REGISTRY FOR RESEARCH ON HORMONAL TRANSPLACENTAL CARCINOGENESIS

What is the Registry?

The Registry for Research on Hormonal Transplacental Carcinogenesis (the Registry) is an international research registry of cancer patients with clear cell adenocarcinoma (CCA) of the vagina and/or cervix or other specific gynecologic cancers who may or may not have been exposed to diethylstilbestrol (DES) or other synthetic hormones in utero (while still in their mother's womb). The Registry was established in 1971 at Massachusetts General Hospital by Dr. Arthur L. Herbst and colleagues to investigate the development of CCA of the vagina and/or cervix in young women born since 1940 and in 1976 it was moved with Dr. Herbst to the University of Chicago.  The development of most of the vaginal tumors has been linked to the ingestion of DES during pregnancy. Because these tumors are rare in young women, the Registry was established to centralize data collection on this rare carcinoma. Varying amounts of information on the epidemiology, clinical aspects and pathology of these tumors has been obtained.

What is DES and when was it used?

DES is a synthetic form of estrogen, which is a female hormone. DES is also an example of an estrogen disruptor, i.e. it is a chemical that interferes with the body’s hormone system. It was first synthesized in 1938 and was the first orally active estrogen. It became very popular for use during pregnancy to prevent miscarriage. It was estrogen in pill-form that could be taken daily in small amounts. It was believed that the extra estrogen taken during pregnancy would help a pregnant woman have a healthy baby. DES was used from approximately 1941 until it was banned for use in pregnancy in 1971. The exact number of women who took DES during pregnancy is unknown, but it has been estimated that approximately two to four million women were treated during pregnancy with DES or other nonsteroidal synthetic estrogens, such as dienestrol or hexestrol.

Reasons to Study DES:

The most important reason to study DES is to provide DES-exposed people and medical professionals with information about the long-term health effects of DES exposure.  DES is often used as a way of studying how chemicals that act like or interfere with hormones in the body affect health. Although numerous cancer-causing agents are known to pass from the placenta to the fetus in animals, DES is unique because it is the only agent known to do the same in humans.
Finally, the study of DES may aid in understanding the effects of hormones, in general, during the development of the fetus.

What is CCA?

Clear cell adenocarcinoma (CCA) of the vagina and/or cervix is a very rare type of cancer, so named because of the way the cells look under a microscope. The Registry specifically studies CCA of the vagina and cervix in young women born after 1948. The age range (age at diagnosis) of DES-exposed females with this type of cancer who have been reported to the Registry is from 7 to 62 years of age, although most of the known cases of CCA of the vagina and cervix have occurred in women in the United States in their late teens and early twenties. Previously (in the pre-DES era) these vaginal cancers were found only rarely and then primarily in women over 50. The upper age limit for developing CCA is unknown.

Current Registry Accessions:

The Registry, as of April 2015, has accessioned approximately 775 cases of clear cell adenocarcinoma (CCA), 2/3 of which are associated with prenatal diethylstilbestrol (DES) exposure. The initial age-incidence curve showed a peak between ages 15-25 years among the DES-exposed. There is a suggestion of a possible increase in frequency among DES-exposed beginning to appear in those over 40 years of age. Cases of primary adenocarcinoma of the endometrium in patients under age 40 have been reported to the Registry, as well as isolated cases of primary mucinous adenocarcinoma of the vagina in the DES-exposed. These sporadic occurrences are currently under investigation.

Therefore, we accession the following cases:

    • any cases of CCA of the vagina and/or cervix in a patient born since 1948 regardless of DES exposure.
    • mucinous carcinoma of the vagina in the DES-exposed,
    • fallopian tube carcinoma in a DES-exposed woman, and

These categories provide areas of investigation to determine:

    • if there is a second rise in the age-incidence curve beyond the age of 40 years in the DES-exposed
    • if mucinous adenocarcinoma of the vagina begins to occur in excess in this cohort
    • if carcinoma of the fallopian tube begins to occur (currently, no cases have been reported).

WHO CAN I CONTACT TO REGISTER MYSELF?

