Author: Fang Jingyu
There is a cancer study that lasted more than 50 years, carried out six rounds, included more than 21,000 volunteers, contributed more than 40 high-quality research papers, and is one of the few cancer studies in the world that spans three generations.
However, the study has been called "the largest remedy in the history of medicine". It is the DES Follow-up Study conducted by the National Cancer Institute (NCI).
Diethylstilbestrol, now known as a Class I carcinogen, was taken by nearly 10 million women as a "fetal medicine" 70 years ago. Its disastrous consequences continue today in the 21st century.
The birth of the "fetal protection miracle medicine"
Diethylstilbestrol was born in 1938, and British chemist Charles Dodds accidentally synthesized a substance that does not have the typical structure of estrogen, but still has obvious estrogenic activity.
Since the discovery of conjugated estrogen (BETA) in 1942 was officially used in the clinical treatment of conditions such as menopausal syndrome, estrogen supplementation therapy (ERT) has been increasingly accepted by women.
However, natural sources of estrogen need to be extracted from the placenta or horse urine, often limited by the shortage of raw material supply, and the emergence of diethylstilbestrol, which is simple in structure and inexpensive to synthesize, has given the medical community new hope for estrogen deficiency.
After a simple clinical study, the US Food and Drug Administration (FDA) approved diethylstilbestrol for the treatment of menopausal syndrome in 1941.
However, after entering the market, the sales of diethylstilbestrol were not good.
This is because, although menopausal syndrome is a common disease, the conservative social atmosphere makes women's awareness of the disease not high, and if this small market is spread evenly among dozens of pharmaceutical companies, it is even more pitiful.
The turnaround soon followed. Some pharmaceutical companies have found that some obstetricians and gynecologists will prescribe estrogen preparations to pregnant women to "save the fetus".
At the time, it was widely believed in the medical community that miscarriage and premature birth were associated with imbalanced estrogen and progesterone levels during pregnancy, and estrogen supplementation became a means for doctors to "prevent miscarriage and premature birth".
In 1946, the Smiths of Harvard University, an authority in obstetrics and gynecology, published a study in the American Journal of Obstetrics and Gynecology (AJOG)[2], showing that diethylstilbestrol can correct abnormal levels of progesterone in the placenta, which may play a role in "preventing preterm birth".
The study was funded by pharmaceutical companies that produce diethylstilbestrol.
At that time, the drug regulatory system in the United States was in chaos, and although the 1937 sulfa elixir poisoning incident gave rise to the Federal Food, Drug, and Cosmetic Act of 1938[3], the marketing requirements for prescription drugs were still a formality.
In 1947, the FDA approved diethylstilbestrol for the prevention of miscarriage and preterm birth. The following year, Oliver Smith published another article in AJOG[4], stating that 72% of pregnant women in his study successfully delivered healthy babies after taking diethylstilbestrol, and proposed the "Smith Protocol" that has been used by obstetricians and gynecologists for decades.
Diethylstilbestrol tablets, at that time, dozens of pharmaceutical companies were producing and promoting diethylstilbestrol (Source: wonderdrugthemovie.com)
Out of trust in regulatory authorities and medical authorities, since the 50s of the 20th century, doctors have prescribed a large number of diethylstilbestrol to pregnant women, which was once regarded as a "fetal miracle drug".
According to statistics, in the more than 30 years after the approval of diethylstilbestrol, nearly 10 million women have taken diethylstilbestrol during pregnancy.
Is it a miracle medicine, or a placebo?
In the mid-20th century, U.S. law prohibited direct-to-consumer promotion of prescription drugs. As a result, pharmaceutical companies turned to doctors: advertising diethylstilbestrol in professional journals, sending medical representatives to promote diethylstilbestrol to doctors, or directly sponsoring diethylstilbestrol-related papers.
The main pharmaceutical company that produces diethylstilbestrol has sent a large number of medical representatives to assist obstetricians and family health care doctors across the United States, and has placed an advertisement for medical representatives in professional journals promoting their medical representatives as doctors' right-hand men.
The pharmaceutical company said, "We Pay Him But He Works for You!" The advertising slogan hopes to establish a close relationship between doctors and medical representatives.
A rare advertisement of pharmaceutical companies in the history of medicine that does not promote specific products (Source: desaction.org)
However, not all obstetrician-gynecologists are welcoming to diethylstilbestrol.
Professor William Dickman, chief of obstetrics and gynecology at Chicago Maternity Hospital, believes that the open-label studies and case review analyses conducted by the Smiths are likely to have produced a strong placebo effect, creating the illusion that diethylstilbestrol works. What's more, the Smiths' research involving diethylstilbestrol has received funding from pharmaceutical companies, and this interest association also greatly reduces the gold content of the research.
