Intrauterine exposure to diethylstilbestrol: long-term effects in humans

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 2000

Abstracts

DES is the most carefully scrutinized EDC and its history provides valuable insights into the current evaluation of less well-studied EDCs. This review summarizes the health effects of prenatal exposure to diethylstilbestrol (DES) and emphasizes the role of DES as the first endocrine disrupting chemical (EDC).

Daughters

Vaginal clear cell adenocarcinoma (CCAC), the most severe consequence of prenatal exposure to DES, affected only 0.1% of exposed females, while the far more prevalent teratogenic and reproductive effects of DES were only discovered when DES daughter were screened for CCAC. Initial studies, conducted before most DES daughters had tried to conceive, examined vaginal cancer and vaginal, cervical and uterine abnormalities. Subsequently, several controlled studies demonstrated the increased risk of adverse reproductive outcomes in DES daughters. While most DES daughters can eventually experience a live birth, this is less likely in women with genital tract abnormalities, in whom there is a two-thirds chance that each pregnancy will be unsuccessful.

Sons

In DES sons, who have been far less studied, results suggest male reproductive toxicity, but are less consistent. The importance of dose and gestational age at initial exposure are discussed, and the implications of DES findings for the evaluation of risks from current EDCs emphasized.

Because of the dramatic development of vaginal/cervical clear cell adenocarcinoma in DES daughters, an increased risk of testicular cancer in DES sons has long been postulated. However, studying this association is difficult since both the disease and the exposure are uncommon. Only two cohort studies have examined testicular cancer, one reporting a testicular teratoma and the other two germ cell cancers in the exposed and none in the unexposed. In the six case-control studies published, exposure was broadly defined, and none studied DES specifically. These studies examined testicular cancer in relation to a maternal history of any hormone medication during the pregnancy, or any drug for bleeding, spotting or threatened abortion or prevention of miscarriage. The strongest association was seen in the one study that restricted exposure to the first trimester, which reported a relative risk estimate of 8.0 (p=0.02). These case-control studies were all of low statistical power. One of the largest, with 225 cases, did not have the power to rule out a relative risk of 7.0 (assuming alpha=0.05 and beta=0.80 and a 1% exposure to DES). Thus, while no consistent pattern of testicular cancer risk is seen for prenatal hormone exposure (featured image), an increased risk of testicular cancer in association with prenatal hormone use cannot be ruled out. Prenatal exposure to DES, specifically, is currently being examined in the DES Combined Cohort Studies (DCCS), a cohort study that includes 2,000 DES sons and 2,000 controls. However, it should be remembered that CCAC occurred in only one DES-daughter per thousand. If DES caused an equally rare form of genital tract cancer in DES sons, it is unlikely to be detected in this cohort study.

Several authors have reported increased urogenital tract abnormalities in males exposed in utero to DES. In Depue, an analysis of birth outcomes from the Collaborative Perinatal Project, the (matched) relative risk for cryptorchidism and mother’s use of estrogen (estradiol or DES) was 2.80 (p=0.06). Genital tract abnormalities were studied in the Dieckmann cohort by Bibbo, Gill and and Wilcox.

Several other authors studied cohorts identified in a single hospital or city. Most of these studies found a significant excess of one or more genital tract abnormalities, including epididymal cysts, hypertrophic or undescended testis, capsular induration, hypoplastic penis or hypospadias.

In addition, several studies examined the relationship between prenatal DES exposure and semen quality. The findings were mixed, with some studies finding significantly impaired semen quality in exposed males, and others finding little or no association. Leary and colleagues examined 265 exposed and 274 unexposed men born at the Mayo Clinic. They did not find increases of genitourinary abnormalities or infertility. As noted above, the median total dose their mothers received was only 720 gms. This should be compared to median doses of 11,025 and 2,530 gms for DESAD participants with and without structural anomalies.