Arthur L. Herbst, M.D., Director
Diane Anderson, Program Administrator
Email: danderso1@babies.bsd.uchicago.edu
Phone: (773) 702-6671
Fax: (773) 834-2341

Related Sources of Information:

  • National Cancer Institute: https://www.desfollowupstudy.org
  • The DES Cancer Network is an non-profit support organization made up of women who have had CCA and are exposed to DES
  • DES Action USA is a national, non-profit consumer organization dedicated to informing the public about DES and helping DES-exposed individuals.

What other health problems are associated with DES exposure?

DES-exposed Men and Women (sons and daughters):

Medical conditions among adult offspring prenatally exposed to diethylstilbestrol. Troisi, R., Hyer, M., Hatch, E.E., Titus-Ernstoff, L., Palmer, J.R., Strohsnitter, W.C., Herbst, A.L., Adam, E., Hoover, R.N., Epidemiology 2013 May; 24(3):430-8.
The associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis and related conditions among 5,590 exposed and unexposed daughters and 2,657 exposed and unexposed sons were studied in the NCI Combined DES Follow-up Study. The associations took into account the participants’ birth year, sex, weight adjusted for height, smoking status, alcohol use, educational status, number of general physical examinations in the past 5 years, and study site.
Comparing participants exposed prenatally to DES with those who were not exposed, there were increases in the risk of developing cardiovascular disease (27%), heart attacks (28%), hypertension (14%), and high cholesterol (12%). In addition, the risks of developing diabetes, coronary artery disease, osteoporosis and fractures were elevated, but these findings were possibly due to chance. The associations of DES and the medical conditions did not differ by dose and timing of DES exposure, nor, in the women, by presence or absence of vaginal epithelial changes (a marker of DES host susceptibility).
This study raises the possibility that prenatal DES exposure is associated with several common medical conditions in adulthood, although there is the possibility that our results are explained by differences in the reporting of conditions by the exposed and unexposed participants, or by other factors related to both the conditions and DES exposure status that were not accounted for in the study, such as dietary intake and physical activity. We plan to continue to study these associations by obtaining medical records to confirm the diagnoses in the current round of the study.

DES-exposed Daughters:

Structural Changes and Infertility:   DES-exposed female babies may have structural changes in the vagina, cervix, uterus and/or fallopian tubes. Sometimes these structural changes can contribute to problems later, when the child becomes an adult. These structural abnormalities can make it more difficult to conceive a child or to carry a pregnancy to full term. An unfavorable pregnancy outcome (particularly premature birth, mid-trimester miscarriage, and tubal pregnancies) may occur in almost half of the DES-exposed daughters.
A study published in 2001, based on the National Cooperative Diethylstilbestrol Adenosis Study (DESAD) and another cohort of DES exposed and unexposed daughters, found that DES daughters were more likely to have had premature births, miscarriages, and ectopic pregnancies. In addition, the study indicated that the risk of infertility was higher in DES daughters than in unexposed women, and that the increased risk of infertility was mainly due to uterine or tubal problems. A comprehensive review of the health outcomes of DES exposed daughters published in October 2011 reports that exposed daughters were 2.37 times as likely as unexposed women to have infertility, and that exposed women who became pregnant at least once were 1.64 times as likely to have spontaneous abortion and 4.68 times as likely to have a preterm birth. These adverse events are common in the general population, and even more likely among exposed daughters.
Early Menopause: Researchers have found that daughters whose mothers were given DES during pregnancy are two times more likely to have menopause prior to age 45, compared to women who were not exposed to DES. They estimate that 3% of DES-exposed women have experienced early menopause due to their exposure to DES.
Autoimmune Diseases: Autoimmune disease is a class of diseases where antibodies usually meant to recognize foreign organisms instead react to a person's own cells and tissues.  The NCI-funded collaborative research group studied autoimmune disease in depth and their findings were published in 2010. They found no differences in overall autoimmune disease rates between women who were exposed and those who were not exposed. There was also no difference in lupus and optic neuritis rates between the two groups. With regard to Rheumatoid Arthritis (RA), they observed a possible increase in RA among DES-exposed women but this was confined to women under the age of 45 years. There was no significant difference in multiple sclerosis rates between women who were DES-exposed and those who were not exposed. This information was based on a preliminary review of earlier data and has not been as extensively studied as the other autoimmune diseases mentioned here. 
Breast Cancer:
Prenatal diethylstilbestrol exposure and risk of breast cancer. Palmer JR, Wise LA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter W, Kaufman R, Herbst AL, Noller KL, Hyer M, Hoover RN. Cancer Epidemiol Biomarkers Prev; 2006 Aug;15(8):1509-14
Using data collected by participants in the National Cancer Institute’s DES Follow-up Study, it was found that DES-exposed daughters do not appear to have an increased risk of breast cancer through age 40. For women aged 40 and older, prenatal DES exposure may increase the risk of breast cancer, with exposed women having about two times the risk in comparison to unexposed women. However, it is still important to remember that breast cancer is relatively rare even among DES-exposed women: for every 1,000 DES-exposed women aged 45-49, we would expect about 4 new cases of breast cancer each year, compared to 2 new cases per year in 1,000 unexposed women. These findings underscore the need for regular screening for breast tumors.

