DES Grand Daughters Menstrual and Reproductive Characteristics

image of menstrual-cup
This 2006 data provide evidence of menstrual irregularity, delayed menstrual regularization, and increased infertility in DES Grand Daughters. Although this 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 cup.

Abstract

Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES), International journal of epidemiology, NCBI PubMed PMID: 16723367, 2006 Aug.

Full text: Oxford Journals, Medicine & Health, International Journal of Epidemiology, Volume 35, Issue 4Pp. 862-868, doi: 10.1093/ije/dyl106, August 2006.

Background
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.

Methods
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.

Results
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).

Conclusions
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.

Excerpts and Discussion

The mean birth weight of offspring appeared lower in daughters of the exposed than in the unexposed (3374.2 g vs. 3540.5 g) (P = 0.08).

Our data indicate that DES Grand Daughters attain menstrual regularity at a slightly later age than daughters of the unexposed and are more likely to experience menstrual irregularity.

Our study suggests that infertility may also be more frequent in the DES Grand Daughters, and that DES exposure may exacerbate age-related infertility, a possibility compatible with findings in men who were exposed to DES in utero. The proportion of third-generation women affected by infertility (5%) in this study was far lower than that observed in the (second) 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.

Click to download the full study.

More DES DiEthylStilbestrol Resources

Reducing the Adult Height of Tall Girls with DES: Effects on Fertility

image of tall-girls
Estrogens have been used to reduce the height of unusually tall girls since the 1950s based upon the concept that, during normal puberty, increased estrogen levels lead to epiphyseal fusion in the long bones. DES treatment in adolescence seems to reduce female fertility in later life by 40%.

Abstract

Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility, Lancet (London, England), NCBI PubMed PMID 15500896, 2004 Oct.

BACKGROUND
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.

METHODS
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.

FINDINGS
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.

INTERPRETATION
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.

More DES DiEthylStilbestrol Resources

Five Scary and Shocking Facts about Diethylstilbestrol

1. As early as 1939, researchers had shown that DES Diethylstilbestrol could cause cancer and changes in the reproductive tracts of mice and rats, but drug companies ignored these results ; they also tested DES on pregnant women without consent.

Image from A Healthy Baby Girl, a 1996 documentary in which filmmaker Judith Helfand chronicles the health consequences of her in utero exposure to diethylstilbestrol
DES did not lead to healthier babies, nor did it prevent miscarriages, according to research that began appearing in 1953

2. In 1953, a study of 2000 women at the University of Chicago showed that DES did not prevent miscarriage; on the contrary, it was associated with increases in premature labor and a higher rate of abortions.

3. Despite this study, the drug continued to be used.  It wasn’t until 1971 that American drug companies were legally obliged to label DES “unsuitable for pregnant women”.  The FDA did not ban the drug but issued a contraindication which means that the drug DES continued to be prescribed to pregnant women even after the link between a rare form of vaginal cancer in young women and prenatal exposure to DES was established.

4. A whole generation of new medical students and doctors don’t know about Diethylstilbestrol, yet a study published in 2011 confirmed lifetime risk of adverse health effect in DES daughters (the youngest are in their mid 30’s early 40’s).  DES is one of those cases where the patients often know more about its effects than the doctors.

5. DES is a multi-generational tragedy.  Research by the Netherlands Cancer Institute in 2002 suggests that hypospadias a misplaced opening of the penis occurred 20 times more frequently among third-generation sons.  In laboratory studies of elderly third-generation DES-exposed mice born to DES daughter mice, an increased risk of uterine cancers, benign ovarian tumors and lymphomas were found.  Third-generation male mice were shown to be at risk for certain reproductive tract tumors.

Are we going to ignore these results like we did in 1939?

Third-generation children, the offspring of DES daughters and DES sons, are just beginning to reach the age when relevant health problems can be studied.  Funding for more research is critically needed to continue to look for evidence of reproductive abnormalities and cancers among third-generation DES women and men to ensure they receive appropriate follow-up care.