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Logo of D.E.S is it, DES Action group in France (Diethylstilbestrol)

DES Timeline

1930 - 1935

History of the Synthesis of Diethylstilbestrol

In the 1930s, some scientists managed to isolate and characterize estrogen hormones. They discover that there are five: estrone1, estriol, estradiol2, equilin and equilenin, all of which have biological activity.

 

Based on this discovery, they then sought to produce a simple estrogenic substance with similar activity3.

They discover that natural estrogens contain a phenanthrene nucleus. They then prepare derivatives in order to administer them to ovariectomized rats (OVX) to carry out experiments. One of these derivatives has a very important estrogenic activity (EA). They note that changes in the structure of the vagina, under the influence of oestrus, look like the proliferation caused by an application of carcinogenic hydrocarbon.

1936 - 1937

Scientists discover that compounds, structurally different from natural estrogens, are biologically active. They are considering the possibility, for the sake of simplification, of not using a phenanthrene nucleus. They then create a first compound not derived from phenanthrene, which meets their expectations4.

 

In order to further simplify, compounds from two benzoic groups are studied. The first group shows weak biological activity.

These researchers then chose to study the effects produced by the positioning of a carbon atom between these two benzoic groups: dihydroxy-diphenyl-methane, dihydroxy-diphenyl-ethane, then dihydroxy-stilbene compounds were tested. They conlude that Stilbene is active.

 

They wonder if it is necessary to have two benzoic groups and replace one of the Stilbene groups with a methyl group. They get an anol derivative, very active and so satisfying that it results in a scientific publication5.

1938

But when the experiment is repeated, the estrogenic activity is highly variable, which suggests that the activity sought may have originated in a contaminating product. Thus, the researchers identify this product as anol, and isolate the active substance from the residue of its crystallization: they then obtain dianol.

 

Researchers are joining forces with Sir Robert Robinson and his Oxford colleagues to arrive at the preparation of synthetic estrogens with a structure similar to estrone.

From this collaboration was born diethyl-stilbene (or stilboestrol), the first synthetic estrogen6.

 

Structure of Diethylstilbestrol, the first synthetic estrogen
Structure of Diethylstilbestrol
IUPAC Name: 4-[(E)-4-(4-hydroxyphenyl)hex-3-en-3-yl]phenol
Other names: DES; Stilboestrol

 

Later, two other artificial estrogens are created: dienoestrol (or dienestrol) and hexoestrol (or hexestrol), structurally similar to DES.

1938 - 1942

The foreseeable tragedy of diethylstilbestrol

From 1938, the carcinogenic properties of synthetic estrogens were debated7, and there were indications of the danger of diethylstilbestrol; Dodds himself warns that DES exposure could pose health risks, such as cancer and intersexuality8.

Despite these facts, this molecule is preferred over natural hormones.

 

At this time, specialties of diethylstilbestrol were used as an abortifacient for bitches and heifers, to artificially cause "heat", or to induce or inhibit (depending on administered doses) lactation in mares and goats.

 

Studies published between 1938 and 1942 show that diethylstilbestrol causes in animals:

  • atrophy of the male reproductive organs9
  • "resting" the thyroid gland of the rats10
  • atrophy of the thymus11
  • or the feminization of male embryos12

 

Implantation instrument for chemical caponisation of poultry.
Implantation instrument for chemical caponisation of poultry.

 

Because diethylstilbestrol causes feminization of roosters, breeders use it to practice "chemical castration", which is cheaper than surgical castration.

 

In 1940, following the study of Lacassagne A., a French medical journal reports that diethylstilbestrol causes mammary tumors in male rats13.

1945

Commercialisation of diethylstilbestrol

The french Scientific Committee for Specialties issues a marketing authorization to diethylstilbestrol - Join the DES France group association!

On February 11, 1945, the Scientific Committee for Specialties issues it a marketing authorization (updated in August 1950)14.

