DES effects on the mammary gland: rodent models and epidemiological studies

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, 2015

Abstract

In addition to the better-known effects of early-life DES exposure on reproductive tract development and vaginocervical cancer in humans, animal studies have also shown that DES exposure affects mammary glands. In utero and lactational exposure to high doses of DES increased mammary gland growth and decreased the number of TEBs. Neonatal high-dose exposure to DES triggered extensive ductal dilation at P33 and promoted precocious lactogenesis in postpubertal, nulliparous 12-week-old female mice. In contrast, low-dose DES reduced ductal branching at P6 and P33. Low-dose exposure to DES during pregnancy caused impaired lactation in rats.

Gestational exposure of DES in rats resulted in an increase in spontaneous mammary gland tumors. Furthermore, multiple studies in mice showed that prenatal exposure to DES increased the risk of mammary tumorigenesis in females exposed to a known carcinogen, as well as the numbers of TEBs. In mice treated prenatally with DES there was a significant increase in enhancer of Zeste homolog 2 (EZH2) protein and EZH2 activity (measured by increased mammary histone H3 trimethylation)—a histone methyltransferase that may be linked to breast cancer risk and epigenetic regulation of tumorigenesis, as well as an increase in adult mammary gland EZH2. However, two studies found that relatively high-dose exposure during neonatal development reduced TEB numbers and prevented spontaneous mammary gland tumors. The mechanism for effects of DES on reproductive tissues likely varies by tissue. Taken together, this highlights the likelihood that DES daughters may have increased risk of adverse breast outcomes, cancer, and developmental abnormalities of the vagina.

References

  • Full study (free access) : EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, Endocrine Reviews, Volume 36, Issue 6, Pages E1–E150, doi.org/10.1210/er.2015-1010, 1 December 2015.
  • Image credit Esther Wechsler.
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DES Daughters susceptibility of the mammary gland during the perinatal period

Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, Endocrine Reviews, 2009

Abstract

Direct evidence of prenatal estrogen exposure and breast cancer risk is being gathered from the cohort of women born to mothers treated with DES during pregnancy and is discussed above (see Sections II and III).

These women are now reaching the age at which breast cancer becomes more prevalent.

In the cohort of these women who are aged 40 yr and older, there is a 2.5-fold increase in the incidence of breast cancer compared with unexposed women of the same age, suggesting that indeed, prenatal exposure to synthetic estrogens may play an important role in the development of breast neoplasms.

Consistent with this, experiments in rats showed that prenatal exposure to DES resulted in increased mammary cancer incidence during adulthood. These experiments illustrated that rats exposed prenatally to DES and challenged with the chemical carcinogen dimethylbenzanthracene (DMBA) at puberty had a significantly greater incidence of palpable mammary tumors at 10 months of age than animals exposed prenatally to vehicle. In addition, the tumor latency period was shorter in the DES-exposed compared with the vehicle-exposed group.

Both the epidemiological and experimental data are consistent with the hypothesis that excessive estrogen exposure during development may increase the risk of developing breast cancer.

In summary, exposure to estrogens throughout a woman’s life, including the period of intrauterine development, is a risk factor for the development of breast cancer. The increased incidence of breast cancer noted during the last 50 yr may have been caused, in part, by exposure of women to estrogen-mimicking chemicals that have been released into the environment from industrial and commercial sources. Epidemiological studies suggest that exposure to xenoestrogens such as DES during fetal development, to DDT around puberty, and to a mixture of xenoestrogens around menopause increases this risk.

References

  • Full study (free access) : Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement, Endocrine Reviews, NCBI PubMed PMC2726844, 2009 Jun.
  • Image credit pino naigro.
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Prenatal DES exposure and risk of multiple sclerosis

This is the first study to assess directly the relation between prenatal DES exposure and risk of multiple sclerosis (MS). Small preliminary studies have suggested an increased risk of any autoimmune disease or, more broadly, of diseases involving impaired immune function among individuals with prenatal DES exposure. Experimental studies in laboratory animals as well as human case series have also indicated altered immune cell function associated with DES exposure, such as abnormal natural killer cell activity, T cell-mediated immunity, and thymic development.

Prenatal and Perinatal Factors and Risk of Multiple Sclerosis, 2009

Abstract

Background
A potential role of prenatal and perinatal exposures in autoimmunity has been hypothesized, but few studies have examined the relation between various prenatal and perinatal factors and risk of multiple sclerosis (MS).

Methods
The study population included participants in the Nurses’ Health Studies, 2 prospective cohorts that together comprise 238,381 female nurses, who self-reported exposure to prenatal and perinatal factors. In addition, 35,815 nurses’ mothers participated by providing detailed information regarding experiences surrounding their daughter’s birth. The following prenatal and perinatal factors were studied in relation to MS: fetal growth, birth season, preterm birth, mode of delivery, maternal weight gain, medical conditions, medication use, diethylstilbestrol exposure, prenatal health care, maternal activity level, maternal obstetric history, parental age, and prenatal and childhood passive smoke exposure.

