The history of Distilbène® (Diethylstilbestrol) told to grandchildren--the transgenerational effect.

The Distilbène® story is a dramatic episode which belongs to the history of medicine. It provided several useful lessons such as the importance of evidence-based medicine and the hazard to develop treatments during pregnancy without careful animal verifications. However, this experience has also provided unexpected progress by suggesting new pathophysiological concepts: fetal programming of adult diseases and/or transgenerational transmission of environmental effects through epigenetic modifications.

The history of DES, lessons to be learned.

Since the 1940s, diaethylstilbestrol (DES) has been used by millions of pregnant women to prevent miscarriages and many other disorders in pregnancy. In 1971, it became clear that this apparently innocent treatment proved to be a time bomb for the infants exposed to DES during the first trimester of pregnancy. DES is now associated with an increased risk of breast cancer, clear cell adenocarcinoma (CCAC) of the vagina and cervix, and reproductive anomalies. This article summarises the potential long-term health implications of DES on the mother, DES daughters and DES sons, and the possible side effects on the third generation. Health care professionals have to know the history of DES to prevent future disasters with drugs prescribed.

Lessons learned from perinatal exposure to diethylstilbestrol.

The synthetic estrogen diethylstilbestrol (DES) is well documented to be a perinatal carcinogen in both humans and experimental animals. Exposure to DES during critical periods of differentiation permanently alters the programming of estrogen target tissues resulting in benign and malignant abnormalities in the reproductive tract later in life. Using the perinatal DES-exposed rodent model, cellular and molecular mechanisms have been identified that play a role in these carcinogenic effects. Although DES is a potent estrogenic chemical, effects of low doses of the compound are being used to predict health risks of weaker environmental estrogens. Therefore, it is of particular interest that developmental exposure to very low doses of DES has been found to adversely affect fertility and to increase tumor incidence in murine reproductive tract tissues. These adverse effects are seen at environmentally relevant estrogen dose levels. New studies from our lab verify that DES effects are not unique; when numerous environmental chemicals with weak estrogenic activity are tested in the experimental neonatal mouse model, developmental exposure results in an increased incidence of benign and malignant tumors including uterine leiomyomas and adenocarcinomas that are similar to those shown following DES exposure. Finally, growing evidence in experimental animals suggests that some adverse effects can be passed on to subsequent generations, although the mechanisms involved in these trans-generational events remain unknown. Although the complete spectrum of risks to DES-exposed humans are uncertain at this time, the scientific community continues to learn more about cellular and molecular mechanisms by which perinatal carcinogenesis occurs. These advances in knowledge of both genetic and epigenetic mechanisms will be significant in ultimately predicting risks to other environmental estrogens and understanding more about the role of estrogens in normal and abnormal development.

How to treat a menopausal woman: a history, 1900 to 2000.

Over the course of the 20th century, physicians had a variety of hormonal treatments to offer their menopausal patients. This paper traces the development and deployment of these therapies, which ranged from desiccated ewe ovary to the modern estrogen replacement therapy. In addition, this paper demonstrates that women often medicated themselves at menopause, turning perhaps to Lydia Pinkham's vegetable tonic or the more modern Change-O-Life elixir. Finally, this paper discusses the larger societal approaches to eliminating menopausal symptoms.

The stilbestrol disorders in historical perspective.

In the late 1960's when a series of adolescent girls with adenocarcinoma of the vagina presented themselves to our hospital, we did not immediately suspect the cause. Previous experience with radical hysterectomy and with vaginal reconstruction had prepared us technically to treat them sucessfully. Then a clue to etiology from one mother's observation regarding DES as a pregnancy supportive medication was quickly and conclusively converted into fact by an investigation with case controls. Rapid expansion of our knowledge came about through information accumulated in a Registry, and untoward effects other than cancer soon came to notice as young asymptomatic women presented themselves for examination because of known fetal exposure. The dominant event is clearly recognizable ss teratogenic, resulting in anomalous development of the vagina and cervix. Although the appearance of clear cell adenocarcinoma in a small fraction of DES-daughters is a consequence, the role of DES in its carcinogenesis is still unproved.

Development of the oral contraceptives.

PIP: The development of oral contraceptives (OCs) is briefly discussed. From reviewing the literature it was seen that the 1st "OC" was the harmless, nontoxic, safe, and very inexpensive synthetic estrogen diethylstilbestrol, or stilbestrol, which is still the best OC in 1975. This OC is still prescribed because a toxic dose, even up to 300,000 mg yearly, has never been encountered. The regimen consists of 3-5 mg daily for 26 nights with 3-5 nights shipped, plus a potent B-complex vitamin (Livitamin) 2-3 times daily. This OC is unique in that ovulation and menstrual flow can be inhibited for 60-120 days. The patient can miss from 7-14 days before ovulation occurs, after 1 course of this OC. This regimen provides a harmless, nontoxic, and 100% effective OC.^ieng