1946 - 1947

In 1946, diethylstilbestrol is marketed on the East Coast of the United States15.

desPLEX DES Advert to prevent abortion, miscarrage ans premature labor - Join the DES France group for free
Publicité pour le desPlex®
(nom commercial du diéthylstilbestrol aux Etat-Unis)

 

In 1947, the FDA (American Food and Drug Agency) issues a marketing authorization for diethylstilbestrol as a treatment to prevent miscarriages16.

1947

Le Stilboestrol - E. Daubresse, E.C Dodds, H. Scribe, CL. Beclere, J. Peters - Medical News n°4 - Brussels Conference, March 9, 1947.
LE STILBOESTROL
E. Daubresse, E.C Dodds, H. Scribe, CL Beclere, J. Peters
Medical News n°4 - Brussels Conference, March 9, 1947.

 

On March 9, 1947, a "Stilboestrol Conference", chaired by Professor E.C Dodds, is organized in Brussels and brought together: chemists, doctors and veterinarians.

Diethylstilbestrol, tested by researchers since 1943 in more than 350 cases of various diseases (eczema, psoriasis, staphylococcal infections, vitiligo, alopecia artery, circulatory diseases of the limbs, asthma, polyarthritis...) is presented as THE miracle cure17.

1948

French Distilbène medication, by laboratoires M Borne. Each tablet contain 1 mg diethylstilbestrol - Join the DES France group for free
Distilbène® medicine box.
Each tablet contain 1 mg diethylstilbestrol.
By M Borne laboratory (France).

 

In 1948 DES is marketed in the departments of Algeria, then in metropolitain France, under the following brand names drugs:

  • Distilbène® (mainly) by BORNE Laboratories, UCB-Fraysse (in 1950) Laboratories and then UCEPHA (acquired by UCB Pharma) Laboratories;
  • Stilboestrol-Borne® by BORNE Laboratories (now Norvatis Laboratories);

A delayed release form (drug is released only at some point after the initial administration) has been marketed under the following brand name:

  • Furostilboestrol® by UCEPHA Laboratories (acquired by UCB Pharma);

This medication is prescribed for pregnant women to prevent spontaneous abortion, to reduce your risk of premature birth and to treat pregnancy-related bleeding.

At that time, medical doctors believe that the drop in the level of some hormones observed during a miscarriage result from the miscarriage, thus confusing the effects with the cause.

Other synthetic estrogens similar to diethylstilbestrol are prescribed for the following indications:

  • Hexanoestrol® (Hexestrol), by Laroche-Navarron Laboratories (90% owned by the American group Syntex)18, used to treat low estrogen levels in women19 and, sometimes, to treat placental insufficiency (or placental dysfunction) in pregnant women20 ;
  • Cycladiène® (Dienestrol), by Bruneau & C Laboratories, is used in postmenopausal women and to supress lactation after delivery.

 

Cycladiène® medicine box - Tube of 20 tablets. Each tablet contain 1/2 mg dienestrol, Nonsteroidal estrogen similar to diethylstilbestrol - Bruneau and Cie laboratories.
Cycladiène® medicine box.
Each tablet contain 1/2 mg dienestrol.
Bruneau and Cie laboratories.

 

In 1948 diethylstilbestrol is marketed in Belgium and Switzerland.

1950

Diethylstilbestrol is administered to farm animals (cattle, sheep, poultry, etc.), because its anabolic properties (increase of lipogenesis and proteinogenesis) – resulting from an antithyroid action - make it possible to fatten them, and therefore to make more profit.

 

1950s Farm Ad promoting Stilbestrol as a dietary supplement in cattle.
1950s Farm Ad promoting Stilbestrol as a dietary supplement in cattle.

 

In 1950, an article by Frederick Othman entitled "Hormonized Chickens" denounced the side effects of administering diethylstilbestrol to chickens: their consumption leads to breast growth in humans22.

