Transgenerational transmission of DES-related epigenetic alterations in humans

Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol

2006 Study Abstract

In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES.

Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure.

Mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05), and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02-2.32)]. A possible association between mothers’ DES exposure and daughters’ infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95-5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005).

The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.


DES is an established transplacental chemical teratogen and carcinogen in humans. The effects of DES on prenatally exposed women include menstrual irregularity, infertility, adverse reproductive outcomes, anomalies of the reproductive tract, and elevated risk of gynaecological tumours, specifically clear cell adenocarcinoma of the vagina.

Most of the outcomes seen in women have been replicated in prenatally exposed mice; thus, the mouse model is useful for investigating DES-related mechanisms. Studies of developmentally exposed rodents indicate that DES exerts its influence on reproductive tissues through epigenetic (non-mutational) mechanisms involving disrupted oestrogen signalling and permanent changes in gene expression, probably due to altered DNA methylation. Rodent studies have identified altered expression in multiple genes, including those inducible by oestrogen, such as lactoferrin, oestrogen receptor, epidermal growth factor, and specific proto-oncogenes, as well as genes involved with structural development of the reproductive tract, and those governing embryonic development.

Of relevance to our study, studies in mice have shown that some DES-related outcomes seen in prenatally exposed animals are also observed in their female descendants. Transgenerational effects include reproductive tract tumours, similar to those seen in their prenatally exposed mothers, but may not include increased infertility. To the extent epigenetic heritability is relevant to humans, the mouse model indicates potentially similar effects in the descendants, but allows for some degree of divergence.

Studies of the Dieckmann cohort indicate DES does not influence mean age at menarche in the prenatally exposed, or in the daughters of the exposed, based on the mothers’ reports. Our data, self-reported by the third-generation women, are consistent with the latter finding, indicating a comparable age at menarche for daughters of the exposed and unexposed women. However, the Dieckmann studies also indicate that menstrual irregularity and use of hormones to manage menstrual regularity are more common in the prenatally exposed women, compared with the unexposed. Similarly, our data indicate that daughters of the exposed women attain menstrual regularity at a slightly later age than daughters of the unexposed and are more likely to experience menstrual irregularity.

The association between prenatal DES exposure and infertility is well established. Our study suggests that infertility may also be more frequent in the daughters of the exposed women, and that DES exposure may exacerbate age-related infertility, a possibility compatible with findings in men who were exposed to DES in utero. None of the women in our study attributed infertility to the male partner, but because most women did not know the reason for their infertility experience, we cannot be certain our findings pertain exclusively to female infertility. Nevertheless, the possible effect observed here could be attributed to male infertility only if the DES-exposed women were more likely than the unexposed to marry infertile men, and this seems unlikely.

The proportion of third-generation women affected by infertility (5%) in this study was far lower than that observed in the generation of women exposed in utero to DES (30%). In the prenatally exposed women, infertility is primarily due to anatomic anomalies of the uterus or fallopian tubes; other diagnoses, including hormonal/ovulatory problems, play a less striking role. Anatomic and tissue anomalies were not observed in a study of 28 third-generation women, but the number of participants was too small to rule out a low prevalence, and some irregularities (e.g. uterine, tubal) might not be evident on physical examination. Further follow-up is needed to confirm the possible infertility in the third-generation women, and to evaluate specific diagnoses, which may provide insight into DES-related mechanisms.

It is well-known that women exposed to DES in utero have increased pregnancy complications and adverse birth outcomes, including ectopic pregnancy, pregnancy loss, and preterm delivery. Our data are not conclusive regarding adverse pregnancy outcomes in third-generation women, although daughters of the exposed had somewhat fewer live born children and babies of slightly lower average birth weight. Further follow-up will be essential to assess reproductive outcomes as more of the third-generation women enter their reproductive years.

We cannot exclude the possibility that exposed third-generation women with menstrual or reproductive concerns were more likely to participate in our study, or that their mothers were more likely to provide their contact information, which might account for the small differences observed. However, 28% of the daughters of DES-exposed women were unaware of their mothers’ exposure, and 60% of daughters of the unexposed either believed their mothers were DES-exposed or were uncertain of their mothers’ exposure status. In addition, the medical surveillance was similar for daughters of the exposed and unexposed, suggesting the two groups are similar with regard to health consciousness and concerns.

We believe our study, based on a unique cohort of women, is the first to show possible transgenerational transmission of phenotypes associated with documented prenatal chemical exposure. Our data provide evidence of menstrual irregularity and delayed menstrual regularization in the daughters of women exposed in utero to DES. We also found possible evidence of increased infertility, particularly in older women. While these findings are preliminary, they are compatible with outcomes seen in the prenatally exposed women and are consistent with speculation that DES exposure during a critical window in human development results in heritable changes in gene function. Although our data provide limited evidence of an increased frequency of adverse pregnancy outcomes in third-generation women, most have not married or attempted to start families, and further follow-up will assess their reproductive experience.


  • Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol, International journal of epidemiology, NCBI PubMed, PMID: 16723367, 2005 Apr 10. Full text (free access) on academic.oup.
  • Featured image credit Gabriele Diwald.

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