Use Of Diethylstilbestrol Research Articles

Erratum - June 2001

Erratum| June 01 2001 Erratum - June 2001 Pediatrics (2001) 107 (6): 1450. https://doi.org/10.1542/peds.107.6.1450 Connected Content This is a correction to: Prenatal Treatment of Congenital Adrenal Hyperplasia: Author Differs With Technical Report Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Erratum - June 2001. Pediatrics June 2001; 107 (6): 1450. 10.1542/peds.107.6.1450 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP Grand RoundsAAP NewsAll AAP Sites Search Advanced Search Subjects: For Your Benefit Topics: memory, prenatal care, thalidomide, congenital adrenal hyperplasia, dexamethasone, diethylstilbestrol An editing error occurred in a response to a letter to the editor that appeared in the April 2001 issue of Pediatricsentitled “Prenatal Treatment of Congenital Adrenal Hyperplasia: Author Differs With Technical Report.” On page 805, the last sentence of the reply by Frias et al reads: The memory of the tragedies associated with prenatal use of dexamethasone and thalidomide demands no less. That sentence should read: The memory of the tragedies associated with prenatal use of DES (diethylstilbestrol) and thalidomide demands no less. View Original Article You do not currently have access to this content.

Squamous Cell Carcinoma Arising in Hormonally Treated Adenocarcinoma of the Prostate

Adenocarcinoma of acinar origin comprises almost all of the primary prostatic carcinomas. In contrast, prostatic squamous cell carcinoma is extraordinarily rare. We report a case of primary squamous cell carcinoma of the prostate that developed in a 64-year-old man, 3 months after treatment with diethylstilbestrol (DES) and flutamide for stage D2 adenocarcinoma of the prostate. This case report describes a transformation from adenocarcinoma to pure squamous cell carcinoma following the use of DES. The etiology of the squamous cell carcinoma in the present case and those previously reported in the literature are discussed.

Cancer from Beef: DES, Federal Food Regulation, and Consumer Confidence by Alan Marcus

396 Book Reviews TECHNOLOGY AND CULTURE Cancerfrom Beef: DES, FederalFood Regulation, and Consumer Confidence. By Alan Marcus. Baltimore:Johns Hopkins University Press, 1994. Pp. x+235; notes, bibliography, index. $38.50. Cancerfrom Beefis, the story of a public controversy that involved the application of scientific research in industry, the development of sophisticated assay methods, the imposition of legal guidelines on food production, and consumers’ concerns about the healthfulness of modern food production methods. Alan Marcus details the fascinating history of DES (diethylstilbestrol) as a cattle feed ad­ ditive. He relates how scientists were dethroned from their privi­ leged position in a tripartite “partnership” of scientists, industry, and government. Since the late 19th century, scientists have been the arbiters of special knowledege generated through rigorous, methodical, unbi­ ased research. By the 1920s, scientists in both industry and govern­ ment were believed capable of and interested in solving social prob­ lems through science. By the 1930s, Marcus argues, this had created a nonhierarchical “regulatory relationship” between the two (p. 4). DES fractured this relationship. Was the addition of DES to beef feed harmful or not harmful to the human consumer? Scientists con­ ceded that they did not have the evidence to answer this question definitively. Modified regulatory procedures incorporated a costbenefit analysis and were opened up to various other constituencies, including consumers. Marcus documents the written and oral, formal and informal means by which the scientist Wise Burroughs disseminated informa­ tion about DES in cattle feed in the early 1950s, even before any patents had been awarded and before the Food and Drug Adminis­ tration (FDA) had considered the safety of DES additives. (The FDA was involved because DES was considered a drug.) While expanding on the intellectual, professional, and economic reasons that Bur­ roughs and other scientists had for pushing DES, Marcus also consid­ ers the role played by Eli Lilly and Company in patent development. By the 1960s, science had “lost its cherished regulatory place” (p. 48). In Marcus’s view, regulation was no longer an example of cooperative partnership based on scientific consensus. The FDA was moving from after-the-fact enforcement to research-based preven­ tion. Rather than relying on science and scientists drawn from indus­ try, the agency began to depend more on its own scientists. New legislation, most especially passage of the 1958 Delaney clause prohibiting the sale of food containing substances found to induce cancer in humans or other animals, moved regulation far­ ther from science into legal argumentation. Application of the Dela­ ney clause to DES highlighted troubling questions. How can we de­ termine the long-term effects of minute doses of potentially carcinogenic substances? What is a functional and acceptable assay TECHNOLOGY AND CULTURE Book Reviews 397 method? What constitutes evidence of harm or safety? When science and technology did not provide simple, unequivocal answers to these questions, nonscientists entered the arena with their own interpreta­ tions of the evidence. At regulatory hearings, in the courts, in the halls of Congress, and in the media, a multitude of interested par­ ties—including consumers, beef producers, and government offi­ cials—participated in the debates. A short review can only suggest the depth of research presented in Cancerfrom Beef Marcus’s text describes the scientific and techno­ logical disputes over the use of DES from the 1950s into the 1980s, the procedural maneuvers used by regulatory agencies such as the FDA, and the court battles mounted over the use of DES in cattle feed. It enumerates the shifting allegiances within the scientific com­ munity and among scientists, feed and pharmaceutical companies, and regulators. The analysis is so dense that at times it is difficult to follow the line of argumentation. And, even with its wealth of data, the book is in the end unsatis­ fying. Marcus is so intent on documenting the “lost reverence” (p. 151) for experts and expertise that he does not address the im­ portant issue of how one should choose among competing claims to scientific and technological authority. Scientists who disagreed with Burroughs are relegated to the margins ofthe scientific commu­ nity; consumers who resisted DES-fed cattle are considered dupes of false science. It is important that we understand the...