For in utero diethylstilbestrol (DES) exposure, assessed in the NHS-II in 1993, a confirmation questionnaire was sent to all nurses who self-reported DES exposure to classify the level of certainty (very certain, somewhat certain, not certain, or not exposed). The current analysis uses a conservative approach and compares those who were very certain of DES exposure with those who self-reported as nonexposed.

Results
The sample included 723 confirmed MS cases, including 383 with diagnosis after reporting prenatal and perinatal factors. Few associations were observed. These included an increased risk among women whose mothers reported late initiation of prenatal care (after the first trimester) (27 cases, rate ratio = 1.6; 95% confidence interval = 1.0–2.4), diabetes during pregnancy (2 cases; 10;2.5–42), and maternal prepregnancy overweight/obesity (20 cases; 1.7; 1.0–2.7). Results also suggested a possible increase in incident MS risk among women with prenatal diethylstilbestrol exposure (9 cases; 1.8; 0.93–3.5).

The featured image shows the univariate age-adjusted and multivariate-adjusted RRs and 95% CIs for the association between self-reported prenatal DES exposure and risk of MS in the NHS-II. The univariate analysis restricted to all incident cases and that restricted to cases diagnosed after 1993 both showed an increased risk of MS associated with in utero exposure to DES, with effect estimates exceeding 2.

Conclusions
This study provides modest support for a role of prenatal factors in MS risk. The results should be interpreted cautiously due to the limited statistical power, potential for exposure misclassification, and possibility of chance findings.

References

  • Full study (free access) : Prenatal and Perinatal Factors and Risk of Multiple Sclerosis, Epidemiology, NCBI PubMed, PMC3132937, 2009 Jul.
  • Featured image table/T2.
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Hysteroscopic Metroplasty for the DES Drug Related Uterus

Review and meta-analysis, Journal of minimally invasive gynecology, 2013

Study Abstract

The introduction of hysteroscopy to diagnose and treat intrauterine conditions, specifically to divide the uterine septum, or metroplasty, has replaced the traditional laparotomy approach, and objective results demonstrate its salutary effects in women treated.

Hysteroscopic metroplasty averts the implications of major invasive abdominal surgery, with good and satisfactory results in pregnancy and live-birth rates, despite the lack of prospective, randomized, controlled studies.

A careful review of the published results supports this type of treatment when the uterine septum adversely affects normal reproductive function.

References

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DES Daughters : Metroplasty for Uterine Enlargement

Diethylstilbestrol exposure in utero. Polemics about metroplasty. The cons, 2007

Study Abstract

Uterine malformations in DES-exposed women are not the only aetiologies for infertility, miscarriages, and other problems in their reproductive life. A global screening of fertility factors of the couple may, for instance, show in them vascular uterine abnormalities which reduce their reproductive potential. Furthermore, these abnormalities are not always predictive of losses of pregnancy, and many exposed women with patent uterine abnormalities can carry a pregnancy to term.

Metroplasty for uterine enlargement is a surgical procedure suggested for restoring the size and shape of the uterine cavity. There are no comparative studies for assessing efficacy and safety of metroplasty. Therefore, metroplasty should not be performed routinely, but should only be considered after the couple has undergone a full fertility workup, and the best possible level of fertility has been achieved.

References

  • Diethylstilbestrol exposure in utero. Polemics about metroplasty. The cons, Gynécologie, obstétrique et fertilité, NCBI PubMed PMID: 17719825, 2007 Sep.
  • Featured image researchgate.
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Prenatal DES Exposure and Cardiovascular Disease Risk

DES Daughters are at increased risk for coronary artery disease and myocardial infarction

Study Abstract

Purpose
Prenatal exposure to diethylstilbestrol (DES), a prototype endocrine-disrupting chemical, is associated with risk for adverse reproductive outcomes and cancer in women. We investigated whether cardiovascular disease (CVD) risk might also be greater in women prenatally exposed to DES.

Methods
DES-exposed (n = 3941) and -unexposed (n = 1705) women participating in the Combined DES Cohort Follow-up Study were followed prospectively from 1994 to 2013. Prenatal DES exposure (or lack of exposure) was documented in the birth record or physician’s note. Participants reported by questionnaire any “serious medical conditions requiring hospitalization, surgery or long-term treatment,” including coronary artery disease (CAD), myocardial infarction (MI), and stroke. We sought physician’s verification of self-reports and identified CVD deaths from the National Death Index. Hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox proportional hazard regression models estimated associations between DES exposure and CVD incidence, adjusted for birth year, original cohort, and potential confounders.

