Female Genital Tract Changes Related to Prenatal Diethylstilbestrol Exposure

  • Stanley J. Robboy
  • Robert H. Young
  • Arthur L. Herbst


Diethylstilbestrol (DES) and the chemically related drugs hexestrol and dienestrol are synthetic, nonsteroidal estrogens that were frequently administered to mothers for high-risk pregnancies during the 1940s through the 1960s.12,30,36 In 1971, the rare development of clear cell adenocarcinoma of the vagina in young women was linked to their exposure in utero to these drugs.25 Subsequently a number of non-neoplastic changes were identified in the genital tract of DES-exposed daughters, such as adenosis (glandular epithelium or its secretory products in the vagina), cervical ectropion, various types of cervicovaginal ridges, and structural abnormalities of the uterine corpus and fallopian tube. This chapter describes the pathology and pertinent clinical aspects of clear cell adenocarcinoma of the vagina and cervix as well as the non-neoplastic changes associated with, or possibly related to, DES exposure. Recommendations for the identification and management of exposed daughters,44 possible sequelae in mothers6,7 and sons,51,532,51 animal models for the study of DES exposure,34,39 and general reviews12,18 are presented elsewhere.


Obstet Gynecol Lamina Propria Clear Cell Carcinoma Squamous Metaplasia Glandular Epithelium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Antonioli DA, Burke L, Friedman EA (1980) Natural history of diethylstilbestrol-associated genital tract lesions: Cervical ectopy and cervicovaginal hood. Am J Obstet Gynecol 137: 847–853PubMedGoogle Scholar
  2. 2.
    Antonioli DA, Rosen S, Burke L, Donahue V (1979) Glandular dysplasia in diethystilbestrol-associated vaginal adenosis. A case report and review of the literature. Am J Clin Pathol 71: 715–721PubMedGoogle Scholar
  3. 3.
    Barnes AB (1979) Menstrual histories of young women exposed in utero to diethylstilbestrol. Fertil Steril 32: 148–153PubMedGoogle Scholar
  4. 4.
    Barnes AB, Colton T, Gundersen JH, Noller KL, Tilley BC, Strama T, Townsend DE, Hatab P, O’Brien PC (1980) Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol: Preliminary findings from the DESAD Project. N Engl J Med 302: 609–613PubMedCrossRefGoogle Scholar
  5. 5.
    Bibbo M, Gill WB, Azizi F, Blough R, Fang VS, Rosenfield RL, Schumacher GFB, Sleeper K, Sonek MG, Wied GL (1977) Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol 49: 1–8PubMedGoogle Scholar
  6. 6.
    Bibbo M, Haenszel WM, Wied GL, Hubby M, Herbst AL (1978) A twenty-five-year follow-up study of women exposed to diethylstilbestrol during pregnancy. N Engl J Med 298: 763–767PubMedCrossRefGoogle Scholar
  7. 7.
    Brian DD, Tilley BC, Labarthe DR, O’Fallon, Noller KL, Kurland LT (1980) Breast cancer in DES-exposed mothers. Absence of association. Mayo Clin Proc 55: 89–93PubMedGoogle Scholar
  8. 8.
    Burke L, Antonioli D, Rosen S (1978) Vaginal and cervical squamous cell dysplasia in women exposed to diethylstilbestrol in utero. Am J Obstet Gynecol 132: 537–544PubMedGoogle Scholar
  9. 9.
    Cosgrove M, Benton B, Henderson B (1977) Male genitourinary abnormalities and maternal diethylstilbestrol. J Urol 117: 220–222Google Scholar
  10. 10.
    Dickersin GR, Welch WR, Erlandson R, Robboy SJ (1980) Ultrastructure of 16 cases of clear cell adenocarcinoma of the vagina and cervix in DES exposed young women. Cancer 45: 1615–1624PubMedCrossRefGoogle Scholar
  11. 11.
