Risk Factor: XM
Class: Hormones/ Estrogens
Fetal Risk Summary
Between 19401971, an estimated 6 million mothers and their fetuses were exposed to diethylstilbestrol (DES) to prevent reproductive problems such as miscarriage, premature delivery, intrauterine fetal death, and toxemia (1,2,3 and 4). Controlled studies have since proven that DES was not successful in preventing these disorders (5,6). This use has resulted, however, in significant complications of the reproductive system in both female and male offspring (1,2,3,4,5,6,7,8,9,10,11 and 12). Two large groups have been established to monitor these complications: the Registry for Research on Hormonal Transplacental Carcinogenesis and the Diethylstilbestrol Adenosis (DESAD) Project (4). The published findings and recommendations of the DESAD project through 1980, plus a number of other studies including the Registry, were reviewed in a 1981 National Institutes of Health booklet available from the National Cancer Institute (4). This information was also reprinted in a 1983 journal article (13). The complications identified in female and male children exposed in utero to DES are: Female Lower Mllerian tract Vaginal adenosis Vaginal and cervical clear cell adenocarcinoma Cervical and vaginal fornix defects (10) Cock’s comb (hood, transverse ridge of cervix) Collar (rim, hood, transverse ridge of cervix) Pseudopolyp Hypoplastic cervix (immature cervix) Altered fornix of vagina Vaginal defects (exclusive of fornix) (10) Incomplete transverse septum Incomplete longitudinal septum Upper Mllerian tract Uterine structural defects Fallopian tube structural defects Male Reproductive dysfunction Altered semen analysis Infertility The Registry was established in 1971 to study the epidemiologic, clinical, and pathologic aspects of clear cell adenocarcinoma of the vagina and cervix in DES-exposed women (2). More than 400 cases of clear cell adenocarcinoma have been reported to the registry. Additional reports continue to appear in the literature (14). The risk of carcinoma is apparently higher when DES treatment was given before the 12th week of gestation and is estimated to be 0.141.4/1000 for women younger than 25 years of age (2,4).
The first known case of adenosquamous carcinoma of the cervix in an exposed patient was described in 1983 (15). In a second case, a fatal malignant teratoma of the ovary developed in a 12-year-old exposed girl (16). The relationship between these tumors and DES is unknown.
The frequency of dysplasia and carcinoma in situ (CIS) of the cervix and vagina in 3,980 DESAD Project patients was significantly increased over controls with an approximately 2- to 4-fold increase in risk (11). These results were different from earlier studies of these same women, which had indicated no increased risk for dysplasia and CIS (17,18). Researchers speculated that the increased incidence now observed was related to the greater amount of squamous metaplasia found in DES-exposed women (11). Scanning electron microscopy of the cervicovaginal transformation zone has indicated that maturation of epithelium is slowed or arrested at the stage of immature squamous epithelium in some DES-exposed women (19). This process may produce greater susceptibility to such factors as herpes and papillomavirus obtained through early coitus with multiple partners, and result in the observed increased rates of dysplasia/CIS (11). Of interest in this regard, a 1983 article reported detectable papillomavirus antigen in the cervical-vaginal biopsies of 16 (43%) of 37 DES-exposed women (20).
The incidence of cervical or vaginal structural changes has been reported to occur in up to 85% of exposed women, although most studies place the incidence in the 22%58% range (2,3,5,7,12,21,22,23 and 24). The structural changes are outlined above. The DESAD Project reported an incidence of approximately 25% in 1,655 women (10). Selection bias was eliminated by analyzing only those patients identified by record review. Patients referred by physicians and self-referrals had much higher rates of defects, about 49% and 43%, respectively. Almost all of the defects were confined to the cervical-vaginal fornix area, with only 14 patients having vaginal changes exclusive of the fornix and nearly all of these being incomplete transverse septums (10).
Reports linking the use of DES with major congenital anomalies have not been located. The Collaborative Perinatal Project monitored 614 mother-child pairs with 1st trimester exposure to estrogens, including 164 with exposure to DES (25, pp. 389, 391). Evidence for an increase in the expected frequency for cardiovascular defects, eye and ear anomalies, and Down’s syndrome was found for estrogens as a group, but not for DES (25, pp. 389,391,395). Re-evaluation of these data in terms of timing of exposure, vaginal bleeding in early pregnancy, and previous maternal obstetric history, however, failed to support an association between estrogens and cardiac malformations (26). An earlier study also failed to find any relationship with nongenital malformations (27).