Soon, Professor Dickman received funding from the National Institutes of Health to conduct a randomized, double-blind, placebo-controlled clinical trial of diethylstilbestrol for the prevention of preterm birth.
To be fair, Professor Dickman also deliberately used the "Smith Protocol" to complete diethylstilbestrol treatment in his research - unsurprisingly, after adjusting for many confounding factors, diethylstilbestrol was no different from placebo in preventing miscarriage and preterm birth.
In 1953, Professor Dickman took his findings to the 76th Annual Meeting of the American College of Obstetricians and Gynecologists and "confronted the Smiths" [5].
Mr. Smith said that his research had not been perfected as expected due to age and conditions, and questioned Professor Dickman's research for major methodological flaws; Mrs Smith argued that Professor Dickman's study did not take into account the physiological differences between people, and said that the theoretical basis for diethylstilbestrol treatment is something more than a philosophy.
In the end, although Professor Dickman's research content was recognized by many experts present, he did not have the upper hand in the dispute with the Smiths, and the results of this research did not finally get the attention of the medical community, and diethylstilbestrol continued its "myth".
Taken by millions of women, the impact spans three generations
The day when the "miracle medicine" finally fell off the altar.
In 1970, Sheila Stone, a 17-year-old girl from New York State, was diagnosed with vaginal adenocarcinoma. This is an extremely rare tumor of the reproductive system, and according to information at the time, vaginal adenocarcinoma rarely occurs in women under the age of 30.
Sheila has always been in good health, has no similar history of cancer in her family, and has not been exposed to any known carcinogens, although her mother took diethylstilbestrol for several months during pregnancy.
Sheila thought that her illness might be related to diethylstilbestrol and mentioned this idea to her doctor several times, who then forwarded her medical records to Dr. Arthur Herbst of Harvard University Massachusetts General Hospital.
Sheila's story was subsequently reported by DES Action (Image: DES Action)
Before receiving Sheila's case, Dr. Herbst had just published an article in the famous medical journal Cancer describing 7 young patients with vaginal adenocarcinoma he received from 1966~1969 [6]. After hearing Sheila's medical history, Herbst also hurried to access the information of his patients and found that the mothers of 6 of the patients had taken diethylstilbestrol during pregnancy.
To test his idea, Herbst conducted a case-control study comparing his data on the mothers of 8 patients with vaginal adenocarcinoma (including 1 referral from a colleague) with the data of mothers of 32 healthy women born at the same time, and found that maternal diethylstilbestrol during pregnancy was clearly associated with vaginal adenocarcinoma in daughters.
Herbst's research was subsequently published in NEJM in April 1971 [7] and soon caught the attention of Dr. Peter Greenwald of the New York State Department of Health.
Greenwald also quickly reviewed the data on the New York State Cancer Registry and found 5 young patients with vaginal adenocarcinoma, including Sheila, and case-control studies also showed that their tumors were clearly related to the mother's use of diethylstilbestrol during pregnancy, which was also published in NEJM in August 1971 [8].
Herbst and Greenwald's research was published one after another, which attracted the attention of the FDA. Due to the overwhelming evidence, the FDA issued a notification in November 1971 formally banning diethylstilbestrol in pregnant women and mandating that the labelling of all estrogen preparations, including diethylstilbestrol and natural estrogen preparations, include information on the association of diethylstilbestrol with cancer [9].
Circular issued by FDA (Source: Reference [9])
However, the FDA's notification came too late.
Before this notification came into effect, about 5 million women in the United States alone had taken diethylstilbestrol during pregnancy, and diethylstilbestrol was once used as a veterinary growth promoter for "fattening" livestock and poultry, so the actual number of exposed people may be even more.
On the other hand, many doctors have made prescribing diethylstilbestrol as a common thing as eating and drinking, and the FDA notification does not require diethylstilbestrol to be withdrawn from the market (in the United States, diethylstilbestrol was not officially cancelled until 2000), so until the 80s of the 20th century, there were still doctors who continued to prescribe diethylstilbestrol to pregnant women until pharmaceutical companies were forced to voluntarily stop producing drugs due to lawsuits.
After the FDA issued a ban on diethylstilbestrol, a number of rights groups composed of diethylstilbestrol victims were established in the United States, and under their impetus, the entire society began to pay attention to this catastrophic drug incident.
In 1975, the NCI-led Diethylstilbestrol Adenosis Project (DESAD) was officially launched[10], with the participation of more than 4,000 diethylstilbestrol exposures and more than 1,000 healthy women; In 1992, the DESAD program was officially expanded to include diethylstilbestrol follow-up studies.
However, as the research deepened, the scientific community found that the effects of diethylstilbestrol have long exceeded expectations.