DES-exposed Sons:

Urogenital Abnormalities:
Urogenital Abnormalities in Men Exposed to Diethylstilbestrol in Utero. Palmer, J.R., Herbst, A.L., Noller, K.L., Boggs, D.A., Troisi, R., Titus-Ernstoff, L., Hatch, E.E., Wise, L.A., Strohsnitter, W.C., Hoover, R.N Environ Health 2009;8:37
There is some concern that DES-exposed sons may also have some reproductive abnormalities. To date, some genital tract abnormalities have been reported, such as epididymal cysts, cryptorchidism (undescended testis), and testicular hypoplasia (testis that are not fully developed). Males with undescended testicles or unusually small testicles have an increased risk of developing testicular cancer whether or not they are exposed to DES. A physician should evaluate these situations. Abnormalities in semen analyses have also been reported. An increased risk in the development of malignancy in DES-exposed males has not been demonstrated. Studies in the past have suggested possible infertility problems in DES-exposed males but a recent follow-up study indicates that DES exposure did not impair fertility or sexual function in adult men. This is being studied in a collaborative investigation by the National Cancer Institute.
Infertility: Time to pregnancy and secondary sex ratio in men exposed prenatally to diethylstilbestrol.Wise L, Titus-Ernstoff L, Palmer JR, Hatch EE, Perez KM, Strohsnitter W, Kaufman R, Anderson D, Hoover RN, Troisi R. Am J Epidemiol 2007;166:765-74.
There have been conflicting research results through the years as to whether or not DES sons have higher infertility rates than unexposed males. Data was collected from participants in the National Cancer Institute’s DES Follow-up Study and results show that DES exposure does not adversely affect fertility rates for exposed males. The study found that DES-exposed males were able to father children at similar rates to those for unexposed males. There was a very slight difference in the sex ratio of the children born, with DES-exposed men fathering more girls than boys, but this difference was very small.

DES-exposed Mothers:

Mortality in women given diethylstilbestrol during pregnancy.Titus-Ernstoff L, Troisi R, Hatch EE, Palmer JR, Wise LA, Ricker W, Hyer M, Kaufman R, Noller K, Strohsnitter W, Herbst AL, Hartge P, Hoover RN. Br J Cancer. 2006 Jul 3;95(1):107-11.
Due to the advanced age of the Mothers Cohort, they have not been actively followed since 1994, so survival was assessed through a search of the National Death Index. The results suggested a modest increase in death from breast cancer in the DES-exposed mothers, compared to the unexposed. We did not, however, see an excess of overall mortality in DES-exposed mothers, or an excess of death from any specific cause other than breast cancer. In particular, DES was not associated with an increased mortality from gynecologic cancers.