Alterations in the body of the uterus have led to concern regarding increased pregnancy wastage and premature births (8,22,28,29,30 and 31). Increased rates of spontaneous abortions, premature births, and ectopic pregnancies are well established by these latter reports, although the relationship to the abnormal changes of the cervix and/or vagina is still unclear (8). Serial observations of vaginal epithelial changes indicate that the frequency of such changes decreases with age (4,17,24).
Spontaneous rupture of a term uterus has been described in a 25-year-old primigravid with DES-type changes in her vagina, cervix, and uterus (32). Other reports of this type have not been located.
In a 1984 study, DES exposure had no effect on the age at menarche, first coitus, pregnancy, or live birth, nor on a woman’s ability to conceive (33). One group of investigators found that although anomalies in the upper genital tract increased the risk for poor pregnancy outcome, they could not relate specific changes to specific types of outcomes (34).
Hirsutism and irregular menses were found in 72% and 50%, respectively, of 32 DES-exposed women (35). The degree of hirsutism was age-related, with the mean ages of severely and mildly hirsute women being 28.8 and 24.7 years, respectively. Based on various hormone level measurements, the authors concluded that in utero DES exposure may result in hypothalamic-pituitary-ovarian dysfunction (35). However, other studies in much larger exposed populations have not observed disturbances of menstruation or excessive hair growth (36).
Data on DES-exposed women who had undergone major gynecologic surgical procedures, excluding cesarean section, were reported in a 1982 study (37). Of 309 exposed women, 33 (11%) had a total of 43 procedures. The authors suggested that DES exposure resulted in an increased incidence of adnexal disease involving adhesions, benign ovarian cysts, and ectopic pregnancies (37). Surgical manipulation of the cervix (cryocautery or conization) in DES-exposed patients results in a high incidence of cervical stenosis and possible development of endometriosis (38,39). Both studies concluded, however, that the causes of infertility in these patients were comparable to those in a non-DES-exposed population.
Adverse effects in male offspring attributable to in utero DES exposure have been reported (1,5,40,41,42,43,44,45 and 46). Abnormalities thought to occur at greater frequencies include: Epididymal cysts Hypotrophic testis Microphallus Variococele Capsular induration Altered semen (decreased count, concentration, motility, and morphology) An increase in problems with passing urine and urogenital tract infections has also been observed (40).
DES exposure has been proposed as a possible cause of infertility in male offspring (1). However, in a controlled in vitro study, no association was found between exposure to DES and reduced sperm penetration of zona-free hamster eggs (46). In addition, a study of 828 exposed males found no increase over controls for risk of genitourinary abnormalities, infertility, or testicular cancer (47). Based on their data, the authors proposed that previous studies showing a positive relationship may have had selection biases, differences in DES use, or both.
Testicular tumors have been reported in three DES-exposed patients (6,48). In one case, a teratoma was discovered in a 23-year-old male (6). Two patients, 27 and 28 years of age, were included in the second report (48). Both had left-sided anaplastic seminomas, and one had epididymal cysts. A male sibling of one of the patients, also DES exposed, had severe oligospermia, and two exposed sisters had vaginal adenosis and vaginal adenocarcinoma.
Changes in the psychosexual performance of young boys have been attributed to in utero exposure to DES and progesterone (49,50). The mothers received estrogen/progestogen regimens for diabetes. A trend to less heterosexual experience and fewer masculine interests than controls was shown. A 2-fold increase in psychiatric disease, especially depression and anxiety, has been observed in both male and female exposed offspring (6).
Breast Feeding Summary
No data are available. Decreased milk volume and nitrogen-protein content may occur if diethylstilbestrol is used during lactation (see Mestranol and Ethinyl Estradiol).
- Stenchever MA, Williamson RA, Leonard J, Karp LE, Ley B, Shy K, Smith D. Possible relationship between in utero diethylstilbestrol exposure and male fertility. Am J Obstet Gynecol 1981;140:18693.
- Herbst AL. Diethylstilbestrol and other sex hormones during pregnancy. Obstet Gynecol 1981;58(Suppl):35s40s.
- Nordquist SAB, Medhat IA, Ng AB. Teratogenic effects of intrauterine exposure to DES in female offspring. Compr Ther 1979;5:6974.
