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Consequences of in utero diethylstilbestrol (DES) exposure

The “Distilbène's children” or “DES Daughters and Sons”: second generation exposed to diethylstilbestrol

DES (diethylstilbestrol) is a synthetic estrogen synthesized in 1938 and prescribed between 1948 and 1977 in France to pregnant women to prevent miscarriages and premature births, and to inhibit lactation.

In the early 1970s, an American study revealed an increase incidence of a very rare type of cancer — clear cell adenocarcinoma (CCA) of the vagina or cervix — in "DES Daughters", i.e. women whose mothers had been prescribed DES during pregnancy. The United States raised the alarm and, in 1971, the FDA issued an alert: diethylstilbestrol is now contraindicated during pregnancy. In France, DES continued to be prescribed until 1977.

In France, around 200,000 pregnant women have received diethylstilbestrol (Distilbène®, Stilbestrol-Borne® or Furostilboestrol® — a delayed release form) during pregnancy, and 160,000 children were born from these pregnancies, including 80,000 girls and 80,000 boys. They are called "les enfants du Distilbène" (DES's Children), or DES sons and DES daughters.

This prenatal exposure to DES has led to the definition of a rare disease: diethylstilbestrol syndrome (or distilbene embryofoetopathy). As no PNDS exists, no patient can currently be diagnosed.

DES Timeline Diethylstilbestrol syndrome
 
The consequences of diethylstilbrestrol (DES) exposure on the health of DES Daugters

Health consequences of diethylstilbestrol in utero exposure for DES Daughters

Known health effects for DES Daughters (women exposed in utero to diethylstilbestrol) *:

  • Breast cancer risk is greatly increased1.
  • There is an increased risk (1 out of 1,000) of developing vaginal and cervical cancers (clear-cell adenocarcinoma or CCA)2 ;
  • About 45% have vaginal adenosis (which can disappear over time)3 ;
  • DES daughters are at increased risk for having of structural abnormalities of the uterus and birth defects of the genitals: narrowing of the uterine cavity, abnormalities of the fallopian tubes, deformation of the uterus, T-shaped uterus, hood, cervix or ridge — which may also disappear over time — uterine septum4;
  • These malformations can lead to impaired fertility and a number of obstetric complications such as difficulties in carrying a pregnancy to term: early and late miscarriages, ectopic pregnancy, or premature delivery5. They can also suffer from postpartum hemorrhage;
  • Women exposed in utero to DES who have undergone assisted reproductive technology (ART) have reported embryo implantation defects, uterine vascularization abnormalities, in vitro fertilization (IVF) specific problems, as well as ovarian and oocyte function abnormalities in IVF resulting in fewer live births6.
  • Menstrual irregularities3;
  • Endometriosis7,8 ;
  • A study reports that women who have been exposed to DES in utero undergo menopause 1.45 times earlier than unexposed women, about a year earlier than unexposed women9;
  • They have an increased risk of developing pancreatic cancer10 ;

* non-exhaustive list

Pathological pregnancies linked to diethylstilbestrol (DES)

Since French decrees of June 20, 2006 and July 1, 2010, DES daughters can have their pregnancy(ies) covered from the 1st day they are off work, under the same compensation conditions as for statutory maternity leave.

To do so, DES daughters must ask their obstetrician and/or gynecologist to fill in the specific form S3117 "Avis d'arrêt de travail relatif au congé de maternité exceptionnel pour grossesse pathologique (PDF)" available on the Ameli website at the following address: https://www.ameli.fr/medecin/exercice-liberal/prise-charge-situation-type-soin/situation-patient-maternite.

Health recommendations for women exposed in utero to diethylstilbestrol (DES), or DES Daughters

Health recommendations for DES Daughters

There are no official recommendations in France for women exposed to D.E.S. in utero.

Thus, the recommendations you will find below are taken from the guide "CARING FOR THE DIETHYLSTILBESTROL EXPOSED PATIENT - DES Mothers, DES Daughters, DES Sons, DES Grandchildren, & DES Exposed"11 produced by the American association DES Info and the Diethylstilbestrol (DES) International Information and Research Group, itself based on the recommendations of the National Cancer Institute (NCI).

