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.

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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.

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IVF: effect of in-utero DES exposure on human egg quality and fertilization

Factors such as aneuploidy, embryonic genome expression and ultrastructure have not been assessed in this 1999 study.

Abstract

Effect of in-utero diethylstilboestrol exposure on human oocyte quality and fertilization in a programme of in-vitro fertilization, Human reproduction (Oxford,  England), NCBI PubMed PMID 10357979, 1999 Jun.
Full study: Oxford Journals, Medicine & Health Human Reproduction Volume 14, Issue 6 Pp. 1578-1581 doi: 10.1093/humrep/14.6.1578, February 15, 1999.

Genital tract abnormalities and adverse pregnancy outcome are well known in women exposed in utero to diethylstilboestrol (DES).

Data about adverse reproductive performance in women exposed to DES have been published, including controversial reports of menstrual dysfunction, poor responses after ovarian stimulation, oocyte maturation and fertilization abnormalities.

We compared oocyte quality, in-vitro fertilization results and embryo quality for women exposed in utero to DES with a control group. Between 1989 and 1996, 56 DES-exposed women who had 125 in-vitro fertilization (IVF) attempts were retrospectively compared to a control group of 45 women with tubal disease, who underwent 73 IVF attempts. Couples suffering from male infertility were excluded. The parameters compared were oocyte quality (maturation abnormalities, immature oocyte, mature oocyte), fertilization and cleavage rate (per treated and metaphase II oocytes), and embryo quality (number and grade).

We found no significant difference in oocyte maturational status, fertilization rates, cleavage rates, embryo quality and development between DES-exposed subjects and control subjects. These results suggest that in-utero exposure to DES has no significant influence on oocyte quality and fertilization ability as judged during IVF attempts.

Discussion

In the group of in-utero DES-exposed women analysed here, the prevalence of ovulatory dysfunction and endometriosis was very high, but the number and quality of oocytes retrieved after stimulation were similar to those from women not exposed to DES.

The clinical pregnancy rate (number of cycles with fetal sacs on ultrasound) per embryo transfer was not significantly different between the two groups although lower in the IVF cycles performed in DES-exposed patients. Thus, lower delivery rate could be related to other important variables such as uterine defects and endometrial morphology and thickness as previously reported.

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The history of DES points out prescriptions of a therapeutic without proofs of its efficiency

distilbene drugs image
With DES, the silence of pharmaceutical laboratories created major difficulties for physicians in affording useful information. Many questions are not still resolved.

Abstract

Drug surveillance and reproduction: the bad example of distilbene, Contraception, fertilité, sexualité, NCBI PubMed PMID 8261014, 1993 Sep.

In the 1940’s, diethylstilboestrol (DES) is one of the first hormonal therapeutics which was prescribed to many pregnant women by a lot of gynecologists. Until 1970, the indications of this therapy was enlarged, before carcinologic and reproductive consequences leaded to forbid obstetrical indications of DES (in France, in 1977 only).

In France, 80,000 girls and 80,000 boys are suspected to have been exposed. As far as girls are concerned, the studies estimate between 23% and 36% the rate of infertility. These studies show also an increased incidence of ectopic pregnancy, spontaneous abortions, and premature delivery. The association between various factors of infertility, and typical uterine abnormalities leads to specific therapeutical indications, mostly in assisted procreations.

The history of DES points out prescriptions of a therapeutic without proofs of its efficiency, the silence of pharmaceutical laboratories which did not take into consideration Dieckman’s evaluation, and the difficulties for physicians in affording information.

Nevertheless, the last patients exposed will be 40 years old in 2016 in France. The other hormonal therapeutics which were discovered gave in turn rise hope for enhancing the fertility and providing from miscarriage. Over the examples such as DES are not still resolved questions that patients and physicians ask concerning the lack of adverse effects of a therapy on the foetus, when its clinical efficiency on the pregnancy is supposed to be proved.

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DES Daughters and Reproduction: 1986 update

DES daughters are about 35% less likely than a non-DES-exposed woman of equivalent age and health to have a noneventful pregnancy. Image © Michael Orange.

Abstract

An update on DES in the field of reproduction,, International journal of fertility, NCBI PubMed PMID 2875034, 1986 May.

The general consensus is that a DES daughter is about 35% less likely than a non-DES-exposed woman of equivalent age and health to have a noneventful pregnancy.

It is important to state that fertility rates refer to couples. The male partner is responsible for 40% to 50% of infertility problems. Age is also an important factor, and female fertility is known to decrease with age from the early 20s. These two factors receive little consideration in most articles.

However, it can be said that if there are no marked congenital anomalies present in the cervix and the uterus, then the probability that a DES-exposed daughter will have a normal child is quite good.

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Intractable primary infertility in DES-exposed women

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

Abstract

Intractable primary infertility in women exposed to diethylstilbestrol in utero, The Journal of reproductive medicine, NCBI PubMed PMID 3712361, 1986 April.