- Robboy SJ, Noller KL, Kaufman RH, Barnes AB, Townsend D, Gundersen JH, Nash S. Information for physicians. Prenatal diethylstilbestrol (DES) exposure: recommendations of the Diethylstilbestrol-Adenosis (DESAD) Project for the identification and management of exposed individuals. NIH Publication No. 81-2049, 1981.
- Stillman RJ. In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance in male and female offspring. Am J Obstet Gynecol 1982;142:90521
- Vessey MP, Fairweather DVI, Norman-Smith B, Buckley J. A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring. Br J Obstet Gynaecol 1983;90:100717.
- Prins RP, Morrow P, Townsend DE, Disaia PJ. Vaginal embryogenesis, estrogens, and adenosis. Obstet Gynecol 1976;48:24650.
- Sandberg EC, Riffle NL, Higdon JV, Getman CE. Pregnancy outcome in women exposed to diethylstilbestrol in utero. Am J Obstet Gynecol 1981;140:194205.
- Noller KL, Townsend DE, Kaufman RH, Barnes AB, Robboy SJ, Fish CR, Jefferies JA, Bergstralh EJ, O’Brien PC, McGorray SP, Scully R. Maturation of vaginal and cervical epithelium in women exposed in utero to diethylstilbestrol (DESAD Project). Am J Obstet Gynecol 1983;146:27985.
- Jefferies JA, Robboy SJ, O’Brien PC, Bergstralh EJ, Labarthe DR, Barnes AB, Noller KL, Hatab PA, Kaufman RH, Townsend DE. Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project. Am J Obstet Gynecol 1984;148:5966.
- Robboy SJ, Noller KL, O’Brien P, Kaufman RH, Townsend D, Barnes AB, Gundersen J, Lawrence WD, Bergstrahl E, McGorray S, Tilley BC, Anton J, Chazen G. Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project. JAMA 1984;252:297983.
- Chanen W, Pagano R. Diethylstilboestrol (DES) exposure in utero. Med J Aust 1984;141:4913.
- NCI DES Summary. Prenatal diethylstilbestrol (DES) exposure. Clin Pediatr 1983;22:13943.
- Kaufman RH, Korhonen MO, Strama T, Adam E, Kaplan A. Development of clear cell adenocarcinoma in DES-exposed offspring under observation. Obstet Gynecol 1982;59(Suppl):68S72S.
- Vandrie DM, Puri S, Upton RT, Demeester LJ. Adenosquamous carcinoma of the cervix in a woman exposed to diethylstilbestrol in utero. Obstet Gynecol 1983;61(Suppl):84S7S.
- Lazarus KH. Maternal diethylstilboestrol and ovarian malignancy in offspring. Lancet 1984;1:53.
- O’Brien PC, Noller KL, Robboy SJ, Barnes AB, Kaufman RH, Tilley BC, Townsend DE. Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. Obstet Gynecol 1979;53:3008.
- Robboy SJ, Kaufman RH, Prat J, Welch WR, Gaffey T, Scully RE, Richart R, Fenoglio CM, Virata R, Tilley BC. Pathologic findings in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. Obstet Gynecol 1979;53:30917.
- McDonnell JM, Emens JM, Jordan JA. The congenital cervicovaginal transformation zone in young women exposed to diethylstilboestrol in utero. Br J Obstet Gynaecol 1984;91:5749.
- Fu YS, Lancaster WD, Richart RM, Reagan JW, Crum CP, Levine RU. Cervical papillomavirus infection in diethylstilbestrol-exposed progeny. Obstet Gynecol 1983;61:5962.
- Ben-Baruch G, Menczer J, Mashiach S, Serr DM. Uterine anomalies in diethylstilbestrol-exposed women with fertility disorders. Acta Obstet Gynecol Scand 1981;60:3957.
- Pillsbury SG Jr. Reproductive significance of changes in the endometrial cavity associated with exposure in utero in diethylstilbestrol. Am J Obstet Gynecol 1980;137:17882.
- Professional and Public Relations Committee of the Diethylstilbestrol and Adenosis Project of the Division of Cancer Control and Rehabilitation. Exposure in utero to diethylstilbestrol and related synthetic hormones. Association with vaginal and cervical cancers and other abnormalities. JAMA 1976;236:11079.
- Burke L, Antonioli D, Friedman EA. Evolution of diethylstilbestrol-associated genital tract lesions. Obstet Gynecol 1981;57:7984.
