Some epigenetic alterations that influence cancer risk are inherited through the germline from the DES-exposed to offspring and are observed in multiple DES generations of victims
2008 Study Abstract
Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influence cancer risk are inherited through the germline from parent to child and are observed in multiple generations. Epigenetic changes may be inherited as Mendelian, non-Mendelian, or environmentally induced traits. Here, we will discuss Mendelian, non-Mendelian, and environmentally induced patterns of multigenerational epigenetic alterations as well as some possible mechanisms for how these events may be occurring.
One example of multiple generations in families showing effects of an environmental agent are daughters of mothers who were exposed to diethylstilbestrol (DES) during the first trimester.
The daughters show developmental abnormalities and an increased risk of developing a rare type of clear-cell adenocarcinoma. DES daughters also show a 2.5-fold increase in breast cancer risk after 40 years of age. To prove that this indeed is an inherited transgenerational effect, granddaughters and great granddaughters of the exposed mothers will need to show a DES phenotype. This analysis has not yet been completed.
Mouse studies have shown that the F2 generation from a DES-exposed pregnant female had strikingly similar effects as the F1 generation, including abnormal uterine development and uterine cancer. The proposed mechanism of action of DES is aberrant CpG methylation of key uterine cancer genes. The changes in CpG methylation may be stable throughout gametogenesis, providing insight into the transgenerational effects of DES.
Sources and more information
Full study (free access) : The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk, Perspectives in Cancer Research, NCBI PubMed PMC4423451, 2008 Nov.
Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy
Gene expression can be altered as a consequence of mutations or epigenetic changes. In contrast to gene mutations within the DNA, epigenetic changes involve post-transcriptional modifications; that is, methylation of gene promoter regions, histone modifications, deposition of certain histone variants along specific gene sequences and microRNA (miRNA) expression. Although both changes are heritable, an important distinction between the two is that mutations are not reversible, but epigenetic modifications generally are.
Probably the most common mechanism of epigenetic gene silencing is methylation, and it might also be the most important. DNA methyltransferases (DNMTs) catalyze the methylation of genomic DNA by adding a methyl group (CH3) onto the 5-carbon of the cytosine ring within CpG dinucleotides. Histone modifications are complex, as they involve not just histone methylation but also acetylation, deacetylation and other post-translational changes. These modifications occur in the amino-terminal tails of histones and affect the ‘openness’ of the chromatin, which determines whether a gene is expressed or silenced (for example, acetylation allows transcription, while deacetylation represses transcription). Trimethylation of histone H3 at lysine K27 is catalyzed by the Polycomb group (PcG) protein enhancer of Zeste-2 (EZH2) and results in gene silencing. PcG/H3K27me3 interact with DNMTs, and together they establish and maintain silencing of PcG target genes. Over 2,000 different PcG target genes have been identified and they include some tumor suppressor genes. Many of the PcG target genes regulate cell fate, including apoptosis, proliferation and stem cell differentiation. As discussed in more detail below, methylation of PcG target genes is linked to increased breast cancer risk.
DNMTs may be key players in regulating histones and the entire epigenomic machinery, since DNA methylation events often precede histone modifications. Upregulation of DNMTs increases the expression of EZH2 and other polycombs; this may happen by DNMTs inducing methylation of non-coding miRNAs that target the polycombs.
We and others have observed that the expression of DNMTs is persistently altered in estrogen-regulated tissues following estrogenic exposures during early life. In utero exposure to DES is reported to increase the expression of DNMT1 in the epididymis and uterus . We found that DNMT1 expression is increased in the mammary glands of adult rat offspring of dams exposed to ethinyl estradiol during pregnancy. These changes provide a key regulatory layer to influence gene expression in the mammary gland and perhaps breast tumors of individuals exposed to DES or other estrogenic compounds in utero.
In utero DES exposure alters methylation patterns of several genes in estrogen’s target tissues, including Hox genes, c-fox, and Nsbp1, but it has not been studied whether changes in methylation patterns occur in the mammary gland. We have explored changes in methylation in the mammary glands of adult rats exposed in utero to the synthetic estrogen ethinyl estradiol using global sequencing approaches. Among the genes that exhibited increased promoter methylation were several PcG target genes, suggesting that a maternal exposure to synthetic estrogens during pregnancy causes long-lasting changes in the methylation of genes that regulate cell fate, including stem cell differentiation.
