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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DES exposure in utero associated with cryptorchidism, testicular hypoplasia and semen abnormalities

Severe pathological changes found in many DES Sons’ sperm.

Abstract

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities, The Journal of urology, NCBI PubMed PMID: 37351, 1979 Jul.

Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls.

Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent).

Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism.

Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent.

Although none of our Diekmann’s lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid.

A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.

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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.

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Structural and functional abnormalities in the sex organs of male offspring of mothers treated with DES

Severe pathological changes and sperm abnormalities found in many DES Sons. Santalum freycinetianum.

Abstract

Structural and functional abnormalities in the sex organs of male offspring of mothers treated with diethylstilbestrol (DES), The Journal of reproductive medicine, NCBI PubMed PMID: 772199, 1976 Apr.

The in utero effects of DES (Diethylstilbestrol) on the human male genital tract are reported in this follow-up study of male offspring of DES-treated mothers.

Both anatomical and functional abnormalities were significantly greater in the DES-exposed males as compared to control males whose mothers were all participants in a prospective, randomized double blind study of the effects of DES on pregnancy at the Chicago Lying-in Hospital during the early 1950s.

Epididymal cysts, hypotrophic testes and capsular induration of the testes were among the more common genital lesions found in 27 per cent of 134 DES-exposed males as compared to a 7 per cent incidence in 119 control males.

Spermatozoa analyses revealed severely pathologic changes (Eliasson score greater than 10) in 29 per cent of 28 DES-exposed males and 0 per cent of 18 control males (with or without genital i.e., physical abnormalities). Abnormal findings on physical examination combined with sperm abnormalities (Eliasson score greater than or equal to 5) were found in 29 per cent of DES-exposed males versus 0 per cent of 18 control males.

Cytologic examinations did not reveal malignant cells from the following materials: urines before and after prostatic massage or ejaculation, prostatic fluids and aspirates from epididymal cysts.

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