenne de 1985 relative aux produits défectueux (transposée en France en 1998), les firmes pharmaceutiques n’ont plus d’obligation de sécurité de résultat vis-à-vis des patients. En l’absence de faute ou quand le produit est considéré comme non défectueux (l’effet indésirable figurait dans la notice), ce qui représente la grande majorité des cas, les firmes ne sont pas considérées comme responsables.
  • En pratique, dans les États membres de l’Union européenne qui ont mis en place une procédure de règlement amiable des litiges relatifs aux accidents médicaux, dont la France fait partie, deux voies d’action sont possibles pour les victimes :
    1. Si la responsabilité d’une firme ou d’un professionnel de santé est engagée, la victime pourra engager soit une procédure contentieuse devant les tribunaux, celle-ci étant souvent longue, coûteuse et éprouvante ; soit une procédure “amiable” devant le mécanisme d’indemnisation national ;
    2. En l’absence de responsabilité pour faute ou lorsque la responsabilité d’un producteur d’un produit de santé à l’origine d’un dommage ne peut pas être engagée (produit non défectueux, exonération par le risque de développement, prescription de l’action), alors la victime pourra se tourner vers le mécanisme d’indemnisation national et la solidarité nationale, l’Office national d’indemnisation des accidents médicaux (ONIAM) peut être amenée à indemniser la victime en France.
  • Le système français d’indemnisation amiable par l’ONIAM, mis en place par la loi Kouchner de 2002 relative aux “droits des malades”, a été une avancée importante pour les victimes d’infections nosocomiales et d’accidents médicaux hors
    affection iatrogène.
  • Cependant, il n’est pas adapté aux victimes d’effets indésirables graves de médicaments (alias aléas thérapeutiques) qui ont notamment les plus grandes difficultés à :
    • démontrer l’imputabilité du médicament dans la survenue d’un effet indésirable, avec de très grandes variations d’interprétation entre les Commissions de conciliation et d’indemnisation (CCI) et selon les rapports d’expertise établis_;
    • démontrer l’atteinte du seuil de gravité élevé requis pour être indemnisé.
  • De plus, la date d’administration du traitement en cause, qui doit être postérieure au 4 septembre 2001, exclut arbitrairement de nombreuses victimes.
  • Une meilleure reconnaissance des victimes de médicaments contribuerait pourtant à davantage responsabiliser l’ensemble des acteurs de santé (notamment les firmes pharmaceutiques, les soignants, et les autorités sanitaires), et par conséquent à une amélioration de la qualité des soins.

Recommandations

Cette note de synthèse conjointe s’intéresse aux moyens d’améliorer la situation des victimes.

  • Nos recommandations concrètes s’organisent en 2 objectifs :
    1. améliorer la reconnaissance et l’indemnisation des victimes ;
    2. prévenir la survenue d’effets indésirables médicamenteux.
  • En France, dans le cadre de la loi de santé publique en discussion en 2015, la modification de quelques dispositions du Code de la santé publique permettrait de prolonger et compléter les avancées accomplies en matière d’indemnisation des usagers du système de santé par la loi du 4 mars 2002 :
    • les actions de groupe en santé rendraient la voie contentieuse plus accessible aux victimes ;
    • tandis que la création d’un fonds d’indemnisation “produit de santé” spécifique, notamment financé par les firmes pharmaceutiques et dont la gestion serait confiée à l’ONIAM, permettrait aux victimes d’effets indésirables graves de médicaments d’être indemnisées de leurs préjudices en l’absence de responsabilité du producteur. Cette option a déjà été retenue dans plusieurs pays, dont le Japon et Taïwan, et est compatible avec la réglementation européenne (pas de modification de fond du droit de la responsabilité).
DES DIETHYLSTILBESTROL RESOURCES

Toutes les victimes de tous les médicaments doivent être indemnisées

Arnaud de Broca, co-président du CISS et secrétaire général de la FNATH répond aux questions de l’humanite, 17 Novembre, 2016

Quelle est la position du CISS (collectif interassociatif sur la santé) et de la FNATH (Fédération Nationale des Accidentés du Travail et des Handicapés) sur cette affaire de la Dépakine ?