As an increase in EZH2 expression in the mammary glands of mice exposed to DES in utero has been reported, histone modifications also seem to be influenced by maternal exposure to synthetic estrogens during pregnancy. Jefferson and colleagues recently investigated whether upregulation of lactoferrin and sine oculis homeobox 1 (Six1) in the uterus of adult mice exposed to DES neonatally is caused by histone modifications. Their data indicate that neonatal DES exposure induces changes during the early postnatal period in the expression of multiple chromatin-modifying proteins but these changes do not last to adulthood. However, alterations in epigenetic marks at the Six1 locus in the uterus were persistent. Similarly, changes in the methylation of Nsbp1 and expression of DNMTs in the uterus of DES-exposed offspring are different in the early postnatal period compared to adulthood. This suggests that some epigenetic alterations are further influenced by factors operating during postnatal development, such as a surge of estrogens and progesterone from the ovaries at puberty onset.
Maternal exposures during pregnancy have been found to induce persistent changes in miRNA expression in the offspring. miRNAs are short non-coding single-stranded RNAs composed of approximately 21 to 22 nucleotides that regulate gene expression by sequence-specific base-pairing with the 3’ untranslated region of target mRNAs. miRNA binding induces post-transcriptional repression of target genes, either by inducing inhibition of protein translation or by inducing mRNA degradation. Expression of many miRNAs is suppressed by estrogens. Although the effects of maternal DES exposure during pregnancy on miRNA expression in the offspring have not been investigated, it is known that many other manipulations, such as maternal low protein diet, alter miRNA patterns among the offspring. We recently found that in utero exposure to ethinyl estradiol lowers the expression of many of the same miRNAs in the adult mammary gland as are downregulated by E2 in MCF-7 human breast cancer cells. Since miRNAs can be silenced by methylation or as a result of increased PcG expression, and they target DNMTs, histone deacetylases and polycomb genes, the observed increase in DNMT expression, histone marks and EZH2 in the in utero DES-exposed offspring may be a result of epigenetic silencing of miRNAs that target them.
2014 Study Conclusions
In summary, women exposed to DES in utero are destined to be at an increased risk of developing breast cancer, and this risk may extend to their daughters and granddaughters as well. It is of critical importance to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.
Sources and more information
Full text (free access) : Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, Breast Cancer Research, NCBI PubMed, PMC4053091, 2014 Apr 30.
Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy featured image credit PMC4053091/figure/F1.
Exposure to DES may reveal pre-existing difficulties from generation to generation
1996 Study Abstract
The psychological consequences resulting from the exposure to diethylstilbestrol (DES), a non-steroidal oestrogen, on the mother-daughter relationship are studied using semi-directive interviews with 43 daughters and 7 mothers treated with DES during their pregnancies.
Prenatal exposure to diethylstilbestrol and the mother-daughter relationship, US National Library of Medicine, European journal of obstetrics, gynecology, and reproductive biology, NCBI PubMed PMID: 8730622, 1996 Apr.
These women referred to gynaecological consultation for DES-related problems.
The daughters, exposed to DES during their foetal life, learned about DES after a pregnancy mishap (35% of the cases), or by accident (65% of the cases).
All of them were shocked when the existence of DES and its side effects were revealed to them.
Consequences on the mother-daughter relationship were
absent in 60% of the cases,
favourable in 20%,
and negative in 20%.
Five percent of the women showed hostility towards the medical practice, but 65% were not suspicious of the drugs administered to them during their pregnancies. For 64% of them, administration of DES to their mother had been kept secret. In 7 out of 50 cases, parents alone came for medical assistance in order to manage the secret.
Exposure to DES may reveal pre-existing difficulties not only between the mother and the daughter, but sometimes beyond from generation to generation.
