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. 1993 Aug;101(3):208–213. doi: 10.1289/ehp.93101208

Gender-related behavior in women exposed prenatally to diethylstilbestrol.

R R Newbold 1
PMCID: PMC1519765  PMID: 8404755

Abstract

Accumulating evidence in experimental animals over the past three decades suggests that mammalian brain development and differentiation of the central nervous system are influenced by perinatal exposure to sex hormones. Hence, changes in human behavioral patterns may be associated with prenatal exposure to estrogenic substances such as diethylstilbestrol (DES). This paper reviews relevant studies from a series of laboratories and finds that no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior, although the physical and psychological impact of the problems associated with exposure to DES are well documented. If both prenatal and postnatal influences such as social, economic, and environmental factors are taken into consideration, individual variation is more apparent than differences in gender-related behavior between unexposed and DES-exposed women. In summary, gender-related behavior is determined by a complex array of interacting factors, and prenatal influences are only one of many developmental events. More studies are needed using larger populations with carefully controlled selection criteria to suggest a direct role of prenatal DES exposure on subsequent gender-related behavior.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen L. S., Gorski R. A. Sex difference in the bed nucleus of the stria terminalis of the human brain. J Comp Neurol. 1990 Dec 22;302(4):697–706. doi: 10.1002/cne.903020402. [DOI] [PubMed] [Google Scholar]
  2. Allen L. S., Gorski R. A. Sexual dimorphism of the anterior commissure and massa intermedia of the human brain. J Comp Neurol. 1991 Oct 1;312(1):97–104. doi: 10.1002/cne.903120108. [DOI] [PubMed] [Google Scholar]
  3. Allen L. S., Hines M., Shryne J. E., Gorski R. A. Two sexually dimorphic cell groups in the human brain. J Neurosci. 1989 Feb;9(2):497–506. doi: 10.1523/JNEUROSCI.09-02-00497.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Allen L. S., Richey M. F., Chai Y. M., Gorski R. A. Sex differences in the corpus callosum of the living human being. J Neurosci. 1991 Apr;11(4):933–942. doi: 10.1523/JNEUROSCI.11-04-00933.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barnes A. B., Colton T., Gundersen J., Noller K. L., Tilley B. C., Strama T., Townsend D. E., Hatab P., O'Brien P. C. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med. 1980 Mar 13;302(11):609–613. doi: 10.1056/NEJM198003133021105. [DOI] [PubMed] [Google Scholar]
  6. Beach F. A. Historical origins of modern research on hormones and behavior. Horm Behav. 1981 Dec;15(4):325–376. doi: 10.1016/0018-506x(81)90001-5. [DOI] [PubMed] [Google Scholar]
  7. Bibbo M., Gill W. B., Azizi F., Blough R., Fang V. S., Rosenfield R. L., Schumacher G. F., Sleeper K., Sonek M. G., Wied G. L. Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol. 1977 Jan;49(1):1–8. [PubMed] [Google Scholar]
  8. Brawer J. R., Naftolin F., Martin J., Sonnenschein C. Effects of a single injection of estradiol valerate on the hypothalamic arcuate nucleus and on reproductive function in the female rat. Endocrinology. 1978 Aug;103(2):501–512. doi: 10.1210/endo-103-2-501. [DOI] [PubMed] [Google Scholar]
  9. Dörner G., Döcke F., Hinz G. Paradoxical effects of estrogen on brain differentiation. Neuroendocrinology. 1971;7(3):146–155. doi: 10.1159/000121962. [DOI] [PubMed] [Google Scholar]
  10. Ehrhardt A. A. Behavioral effects of estrogen in the human female. Pediatrics. 1978 Dec;62(6 Pt 2):1166–1170. [PubMed] [Google Scholar]
  11. Ehrhardt A. A., Feldman J. F., Rosen L. R., Meyer-Bahlburg H. F., Gruen R., Veridiano N. P., Endicott J., Cohen P. Psychopathology in prenatally DES-exposed females: current and lifetime adjustment. Psychosom Med. 1987 Mar-Apr;49(2):183–196. doi: 10.1097/00006842-198703000-00008. [DOI] [PubMed] [Google Scholar]
  12. Ehrhardt A. A. Gender differences: a biosocial perspective. Nebr Symp Motiv. 1984;32:37–57. [PubMed] [Google Scholar]