    Fenoglio CM, Ferenczy A, Richart RM, Townsend D (1976) Scanning and transmission electron microscopic studies of vaginal adenosis and the cervical transformation zone in progeny exposed in utero to diethylstilbestrol. Am J Obstet Gynecol 126: 170–180PubMedGoogle Scholar
  12. 12.
    Fink DJ (1979) DES Task Force Summary Report. DHEW publication no. 79–1688Google Scholar
  13. 13.
    Fu YS, Reagan JW, Richart RM, Townsend DE (1979) Nuclear DNA and histologic studies of genital lesions in diethylstilbestrol-exposed progeny. I. Intraepithelial glandular abnormalities. Am J Clin Pathol 72: 515–520PubMedGoogle Scholar
  14. 14.
    Fu YS, Robboy SJ, Prat J (1978) Nuclear DNA study of vaginal and cervical squamous cell abnormalities in DES exposed progeny. Obstet Gynecol 52: 129–137PubMedGoogle Scholar
  15. 15.
    Gill WB, Schumacher GFB, Bibbo M, Straus FH II, Schoenberg HW (1979) Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J Urol 122: 36–39PubMedGoogle Scholar
  16. 16.
    Haney AF, Hammon CB, Soules MR, Creasman WT (1979) Diethylstilbestrol-induced upper genital tract abnormalities. Fertil Steril 31: 142–146PubMedGoogle Scholar
  17. 17.
    Hart WR, Townsend DE, Aldrich JO, Henderson BE, Roy M, Benton B (1976) Histopathologic spectrum of vaginal adenosis and related changes in stilbestrol-ex-posed females. Cancer 37: 763–775PubMedCrossRefGoogle Scholar
  18. 18.
    Herbst AL, Bern H (1981) Developmental effects of DES in pregnancy. New York, Thieme StrattonGoogle Scholar
  19. 19.
    Herbst AL, Cole P, Colton T, Robboy SJ, Scully RE (1977) Age-incidence and risk of diethylstilbestrol related clear cell adenocarcinoma of the vagina and cervix. Am J Obstet Gynecol 128: 43–50PubMedGoogle Scholar
  20. 20.
    Herbst AL, Cole P, Norusis MJ, Welch WR, Scully RE (1980) Epidemiologic aspects and factors related to survival in 384 Registry cases of clear cell adenocarcinoma of the vagina and cervix. Am J Obstet Gynecol 135: 876–886Google Scholar
  21. 21.
    Herbst AL, Hubby MM, Blough RR, Azizi F (1980) A comparison of pregnancy experience in DES-exposed and DES-unexposed daughters. J Reprod Med 24: 62–69PubMedGoogle Scholar
  22. 22.
    Herbst AL, Norusis MJ, Rosenow PJ, Welch WR, Scully RE (1979) An analysis of 346 cases of clear cell adenocarcinoma of the vagina and cervix with emphasis on recurrence and survival. Gynecol Oncol 7: 111–122PubMedCrossRefGoogle Scholar
  23. 23.
    Herbst AL, Poskanzer DC, Robboy SJ, Fried-lander LM, Scully RE (1975) Prenatal exposure to stilbes-trol: A prospective comparison of exposed female offspring with unexposed control. N Engl J Med 292: 334–339PubMedCrossRefGoogle Scholar
  24. 24.
    Herbst AL, Robboy SJ, Scully RE (1975) Problems in the examination of the DES-exposed female. Obstet Gynecol 46: 353–355PubMedGoogle Scholar
  25. 25.
    Herbst AL, Ulfelder H, Poskanzer DC (1971) Ade-nocarinoma of the vagina: Association of maternal stilbes-trol therapy with tumor appearance in young women. N Engl J Med 284: 878–881PubMedCrossRefGoogle Scholar
  26. 26.
    Johnson LD, Driscoll SG, Hertig AT, Cole PT, Nickerson RJ (1979) Vaginal adenosis in stillborns and neonates exposed to diethylstilbestrol and steroidal estrogens and progestins. Obstet Gynecol 53: 671–679PubMedGoogle Scholar
  27. 27.