Physical and psychological problems associated with exposure to DES
1988 Study Abstract
The synthetic hormone diethylstilbestrol (DES) was widely prescribed between 1943 and 1971 to minimize pregnancy complications.
It has caused serious physical and psychological damage to the women who took it and to their offspring. DES-exposed mothers may suffer a higher incidence of breast cancer, their exposed daughters are at risk for reproductive tract cancers and infertility, and their exposed sons are more likely to have genital abnormalities and reproductive dysfunction.
Depression and diethylstilbestrol exposure in women, US National Library of Medicine, Hospital & community psychiatry, NCBI PubMed PMID: 3276594, 1988 Jan.
Psychiatric disorders among DES-exposed persons are reportedly twice as common as for nonexposed persons, with anger, anxiety, low self-worth, identity confusion, and guilt the most frequent symptoms. The author describes therapeutic interventions designed to alleviate these problems.
Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed children
In utero exposure to diethylstilbestrol (DES) was initially linked to vaginal-cervical cancer and subsequently to reproductive difficulties. These unanticipated and ongoing health risks to female offspring may constitute a chronic source of stress for DES mothers.
Vulnerability to stress among women with in utero diethylstilbestrol (DES) exposed daughters, US National Library of Medicine, Journal of human stress, NCBI PubMed PMID: 3855173, 1985.
We interviewed 60 mothers of exposed daughters and 30 acquaintance controls. Two hypotheses were tested in regard to DES mothers: DES discovery and its aftermath have a direct, long-term, negative effect on psychological health and the DES experience intensifies the negative psychological effects of other adverse life circumstances.
To operationalize psychological health, we measured symptoms of “demoralization” and positive health practices–the latter as a behavioral indicator of mastery and personal control. We also measured adversities that may mediate the threat posed by DES, including stressful events, medical problems, and chronic burdens. We found DES history to be associated with poorer psychological health only when mothers encountered other losses and threats to themselves and their families.
We concluded that DES mothers may manifest increased vulnerability to subsequent stresses in their lives.
Physicians can help the DES-exposed deal with their emotional issues
The emotional impact of diethylstilbestrol (DES) exposure is described in a series of 50 mothers and daughters interviewed by psychiatrists. Patterns of response to this trauma and methods of resolution are discussed, and opportunities for preventive intervention by gynecologists are suggested. Specific, open dialogue about DES with the patient as a colleage can minimize the emotional sequelae of the experience.
Observations on the psychological impact of diethylstilbestrol exposure and suggestions on management, US National Library of Medicine National Institutes of Health, The Journal of reproductive medicine, NCBI PubMed PMID: 7373597, 1980 Mar.
This study analyzes the emotional impact of diethylstilbestrol (DES) exposure in an index population consisting of 50 women at risk plus 30 mothers who were all interviewed about their DES experience in an open-ended, in-depth, clinical style. The findings show that significant emotional upset is the normal response to the knowledge that the ingestion of a drug during pregnancy can cause or has caused some abnormality in the offspring.
Nevertheless, the capacity of a woman to come to terms with the anxiety DES has generated, once she had been given the chance to express her feelings and fears, was impressive.
DES daughters reacted to the DES experience in one of 3 ways, in descending order of frequency:
trust (80%). Most DES daughters rationalized that their mothers and doctors did the best they could, and were generally cooperative in their follow-up care;
and fear (10%).
90% of DES mothers came to terms with the knowledge and implications of DES exposure in ways characteristic of their life-long personality styles; in contrast, the remaining 10% who did not come to terms with the reality of DES exposure felt overwhelmed by quilt, paranoid rage, fear, and despair.
Physicians can help patients deal with such problems by:
acknowledging problematical feelings and expecting them to be difficult to deal with;
noting the patient’s pattern of response, and supporting her strengths;
giving factural information matter-of-factly;
listening to reactions to this information;
giving a structured plan in which the woman participates and be available for follow-through on it (eg, periodic colposcopic examinations);
and referring the women to support groups for an extended network of information and continued support.
Initial anxiety was usually followed by acceptance of the condition after examination and counseling. Patients responded best when informed of their problem by their mothers and when the relationship between mother and daughter was good.
