Aaron M. Levine & Associates have traveled around the world to personally interview and visit the laboratories of the leading researchers in DES (Diethylstilbestrol) side effects. They are performing the molecular, genetic and clinical research that is answering the following questions:
During embryonic development, the uterus and upper cervix should normally develop glandular function and distensibility to provide for the ability to receive and implant a fertilized ovum. The lower half of the cervix and the entire vagina should develop differently into a proper smooth muscle tract lined by a tough epithelial lining called stratified squamous epithelium. DES unfortunately turns this process on its head and results in numerous genetic abnormalities which ultimately lead to significant glandular development and in some cases, glandular cancers in the vagina and cervix. A mouse model exposed to DES results in a condition very similar to what is seen in humans. A key protein in mice called p63 needed for proper vaginal development is absent with exposure to DES and this results in the presence of vaginal adenosis in that model (29).
DES exposure in utero in mice alters the expression of multiple genes that are responsible for the proper production and ratio of a variety of proteins in the skin, tail, gastrointestinal tract and especially the female genital tract. These mouse models accurately reproduce the conditions seen in humans and provide a rationale for the development of a short or incompetent cervix, uterine hypoplasia, uterine fibrosis and the obvious reproductive consequences of these anomalies (29, 30).
Given the multiple birth defects that are seen in DES daughters, it is not surprising that the ability to conceive and deliver a pregnancy to term would be severely limited. Unfortunately, the scourge of DES is not going away and the effects its widespread administration decades ago are still being felt today. Not only is term pregnancy less likely after intrauterine DES exposure, but so is the possibility of delivering a child who has neurobehavioral abnormalities as a proximal result of preterm delivery caused by DES (5, 10, 11).
DES exposure in utero can result in the later development of endometriosis, which is the third most common cause of gynecological hospitalizations nationwide. Endometriosis can result in bleeding and painful adhesions requiring medications and surgery to control depending on clinical severity. Recently, investigators have also determined a link between DES in utero and the development of uterine fibroids, which can cause pain, bleeding, anemia and a need for transfusions, surgery, embolization and other remedies (8, 26).
In Luna et al., the investigators used FSH (follicle stimulating hormone) levels and age to predict which women could still salvage any hope of pregnancy after IVF. Unfortunately (since DES was removed from the market in 1971) a higher percentage of women who were exposed to DES in utero are approaching the cutoff of 40 years of age in whom a high FSH level means that IVF will be unsuccessful. IVF has not uniformly resulted in term pregnancies. Pal et al in 1997 described poor IVF outcomes of 17 infertile DES who underwent 27 cycles of assisted reproductive technology (ART) and compared the results in these women to a control group of 20 patients with infertility of unknown cause who also underwent 27 cycles of ART simultaneously. The DES daughters had significantly reduced implantation and pregnancy rates following IVF and embryo transfer despite similar responses to controlled ovarian hyperstimulation (COH). Specifically, the DES daughters had a clinical pregnancy rate of 11.8% per embryo transfer compared to 40% for the control group which approached, but did not reach statistical significance (P = 0.07) because of the small numbers in the study. The implantation rates, considering only the first attempts at IVF, were 4.2% versus 13.7% for the DES and control groups respectively (31).
These authors described the link between DES exposure and ectopic pregnancy and alterations in the utero-tubal junction. Essentially, DES causes abnormal development and function of the fallopian tubes and their connection with the uterus, leading to degeneration ("withered tubes"), scar tissue and other alterations that heighten the later risk of ectopic pregnancy. Normal flow of an ovum is hindered by the abnormal structure and cellular makeup of the Fallopian tube, delaying the movement of a released ovum and increasing the likelihood that such an ovum will be fertilized inappropriately in the Fallopian tube (17, 18, 19).
Diethylstilbestrol is known to cause a wide variety of gynecological abnormalities, resulting in a lower likelihood that such women can carry a pregnancy to term. This longitudinal federal cohort study has been tracking diethylstilbestrol daughters for decades and these data provide a wealth of information on the incidence, severity and complications arising from these abnormalities (4).
Diethylstilbestrol causes proliferation of breast ducts in female fetuses during embryogenesis. This results in a higher incidence of ductal carcinoma of the breast in women over 40. Breast cancer can be highly aggressive and fatal. All women will require some form of treatment including combinations of surgery, radiation, chemotherapy and oral adjuvant therapy where indicated. The entire process to be rid of breast cancer may take several years (25). Be sure to read our article on DES and Breast Cancer.
4. Swan S.H. Intrauterine Exposure to Diethylstilbestrol: Long-term Effects in Humans. APMIS 108:793-804, 2000.
5. Kaufman R.H. et al. Upper Genital Tract Changes and Pregnancy Outcome in Offspring Exposed in Utero to Diethylstilbestrol. Am J. Obstet. Gynecol. 137:3: 299-308, June 1980.
8. Missmer S.A. et al. In Utero Exposures and the Incidence of Endometriosis. Fertility and Sterility. 82; 6:1501-1507, December 2004.
10. Palmer J.R. et al. Infertility among Women Exposed Prenatally to Diethylstilbestrol. Am. J. Epidemiology. 154; 4: 316-21, 2001.
11. Salle B. et al. Transvaginal Ultrasound Studies of Vascular and Morphological Changes in Uteri Exposed to Diethylstilbestrol In Utero. Human Reproduction. 11; 11: 2531-2536, 1996.
17. Ankum W.M. et al. Risk Factors for Ectopic Pregnancy: A Meta-analysis. Fertility and Sterility. 65; 6: 1093-1099, June 1996.
18. DeCherney A.H. et al. Structure and Function of the Fallopian Tubes Following Exposure to Diethylstilbestrol (DES) During Gestation. Fertility and Sterility. 36; 6: 741-745, December 1981.
19. Newbold R.R. et al. Developmentally Arrested Oviduct: A Structural and Functional Defect in Mice Following Prenatal Exposure to Diethylstilbestrol. Teratology. 27: 417-426, 1983.
25. Palmer J.R. et al. Prenatal Diethylstilbestrol Exposure and Risk of Breast Cancer. Cancer Epidemiology, Biomarkers and Prevention. 15; 8: 1509-1514, August 2006.
26. Baird, D.D. and Newbold, R. Prenatal Diethylstilbestrol (DES) Exposure is Associated with Uterine Leiomyoma Development. Reproductive Toxicology. 20:81-84, 2005.
29. Kurita et al. Roles of P63 in the Diethylstilbestrol-Induced cervicovaginal Adenosis. Development and Disease. 131; 7: 1639-1649, 2004.
30. Huang W. et al. Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation. Molecular Endocrinology. 19; 3: 669-681, March 2005.
31. Luna M. et al. Moderately Elevated Levels of Basal Follicle-Stimulating Hormone in Young Patients Predict Low Ovarian Response, But Should Not Be Used to Disqualify Patients from Attempting In Vitro Fertilization. Fertility and Sterility. 87; 4: 782-791, April 2007.