1953

In 1953, a study by W.J. Dieckmann, a gynecologist, is published in the American Journal of Obstetrics & Gynecology: the ineffectiveness of diethylstilbestrol, in all the indications for which the drug is prescribed in pregnant women, is demonstrated22.

 

Dieckmann, William J. - 1950
Dieckmann, William J., 1950
University of Chicago Photographic Archive, [apf1-02168],
Special Collections Research Center, University of Chicago Library.

 

Despite this fact, the marketing and promotion of diethylstilbestrol continues.

1964

Sir Edward Charles Dodds 1st Bt - diethylstilbestrol - D.E.S is it Sir Edward Charles Dodds 1st Bt - diethylstilbestrol - D.E.S is it french group
Sir (Edward) Charles Dodds, 1st Bt
by Godfrey Argent
bromide print, 25 February 1970
© National Portrait Gallery, London

 

In 1964, in England, E.C. Dodds was knighted for his role in medical research23.

1970 - 1971

The DES drug scandal broke

Herbst, Arthur L - University of Chicago Photographic Archive, [apf1-02767], Special Collections Research Center, University of Chicago Library.
Herbst, Arthur L.
University of Chicago Photographic Archive, [apf1-02767],
Special Collections Research Center, University of Chicago Library.

In 1970, A.L Herbst, an American professor, published his epidemiological study which revealed an increased incidence of vaginal cancer, a very rare cancer, called clear cell adenocarcinoma (CCA), in DES Daughters (exposed in utero)24.

 

Following this study, in 1971, in the United States, the FDA issued an alert25 about its use during pregnancy.

 

In France, although the French government is informed, diethylstilbestrol continues to be prescribed.

1972 - 1973

diethylstilbestrol use in growing-finish Anabolic Steroids, Cattle, Diethylstilbestrol, Growth Promoters, History, Sheep

In 1972, the FDA ban the use of DES in cattle feed. The following year, DES implants in cattle is banned. These decisions are not effective until 1979. Canada make similar decisions in 1974.

 

In 1973 England ban diethylstilbestrol.

 

In France, in 1973, two orders were issued to clarify and regulate Decree 59-450 of March 20, 1959, which prohibited the use of estrogenic substances in animals intended for human consumption26.

1974 - 1976

In 1974, J. Henry-Suchet and J. Belaïsch observe cervical anomalies and vaginal adenosis in women exposed to DES in utero27.

 

In 1974, J. Barrat observe the first French case of clear-cell vaginal adenocarcinoma in a young woman, and published it in 1975. The publication is accompanied by a preventive warning28.

 

Diethylstilbestrol is ban in 1975 in Belgium and the Netherlands, and in 1976 in Ireland.

 

In 1976, the indication "threat of abortion" is removed from the Vidal medical dictionary by the Ministry of Health (France)29.

1977

In 1977, J. Henry-Suchet denounces the veterinary use of diethylstilbestrol in food animals.

 

On February 5, 1977, in France, drugs containing diethylstilbestrol or an equivalent synthetic estrogenic substance are contraindicated for women who are pregnant, six years after the American alert15.

However, some physicians continue to prescribe DES after 1977.

1981

In July 1981, the Council of the European Communities adopts a directive (reaffirmed by Council Directive 96/22/EC of 29 April 1996) prohibiting: "the placing on the market of stilbenes, stilbene derivatives, their salts and esters and thyrostatic substances for administering to animals of all species"30.

1982 - 1983

In 1982, Dr Anne Cabau, a gynecologist, discovers that some DES daughters (exposed to diethylstilbestrol in utero), have abnormalities of the uterus.

 

In 1983, the French newspaper Le Monde publishes an article based on the publication of Dr. Anne Cabau's work entitled "A Monumental Medical Error: The Children of Distilbène" (A Monumental Medical Error: The DES's children).

 

The DES scandal broke in France.

