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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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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Impaired reproductive performance in Diethylstilbestrol-exposed women

image of infertility
It is probable that the high rate of infertility and pregnancy wastage in the DES-exposed is related to the uterine structural abnormalities encountered. Image © Infertility. Sticky paralyzing discovery.

Abstract

Impaired reproductive performance in DES-exposed women, Obstetrics and gynecology, NCBI PubMed PMID 7352058, 1980 Jan.
Full text: Obstetrics & Gynecology, January 1980 – Volume 55 – Issue 1, 1980/01000.

The reproductive history of 69 women with demonstrated diethylstilbestrol (DES)-related cervical-vaginal abnormalities is reviewed.

All of the patients were sexually active non-contraceptive users who were studied over an 8-year period.

  • Forty-six patients conceived, for an uncorrected fertility rate of 66.7%. Fourteen patients elected therapeutic abortion.
  • The 32 remaining patients had 62 pregnancies which resulted in 26 living children, for a success rate of 41.9%. However, cervical cerclage was required for continuation of 8 of these successful pregnancies.
  • The 36 pregnancy failures consisted of 19 first- and 11 second-trimester spontaneous abortions, 3 third-trimester losses due to permaturity, and 3 tubal pregnancies.
  • Uterine abnormalities were found in all of the 25 patients who underwent hysterosalpingograms.

Although other reproductive diseases unrelated to DES exposure in utero were also present in this select group of patients, it is probable that the high rate of infertility and pregnancy wastage is related to the uterine structural abnormalities encountered.

Click to download the full study.

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Fertility and outcome of pregnancy in women exposed in utero to DES

fertility
An increased risk of unfavorable outcome of pregnancy is associated with DES exposure.

Abstract

Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol, The New England journal of medicine, NCBI PubMed PMID: 7351908, 1980 Mar 13.

Fertility and outcome of pregnancy were examined in women participating in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project.

We compared 618 subjects who had prenatal exposure to DES with 618 control subjects. Fertility, measured in terms of pregnancies achieved, did not differ between the women exposed to DES and the controls.

An increased risk of unfavorable outcome of pregnancy was associated with DES exposure (the relative risk of any unfavorable outcome of pregnancy was 1.69; P less than 0.001). Speculation on biologic mechanisms that might produce this difference is premature, since additional data about these subjects must be collected.

Among DES-exposed women who became pregnant, 81 per cent had at least one full-term live birth.

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Infertility among women exposed prenatally to diethylstilbestrol

This 2001 study, which is larger and includes a considerably longer follow-up period than any previous study, indicates that women exposed to diethylstilbestrol in utero have an increased risk of infertility, both primary and secondary, and that the increase is primarily due to tubal and uterine factors. I is for Infertility.

Abstract

Infertility among women exposed prenatally to diethylstilbestrol, American journal of epidemiology, NCBI PubMed PMID: 11495854, 2001 Aug.
Full study: Am. J. Epidemiol, doi: 10.1093/aje/154.4.316, January 17, 2001.

Although it is well established that women exposed to diethylstilbestrol in utero have an increased risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, it is not known whether they also have an increased risk of infertility. The authors assessed this question in data from a collaborative follow-up study of the offspring of women who took diethylstilbestrol during pregnancy.

In 1994, 1,753 diethylstilbestrol-exposed and 1,050 unexposed women from an ongoing cohort study (National Cooperative Diethylstilbestrol Adenosis Study and Dieckmann cohorts) provided data on difficulties in conceiving and reasons for the difficulty. Age-adjusted relative risks were computed for the association of diethylstilbestrol exposure with specific types of infertility.

  • A greater proportion of exposed than unexposed women were nulligravid (relative risk (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.5),
  • and a greater proportion had tried to become pregnant for at least 12 months without success (RR = 1.8, 95% CI: 1.6, 2.1).
  • Diethylstilbestrol exposure was significantly associated with infertility due to uterine and tubal problems, with relative risks of 7.7 (95% CI: 2.3, 25) and 2.4 (95% CI: 1.2, 4.6), respectively.

The present findings indicate that diethylstilbestrol-exposed women have a higher risk of infertility than do unexposed women and that the increased risk of infertility is primarily due to uterine or tubal problems.

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Female fertility prognosis and diethylstilbestrol. Personal data and review of the literature

In spite of their difficult past reproductive history 4 young DES-women conceived successfully with adapted psychological and medical care in 1998 in France. Las manos del destino.

Abstract

Female fertility prognosis and diethylstilbestrol, Journal de gynécologie, obstétrique et biologie de la reproduction, NCBI PubMed PMID: 9648005, 1998 Apr.
Full study: em-consulte, Doi : JG-05-1998-27-3-0368-2315-101019-ART95, 1998.

Diethylstilbestrol (DES) exposure in utero in females is a cause of clear-cell adenocarcinoma of the cervix and of several anatomical and functional disorders of the genital tract. DES exposure must be evoked whenever counselling women for reproductive disorders.

In France around 80,000 women have had in utero DES exposure. The cases of four young women who consulted our Reproduction Center for reproductive disorders illustrate the usual difficulties faced by these patients.

In spite of their difficult past reproductive history (uterine malformations, repeated miscarriages, ectopic pregnancies) and low fertility rate, all four women conceived successfully, either after spontaneous or induced ovulation. We stress the need for adapted psychological and medical care which can lead to successful childbearing in the vast majority of these high-risk patients.

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