Comparison of sales of diethylstilbestrol (black line) with the incidence of vaginal adenocarcinoma corresponding to 20 years later (purple line) (Source: Reference [10])
According to data from a recent diethylstilbestrol follow-up study, in addition to directly causing vaginal clear cell adenocarcinoma, diethylstilbestrol can also affect multiple genes involved in reproductive system development [11], which can induce abnormal development of the female reproductive tract.
In addition, diethylstilbestrol may also alter some genes in exposed female offspring (third-generation diethylstilbestrol infants) through epigenetic mechanisms [12], allowing adverse effects to spread to three generations, such as an increased risk of hypospadias and an increased risk of ovarian cancer.
Close the stable door after the horse has bolted
Historically, the diethylstilbestrol incident is similar to the "reaction stop" event in Europe at the same time, both drugs developed for use in pregnant women, both brought to the market with unclear clinical evidence, and both led to disastrous outcomes.
However, diethylstilbestrol events receive far less attention than reaction stop events.
Perhaps because the consequences of the reaction stop event are more intuitive and disastrous, and the harm of diethylstilbestrol is often slowly exposed; It may also be because the FDA's rejection of thalidomide has become a "meritorious event" in the history of medicine, to a certain extent, covering up the bad impact of the subsequent diethylstilbestrol incident, and the movie "Wonder Drug" even called diethylstilbestrol "invisible thalidomide".
But there is no doubt that the diethylstilbestrol incident had a profound impact on the FDA.
Because the abuse of diethylstilbestrol is largely due to regulatory inaction, the FDA has since developed a very strict medication system for pregnancy, mandating pre-marketing animal reproductive studies, and establishing a grading of medication for pregnancy, or ABCDX system.
The FDA's "five-letter system" was abolished in 2015. The new rules require detailed information in the drug label, leaving it to the doctor's discretion to administer the drug. (Source: Lilac Garden Clinical Medication Guide)
In addition, the FDA has also established a normalized drug-related birth defect reporting and evaluation network, which has helped the FDA discover several drugs with strong teratogenic effects, effectively avoiding the occurrence of a large number of birth defects.
For example, acitretin ester for psoriasis was marketed in the United States in 1986, but there was later evidence that acitretin ester caused serious congenital malformations and was difficult to metabolize in the human body, remaining for more than 3 years or even life. As a result, acitretin ester was withdrawn from the market in 1998.
As another example, topiramate was approved in 1996 as a grade C of pregnancy, and after the North American Antiepileptic Drug Registry of Pregnancy (NAAED) found that it caused cleft lip and palate, the FDA adjusted it to grade D and recommended its use in the first trimester [14].
There is also the treatment of AIDS dolutegravir, after approval after observational studies proved that dolutegravir causes neural tube malformations, the FDA immediately added dolutegravir teratogenic content in the instructions, and recommended not to use the drug in the second and third trimesters of pregnancy.
To this day, diethylstilbestrol follow-up studies continue their own pace, and according to the NCI's plan, the seventh round of diethylstilbestrol follow-up studies will be carried out as originally planned after the epidemic situation stabilizes. For the world, the study is more like a wake-up call, a constant reminder not to let the tragedy repeat itself.
Acknowledgements: This article has been professionally reviewed by Zhao Tianjiao, deputy chief physician of the Department of Obstetrics and Gynecology, Wuqing District People's Hospital of Tianjin
【Note】
Zhao Tianjiao, Deputy Chief Physician, Department of Obstetrics and Gynecology, Wuqing District People's Hospital, Tianjin Review comments:
There is an old saying in China - medicine is three points of poison. Medicine can both cure and cause disease.
The estrogen replacement diethylstilbestrol discussed here has been widely used in clinical practice.
It can replenish estrogen deficiency in the body, such as atrophic vaginitis, female gonadal dysplasia, menopausal syndrome, senile vulvar dry disease and vaginitis, after oophorectomy, primary ovarian absence. Prevention of postpartum lactation, withdrawal (or return) of milk, etc. It can be said to bring good news to many patients.
However, the premise of medication is the exclusion of contraindications. Contraindications:
A) Patients with breast cancer (except those selected for treatment with metastatic disease) are contraindicated
B) Patients with estrogen-dependent tumors are banned
C) Prohibition of pregnant patients
D) Patients with undiagnosed abnormal genital bleeding are banned
E) Patients with thrombophlebitis, thrombosis or thromboembolic diseases are contraindicated.
Drug treatment is the use of chemicals to change a specific biological process in the human body, can not leave the dose, can not ignore the contraindications to talk about the efficacy, otherwise good medicine will also become poison.
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Executive Producer: Gyouza
Starter: Lilac Garden
Bibliography:
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[3] Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995;122(6):456-61. doi: 10.7326/0003-4819-122-6-199503150-00009
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