 

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Interview with Dr Anne CABAU, gynecologist at the MGEN, who discovered the dangers of Distilbene® (DES).
Antenne 2 Midi, February 16, 1983

1984

On July 16, 1984, the so-called "Loi Rocard" Act No. 84-609 repealed the "Loi Ceyrac". Its Article 1 now stipulates that: "It is prohibited to administer, place on the market and hold with a view to administering, even for therapeutic purposes, to animals of any species, products containing stilbenes, their derivatives, salts or esters, as well as any substances having a thyrostatic action.” 31

1986 - 1989

In 1986, Dane Hervouet (today Dane Morin-Delacroix) founds the first association "DES action France": DANE 45, allowing victims to group together32.

 

On January 16, 1988, the 1st Colloquium for Victims of Distilbène is held in France, organized by the association DANE 45.

 

July 13, 1988 – Interview with the HERVOUET family, an example of the dangers of the DISTILBENE.

– DANE HERVOUET, the mother, explains that she was prescribed this medication during her pregnancies and that her children suffer from genital malformations. Astrid, 20 years old; Béatrice, 15 years old; Yves, 17 years old who has already undergone 7 operations.

– Office of the Association DES France, for the defense of the victims of DISTILBENE.

– Interview with Prof. Michel TOURNAIRE, gynecologist at Saint Vincent de Paul Hospital, on the importance of informing doctors.

Images from the INA National Audiovisual Institute archive.

 

The DANE 45 association organizes an event on the Champs Elysées in Paris. "Women, animals, same hormone: Distilbene" and "We are the DES children that France hides" are their slogans.

1989

Thanks to the work carried out upstream by the DANE 45 association, the Minister for Solidarity and Health (France) published a first brochure intended for health professionals to inform them of the iatrogenic effects of taking DES: "Exposition au DES (diéthylstilbestrol) in utero : prise en charge par le praticien" (Exposure to DES (diethylstilbestrol) in utero: medical care by the practitioner)33.

1990 - Aujourd'hui

The Never Ending Story of DES

In France, other associations have succeeded to DANE 45.

Please find below the list of organizations and/or websites around the world:

Australia:

Belgium:

Canada :

  • D.E.S. Action Canada (seems not to be active anymore)

United States:

France :

United Kingdom:

Netherlands:

 

Find out why we decided to create a new organization, by browsing our "Our Organization"  page.

 

Diethylstilbestrol, as a model of endocrine disruptors, is among the most studied. The scientific literature on DES is abundant, but not readily accessible to the general public (language, technical vocabulary...).

Subscribe to our blog to discover our popularization work on DES.