Fertility factors were examined in 50 women with primary infertility and presumed in utero diethylstilbestrol (DES) exposure and in 50 age-matched controls.

Uterine deformities and endometriosis were more frequent in the DES-exposed women than the controls.

When managed from one to four years, only 4% of DES-exposed women with primary infertility conceived (with no conceptions resulting in a viable fetus) as compared to 44% of controls.

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

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Primary infertility in DES-exposed women

In this 1986 study, more than 50% of the DES-exposed females showed primary infertility. Quiet in the Park.

Abstract

Primary infertility in women exposed to diethylstilboestrol in utero, British journal of obstetrics and gynaecology, NCBI PubMed PMID 3707881, 1986 May.

In a selected group of 40 women who had been exposed to diethylstilboestrol in utero, 18 conceived without difficulty and 22 had primary infertility.

Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility.

Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs.

Spontaneous abortion and tubal pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups.

Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia–a hithero unreported finding for such women.

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Infertility and upper genital tract changes in DES-exposed women

infertility-woman
In this 1986 study, more than 70% of the DES-exposed females showed abnormal hysterosalpingograms.

Abstract

Upper genital tract changes and infertility in diethylstilbestrol-exposed women, American journal of obstetrics and gynecology, NCBI PubMed PMID 3717241, 1986 Jun.

A possible relationship of upper genital tract abnormalities in the diethylstilbestrol-exposed woman and infertility was studied.

Six hundred thirty-two women had roentgenography performed. Three hundred sixty-seven of these women were not using contraception and were actively trying to become pregnant.

  • One hundred thirty-four (36%) of these women reported difficulties conceiving for a period of 1 or more years.
  • Seventy-three percent of these women had abnormal hysterosalpingograms.
  • The frequency of abnormal x-ray films in the women who did conceive within 1 year was essentially the same (74%). Furthermore, a similar number of women with normal x-ray films (37%) had difficulty conceiving as did women with abnormal x-ray films (36%).
  • When specific hysterosalpingographic abnormalities were related to the presence or absence of infertility, it was observed that the presence of a constriction of the upper uterine cavity resulted in a 2.26-times greater likelihood that a woman would not be able to conceive.
  • If a T-shaped uterus was found in association with constriction of the upper uterine cavity, the odds ratio for inability to conceive was found to be 2.63.
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Relationship between DES exposure in utero and male infertility

In this 1981 study, 80% of the DES-exposed males qualified as infertile and demonstrated at least one abnormality of the reproductive organs.

Abstract

Possible relationship between in utero diethylstilbestrol exposure and male fertility, American journal of obstetrics and gynecology, NCBI PubMed PMID: 7234914, 1981 May.

Seventeen men who were exposed in utero to diethylstilbestrol (DES), 12 non-DES-exposed volunteers, and 11 fertile control subjects were evaluated by physical examination, seminal fluid analysis, and sperm penetration assay (SPA).

  • Fourteen of the 17 male subjects exposed to DES in utero and two of the 12 non-DES-exposed volunteers had SPAs of less than 14% and qualified as infertile by the criteria of this test.
  • All 11 fertile control subjects had demonstrated SPA values in the fertile range.
  • Thirteen of the 17 DES-exposed male subjects, four of the 12 non-DES-exposed volunteers, and four of the 11 fertile control subjects demonstrated at least one abnormality of the reproductive organs.
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Infertility in women exposed to DES in utero

fertility-test
Infertility among women exposed prenatally to DES. Image © Woman holding pregnancy test

Abstract

Infertility in women exposed to diethylstilbestrol in utero, The Journal of reproductive medicine, NCBI PubMed PMID 6663585, 1983 Dec.

To evaluate the reproductive consequences of prenatal diethylstilbestrol (DES) exposure, 33 infertile couples were studied in whom the female had been exposed to DES in utero.

Infertility was attributed to

  • uterotubal junction obstruction in 3 couples,
  • anovulation in 7,
  • endometriosis in 11,
  • cervical obstruction in 2,
  • adnexal adhesions in 2,
  • oligospermia in 1
  • and luteal insufficiency in 3;
  • in 4 couples no cause of infertility could be identified.

No unique intraabdominal abnormalities attributable to DES exposure were observed. Four tubal pregnancies occurred in women with grossly normal oviducts. Nine of 11 women who had previously undergone surgical manipulation of the cervix (cryosurgery, cautery or conization) developed cervical stenosis, and 8 of them were found to have endometriosis.

Despite our not having an appropriate referral infertility population for comparison, these findings are consistent with the following hypotheses regarding women prenatally exposed to DES:

  1. surgical manipulation of the cervix more frequently leads to cervical stenosis and ultimately pelvic endometriosis,
  2. tubal pregnancies may occur by a mechanism unrelated to salpingitis,
  3. the spectrum of problems causing infertility is similar to that in the non-DES-exposed population.
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