The majority of patients found colposcopy to be unpleasant; they tended to be disturbed in proportion to the degree of being upset about DES exposure. The most common problem among mothers was guilt.
A questionnaire survey of physicians showed that they had less concern for psychological problems than patients or mothers did. Sensitivity and good communication on the part of medical personnel are recommended.
In view of the reported association between exposure in utero to diethylstilbestrol (DES) and clear-cell adenocarcinoma of the vagina, data on the prenatal use of DES in some 51,000 pregnancies in 12 hospitals between the years, 1959 and 1965, were examined. Among these women, in whom prenatal drug exposure was carefully documented, there was considerable variation in DES usage, the frequency being highest in the Boston LyingIn Hospital (exposure in 1.5% of pregnancies) and the Children’s Hospital, Buffalo (exposure in 0.8% of pregnancies). Data from two marketing research sources were used to estimate DES usage in the United States. It is calculated that a maximum of 50,000 liveborn females per year, born between 1960 and 1970, were exposed to DES in utero, while the most likely estimate is in the range 10,000 to 16,000.
DIETHYLSTILBESTROL IN PREGNANCY, Frequency of Exposure and Usage Patterns, From The Boston Collaborative Drug surveillance Program, Boston University Medical Center, Manuscript Prepared by OLLI P. HEINONEN, MD, ER March 1973.
There is now substancial evidence that the administration of diethylstilbestrol (DES) during pregnancy may produce clearcell adenocarcinoma of the vagina in female offspring. More than 60 cases of this malignancy, which has hitherto been extremely rare in young females, have now been reported to the Registry of Clear-Cell Carcinoma of the Genital Tract in the United States. The size of the population exposed to DES during the past two to three decades is unknown. The present report is concerned with a description of the use of DES in some 51,000 pregnancies seen in 12 hospitals. Prescription data obtained from two marketing research groups concerning DES usage in the population of the United States at large are also reported.
The information from the hospitals was collected as part of the Collaborative Study on Cerebral Palsy, Mental Retardation, and Other Neurological and Sensory Disorders of Infancy and Childhood of the National lnstitute of Neurological Diseases and Stroke (Collaborative Perinatal Study-CPS). It should be noted that this study had no influence in determining the medical care provided. The study design and methods of data collection employed by the CPS have been described in detail previous1y.l For the purposes of the present report, the following details are emphasized. On entry into the study, each woman was interviewed to obtain a medical, social, and medication history. Irrespective of the time of entry into the study, a detailed history of drug use was obtained for each woman including the one month prior to her last menstrual period. The systematic interview on medication intake was repeated at four weekly intervals. With few exceptions, each medication history was confirmed by the attending physician. To secure complete information on medications, hospital records and charts from private doctors were aIso reviewed. The data were abstracted, coded, placed on computer tape, and processed. In the present study, the original record of each woman identified from the computer tape as having received DES was reviewed by hand.
The original material consisted of 58,807 pregnancies from 12 participating hospitals. Cases were excluded for the following reasons: entry into the study during labor; abortion: stillbirth; multiple birth; race other than Caucasian, Negro, or Puerto Rican; and use of an unidentified drug during the first 4 lunar months of pregnancy. In the final analysis, 51,071 pregnancies were considered.
In nine hospitals, the sampling scheme was systematic; in one, it was random, and, in two, all patients presenting were entered into the study. About 20% of the participating women had more than one pregnancy while in the study.
Age, parity, socioeconomic status, and other characteristics of the study cohort have been described in detail elsewhere.
The 51,071 pregnancies included 23,096 Caucasians, 24,443 Negroes, and 3,532 Puerto Ricans. Their mean age was 24.1 years (whites including Puerto Ricans, 24.7 years; non-whites, 23.7 years). The proportion of nulliparous women was 28.1%, and the mean parity was 2.8 (whites, 2.8; non-whites, 2.9). The mean socioeconomic index was 6.8 (whites, 8.3; non-whites, 5.5). Most of the women (63.0%) entered the study during the first and second trimester, the mean time of entry being 21.6 weeks from the last menstrual period. Vaginal bleeding during the first trimester was recorded in 13.5% of the pregnancies.