References

  1. A. Butenandt, 1932
  2. E.A Doisy, 1935
  3. Cook, E.C Dodds et Hewett, 1933
  4. E.C Dodds et W. Lawson, 1936
  5. E.C Dodds et W. Lawson 1937
  6. E.C Dodds, Goldberg, W. Lawson et Robinson, 1938
  7. Nancy Langston, Modern Meat: Synthetic Hormones, Livestock, and Consumers in the Post-WWII Era, cf. [Archive]
  8. [En ligne] Germline Exposures; "A DES Victim Tells the Story of the Largest Drug Disaster in History", 10/22/2016.
  9. A. Lacassagne, 1938 ; Kreitmair, Sieckmann, Ueber, 1939.
  10. Kreitmair, Sieckmann, Ueber, 1939 ; P. Grumbrecht, P. Loeser, 1939
  11. K. Ehrhardt, H. Kramann, H. Schaefer, 1939
  12. A. Raynaud, 1942
  13. Lacassagne A. The appearance of mammary adenocarcinomas in male mice treated by a synthetic estrogenic substance. Weekly reports of the Society of biology and its affiliates 1938; 12: 641-3
  14. [En ligne] Archives Nationales - Santé ; Direction de la pharmacie et du médicament ; Division enregistrement des médicaments (1942-1985) URL: https://www.siv.archives-nationales.culture.gouv.fr/siv/rechercheconsultation/consultation/ir/consultationIR.action?irId=FRAN_IR_017805&udId=d_3_2&details=true
  15. a b Agnès Walter-Kull. Le diéthylstilbestrol: mise au point des connaissances en 2002. Sciences du Vivant [q-bio]. 2002. ffhal-01738902
  16. Institute of Medicine (US) Committee on Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies; Mastroianni AC, Faden R, Federman D, editors. Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume I. Washington (DC): National Academies Press (US); 1994. C, DES Case Study. Available from: https://www.ncbi.nlm.nih.gov/books/NBK236538/
  17. E. Daubresse, E.C Dodds, H. Scribe, CL Beclere, J. Peters ; Actualités Médicales n°4. Conférence de Bruxelles, 9 mars 1947.
  18. [En ligne] Le Monde - Le laboratoire Laroche-Navarron passe sous le contrôle du groupe americain Syntex - 1980
  19. I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 140–. ISBN 978-94-011-4439-1.
  20. Laboratoires Laroche-Navarron - Les avortements spontanés à répétition. Fiche n°6 Frénantol Avril 1953.
  21. [En ligne] Coupure de presse : https://newspapers.digitalnc.org/lccn/sn88063132/1950-12-20/ed-1/seq-2.pdf
  22. WJ Dieckmann et et al., « Does the administration of diethylstilbestrol during pregnancy have therapeutic value ? », American Journal of Obstetric and Gynecology, vol. 66, 1953, p.1062-1081.
  23. How Organic Pollutants Poison Our Health: Unsafe at Any Level. By Penny May Hopkins. This book first published 2019. Cambridge Scholars Publishing. ISBN: 1-5275-2467-1
  24. Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer. 1970 Apr;25(4):745-57. doi: 10.1002/1097-0142(197004)25:4<745::aid-cncr2820250402>3.0.co;2-2. PMID: 5443099.
  25. Selected item from the FDA drug bulletin-november 1971: diethylstilbestrol contraindicated in pregnancy. Calif Med. 1972;116(2):85-86.
  26. Décret n°59-450 du 20 mars 1959 PRODUITS DESTINES A L'ALIMENTATION DES ANIMAUX ET COMMERCE DES DENREES ALIMENTAIRES D'ORIGINE ANIMALE POUR L'APPLICATION DE LA LOI DU 1 août 1905 JORF du 24 mars 1959
  27. Site Web du Dr. Jeanine Henry-Suchet : https://www.jeaninehenrysuchet.com/scientifique
  28. Barrat J, Brochoriou C, Maria B, et al. Adénocarcinome vaginal à cellules claires chez la jeune fille. A propos d’une observation personnelle. J Gynecol Obstet Biol Reprod 1975; 4: 1093-102
  29. FILLION Emmanuelle, TORNY Didier, « Un précédent manqué : le Distilbène® et les perturbateurs endocriniens. Contribution à une sociologie de l’ignorance », Sciences sociales et santé, 2016/3 (Vol. 34), p. 47-75. DOI : 10.3917/sss.343.0047. URL : https://www.cairn.info/revue-sciences-sociales-et-sante-2016-3-page-47.htm
  30. Directive 96/22/CE du Conseil, du 29 avril 1996, concernant l'interdiction d'utilisation de certaines substances à effet hormonal ou thyréostatique et des substances ß-agonistes dans les spéculations animales et abrogeant les directives 81/602/CEE, 88/146/CEE et 88/299/CEE
  31. Loi n° 84-609 du 16 juillet 1984 relative à l'usage vétérinaire de substances anabolisantes et à l'interdiction de diverses autres substances.
  32. Dane Morin-Delacroix. L'affaire Distilbène ou Mutilations sur ordonnances, 09/10/2013. Éditions Edilivre. ISBN : 9782332592040
  33. Imprimerie nationale, mars 1989.

 

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