 

DES Daughters are encouraged to perform:

  • Monthly self-breast exams. This examination consists of carefully palpating the breasts — including the nipples, clavicle and armpits — in search of any deep-seated or superficial abnormalities. 
    If you notice any abnormality, such as changes in the shape, size and color of your breasts, puckering or bulging of the skin, scaling or a rash on your nipples, redness, soreness, rash or swelling... make an appointment with your doctor.
  • Annual breast screenings (included in the annual gynecological exam).
  • The guide recommends yearly clinical breast exams, which essentially consists of a mammogram. In France, screening mammography is usually offered every two years to women between 50 and 74 years old. We recommend that you ask your doctor for medical advice. He will be able to determine the necessity and frequency of this examination, and may prescribe others in addition (ultrasound, MRI scan, ...).
  • Annual gynecological examinations should ensure the absence of clear cell adenocarcinoma (CCA) of the vagina and/or cervix, with DES daughters having a 40 times higher lifetime risk than unexposed women.
  • An important aspect of the annual gynecological exam is palpation of the vagina to check for cancerous masses under the surface, particularly in the vagina.
  • Women who have had a hysterectomy or are postmenopausal should continue to have this annual exam to screen for vaginal or cervical cancers.
Download the complete guide
 
 

Known health effects for both DES Daughters and Sons

non-exhaustive list

French study report on DES psychiatric side effects, by the association Hhorages, 2011, Mar.

 
Health consequences of in utero exposure to diethylstilbestrol for DES sons

Health consequences of diethylstilbestrol in utero exposure for DES Sons

In men exposed in utero to diethylstilbestrol (DES), it has been found*:

  • No difference in overall cancer risk, but there is an increased risk of testicular cancer16.
  • An increased risk of epididymal non-cancerous cysts has been documented consistently in DES Sons in several studies. Epididymal cysts are known to have a deleterious effect on seminal quality, decrease sperm count and, therefore, decline fertility17.
  • Urinary tract infection, kidney and bladder pain, urethral stenosis, discharge, difficulty urinating3.
  • Varicocele18.
  • Abnormalities of sex differentiation: prenatal DES exposure also induces malformations of the external genitalia such as testicular atrophy, cryptorchidism (undescended testicle) and micropenis19. Anomalies of the position of the urinary meatus (hypospadias, epispadias) are more frequent in men exposed to DES in the womb than in the general population. Indeed, the external urethral orifice can be located on the underside of the penis or even at the level of the scrotum20.
  • These anomalies do not seem to affect the ability of DES Sons to father children18.
  • Possible increase in left-handedness18.
  • They are more likely to have same sex partner in adulthood18.
  • A preliminary work, still in progress, carried out from the cohort of the Hhorages association, has highlighted cases of transgenderism (male to female)21.

* non-exhaustive list

Health recommendations for men exposed in utero to diethylstilbestrol (DES), or DES Sons

Health recommendations for DES Sons

There are no official recommendations in France for men exposed to D.E.S. in utero.

Thus, the recommendations you will find below are taken from the guide "CARING FOR THE DIETHYLSTILBESTROL EXPOSED PATIENT - DES Mothers, DES Daughters, DES Sons, DES Grandchildren, & DES Exposed"11 produced by the American association DES Info and the Diethylstilbestrol (DES) International Information and Research Group, itself based on the recommendations of the National Cancer Institute (NCI).

 

DES Sons are encouraged to perform:

  • Monthly testicular self-exams: make sure there are no abnormalities, signs of swelling, changes in size or alignment, masses, or abnormal tenderness.
  • Healthcare professionals are advised to pay particular attention to male genitals for DES sons who report changes.
  • Monthly testicular self-exams (urologist).
 
 
 
 