Effects of diethylstilbestrol (DES) medication during pregnancy: report from a symposium at the 10th international congress of ISPOG.

This article is a report based on presentations at the symposium Effects of Diethylstilbestrol (DES) Medication during Pregnancy at the conference Reproductive Life, 10th International Congress of The International Society of Psychosomatic Obstetrics and Gynaecology (ISPOG) in Stockholm, Sweden June 14-17, 1992. The objective of this symposium, chaired by Eylard van Hall and Ingar Palmlund, was to provide the basis for a discussion of how the risks of DES had been evaluated in different countries. In the general discussion following the presentations everybody present expressed concerns that DES might still be given to pregnant women in many parts of the world, called for measures to alert medical professionals world-wide to the hazards of the use of DES, and requested measures to effect an international ban of DES in medication for pregnant women.

Diethylstilbestrol (DES) and breast cancer.

It is estimated that 2 million US women used diethylstilbestrol (DES), a nonsteroidal estrogen, to reduce the risk of fetal loss from the late 1940s through the early 1960s. The results of clinical trials of the effectiveness of DES in the early 1950s precipitated the eventual decline of DES prescription by the 1960s. Concern about the breast cancer risk associated with the high dose of stilbestrol used led to 2 follow-up studies of these clinical trial participants, as well as 2 other retrospective cohort studies to examine the subsequent risk of breast cancer in DES-exposed women. 3 of the 4 studies reported positive results, with an overall 50% increase in risk for ever using DES during pregnancy and an apparent latency period of more than 20 years. These studies have or more limitations, including the absence of information on dosage taken and duration of use, confusion about the identify of the exposed group and the inability to distinguish between the effect of DES and the effect of indications for using DES. Nevertheless, the findings supported a possible association between DES and breast cancer risk. The 4 studies were published between 1980 and 1984 and included many women who had only recently entered the age period when breast cancer incidence is high. It is possible that the incidence of breast cancer associated with DES may increase with additional follow-up time. Prenatal influences on carcinogenesis have recently become of interest in the etiology of adult cancer, and, in particular, it has been proposed that increased estrogen levels during pregnancy might increase the probability of breast cancer in daughters. It has been demonstrated that DES use during pregnancy can influence the subsequent risk of clear cell adenocarcinoma in offspring, although the issue of whether DES might also influence the subsequent risk of breast cancer in daughters remains to be investigated.

Doctors and detailers: therapeutic education or pharmaceutical promotion?

Pharmaceutical companies in industrialized countries generally view detailers as the most crucial element in the promotion of their products, with the result that over 50 percent of expenditures on promotion are devoted to detailers. Publicly the companies make claims for the scientific knowledge of detailers and for their role in passing on information to physicians, but the main purpose of detailers is to sell their company's products. This emphasis on sales is evident from statements of detailers themselves, from advertisements for detailers, from company documents, and by looking at the groups of physicians that companies specially target for visits by detailers. A variety of explanations are offered as to why physicians see detailers, but on examination none of the reasons is justifiable. Studies from a number of industrialized countries have shown that over 90 percent of physicians see detailers and a substantial percentage rely heavily on detailers as sources of information about therapeutics. Detailers are highly successful in altering physicians' prescribing habits, but almost all the literature available shows that the more reliant doctors are on commercial sources of information, the less appropriate they are as prescribers. Widespread use of DES (diethylstilbestrol) and the Dalkon Shield was encouraged by detailers. Although detailers have received the endorsement of both physicians' groups and government bodies, seeing detailers is detrimental to the practice of good medicine, and the best interests of doctors and their patients would be served if physicians had nothing further to do with detailers.