DES was received by 217 pregnant women in this series (0.42%). The distributions of patients by hospital and ethnic group are given in Table 1 (below).
The mean age of the DES recipients was 27.6 years, and 10.6% were nulliparous. As expected, the frequency of vaginal bleeding during the first trimester was higher in women who received DES (36.3%). DES usage had no effect on the sex ratio observed in the liveborn.
Variation of DES usage frequency, by hospital
The frequency of DES usage was relatively high in 2 of the 12 hospitals. The drug was administered in 174 pregnancies at the Boston Lying-In Hospital (1.5%), and in 19 pregnancies at the Children’s Hospital in Buffalo (0.8%).
In the remaining 10 hospitals, the drug was given in only 24 out of 37,821 pregnancies (0.0670), and in two of these hospitals-the Johns Hopkins Hospital, Baltimore, and the Columbia-Presbyterian Hospital, New Yorknone of the women received the drug.
Dosage and duration
The total doses of DES received by women in the 12 hospitals are summarized in Table 2 (below).
At the Boston Lying-In Hospital, 146 out of 174 pregnancies were treated with the following schedule: the drug was started at a relatively low dose (0.0025 – 0.05 g/day) as early as feasible in the pregnancy. The dose was then increased every 2 weeks until a daily dose of 0.15 g/day was reached. The total dose received with this regimen varied from a low of 0.175 g to a high of 46.6 g, and the duration of treatment varied from 10 days to 9 lunar months. In the remaining 28 pregnancies, constant doses were generally used for short periods of time; in only two did the total DES dose reach high levels (16.5 g and 19.0 9). The total dose was less than 1 g in 19 pregnancies, and, in 10, DES was administered for less than 1 week.
At the Children’s Hospital, Buffalo, dosage was generally constant (0.1 to 5.0 mg per day). In 5 of 19 pregnancies in which DES was used, the total dose was 0.1 to 1.3 g, while, in 14, the total doses were all less than 0.1 g. In the remaining 10 hospitals, 22 out of 24 DES recipients received total doses of less than 1 g. One woman received 1.6 g, and one received 16.5 g.
Table 3 (below) shows the total dose of DES, across hospitals, divided according to whether constant or increasing daily dosage schedules were recieved.
The table 3 (above) shows that, as expected, high total doses were closely related to increasing daily dosage schedules.
Table 4 (above) summarizes the total dose, duration of administration, and time during pregnancy when exposure to DES commenced. The data on the 217 pregnancies exposed to DES are shown as percentile distributions. The table shows that more than 10 g were administered during half of the pregnancies.
In all hospitals in the study, the frequency of exposure to DES remained reasonably stable between the years, 1959 and 1965.
The reported association between maternal diethylstilbestrol usage and the subsequent development of adenocarcinoma of the vagina in female offspring has been given considerable publicity. Furthermore, it has been suggested that females known to have been exposed in utero to DES should undergo regular and frequent gynecological examinations. Any public health action, however, would depend upon the size of the population exposed, and the risk of developing vaginal adenocarcinoma in an exposed individual. While the present CPS data do not provide any direct information concerning the magnitude of the risk which is to date unknown, they do provide information on the population at risk after exposure to DES in 12 hospitals in the United States between the years, 1959 and 1965.
The data reveal that use of the drug varied considerably between hospitals located in different areas of the United States. Its use was uncommon in 10 of the 12 hospitals and, when used in these hospitals, the total dose was generally low. In only two hospitals was the usage relatively high in terms of either frequency or dosage.
For certain types of cancer, there is considerable evidence that the dose, duration, and time of exposure to carcinogens are all important determinants of risk. In the investigation of the relationship between intrauterine exposure to DES and the development of vaginal clear-cell adenocarcinoma, the relative importance of these factors remains to be established.
The present data suggest that increasing dose regimens generally result in high total doses while constant dosage regimens do so infrequently. Knowledge of the regimen employed might provide a reasonable index for investigators obtaining DES medication histories in pregnancies which occurred some 15 or more years previously. On the other hand, the CPS data suggest that knowledge of the duration of exposure alone will not provide a completely satisfactory index of the total dose administered.