  13. Ehrhardt A. A., Meyer-Bahlburg H. F., Feldman J. F., Ince S. E. Sex-dimorphic behavior in childhood subsequent to prenatal exposure to exogenous progestogens and estrogens. Arch Sex Behav. 1984 Oct;13(5):457–477. doi: 10.1007/BF01541430. [DOI] [PubMed] [Google Scholar]
  14. Ehrhardt A. A., Meyer-Bahlburg H. F., Rosen L. R., Feldman J. F., Veridiano N. P., Elkin E. J., McEwen B. S. The development of gender-related behavior in females following prenatal exposure to diethylstilbestrol (DES). Horm Behav. 1989 Dec;23(4):526–541. doi: 10.1016/0018-506x(89)90040-8. [DOI] [PubMed] [Google Scholar]
  15. Ehrhardt A. A., Meyer-Bahlburg H. F., Rosen L. R., Feldman J. F., Veridiano N. P., Zimmerman I., McEwen B. S. Sexual orientation after prenatal exposure to exogenous estrogen. Arch Sex Behav. 1985 Feb;14(1):57–77. doi: 10.1007/BF01541353. [DOI] [PubMed] [Google Scholar]
  16. Fuller G. B., Yates D. E., Helton E. D., Hobson W. C. Diethylstilbestrol reversal of gonadotropin patterns in infant rhesus monkeys. J Steroid Biochem. 1981 Dec;15:497–500. doi: 10.1016/0022-4731(81)90321-6. [DOI] [PubMed] [Google Scholar]
  17. Haney A. F., Hammond C. B., Soules M. R., Creasman W. T. Diethylstilbestrol-induced upper genital tract abnormalities. Fertil Steril. 1979 Feb;31(2):142–146. [PubMed] [Google Scholar]
  18. Haney A. F., Hammond M. G. Infertility in women exposed to diethylstilbestrol in utero. J Reprod Med. 1983 Dec;28(12):851–856. [PubMed] [Google Scholar]
  19. Haney A. F., Newbold R. R., McLachlan J. A. Prenatal diethylstilbestrol exposure in the mouse: effects on ovarian histology and steroidogenesis in vitro. Biol Reprod. 1984 Mar;30(2):471–478. doi: 10.1095/biolreprod30.2.471. [DOI] [PubMed] [Google Scholar]
  20. Herbst A. L., Cole P., Colton T., Robboy S. J., Scully R. E. Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. Am J Obstet Gynecol. 1977 May 1;128(1):43–50. doi: 10.1016/0002-9378(77)90293-9. [DOI] [PubMed] [Google Scholar]
  21. Herbst A. L., Kurman R. J., Scully R. E., Poskanzer D. C. Clear-cell adenocarcinoma of the genital tract in young females. Registry report. N Engl J Med. 1972 Dec 21;287(25):1259–1264. doi: 10.1056/NEJM197212212872501. [DOI] [PubMed] [Google Scholar]
  22. Herbst A. L., Ulfelder H., Poskanzer D. C. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971 Apr 15;284(15):878–881. doi: 10.1056/NEJM197104222841604. [DOI] [PubMed] [Google Scholar]
  23. Hines M., Alsum P., Roy M., Gorski R. A., Goy R. W. Estrogenic contributions to sexual differentiation in the female guinea pig: influences of diethylstilbestrol and tamoxifen on neural, behavioral, and ovarian development. Horm Behav. 1987 Sep;21(3):402–417. doi: 10.1016/0018-506x(87)90024-9. [DOI] [PubMed] [Google Scholar]
  24. Hines M., Goy R. W. Estrogens before birth and development of sex-related reproductive traits in the female guinea pig. Horm Behav. 1985 Sep;19(3):331–347. doi: 10.1016/0018-506x(85)90031-5. [DOI] [PubMed] [Google Scholar]
  25. Hines M. Prenatal gonadal hormones and sex differences in human behavior. Psychol Bull. 1982 Jul;92(1):56–80. [PubMed] [Google Scholar]
  26. Kaufman R. H., Binder G. L., Gray P. M., Jr, Adam E. Upper genital tract changes associated with exposure in utero to diethylstilbestrol. Am J Obstet Gynecol. 1977 May 1;128(1):51–59. doi: 10.1016/0002-9378(77)90294-0. [DOI] [PubMed] [Google Scholar]
  27. Kaufman R. H., Korhonen M. O., Strama T., Adam E., Kaplan A. Development of clear cell adenocarcinoma in DES-exposed offspring under observation. Obstet Gynecol. 1982 Jun;59(6 Suppl):68S–72S. [PubMed] [Google Scholar]
  28. Kaufman R. H., Noller K., Adam E., Irwin J., Gray M., Jefferies J. A., Hilton J. Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol-exposed progeny. Am J Obstet Gynecol. 1984 Apr 1;148(7):973–984. doi: 10.1016/0002-9378(84)90540-4. [DOI] [PubMed] [Google Scholar]
  29. Kester P., Green R., Finch S. J., Williams K. Prenatal 'female hormone' administration and psychosexual development in human males. Psychoneuroendocrinology. 1980 Dec;5(4):269–285. doi: 10.1016/0306-4530(80)90032-3. [DOI] [PubMed] [Google Scholar]