Identification and Management of DES-Exposed Women

Diethylstilbestrol (DES), a synthetic estrogen compound, was prescribed to many women with history of miscarriage between the years 1940 and 1971. As a result of prolonged use of DES in gynecological practice, an estimated 1 million to 1.5 million women were exposed prenatally, resulting in multiple upper and lower genital tract abnormalities. These anomalies may affect reproductive function and place women at greater risk for developing clear cell adenocarcinoma (peak incidence at age 19) and squamous cell carcinoma of the vagina and cervix (peak incidence at ages 35 to 40). Emphasis has been placed on screening for clear cell adenocarcinoma rather than squamous cell carcinoma and reproductive alterations. Despite the previous emphasis during the 1970s and a subsequent decline in public and practitioner awareness, women are at risk for the known effects of DES exposure until the year 2010. Greater effort must be made by practitioners to identify and screen for DES exposure in their practices, as well as to educate the public regarding the health risks posed by DES exposure so that affected women may be reached and receive care.

Diethylstilbestrol-induced cervical and vaginal adenosis using the neonatal mouse model.

The relevance of diethylstilbestrol (DES) administration to neonatal mice as a model for human pathology attributed to the use of DES in high-risk pregnancies has been investigated, particularly with respect to cervical and vaginal changes in female offspring. Neonatal DES treatment of mice results in tonic pituitary gonadotropin release and continuous estrogen secretion by the ovary. Studies were designed to determine the effect of this altered ovarian endocrine activity on cervical and vaginal histopathology. Ovariectomy of DES-treated mice, with or without estradiol replacement, did not eliminate the lesions, nor did estrogen and progesterone administered in a regimen intended to mimic estrous cycle changes. Induction of the constant estrus state by neonatal estradiol benzoate or testosterone propionate administration or by exposure to constant light did not produce the type of vaginal or cervical changes seen in DES mice. Thus, altered ovarian function is apparently not required for the vaginal and cervical changes appearing in later life. A role for endogenous (or exogenous) ovarian hormones in the developmental progression toward normality is suggested.

Fertility of female mice fed coumestrol and diethylstilbestrol.

Coumestrol, a compound produced by various legumes which exerts estrogen-like activity in animals, and diethylstilbestrol (DES) were studied as chemical agents for controlling reproduction in mice. Female mice were fed control diets or diets containing 100 ppm coumestrol for eight days. Female mice were exposed to males and reproductive tracts examined 14 days later. Litter size was not affected by 100 ppm dietary coumestrol but feed consumption was reduced 17%. Similar trials were conducted with mice fed 1 ppm DES. Vaginal plugs were present in 50% of the females fed 1 ppm DES, but no fetal pups were present. Feed intake was reduced 37% by the DES. Levels of 0, .1, .25, .50, .75 and 1.0 ppm DES were compared in two strains of mice, Swiss and ICR. Reproduction in both strains was totally inhibited by all DES treatments. The use of DES to control rodent populations warrants further investigation.

Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters

Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago. A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less. A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known. Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001). The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005). An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges. However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child. More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group. The spectrum of diseases at operation in both groups was similar. Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar. For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.

Battles continue over DES use in fattening cattle

Federal investigators are uncovering widespread disregard of the Food and Drug Administration's ban on use of diethylstilbestrol (DES) to help slaughter animals gain weight (<i>JAMA</i>[MEDICAL NEWS] 242:1010, 1979). In the meantime, alternative compounds for this purpose are under study. The FDA officials say the illegal use of DES so far involves more than 420,000 cattle, some 30,000 of which already have been slaughtered. Some violators may be prosecuted, and the US Department of Agriculture (USDA) is increasing surveillance to prevent further violations. The FDA and the USDA contend that "DES is a known carcinogen in both animals and humans" and that "DES residues have been found in animals intended for human food." All this results from an FDA decision of about a year ago in which the agency declared the following: Effective July 13, 1979, DES was not to be manufactured or shipped. (Some manufacturers since have filed suit,

Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix

This study was based on cases accessioned in the Registry of Clear Cell Adenocarcinoma of the Genital Tract in Young Females to ascertain the incidence of diethylstilbestrol (DES)-related cancers by age and year of birth. For accuracy in estimating the size of the reference population for the incidence rates, calculations were restricted to 127 white residents of the United States who were exposed prenatally to DES or other nonsteroidal synthetic estrogens. The disease is exceedingly rare prior to age 14 when the incidence rate begins to rise rapidly. The incidence peaks at age 19 (median 19.2 years) and then drops precipitately. Thus, DES-related clear cell adenocarcinoma is unusual in that nearly all cancers have been diagnosed in a narrow age range of 10 years (14 to 23 years). Women born in 1951 to 1953 have higher incidence rates than those born in the previous or subsequent three-year period. This suggests that the prevalence of pregnancy-related use of DES was at a peak in the early 1950's. The cumulative risk of this type of genital cancer, through age 24, for DES-exposed female subjects is estimated to be in the range of 0.14 to 1.4 per thousand. The wide limits are due to the fact that the number of young women exposed is not known precisely. The low risk of disease and the narrow age range of the cases, relative to the long latency period, suggest that DES is an incomplete carcinogen. Other factors, possibly related to puberty, may be involved in the causation of this disease.