Since the material from 12 hospitals studied in the CPS cannot be considered as representative of the country at large, and in view of the large differences in DES use between the participating institutions, it is clear that no approximation of the number of DES users for the United States can be made from these data alone. However, in view of the importance of providing some estimate of DES exposure, albeit provisional and approximate, we requested and obtained information from two further sources.
The first of these, Lea, Inc. (Ambler, Pa.), obtains information from 1,500 private physicians who report on all pharmaceutical products which they prescribe, together with the indication for each drug and some selected patient characteristics. This information is obtained four times a year and covers a 48-hour period of practice. The sample of physicians is continuously changed. It consists of slightly less than 1% of the prescribing physicians in the United States who are mainly in private practice. The sample is selected at random from 72 region and specialty strata, each subsample being of equal size. Data were collected uninterruptedly from 1960 to 1970, and the reporting periods were equally distributed over time. The response rate was approximately 70y0. In order to derive estimates for the entire United States, the projection factor for each stratum was calculated monthly.
The second source, R. A. Gosselin and Company, Inc. (Dedham, Mass.), is based on new and refill prescription data collected on a 2-week basis, from 1964 to 1970, from 400 randomly selected pharmacies throughout the United States. The methods of sampling and projection were similar to those described for the first source. An average of 100,000 prescriptions per month were collected.
For the years, 1964 to 1970, the data from these two sources are in substantial agreement concerning the average total number of prescriptions which have been written for DES in the United States. The first source estimates 2.51 million prescriptions per year, and the second, 2.49 million per year.
In addition to obtaining the total number of prescriptions for each drug, the first source determines the indication for drug therapy. The data show that during the period between 1960 and 1970, an average of 100,000 prescriptions for DES, per year, were written in the United States for women who were pregnant. It is interesting to note that there was regional variation. If nine United States’ census areas are combined into four geographical regions, the drug was more commonly used for prenatal care in the East and Midwest than in the South and West (3.67 and 2.93 vs. 1.94 and 1.68 DES prescriptions per 100 livebirths).
Of the 100,000 DES prescriptions written each year for pregnant women, approximately 50,000 might have affected female offspring. It can be assumed, however, that not all of these pregnancies would have resulted in liveborn infants particularly since threatened abortion is a common indication for this drug. Since there are no data concerning rates of DES use in pregnancies resulting in abortion or stillbirth on the one hand, compared with pregnancies resulting in a liveborn child on the other, we examined the CPS material. Somewhat less than 5% of DES use occurred in the stillbirth/abortion group, and this proportion was similar at the Boston Lying-In Hospital, the Children’s Hospital in Buffalo, and at the other participating hospitals. However, it should be borne in mind that abortions are likely to be underrepresented in the CPS data because of the study design.
Unfortunately, information concerning the number of DES prescriptions per pregnancy is not available from the marketing research data. However, if it is assumed that DES is usually prescribed every 4 weeks, then the number of prescriptions, for any individual pregnancy, could not exceed 10. If the average number is between three and five, then the number of liveborn female offspring exposed to DES in utero would be between 10,000 and 16,000 per annum in the United States during the period 1960 to 1970. In the CPS material, it is of interest that the average number of prescriptions for DES was 4.4 per pregnancy, assuming the prescription was given every 4 weeks.
Herbst et al reported that DES was used in 4.60%, of pregnancies at the Boston Lying-In Hospital between the years, 1946 and 1951. The authors point out that this estimate is derived from all pregnancies including those resulting in abortions and stillbirths. No data are available on exposure to DES during pregnancy in the 1950’s. The current CPS data do not show any major change in usage of DES between 1959 and 1965. Since 1967, however, data from Lea, Inc., suggest a declining use of DES in pregnancy.
Other nonsteroidal synthetic estrogens are also under suspicion. At least one case of vaginal adenocarcinoma following in utero exposure to dienestrol has been reported. Oral use of this drug appears to be rare in pregnancy: no case was observed in the CPS data, and in the prescription data provided by the R. A. Gosselin and Company, Inc., it was used about 100 times less frequently than DES.