Notes & references

  1. ↑ Palmer JR, Boggs DA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter WC, Adam E, Hoover RN. Prenatal DES exposure in relation to breast size. 2013.
  2. ↑ Herbst AL, Scully RE. Adenocarcinoma of th evagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas) Cancer. 1970;25:745–757.
  3. ↑ a ↑ b ↑ c Diethylstilbestrol – Informations à l’usage des spécialistes de la santé, DES ACTION CANADA
  4. ↑ Kaufman RH, Adam E, Noller K, Irwin JF, Gray M. Upper genital tract changes and infertility in diethylstilbestrol-exposed women. Am J Obstet Gynecol 1986 ;154:1312–8
  5. ↑ Afssaps, 2011. Complications liées à l’exposition in utero au diéthylstilbestrol (DES), 2011.
  6. ↑ Sylvie Epelboin, Michel Tournaire, Emmanuel Devouche. Exposition au Distilbène® in utero : effets transgénérationnels. Médecine de la Reproduction. 2022;24(1):37-48. doi:10.1684/mte.2022.0875
  7. ↑ Stillman RJ, Miller LC. Diethylstilbestrol exposure in utero and endometriosis in infertile females. Fertil Steril 1984 ;41:369–72.
  8. ↑ Gaspari, L., Soyer-Gobillard, MO., Paris, F. et al. Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?. Environ Health 20, 96 (2021). https://doi.org/10.1186/s12940-021-00780-5
  9. ↑ Casey E. Reeda and Suzanne E. Fentona. Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects. 2013.
  10. ↑ a ↑ b Troisi, R., Hyer, M., Titus, L., Palmer, J., Hatch, E., Huo, D., Hoover, R. (2020). Prenatal diethylstilbestrol exposure and risk of diabetes, gallbladder disease, and pancreatic disorders and malignancies. Journal of Developmental Origins of Health and Disease, 1-8. doi:10.1017/S2040174420000872
  11. ↑ a ↑ b CARING FOR THE DIETHYLSTILBESTROL EXPOSED PATIENT - DES Mothers, DES Daughters, DES Sons, DES Grandchildren, & DES Exposed. DES Info Association & Diethylstilbestrol (DES) International Information and Research Group - JUNE 20, 2023.
  12. ↑ VERDOUX, H., ROPERS, J., COSTAGLIOLA, D., CLAVEL-CHAPELON, F., & PAOLETTI, X. (2007). Serious psychiatric outcome of subjects prenatally exposed to diethylstilboestrol in the E3N cohort study. Psychological Medicine, 37(9), 1315-1322. doi:10.1017/S0033291707000438
  13. ↑ Distilbène et Troubles du Comportement : Hasard ou Evidence ?, présentation du Dr Marie-Odile Soyer-Gobillard, directeur de recherche émérite honoraire au CNRS et présidente de Hhorages-France (Halte aux HORmones Artificielles pour les GrossessES) lors du colloque du 18 juin 2011 à l'Assemblée Nationale "Distilbène/Médiator, 1977 - 2009, 2 époques, 2 scandales... Et demain ?", organisé par l'association Les filles DES; Revue Prescrire. Diéthylstilbestrol (DES) : troubles psychiques confirmés.2018 ; O'Reilly EJ et coll., American Journal of Epidemiology, Diethylstilbestrol Exposure in Utero and Depression in Women. 2010.
  14. ↑ Verdoux H, Devouche E, Tournaire M, L e v a d o u A. Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome: a national survey of DES daughters and unexposed controls. Arch Womens Ment Health. 2017;20:389-395 https://www.ncbi.nlm.nih.gov/pubmed/28064340
  15. ↑ Find a complete list of studies on Journal of a DES Daughter
  16. ↑ Hom M, Sriprasert I, Ihenacho U, Castelao JE, Siegmund K, Bernstein L, Cortessis VK. Systematic Review and Meta-analysis of Testicular Germ Cell Tumors Following In Utero Exposure to Diethylstilbestrol. 2019.
  17. ↑ Gill WB, Schumacher GF, Bibbo M, Straus FH 2nd, Schoenberg HW. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J Urol. 1979 Jul;122(1):36-9. doi: 10.1016/s0022-5347(17)56240-0. PMID: 37351.
  18. ↑ a ↑ b ↑ c ↑ d Heritable impacts of diethylstilbestrol (DES) – Health outcomes in prenatally DES-exposed men, Linda Titus phD, 12/04/2020.
  19. ↑ Sultan C1, Balaguer P, Terouanne B, Georget V, Paris F, Jeandel C, Lumbroso S, Nicolas J. Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation. 2001.
  20. ↑ Contracept Fertil Sex 1993 Sep ;21(9):658-72; Eur J Cancer 1992;28A(6-7) :1182-9; Int J Epidemiol 1989 Jun;18(2) : 462-3; IARC Sci Publ 1989;(96) : 335-48; Lancet 2002; 359: 1102-07.
  21. ↑ « Trans-sexualisme M-F à l’adolescence : conséquence d’une contamination fœtale par le DES ? », par Charles Sultan, Laura Gaspari, Françoise Paris et M-O Soyer-Gobillard. Colloque de Gynécologie et Obstétrique Pratique, Paris,17 Mars 2016.
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