Diethylstilbestrol in Pregnancy

A question is raised concerning the use of diethylstilbestrol (DES) in the follicular phase of the cycle of women who have infertility without obvious cause in order to improve postcoital tests. Although the use of DES is of little concern in the follicular phase many women are afraid to take it. Thus ethinyl estradiol 20 mcg is recommended from day 5 to 14 daily or every 2 days to improve cervical mucus.

Vaginal cancer: an iatrogenic disease?

Presently we are witnessing two unique occurrences in the field of public health: the first demonstration of transplacental carcinogenesis in humans and the first drug-induced cancer epidemic in women under age 30. This article examines the current status of the vaginal cancer epidemic and possible reasons for the failure of governmental health agencies to recall and test the generation of females who were exposed to diethylstilbestrol (DES) in utero. Epidemiologic evidence indicates that the large majority of "DES daughters" may develop adenosis. The carcinogenicity of other estrogens in wide use is examined. It is pointed out that, although vaginal cancer in daughters exposed to DES in utero provided the clinical evidence to secure a Food and Drug Administration ban on DES as an additive to cattle feed, the FDA approved a new use of DES as a "morning-after pill" contraceptive even though the contraceptive contains 833,000 times the amount of DES banned for human consumption in beef. The lack of standards of informed consent in the testing of the morning-after pill on university women and the additional risk this presents to DES daughters are discussed. The sociopolitical and economic contributing factors to the vaginal cancer epidemic and the extent to which the scientific direction of medical care is influenced by economic factors are examined. Public health measures which might prevent the occurrence of such man-made epidemics in the future are recommended.

Diethylstilbestrol in pregnancy. Frequency of exposure and usage patterns.

In view of the reported association between exposure in utero to diethylstilbestrol (DES) and clear-cell adenocarcinoma of the vagina, data on the prenatal use of DES in some 51,000 pregnancies in 12 hospitals between the years, 1959 and 1965, were examined. Among these women, in whom prenatal drug exposure was carefully documented, there was considerable variation in DES usage, the frequency being highest in the Boston Lying-In Hospital (exposure in 1.5% of pregnancies) and the Children's Hospital, Buffalo (exposure in 0.8% of pregnancies). Data from two marketing research sources were used to estimate DES usage in the United States. It is calculated that a maximum of 50,000 liveborn females per year, born between 1960 and 1970, were exposed to DES in utero, while the most likely estimate is in the range 10,000 to 16,000.

Studies of nuclear DNA in vaginal adenosis and clear-cell adenocarcinoma

Spectrophotometric measurements of nuclear DNA have been made in 3 cases of clear-cell adenocarcinomas of the vagina and 3 with adenosis. There was a history of maternal ingestion of diethylstilbestrol (DES) in all but one of the patients; one patient with an adenocarcinoma was conceived prior to the use of DES in pregnancy. DNA studies showed each of the adenocardinomas to be aneuploid whereas each of the adenosis specimens was in the diploid-tetraploid range. By analogy with results of DNA studies in other gynecologic malignancies, it is suggested that if adenosis is the tissue in which the clear-cell adenocarcinoma arises, it should have a precursor stote with a shift toward aneuploidy which has not been identified in this study.

Diethylstilbestrol cis- trans isomerization and estrogen activity of diethylstilbestrol isomers

Facile isomerization of molecular diethylstilbestrol (DES) occurs by a second order reaction on solution in organic solvents. The isomerization of the disodium salt of DES which occurs in basic methanolic solutions is a reversible first order reaction. Mechanisms of the isomerization processes of molecular and anionic DES are proposed. The estrogenic response of isolated disodium salt of cis-DES was determined to be approximately 45% of the activity observed for trans-DES using a mouse uterine weight assay. Since the trans isomer is believed to be considerably more active biologically because of its structural similarity with estradiol, it appears that the observed appreciable activity of the cis-DES test solution is a consequence of the isomerization in vivo to the trans isomer. These results may have significance in the use of DES as a ruminant growth promoter since estrogenic response appears not to be restricted solely to the amount of trans isomer content.