Results
In comparison of the exposed to the unexposed women, the HRs for reported conditions were 1.74 (95% CI, 1.03 to 2.93) for CAD, 2.20 (95% CI, 1.15 to 4.21) for MI, 1.01 (95% CI, 0.54 to 1.90) for stroke, and 1.31 (95% CI, 0.93 to 1.86) for the combined conditions (i.e., total CVD). The HRs were similar for verified outcomes (CAD, 1.72; MI, 2.67; stroke, 0.92; and total CVD, 1.25) and with additional adjustment for hypertension, diabetes, and high cholesterol (HRs: CAD, 1.67; MI, 2.04; stroke, 0.96; and total CVD, 1.24).

The risks for self-reported coronary artery disease and myocardial infarction were approximately doubled in DES Daughters.

Conclusions
These data demonstrate associations in women who have prenatal DES exposure with CAD and MI, but not with stroke, which appear to be independent of established CVD risk factors.

References

  • Full study (free access) : A Prospective Cohort Study of Prenatal Diethylstilbestrol Exposure and Cardiovascular Disease Risk, The Journal of Clinical Endocrinology & Metabolism doi.org/10.1210/jc.2017-01940, 20 October 2017.
  • Featured image Alexandru Acea.
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Neonatal malformations and hormone therapy during pregnancy

Antenatal DES exposure and cardiovascular malformations

Abstract

The use of pharmacological treatment during pregnancy has always been extremely controversial, especially if the drugs involved are sex hormones, such as diethylstilbestrol.

The percentage of congenital malformations attributable to hormonal therapy during pregnancy is 3%; the period of maximum susceptibility to teratogenic agents is between the 3rd-10th week of gestation, or the period of organogenesis.

The 1st reported case of congenital malformation due to hormonal therapy during pregnancy goes back to 1957; since then the literature has published more on this subject.

One of the most important studies was done in 1977 by Heinonen on a group of 50,282 pregnant women; 1042 had been treated with sex hormones. 19 infants, or 18.2/1000, had cardiovascular defects. Among the remaining 49,240 patients there were 385 cardiovascular malformations, or 7.8/1000.

The problem is still far from being resolved; it is up to the individual physician to give the best possible advice, after careful consideration of the clinical situation of every pregnant patient.

Reference

  • Neonatal malformations and hormone therapy during pregnancy, Minerva ginecologica, NCNI PubMed, PMID: 7290498, 1981 Jul-Aug.
  • Featured image asianage.
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Cardiovascular birth defects and antenatal exposure to female sex hormones

The New England journal of medicine, 1977

Abstract

In a cohort of 50,282 pregnancies 19 children with cardiovascular defects were born to 1042 women who received female hormones during early pregnancy (18.2 per 1000).

Among 49,240 children not exposed in utero to these agents there were 385 with cardiovascular malformations (7.8 per 1000).

Six children with cardiovascular defects were born to a sub-group of 278 women who used oral contraceptives during early pregnancy (21.5 per 1000).

After the data were controlled for a wide variety of potentially confounding factors by multivariate methods, the association between in utero exposure to female hormones and cardiovascular birth defects was statistically significant.

Reference

  • Cardiovascular birth defects and antenatal exposure to female sex hormones, NCNI PubMed, PMID: 830309, 1977 Jan 13.
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Hysteroscopic enlargement metroplasty for T-shaped uterus

24 years’ experience at the Strasbourg Medico-Surgical and Obstetrical Centre (CMCO)

These T-shaped uteruses are most commonly observed in patients who were exposed in utero to diethylstilbestrol (DES). DES is a nonsteroidal synthetic oestrogen that was marketed in France between 1948 and 1977 and prescribed to almost 200,000 women to prevent various obstetrical complications. The number of female infants exposed in utero to DES in France is estimated at 80,000. It was shown to be ineffective for these obstetrical indications in 1953 but its prescription was banned in France only in 1977, long after it had been established that this treatment was harmful: it is associated with an increased risk of clear-cell adenocarcinoma of the vagina. In addition to its cancer-inducing risk, this treatment has been found to cause uterine malformations (in particular, T-shaped uterus) and Fallopian tube dysfunction, with a reduced fertility and increased risk of miscarriage and premature delivery.

Abstract

STUDY QUESTION
What is the impact of hysteroscopic enlargement metroplasty for T-shaped uterus on the live birth rate?

SUMMARY ANSWER
Performing enlargement metroplasty appears to improve the obstetrical prognosis and fertility in patients with a T-shaped uterus.

WHAT IS KNOWN ALREADY
T-shaped uterus is linked to an excess of myometrium in the uterine walls giving rise to a subcornual constriction ring which causes dysmorphism and hypoplasia of the uterine cavity. It is commonly associated with infertility or a sequence of repeated miscarriages.