Cette affaire constitue une nouvelle affaire de santé publique, qui fait suite à d’autres questions qui ont fait la une des médias ces derniers mois, comme le Médiator ou aussi le Distilbène. Au-delà de ce sujet particulier, cela témoigne de la nécessité de réfléchir de manière plus large et profonde à la question des effets indésirables des médicaments et de leur indemnisation. Il n’y a pas de fatalisme à avoir par rapport à ces effets, mais une attitude de prudence et la possibilité de disposer d’informations fiables pour prendre des décisions éclairées.

Que pensez-vous de l’amendement au projet de loi de finances pour 2017 d’instituer un fonds d’indemnisation et est-ce suffisant ?

Il s’agit évidemment d’une bonne nouvelle pour les victimes de la Depakine, utilisée dans le traitement de l’épilepsie et de la bipolarité et prescrite à des milliers de femmes enceintes. Ce médicament a entraîné des malformations et/ou des troubles neuro-développementaux chez les nouveau-nés. L’amendement voté vise donc ni plus ni moins qu’à introduire un dispositif d’indemnisation pour ces victimes. Cela semble donc juste et indispensable, comme cela a été fait il y a quelques années déjà avec les victimes du Mediator. Pour autant cet amendement reste largement insuffisant : d’une part, parce qu’il laisse espérer aux victimes la possibilité d’une indemnisation, alors même que le dispositif mis en place reste long et ne permettra pas à l’ensemble d’entre elles d’être indemnisées. D’autre part, il n’aborde pas la question de fond de l’indemnisation des victimes de médicaments. Ainsi le gouvernement a repris à son compte la fâcheuse habitude, transmissible de gouvernement en gouvernement, d’indemniser le risque médicamenteux à la petite semaine, médicament par médicament, scandale après scandale. Un peu comme si avant de voter la loi Badinter, on avait testé le principe de l’indemnisation des victimes de la circulation, d’abord sur les piétons accidentés par des voitures Renault, puis Citroën… Comme s’il fallait faire la Une des médias pour obtenir un fonds d’indemnisation.

En attendant quelles démarches doivent faire les victimes pour obtenir réparation ? Et que leur conseillez-vous ?

Comme l’a souligné Marisol Touraine, Ministre de la Santé, lors du débat parlementaire, « il va falloir du temps pour que le dispositif se mette en place et s’organise avant que les premières victimes ne perçoivent une indemnisation ». Un comité d’experts sera chargé d’enquêter sur « l’imputabilité » des dommages, puis décidera ou non de transmettre le dossier au comité d’indemnisation. Celui-ci aura alors trois mois pour se prononcer sur la responsabilité des professionnels, des établissements de santé ou de l’Etat. Une proposition d’indemnisation pourra alors être faite par l’entreprise responsable. Si l’offre est insuffisante ou en cas d’absence de proposition, l’Office national d’indemnisation des accidents médicaux (Oniam) indemnisera directement les victimes. Il se fera ensuite rembourser par le ou les responsables désignés par la justice.

Quelle est votre revendication ?

Pour les victimes non médiatiques des médicaments, comme par exemple les victimes du Distilbène® dont les conséquences se font sentir aujourd’hui jusqu’à la 3e génération, ou les victimes des syndromes de Lyell et de Stevens-Johnson, dont les survivants doivent faire face à de terribles (et coûteuses) séquelles, ce dispositif d’indemnisation n’apporte aucune solution. Elles pourront bien continuer à saisir la justice et à se battre, seules, pendant des années, contre les grandes firmes pharmaceutiques. Et l’action de groupe votée en janvier dernier ne changera pas fondamentalement cette situation.

Ainsi le CISS et sept autres associations (le CLAIM, la FNATH, CADUS, L’Association Les Filles DES, Le Réseau D.E.S. France, l’APESAC et AMALYSTE) demandent la mise en place d’un fonds d’indemnisation permettant d’indemniser toutes les victimes de médicament. Il manque une seule chose pour qu’un fonds d’indemnisation pour toutes les victimes de médicaments existe : une volonté politique. Nos associations en appellent également à Madame la Secrétaire d’Etat aux victimes, pour qu’elle se saisisse de cette discrimination cynique, méprisante et devenue inacceptable qui ne réserve la qualité de victimes qu’à la condition que la presse s’en fasse l’écho.

DES DIETHYLSTILBESTROL RESOURCES