    Kaufman, RH, Adam E, Binder GL, Gerthoffer EA (1980) Upper genital tract changes and pregnancy outcome in offspring exposed in utero to diethylstilbestrol. Am J Obstet Gynecol 137: 299–308PubMedGoogle Scholar
  28. 28.
    Kurman RJ, Scully RE (1974) The incidence and histogenesis of vaginal adenosis: An autopsy study. Human Pathol 5: 265–276CrossRefGoogle Scholar
  29. 29.
    Labarthe DR, Adam E, Noller KL, O’Brien PC, Robboy SJ, Tilley BC, Townsend DE, Barnes AB, Kaufman RH, Decker DG, Fish CR, Herbst AL, Gundersen J, Kurland LT (1978) Design and preliminary observations of national cooperative diethylstilbestrol adenosis (DESAD) project. Obstet Gynecol 51:453–458PubMedCrossRefGoogle Scholar
  30. 30.
    Lanier AP, Noller KL, Decker DG, Elveback LR, Kurland LT (1973) Cancer and stilbestrol. A followup of 1,719 persons exposed to estrogens in utero and born 1943–1959. Mayo Clin Proc 48: 793–799PubMedGoogle Scholar
  31. 31.
    Lawrence WD, Shingleton HM, Gore H, Soong SJ (1980) Ultrastructural and morphometric study of di-ethylstilbestrol-associated lesions diagnosed as cervical intraepithelial neoplasia III. Cancer Res 40: 1558–1567PubMedGoogle Scholar
  32. 32.
    Loughlin JE, Robboy SJ, Morrison AS (1980) Risk factors for cancer of the testis. N Engl J Med 303: 112–113PubMedCrossRefGoogle Scholar
  33. 33.
    Mattingly RF, Staff A (1976) Cancer risk in diethyl-stilbestrol-exposed offspring. Am J Obstet Gynecol 126: 543–548PubMedGoogle Scholar
  34. 34.
    McLachlan JA, Newbold RR, Bullock BC (1980) Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res 40: 3988–3999PubMedGoogle Scholar
  35. 35.
    Ng ABP, Reagan JW, Nadji M, Greening S (1977) Natural history of vaginal adenosis in women exposed to diethylstilbestrol in utero. J Reprod Med 18: 1–13PubMedGoogle Scholar
  36. 36.
    Noller KL, Fish DR (1974) Diethylstilbestrol usage: its interesting past, important present, and questionable future. Med Clin North Am 58: 793–810PubMedGoogle Scholar
  37. 37.
    O’Brien PC, Noller K, Robboy SJ, Barnes AB, Kaufman R, Tilley B, Townsend DE (1979) Vaginal epithelial changes in young women enrolled in the national cooperative diethylstilbestrol adenosis (DESAD) project. Obstet Gynecol 53: 300–308PubMedGoogle Scholar
  38. 38.
    Pixley E (1976) Morphology of the fetal and prepubertal cervicovaginal epithelium. In: Jordon JA, Singer A, eds. The cervix. Saunders, Philadelphia, pp 75–86Google Scholar
  39. 39.
    Plapinger L, Bern HA (1979) Adenosis-like lesions and other cervicovaginal abnormalities in mice treated perinatally with estrogen. J Natl Cancer Inst 63: 507–518PubMedGoogle Scholar
  40. 40.
    Robboy SJ, Friedlander LM, Welch WR, Keh PC, Taft PD, Barnes AB, Scully RE, Herbst AL (1976) Cytology of 575 young females exposed prenatally to diethylstilbestrol (DES). Obstet Gynecol 48: 511–517PubMedGoogle Scholar
  41. 41.
    Robboy SJ, Herbst AL, Scully RE (1974) Clear-cell adenocarcinoma of the genital tract in young females. Analysis of 37 tumors that persisted or recurred after primary therapy. Cancer 34: 606–614PubMedCrossRefGoogle Scholar
  42. 42.