STUDY DESIGN
Single-centre observational cohort study in 112 patients who underwent enlargement metroplasty for T-shaped uterus between 1992 and 2016 in a Strasbourg university hospital centre.

MAIN RESULTS
The mean age of patients was 33.2; they had been attempting to conceive on average for 56 months for subfertile patients and 42.2 months for infertile patients. Prior to surgery, patients had succeeded in becoming pregnant 161 times, i.e. a mean gravidity of 1.4 pregnancies. For subfertile patients the mean gravidity was 2.67. Mean parity was 0.04. In the overall population, one hundred pregnancies occurred following enlargement metroplasty. The live birth rate increased in a statistically significant manner following enlargement metroplasty: 4 (2.5%) vs. 60 (60%), p < 0.05. In parallel, the miscarriage rate was statistically reduced: 126 (78.3%) vs. 22 (22%), pnull< .05. Intraoperative complications were 1 case of cervical laceration (0.9%) and 1 case of false passage (0.9%). Subsequent pregnancies remained at risk of miscarriage (22%) and premature delivery (20%) but not extra uterine gestation. Delivery took place by Caesarean section in 61% of cases. In the subgroup of infertile patients, the live birth rate was also markedly increased and 49% of pregnancies which occurred were spontaneous.

LIMITATIONS
This study was descriptive and retrospective.

WIDER IMPLICATIONS
These results are consistent with those in the literature. Hysteroscopic enlargement metroplasty is now a well-established technique with few complications but which should nevertheless be reserved for symptomatic patients.

References

  • Hysteroscopic enlargement metroplasty for T-shaped uterus: 24 years’ experience at the Strasbourg Medico-Surgical and Obstetrical Centre (CMCO), European journal of obstetrics, gynecology, and reproductive biology, NCBI PubMed PMID: 29804025, 2018.
  • Image copyright © Pr P-J Weiller.
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Demographic, lifestyle, and reproductive risk factors for ectopic pregnancy

DES Daughters have a much higher risk of EP,
Fertility and sterility, 2018

Abstract

OBJECTIVE
To evaluate the relationship between demographic, lifestyle, and reproductive factors and the risk of ectopic pregnancy (EP).

DESIGN
Prospective cohort.

SETTING
United States.

PATIENT(S)
Nurses’ Health Study II cohort comprising 41,440 pregnancies from 22,356 women.

INTERVENTION(S)
Demographic, lifestyle, and reproductive factors self-reported in 1989 then updated every 2 years. Multivariable log-binomial regression models with generalized estimating equations were used to estimate adjusted risk ratios (aRR).

MAIN OUTCOME MEASURE(S)
Ectopic pregnancy.

RESULT(S)
Incident EP was reported in 411 (1.0%) pregnancies. Former and current smokers had 1.22 (95% confidence interval [CI], 0.97-1.55) and 1.73 (95% CI, 1.28-2.32) times, respectively, the risk of EP compared with never smokers. The risk of EP 10 years after quitting was similar to never smokers (aRR 0.90; 95% CI, 0.60-1.33). Women consuming ≥10 g/day of alcohol had 1.50 (95% CI, 1.08-2.09) times the risk of EP compared with never consumers. In utero exposure to diethylstilbestrol (aRR 3.55; 95% CI, 2.51-5.01), earlier initiation of oral contraceptives (aRR 2.64; 95% CI, 1.70-4.09 for <16 years vs. never), intrauterine device use (aRR 3.99; 95% CI, 2.06-7.72), or history of infertility (aRR 3.03; 95% CI, 2.48-3.71) or tubal ligation (aRR 16.27; 95% CI, 11.76-22.53) also were associated with a higher risk of EP.

CONCLUSION(S)
Women who were current or former smokers, consumed ≥10 g/day of alcohol, were exposed to diethylstilbestrol in utero, initiated oral contraceptives at earlier than age 16 years (which may be a marker of riskier sexual behaviors), and who had a history of infertility, intrauterine device use, or tubal ligation had a higher risk of EP.

Reference

  • Demographic, lifestyle, and reproductive risk factors for ectopic pregnancy, Fertility and sterility, NCBI PubMed PMID: 30503132, 2018 Dec.
  • Featured image : Transvaginal ultrasound images of an intrauterine pregnancy (IUP) and ectopic pregnancy. (A) An IUP at 6 weeks. The central dark area is the intrauterine gestational sac and within the sac is a circular ringed structure that is the yolk sac. The small oval structure below the yolk sac is the fetus. (B) An ectopic pregnancy. To the right of the image is the normal uterus and to the left of the uterus is the doughnut-shaped ectopic pregnancy – credit BMJ Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians & Gynaecologists.
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