Intrauterine DES-exposure and increased risk of endometriosis
2004 Study Abstract
To investigate the relation between the fetal environment and Endometriosis.
Prospective cohort study.
Nurses’ Health Study II with 10 years of follow-up.
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.
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.
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.
The uterus response differs 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.
Women exposed to 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.
NCBI, PMID: 14998922, Apr 2004 – Full article The Company of Biologists Limited131/7/1639 15 Dec 2003.