Grandchildren (Third Generation):

Offspring of Women Exposed In Utero to Diethylstilbestrol (DES): A Preliminary Report of Benign and Malignant Pathology in the Third Generation. Titus-Ernstoff L, Troisi R, Hatch EE, Hyer M, Wise LA, Palmer JR, Kaufman R, Adam E, Noller K, Herbst AL, Strohsnitter W, Cole BF, Hartge P, Hoover RN. Epidemiology 2008;19:251-257

Several reports have examined DES grandchildren for possible abnormalities. For the granddaughters, these studies indicate that the age of first menstruation is not affected by DES, but that DES-exposed granddaughters have a greater likelihood of menstrual irregularity. In a small clinical study that included pelvic exams, researchers found no evidence of DES-related changes in the granddaughters of women given DES during pregnancy. A study of cancer outcomes in the granddaughters and grandsons showed no overall increased risk of cancer in either gender. An excess of ovarian cancer was seen in the granddaughters of exposed women, but the number of cases was small, so the evidence is considered preliminary. Investigations in Holland and France have shown a higher risk of hypospadias (a genitourinary anomaly) in the grandsons of DES-exposed women, but DES exposure was not verified in these studies. An analysis of NCI data suggested an increased risk of hypospadias in DES-exposed grandsons, but the finding was not conclusive. A study conducted in Holland found an increased risk of tracheo-esophageal fistula in granddaughters, but this also was not seen in the NCI data

DES Collaborative “Follow-up Study” Published Papers (partial list) 

