HONORABLE MENTION MANUSCRIPT THE DES (DIETHYLSTILBESTROL) YEARS: BRIDGING THE PAST INTO THE FUTURE Martin A. Martino, MD, Nicole S. Nevadunsky, BA, Thomas J. Magliaro, MD, and Michael I. Goldberg, MD Between the years 1941–1971, it is estimated that between 5 million and 10 million pregnancies were exposed to diethylstilbestrol (DES). 1 The adverse consequences of this exposure in utero had been reported as early as 1949. 2 How- ever, it was not until the develop- ment of a rare vaginal cancer known as clear-cell adenocarci- noma in 1971 that the implications with regard to teratogenicity of this steroid were identified. 3 The use of anecdotal reports to develop preventive treatments cautions physicians regarding the conse- quences that may result when an- ecdotal reports are relied on to determine medical management rather than evidence-based re- search. This article will review the history and pathology of DES and alert the primary care physician to the misfortunes of our past and the implications they may have in the future. With the increased preva- lence of alternative treatments and homeopathic remedies, the contemporary physician must be mindful of the importance of evi- dence-based medicine when pre- scribing therapeutics. Finally, this article will discuss the importance of evidence-based medicine and remind us to learn from our past experiences when we introduce new treatments in the future. (Prim Care Update Ob/Gyns 2002; 9:7–12. © 2002 Elsevier Science Inc. All rights reserved.) Clear-cell adenocarcinoma (CCA) of the vagina and cervix accounts for approximately 2% of gynecological cancers, and it is estimated that 1 in 1,000 women exposed to diethyl- stilbestrol (DES) in utero will de- velop CCA in addition to other gen- ital anomalies. 4 The original indication for use was to prevent miscarriages in high-risk pregnan- cies. This was derived largely from anecdotal evidence and from an ob- servation that lower hormone levels were associated with miscarriage. Sequelae of DES use include struc- tural abnormalities of the reproduc- tive tracts of daughters exposed in utero and possibly increased inci- dence of breast cancer in patients who took DES. 5 Speculation regard- ing the increased incidence of other cancers, infertility, and other health problems continues to be investi- gated. As many DES daughters are entering perimenopausal and menopausal age groups, they may be at increased risk of developing hormonal-dependent neoplasms. Although knowledge of the morbid- ity and mortality associated with DES is important for the physician caring for the exposed patient, the consequences of DES exposure demonstrate the magnitude of pa- thology possible from iatrogenic disease. Moreover, they underscore the importance of clinical investi- gation before use of pharmaceutical agents and the vigilance that must be undertaken when evaluating the potential use of new therapeutics. Historical Background of DES A National Institutes of Health (NIH) task force has estimated that 5 million to 10 million Americans may have been exposed between 1940 and 1971 to DES in utero, with the majority of this exposure occur- ring between 1940 and 1951. 1 It has been estimated that at least half of these individuals were unaware of this exposure because DES was given in many forms (including pills, shots, suppositories, and vita- mins) and was called by many dif- ferent trade names. 5 DES was the first orally active estrogen discov- ered and was synthesized in 1938 by Charles Dodd. The use of this new agent began in 1941 in Boston, Massachusetts by George Smith, who was the chair of the department of obstetrics and gynecology at Har- vard Medical School at that time. He and his wife had been observing lower hormone levels in women with miscarriages and believed that raising the blood level of DES would prevent threatened miscarriages. In 1948, convinced that DES would effectively treat complications of high-risk pregnancy, the Smiths published anecdotal reports from 117 obstetricians regarding the ben- efits of DES given to mothers with From the Department of Obstetrics and Gynecol- ogy, UMDNJ—Robert Wood Johnson Medical School, New Brunswick, New Jersey. Volume 9, Number 1, 2002 7 © 2002 Elsevier Science Inc., all rights reserved. 1068-607X/02/$22.00 ● PII S1068-607X(01)00095-6