Teaching
Case 3: DES--endocrine disruption begins

Session Objectives

Students will be able to:
  • Describe changes in the thinking of scientists about trans-placental disease
  • Define iatrogenic
  • Describe ways in which pharmaceuticals might have unintended consequences

In this session students will consider a story, based on historical facts, about DES. Read this passage out loud, or ask for a volunteer to do so.

It was the early 1970’s, so the doctors in the elevator wore polyester shirts with long lapels and fat ties. The three men stood in the back of the elevator, discussing their related cases as they descended to the first floor. In the last month their well-renowned clinic associated with one of New England’s most prestigious hospitals had seen 8 young women (all under the age of 26) with a virulent cancer--clear-celled carcinoma of the uterus. This form of cancer was normally very rare, and previously seen only in women well past menopause. Standing in front of them, and closer to the elevator door was a nurse, partly included in their conversation, who worked with them in the clinic, and whose daughter was one of the patients they were discussing. All eight women had gone through surgery which removed their uterus, vagina, ovaries, and pelvic region lymph glands, and the doctors held that their cancer prognosis was good. However, this treatment obviously drastically changed the women’s reproductive future, and posed further health consequences--some of them had not even completed puberty.

They were searching for a factor that linked all the women together, and might explain how they ended up with this disease. This cluster of cases remained enigmatic; so far their commonalities were completely banal, and shared with millions of other women. As the elevator stopped, the bell dinged, and the doors opened to the lobby. Instead of stepping out, the nurse turned to the doctors behind her and said “I wonder if this is related to the DES my obstetrician gave me when I was pregnant with her.”

In the 1930’s Sir Charles Dodds was working to create a synthetic estrogen that could be used pharmaceutically. In 1938 he published a report in Nature, describing a compound stronger than any other he had tested, including the human hormone estradiol.


18beta-estradiol
CAPTION: 17-β Estradiol is the primary female hormone (click image for 3-D interactive animation) CREDIT: ChemIDPlus, National Library of Medicine

Diethylstilbestrol (DES) was soon used in both medicine and agriculture. Originally approved to prevent miscarriages, it was shown to be ineffective to this end in 1953. However, DES was still widely a prescribed and profitable product for another 18 years.

DES
CAPTION: Diethylstilbestrol (DES) is a synthetic chemical that is strongly estrogenic and has been used in humans and livestock (click image for 3-D interactive animation) CREDIT: ChemIDPlus, National Library of Medicine


In 1971 Roy Herst and his colleagues published in the New England Journal of Medicine a description of eight cases of a very rare cancer, seven of which they definitively linked to DES exposure, and DES was pulled from the prescription market. More than 200 companies had manufactured it under over 300 names, and it is estimated that 10 million people have been exposed to it in the United States alone. Since DES was often prescribed for women with alongside pregnancy vitamins, in normal cases as well as those at special risk for miscarriage or premature birth, many women were often unaware of what it was they were taking. Heavy advertising by manufacturers may have encouraged over-use.

Discuss the concept of iatrogenic diseases, and briefly discuss the ideas of transplacental diseases. At first it was thought that the placenta protected the fetus from harm, then that chemicals causing birth defects could pass through it. DES really changed this because it suggested that diseases could make their presence known only much later. Compare the structure of DES and estradiol.

Read this section out loud...

I’m looking for the court hearing on DES,” A man in his early thirties, dressed in a casual suit says as he approaches a security officer in a marble hallway.

“Just down the hall, third door down.”

The young scientist steps into the court room, looking for where he is supposed to sit. It is still an hour before proceedings begin, but the room is busy with the energy of important people. On the side close to the door are rows of seats filled with middle-aged men in expensive silk suits, their leather briefcases beside them or open on their lap. At the table in front of these rows is a highly polished table around which are gathered three men organizing a telescoping folder filled with questions for witnesses. He suddenly wished he had turned down this request and decided to stay in North Carolina to go see that movie The Godfather with his wife. She had succeeded in getting a sitter for the night, and that was no small feat.

Across an aisle was a section much more sparsely populated. Here sat a younger group of men, with longer hair, and wearing corduroy and tweed. Ah, that’s where I’m meant to be, he thought, as the door clicked closed behind him. As he approached the FDA lawyers he saw their clipboards and cardboard boxes stuffed with files and notes. As he approached them, they stood up to greet him, introduced themselves, and offered him a seat. As he settled in his chair, the man with the long mustache briefed him on the procedures, and filled him in on his role in the day’s hearing. Another took the opportunity to size him up while the briefing proceeded. This man, blonde with stringy hair, seemed to find him lacking. Wishing again that he had stayed home, the scientist fiddles with fat striped tie and asks a couple of questions.

A little more than an hour later, he is sitting in a chair in the front of the room, with one of the rumpled agency lawyers across from him. Looking across the room to the table he passed as he came in, he sees the three sharply dressed lawyers are ready and waiting. He looks up and to his left as the judge there at the bench addresses him.

“Are you ready with your statement Doctor?”

Flipping his glasses down from where they had sat on top of his head with his left hand, he removes and unfolds a typed sheet from his jacket pocket with his right hand. Then he reads a statement summarizing what he has learned about DES from experiments on mice in his lab, and relates it to other research on rats, and studies on humans as well.

When he is done reading the statement, he folds the paper back up, and replaces it in his pocket. Shifting to get up and move back to his seat in the audience, he is interrupted by one of the nattily dressed lawyers from the other side of the room.

“Not so fast Doctor, we have some questions for you...”

A difficult hour late, having struggled through questions of whether something was ‘proven’ and what studies of mice meant about humans, he finally was able to take his seat. At the break for lunch, the young scientist sought out the lawyer who had grilled him, suggesting they eat together.

“I think you may be the only person besides my wife who has read all my papers,” he explained.

In agriculture DES was used as a growth promoter, to chemically castrate male chickens, and as birth control for female livestock, until the FDA banned its use in 1972. It was found in tested cattle raised in the U.S. as late as 2000.

The situations and characters in this case are fictionalized, but they represent composites of real people and events.


Case Assignment

Examine the scientific literature on DES and answer the following:
  1. What is the evidence that DES is dangerous and that DES exposed individuals are at risk?
  2. What is the evidence that exposure from agricultural use poses a risk?
  3. What are some other examples of heavily-used pharmaceuticals later pulled for safety reasons? Did advertising play a role in those cases?
  4. How are decisions about the safety of chemicals made?