OLLI P. HEINONEN, MD, received for publication August 26, 1972.
Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility, Lancet (London, England), NCBI PubMed PMID 15500896, 2004 Oct.
Treatment with oestrogen to reduce the adult height of tall girls has been available since the 1950s. We undertook a retrospective cohort study to assess the long-term effects of this treatment on fertility.
Eligible participants were identified from the records of Australian paediatric endocrinologists who assessed tall girls from 1959 to 1993, and from self-referrals. Individuals included girls who had received oestrogen treatment (diethylstilboestrol or ethinyl oestradiol) (treated group) and those who were assessed but not treated (untreated group). Information about reproductive history was sought by telephone interview.
1432 eligible individuals were identified, of whom 1243 (87%) could be traced. Of these, 780 (63%) completed interviews: 651 were identified from endocrinologists’ records, 129 were self-referred. Treated (n=371) and untreated (n=409) women were similar in socioeconomic and other characteristics. After adjustment for age, treated women
were more likely to have ever tried for 12 months or more to become pregnant without success (relative risk [RR] 1.80, 95% CI 1.40-2.30);
more likely to have seen a doctor because they were having difficulty becoming pregnant (RR 1.80, 1.39-2.32);
and more likely to have ever taken fertility drugs (RR 2.05, 1.39-3.04).
Time to first pregnancy analysis showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse (age-adjusted fecundability ratio 0.59, 95% CI 0.46-0.76). These associations persisted when self-referred women were excluded.
High-dose oestrogen treatment in adolescence seems to reduce female fertility in later life. This finding has implications for current treatment practices and for our understanding of reproductive biology.
Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, National Institutes of Health, NCBI PubMed PMCID: PMC3817964, 2013 June.
Although women were prescribed DES to improve the outcomes of their given pregnancy, the results of a double-blind clinical trial of over 1500 women at the University of Chicago by Dieckmann and coworkers in 1953 demonstrated that DES did not reduce the incidence of spontaneous abortion, prematurity or postmaturity, and the study suggested that DES enhanced premature labor. However, it continued to be used for another nearly 20 years.
DES Pregnancy: DES Daughthers
Hoover determined that DES daughters have an increased risk for many pregnancy-related issues including spontaneous abortion (<14 weeks gestation), ectopic pregnancy, loss of pregnancy in the second trimester (14–27 weeks), preeclampsia, preterm delivery (<37 weeks), stillbirth (at >27 weeks), and neonatal death within the first month of life. Many of these outcomes including ectopic pregnancy, miscarriage, and premature delivery have been reported in more than one study, and appear to be exacerbated effects for which DES was prescribed to prevent.
The effects of prenatal DES exposure on the ability to reproduce are substantial. The risk for infertility (defined as ? 12 months of trying to conceive) among DES daughters is reported to be 33% compared to 14% in unexposed women (p<0.001), and full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of DES exposed women (RR=0.76, 95% CI, 0.72–0.80). The Dutch DES cohort reports that 33% of DES daughters are nulliparous at the age of ? 40 yr, compared with only 17% in the Dutch population. Kaufman and co-workers also reported that that once pregnant, 20% of DES daughters experience preterm delivery (versus 8% of unexposed population (RR=2.93; 95% CI, 2.23–3.86)), their risk of ectopic pregnancy was 3 to 5 times higher than unexposed women (RR=3.84; 95% CI, 2.26–6.54), and 20% of the DES-exposed group had a miscarriage during the first pregnancy (versus 10% unexposed (RR=2.00; 95% CI, 1.54–2.60). These adverse pregnancy-related outcomes in DES daughters are also experienced by unexposed women, but the excess risk in those outcomes (not stillbirth) owing to in utero DES exposure was significant. Also, there are strong data suggesting that the presence of vaginal epithelial changes at cohort entry examination adds to the cumulative risk for DES-induced infertility, spontaneous abortion, preterm delivery, and ectopic pregnancy.