  30. Lish J. D., Ehrhardt A. A., Meyer-Bahlburg H. F., Rosen L. R., Gruen R. S., Veridiano N. P. Gender-related behavior development in females exposed to diethylstilbestrol (DES) in utero: an attempted replication. J Am Acad Child Adolesc Psychiatry. 1991 Jan;30(1):29–37. doi: 10.1097/00004583-199101000-00005. [DOI] [PubMed] [Google Scholar]
  31. MacLusky N. J., Naftolin F. Sexual differentiation of the central nervous system. Science. 1981 Mar 20;211(4488):1294–1302. doi: 10.1126/science.6163211. [DOI] [PubMed] [Google Scholar]
  32. McLachlan J. A., Korach K. S., Newbold R. R., Degen G. H. Diethylstilbestrol and other estrogens in the environment. Fundam Appl Toxicol. 1984 Oct;4(5):686–691. doi: 10.1016/0272-0590(84)90089-7. [DOI] [PubMed] [Google Scholar]
  33. McLachlan J. A., Newbold R. R., Bullock B. C. Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res. 1980 Nov;40(11):3988–3999. [PubMed] [Google Scholar]
  34. McLachlan J. A., Newbold R. R., Shah H. C., Hogan M. D., Dixon R. L. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril. 1982 Sep;38(3):364–371. doi: 10.1016/s0015-0282(16)46520-9. [DOI] [PubMed] [Google Scholar]
  35. Meyer-Bahlburg H. F., Ehrhardt A. A., Feldman J. F., Rosen L. R., Veridiano N. P., Zimmerman I. Sexual activity level and sexual functioning in women prenatally exposed to diethylstilbestrol. Psychosom Med. 1985 Nov-Dec;47(6):497–511. doi: 10.1097/00006842-198511000-00001. [DOI] [PubMed] [Google Scholar]
  36. Meyer-Bahlburg H. F., Ehrhardt A. A., Rosen L. R., Feldman J. F., Veridiano N. P., Zimmerman I., McEwen B. S. Psychosexual milestones in women prenatally exposed to diethylstilbestrol. Horm Behav. 1984 Sep;18(3):359–366. doi: 10.1016/0018-506x(84)90022-9. [DOI] [PubMed] [Google Scholar]
  37. Newbold R. R., Bullock B. C., Mc Lachlan J. A. Exposure to diethylstilbestrol during pregnancy permanently alters the ovary and oviduct. Biol Reprod. 1983 Apr;28(3):735–744. doi: 10.1095/biolreprod28.3.735. [DOI] [PubMed] [Google Scholar]
  38. Newbold R. R., Bullock B. C., McLachlan J. A. Progressive proliferative changes in the oviduct of mice following developmental exposure to diethylstilbestrol. Teratog Carcinog Mutagen. 1985;5(6):473–480. doi: 10.1002/tcm.1770050610. [DOI] [PubMed] [Google Scholar]
  39. Newbold R. R., McLachlan J. A. Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res. 1982 May;42(5):2003–2011. [PubMed] [Google Scholar]
  40. Newbold R. R., Tyrey S., Haney A. F., McLachlan J. A. Developmentally arrested oviduct: a structural and functional defect in mice following prenatal exposure to diethylstilbestrol. Teratology. 1983 Jun;27(3):417–426. doi: 10.1002/tera.1420270316. [DOI] [PubMed] [Google Scholar]
  41. Noller K. L., Fish C. R. Diethylstilbestrol usage: Its interesting past, important present, and questionable future. Med Clin North Am. 1974 Jul;58(4):793–810. doi: 10.1016/s0025-7125(16)32122-8. [DOI] [PubMed] [Google Scholar]
  42. Reinisch J. M. Prenatal exposure of human foetuses to synthetic progestin and oestrogen affects personality. Nature. 1977 Apr 7;266(5602):561–562. doi: 10.1038/266561a0. [DOI] [PubMed] [Google Scholar]
  43. Slikker W., Jr, Hill D. E., Young J. F. Comparison of the transplacental pharmacokinetics of 17 beta-estradiol and diethylstilbestrol in the subhuman primate. J Pharmacol Exp Ther. 1982 Apr;221(1):173–182. [PubMed] [Google Scholar]
  44. Stillman R. J. In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance and male and female offspring. Am J Obstet Gynecol. 1982 Apr 1;142(7):905–921. doi: 10.1016/s0002-9378(16)32540-6. [DOI] [PubMed] [Google Scholar]
  45. Tarttelin M. F., Gorski R. A. Postnatal influence of diethylstilbestrol on the differentiation of the sexually dimorphic nucleus in the rat is as effective as perinatal treatment. Brain Res. 1988 Jul 26;456(2):271–274. doi: 10.1016/0006-8993(88)90227-2. [DOI] [PubMed] [Google Scholar]
  46. Yalom I. D., Green R., Fisk N. Prenatal exposure to female hormones. Effect on psychosexual development in boys. Arch Gen Psychiatry. 1973 Apr;28(4):554–561. doi: 10.1001/archpsyc.1973.01750340080013. [DOI] [PubMed] [Google Scholar]

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