    Robboy SJ, Kaufman RH, Prat J, Welch WR, Gaffey T, Scully RE, Richart R, Fenoglio CM, Virata R, Tilley BC (1979) Pathologic findings in young women enrolled in national cooperative diethylstilbestrol adenosis (DESAD) project. Obstet Gynecol 53: 309–317PubMedGoogle Scholar
  43. 43.
    Robboy SJ, Keh PC, Nickerson RJ, Helmanis EK, Prat J, Szyfelbein WM, Taft PD, Barnes AB, Scully RE, Welch WR (1978) Squamous cell dysplasia and carcinoma in-situ of the cervix and vagina after prenatal exposure to diethylstilbestrol. Obstet Gynecol 51: 528–535PubMedCrossRefGoogle Scholar
  44. 44.
    Robboy SJ, Noller KL, Kaufman RH, Barnes AB, Townsend D, Gundersen JH, Nash S (1980) Prenatal diethylstilbestrol (DES-exposure): Recommendations of the Diethylstilbestrol Adenosis (DESAD) Project for the identification and management of exposed individuals. DHEW publication no. 80–2049Google Scholar
  45. 45.
    Robboy SJ, Noller KL, Kaufman RH, Barnes AB, Townsend D, Gunderson JH, Kurland L, Nash S (1981) An atlas of findings in the human female after intrauterine exposure to diethylstilbestrol, DHEW publicationGoogle Scholar
  46. 46.
    Robboy SJ, Prat J, Welch WR, Barnes AB (1977) Squamous cell neoplasia controversy in the DES-exposed female. Human Pathol 8: 483–485CrossRefGoogle Scholar
  47. 47.
    Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richart RM, Gaffey TA, Prat J, Virata R, Hatab PA, McGorray SP, Noller KL, Townsend D, Labarthe D, Barnes AB (1981) Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project. Am J Obstet Gynecol 140: 579–586PubMedGoogle Scholar
  48. 48.
    Robboy SJ, Welch WR (1977) Microglandular hyperplasia in vaginal adenosis associated with oral contraceptives and prenatal diethylstilbestrol (DES) exposure. Obstet Gynecol 49: 430–434PubMedGoogle Scholar
  49. 49.
    Sandberg EC (1968) The incidence and distribution of occult vaginal adenosis. Am J Obstet Gynecol 101: 322–333PubMedGoogle Scholar
  50. 50.
    Sandberg EC, Christian JC (1980) Diethylstilbes-trol-exposed monozygotic twins discordant for cervicovaginal clear cell adenocarcinoma. Am J Obstet Gynecol 137: 220–228PubMedGoogle Scholar
  51. 51.
    Schottenfeld D, Warshauer ME, Sherlock S, Zauber AG, Leder M, Payne R (1980) The epidemiology of testicular cancer in young adults. Am J Epidemiol 112: 232–246PubMedGoogle Scholar
  52. 52.
    Taft PD, Robboy SJ, Herbst AL, Scully RE (1974) Cytology of the clear-cell adenocarcinoma of the genital tract in young females: Analysis of 95 cases from the registry. Acta Cytol 19: 279–290Google Scholar
  53. 53.
    Ulfelder H, Robboy SJ (1976) The embryological development of the human vagina. Am J Obstet Gynecol 126: 769–776PubMedGoogle Scholar
  54. 54.
    Walz KA, Metzger H, Ludwig H (1978) Endocer-vikale erscheinungsform der vaginalen adenosis. Arch Gynakol 225: 293–303PubMedCrossRefGoogle Scholar
  55. 55.
    Welch WR, Robboy SJ, Townsend DE, Barnes AB, Scully RE, Herbst AL (1978) Comparison of histologic and colposcopic findings in DES-exposed females. Obstet Gynecol 52: 457–461PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • Stanley J. Robboy
  • Robert H. Young
  • Arthur L. Herbst

There are no affiliations available

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