https://www.desfollowupstudy.org

Menarche, menopause, years of menstruation, and the incidence of osteoporosis: the influence of prenatal exposure to diethylstilbestrol. Parker SE, Troisi R, Wise LA, Palmer JR, Titus-Ernstoff L, Strohsnitter WC, Hatch EE. J Clin Endocrinol Metab 2014;99:594-601.
Medical conditions among adult offspring prenatally exposed to diethylstilbestrol. Troisi, R., Hyer, M., Hatch, E.E., Titus-Ernstoff, L., Palmer, J.R., Strohsnitter, W.C., Herbst, A.L., Adam, E., Hoover, R.N., Epidemiology 2013 May; 24(3):430-8
Lifetime burden of adverse health outcomes among women exposed in-utero to Diethylstilbestrol (DES). Hoover, R.N., Hyer, M., Pfeiffer, R.M., Adam, E., Bond, B., Cheville, A.L., Colton, T., Hartge, P., Hatch, E.E., Herbst, A., Karlan, B.Y., Kaufman, R., Noller, K.L., Palmer, J.R., Robboy, S.J., Saal, R.C., Strohsnitter, W., Titus-Ernstoff, L., Troisi, R. N Engl J Med. 2011;365:1304-14.
Preterm Birth, Birth Weight and Age at Menarche among Women Exposed Prenatally to Diethylstilbestrol (DES). Hatch, E.E., Troisi, R., Wise, L.A., Titus-Ernstoff, L., Hyer, M., Palmer, J.R., Strohsnitter, W.C., Robboy, S.J., Anderson, D., Kaufman, R., Adam, E., Hoover, R.N. Reprod Toxicol 2011;31:151-7
Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol. Strohsnitter, W.C., Noller, K.L, Troisi, R., Robboy, S.J, Hatch, E.E., Titus-Ernstoff, L., Kaufman, R.H., Palmer, J.R., Anderson, D., Hoover, R.N. J Rheumatol. 2010;37:2167-73.
Birth defects in the sons and daughters of women who were exposed in utero to Diethylstilbestrol (DES). Titus-Ernstoff, L., Troisi, R., Hatch, E.E., Palmer, J.R., Hyer, M., Kaufman, R., Adam, E., Knoller, K., Hoover, R.N. Int J Androl 2009. Int J Androl. 2010;33:377-84.
Urogenital Abnormalities in Men Exposed to Diethylstilbestrol in Utero. Palmer, J.R., Herbst, A.L., Noller, K.L., Boggs, D.A., Troisi, R., Titus-Ernstoff, L., Hatch, E.E., Wise, L.A., Strohsnitter, W.C., Hoover, R.N Environ Health 2009;8:37
Breast Cancer Screening in Women Exposed In Utero to Diethylstilbestrol, Elizabeth A. Camp, Ann L. Coker, Stanley J. Robboy, Kenneth L. Noller, Karen J. Goodman, Linda T. Titus-Ernstoff, Elizabeth E. Hatch, Arthur L. Herbst, Rebecca Troisi, Raymond H. Kaufman, Ervin Adam. Journal of Women's Health 2009;18:547-552.
Cervical Screening and General Physical Exam Behaviors of Women Exposed In-utero to Diethylstilbestrol. Camp EA, Coker AL, Troisi R, Robboy SJ, Noller KL, Goodman K, Titus-Ernstoff L, Hatch EE, Herbst AL, Kaufman RH, Adam E. Journal of Lower Genital Tract Disease 2008;12:111-7.
Offspring of Women Exposed In Utero to Diethylstilbestrol (DES): A Preliminary Report of Benign and Malignant Pathology in the Third Generation. Titus-Ernstoff L, Troisi R, Hatch EE, Hyer M, Wise LA, Palmer JR, Kaufman R, Adam E, Noller K, Herbst AL, Strohsnitter W, Cole BF, Hartge P, Hoover RN. Epidemiology 2008;19:251-257
Preeclampsia risk in women exposed in utero to diethylstilbestrol. Troisi R, Titus-Ernstoff L, Hyer M, Hatch EE, Robboy SJ, Strohsnitter W, Palmer JR, Øgloend B, Adam E, Kaufman R, Herbst AL, Hoover RN. Obstet Gynecol. 2007 Jul;110(1):113-20
Cancer risk in women prenatally exposed to diethylstilbestrol. Troisi R, Hatch EE, Titus-Ernstoff L, Hyer M, Palmer JR, Robboy SJ, Strohsnitter WC, Kaufman R, Herbst AL, Hoover RN. Int J Cancer. 2007 Jul 15;121(2):356-60
Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES). Titus-Ernstoff L, Troisi R, Hatch EE, Wise LA, Palmer J, Hyer M, Kaufman R, Adam E, Strohsnitter W, Noller K, Herbst AL, Gibson-Chambers J, Hartge P, Hoover RN. Int J Epidemiol. 2006 Aug;35(4):862-8. Epub 2006 May 24.
Mortality in women given diethylstilbestrol during pregnancy. Titus-Ernstoff L, Troisi R, Hatch EE, Palmer JR, Wise LA, Ricker W, Hyer M, Kaufman R, Noller K, Strohsnitter W, Herbst AL, Hartge P, Hoover RN. Br J Cancer. 2006 Jul 3;95(1):107-11.
Prenatal diethylstilbestrol exposure and risk of breast cancer. Palmer JR, Wise LA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter W, Kaufman R, Herbst AL, Noller KL, Hyer M, Hoover RN. Cancer Epidemiol Biomarkers Prev; 2006 Aug;15(8):1509-14
Birth Weight and Breast Cancer Risk in Women Exposed and Unexposed to DES In Utero. Troisi R, Hatch EE, Titus-Ernstoff L, Palmer JR, Hyer M, Strohsnitter W, Robboy SJ, Kaufman RH, Herbst AL, Adam E, Hoover RN. Br J Cancer 2006;94:1734-7
In utero exposure to diethylstilbestrol (DES) does not increase genomic instability in normal or neoplastic breast epithelium. Larson PS, Ungarelli RA, de Las Morenas A, Cupples LA, Rowlings K, Palmer JR, Rosenberg CL. Cancer. 2006;107:2122-6
Hypospadias in male offspring of women exposed to diethylstilbestrol in utero. Palmer JR, Wise LA, Robboy SJ, Titus-Ernstoff L, Noller KL, Herbst AL, Troisi R, Hoover RN. Epidemiology. 2005 Jul;16(4):583-6
Risk of benign gynecologic tumors in relation to prenatal diethylstilbestrol exposure. Wise LA, Palmer JR, Rowlings K, Kaufman RH, Herbst AL, Noller KL, Titus-Ernstoff L, Troisi R, Hatch EE, Robboy SJ. Obstet Gynecol(2005;105:167-73
Reproductive outcomes in men with prenatal exposure to diethylstilbestrol. Perez KM, Titus-Ernstoff L, Hatch EE, Troisi R, Wactawski-Wende J, Palmer JR, Noller K, Hoover RN; National Cancer Institute's DES Follow-up Study Group. Fertil Steril 2005;84:1649-56.