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
- Wiseman RA, Dodds-Smith IC. Cardiovascular birth defects and antenatal exposure to female sex hormones: a reevaluation of some base data. Teratology 1984;30:35970.
- Wilson JG, Brent RL. Are female sex hormones teratogenic? Am J Obstet Gynecol 1981;141:56780.
- Herbst AL, Hubby MM, Blough RR, Azizi F. A comparison of pregnancy experience in DES-exposed daughters. J Reprod Med 1980;24:629.
- Barnes AB, Colton T, Gundersen J, Noller KL, Tilley BC, Strama T, Townsend DE, Hatab P, O’Brien PC. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med 1980;302:60913.
- Veridiano NP, Dilke I, Rogers J, Tancer ML. Reproductive performance of DES-exposed female progeny. Obstet Gynecol 1981;58:5861.
- Mangan CE, Borow L, Burnett-Rubin MM, Egan V, Giuntoli RL, Mikuta JJ. Pregnancy outcome in 98 women exposed to diethylstilbestrol in utero, their mothers, and unexposed siblings. Obstet Gynecol 1982; 59:3159.
- Williamson HO, Sowell GA, Smith HE. Spontaneous rupture of gravid uterus in a patient with diethylstilbestrol-type changes. Am J Obstet Gynecol 1984;150:15860.
- Barnes AB. Menstrual history and fecundity of women exposed and unexposed in utero to diethylstilbestrol. J Reprod Med 1984;29:6515.
- Kaufman RH, Noller K, Adam E, Irwin J, Gray M, Jefferies JA, Hilton J. Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol-exposed progeny. Am J Obstet Gynecol 1984;148:97384.
- Peress MR, Tsai CC, Mathur RS, Williamson HO. Hirsutism and menstrual patterns in women exposed to diethylstilbestrol in utero. Am J Obstet Gynecol 1982;144:13540.
- Verkauf BS. Discussion. Am J Obstet Gynecol 1982;144:13940.
- Schmidt G, Fowler WC Jr. Gynecologic operative experience in women exposed to DES in utero. South Med J 1982;75:2603.
- Haney AF, Hammond MG. Infertility in women exposed to diethylstilbestrol in utero. J Reprod Med 1983;28:8516.
- Stillman RJ, Miller LC. Diethylstilbestrol exposure in utero and endometriosis in infertile females. Fertil Steril 1984;41:36972.
- Henderson BE, Benton B, Cosgrove M, Baptista J, Aldrich J, Townsend D, Hart W, Mack TM. Urogenital tract abnormalities in sons of women treated with diethylstilbestrol. Pediatrics 1976;58:5057.
- Gill WB, Schumacher GFB, Bibbo M. Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero. J Urol 1977;117:47780.
- Gill WB, Schumacher GFB, Bibbo M, Strous FH, Schoenberh HW. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J Urol 1979;122:369.
- Gill WB, Schumacher GFB, Bibbo M. Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol (DES). J Reprod Med 1976;16:14753.
- Driscoll SG, Taylor SM. Effects of prenatal maternal estrogen on the male urogenital system. Obstet Gynecol 1980;56:53742.
- Bibbo M, Gill WB, Azizi F, Blough R, Fang VS, Rosenfield RL, Schaumacher GFB, Sleeper K, Sonek MG, Wied GL. Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol 1977;49:18.
- Shy KK, Stenchever MA, Karp LE, Berger RE, Williamson RA, Leonard J. Genital tract examinations and zona-free hamster egg penetration tests from men exposed in utero to diethylstilbestrol. Fertil Steril 1984;42:7728.
- Leary FJ, Resseguie LJ, Kurland LT, O’Brien PC, Emslander RF, Noller KL. Males exposed in utero to diethylstilbestrol. JAMA 1984;252:29849.
- Conley GR, Sant GR, Ucci AA, Mitcheson HD. Seminoma and epididylmal cysts in a young man with known diethylstilbestrol exposure in utero. JAMA 1983;249:13256.
- Yalom ID, Green R, Fisk N. Prenatal exposure to female hormones. Effect on psychosexual development in boys. Arch Gen Psychiatry 1973;28:55461.
- Burke L, Apfel RJ, Fischer S, Shaw J. Observations on the psychological impact of diethylstilbestrol exposure and suggestions on management. J Reprod Med 1980;24:99102.