DiEthylStilbestrol in utero exposure and endometriosis incidence

Intrauterine DES-exposure and increased risk of endometriosis

In this 2004 study, the rate of endometriosis was 80% greater among women exposed to diethylstilbestrol in utero.
Eva Siba image © all rights reserved Special tribute to Marilyn who suffered severe endometriosis .

2004 Study Abstract

OBJECTIVE:
To investigate the relation between the fetal environment and Endometriosis.

DESIGN:
Prospective cohort study.

SETTING:
Nurses’ Health Study II with 10 years of follow-up.

PARTICIPANT(S):
Eighty-four thousand, four hundred forty-six women aged 25-42 who had never been diagnosed with endometriosis, infertility, or cancer at baseline in 1989.

MAIN OUTCOME MEASURE(S):
Incidence of laparoscopically confirmed endometriosis according to birthweight, prematurity, multiple gestation, diethylstilbestrol (DES) exposure, and having been breastfed.

RESULT(S):
During 566,250 woman-years of follow-up, 1,226 cases of laparoscopically-confirmed endometriosis were reported among women with no past infertility. After adjusting for age, calendar time, parity, race, and body mass index at age 18, we observed a linear increase in the incidence rate with decreasing birthweight (rate ratio [RR] = 1.3 for birthweight <5.5 pounds versus 7.0-8.4 pounds, 95% confidence interval [CI] = 1.0-1.8, P value, test for trend = .01). In addition, women who were born as one of a multiple gestation (i.e., twins or greater number) were at increased risk even after controlling for birthweight (RR = 1.7, CI = 1.2-2.5). The rate of endometriosis was also 80% greater among women exposed to diethylstilbestrol in utero (RR = 1.8, CI = 1.2-2.8). Neither premature delivery nor having been breastfed were associated with the incidence of endometriosis. None of these effect estimates were modified by infertility status at the time of endometriosis diagnosis.

CONCLUSION(S):
The fetal environment is associated with subsequent laparoscopically confirmed endometriosis in this cohort of US women.

Sources and more information
  • In utero exposures and the incidence of endometriosis, Missmer SA1, Hankinson SE, Spiegelman D, Barbieri RL, Michels KB, Hunter DJ, Fertil Steril, NCBI PMID: 15589850, Dec 2004.
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Developmental exposure to DES alters uterine response to estrogens in mice: low versus high dose effects

The uterus response differs following high versus low doses of neonatal exposure

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In this 2004 study, the uterus response differed following high versus low doses of neonatal exposure.

2004 Study Abstract

Outbred CD-1 mice received subcutaneous injections on neonatal days 1-5 with DES (0.0001-1000 microg/kg per day), a model xenoestrogen. At 17 days of age, uterine wet weight increase in response to estrogen was altered in neonatally DES-treated mice compared to controls. The response varied depending on the neonatal DES dose; a low dose (0.01 microg/kg) caused an enhanced uterine response but higher neonatal doses dampened the response. Western blots and immunolocalization of estrogen receptor alpha (ERalpha) showed high ER levels at DES 0.01 microg/kg, but decreased levels at higher doses compared to controls. Genes responding through ER-mediated pathways (c-fos, proliferating cell nuclear antigen (PCNA), and lactoferrin (LF)) mirrored altered wet weight responses, i.e., enhancement at low doses and dampening at higher doses. A similar dose-response curve was seen in 4 months old ovariectomized DES-treated mice suggesting the altered response was long-term. These data suggest xenoestrogen exposure during critical developmental windows alters hormone programming so that the uterus responds abnormally to estrogen later in life, and that the response differs following high versus low doses of neonatal exposure.

Sources and Full Study
  • Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: low versus high dose effects, Reprod Toxicol. 2004 May;18(3):399-406. PMID: 15082075.
  • Full study, sciencedirect, doi:10.1016/j.reprotox.2004.01.007, pii/S0890623804000140, May 2004.
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Identifying Diethylstilbestrol DES Exposure and Future Considerations

Although diethylstilbestrol has not been given to pregnant women in the United States for more than 30 years, its effects continue to be seen

Abstract

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Although diethylstilbestrol has not been given to pregnant women in the United States for more than 30 years, its effects continue to be seen.

Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen that was used to prevent miscarriage and other pregnancy complications between 1938 and 1971 in the United States. In 1971, the U.S. Food and Drug Administration issued a warning about the use of diethylstilbestrol during pregnancy after a relationship between exposure to this synthetic estrogen and the development of clear cell adenocarcinoma of the vagina and cervix was found in young women whose mothers had taken diethylstilbestrol while they were pregnant. Although diethylstilbestrol has not been given to pregnant women in the United States for more than 30 years, its effects continue to be seen. Women who took diethylstilbestrol during pregnancy have a slightly higher risk of breast cancer than the general population and therefore should be encouraged to have regular mammography. Women who were exposed to diethylstilbestrol in utero may have structural reproductive tract anomalies, an increased infertility rate and poor pregnancy outcomes. However, the majority of these women have been able to deliver successfully. Recommendations for gynecologic examinations include vaginal and cervical digital palpation, which may provide the only evidence of clear cell adenocarcinoma. Initial colposcopic examination should be considered; if the findings are abnormal, colposcopy should be repeated annually. If the initial colposcopic examination is normal, annual cervical and vaginal cytology is recommended. Because of the higher risk of spontaneous abortion, ectopic pregnancy and preterm delivery, obstetric consultation may be required for pregnant women who had in utero diethylstilbestrol exposure. The male offspring of women who took diethylstilbestrol during pregnancy have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. Routine prostate cancer screening and testicular self-examination should be encouraged.

Sources:
  • Diethylstilbestrol exposure, NCBI, PMID: 15168959, 2004 May 15;69(10):2395-400
  • Full text – Diethylstilbestrol Exposure, American Family Physician, 2004/0515/p2395, 2004 May 15;69(10):2395-2400.
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Roles of p63 in the DiEthylStilbestrol-induced CervicoVaginal Adenosis

Women exposed to DES in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer

Abstract
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Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer.

Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Müllerian duct epithelium. The cell fate of Müllerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Müllerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Müllerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.

Sources

NCBI, PMID: 14998922, Apr 2004 – Full article The Company of Biologists Limited 131/7/1639 15 Dec 2003.

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