The data on infertility in DES sons are quite limited. Wilcox and colleagues found no impairment of fertility in their follow-up of the Dieckmann cohort. In particular, the probability of conception in 119 couples in which the man was DES-exposed did not differ from 104 couples in which the man was unexposed. While a greater excess of genital abnormalities was reported in this study for men exposed prior to week 11, fertility did not differ by week of exposure. However, as noted above, the proportion of men in the Dieckmann cohort who were exposed in very early pregnancy is quite low.

In 1980 Driscoll conducted a controlled study of perinates identified from autopsy records, using a study design similar to that used by Johnson in examining female abortuses and stillbirths with respect to adenosis (discussed above). Blinded to exposure status, Driscoll examined prostate sections from 31 exposed and 62 unexposed pregnancies. Significantly higher rates of prostate abnormalities (abnormalities of the utricle and dilated ducts) were seen in the exposed. The highest rates were in those nine perinates exposed to DES alone; 100% had both a prostatic utricle and dilated ducts with squamous metaplasia. While there have been no reports of prostate abnormalities in adults exposed to DES during fetal life, most DES sons are not yet 50 years old. Since few of these men have reached the age at which benign prostatic hyperplasia (BPH) or prostate cancer increases in frequency, prostate abnormalities in DES sons have not yet been studied and it is important that this cohort be monitored for these endpoints.

A limited number of studies have examined the hypothesis that the development of hemispheric organization and cognitive abilities in humans is influenced by prenatal hormones, and DES in particular. Reinish conducted a double blind study of ten pairs of male siblings. One was exposed to a DES dose exceeding 1000 mg and early exposure (eight of ten were exposed by gestational week ten), while the other was unexposed to any exogenous hormone. This study reported DES exposure significantly associated with reduced hemispheric laterality and lowered spatial ability.

References

  • Intrauterine exposure to diethylstilbestrol: long-term effects in humans, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed PMID: 11252812, 2000.
  • Featured image credit mmcapital.
DES DIETHYLSTILBESTROL RESOURCES

Trends in Male Reproductive Health

Environmental Aspects, Reproductive Toxicology, 1998

Abstract

During the past five years, several researchers have focused on recent trends of declining male reproductive health.

Almost all cancer registries in the Western World have noted a remarkable increase in testicular cancer. Thus, in Scandinavia, where the incidence of testicular cancer is particularly high, there has been a three to four-fold increase during the past 50 years. The same trend has been found among U.S. whites, although no increase has been demonstrated among Afro-Americans who generally have a very low risk of testicular cancer.

During the same period, we have several indications of decrease in semen quality – again the bulk of the data come from the Western World.

There are also data to suggest that the incidence of other genital abnormalities, including hypospadias and undescended testis are weaker.

The fact that the reported changes the reported changes in male reproductive health have occurred simultaneously within a short period of time suggests that common environmental factors are of importance.

As normal sexual differentiation, development of the gonads and normal postnatal development are essential for normal reproductive function in adulthood, it was suggested that a common foetal factor could play a part for the observed trends. Based on epidemiological evidence from studies of children of mothers who were exposed to DES (Diethylstilbestrol) in early pregnancy and experimental evidence from administration of synthetic estrogens to pregnant animals, it was hypothesised that environmental hormone disrupters, which have been demonstrated to be ubiquitously distributed, could play an aetiological role.

References

DES DIETHYLSTILBESTROL RESOURCES

Are estrogens carcinogenic during development of the testes?

Many chemicals in the environment mimic the female sex hormone, estrogen, 1998

Selected Abstracts

Exposure to environmental estrogens during early fetal development was proposed by Sharpe & Skakkebaek as a potential risk factor for subsequent testicular disease, including neoplasia and poor semen quality.

To understand the mechanisms of action of estrogenic chemicals during differentiation of the male genital tract, we have studied developmental exposure to the synthetic estrogen, diethylstilboestrol (DES). While DES is a much more potent estrogen than most environmental chemicals examined, several of these compounds share some of the same properties as DES, such as a relative lack of binding to serum estrogen carrying proteins.

Prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism and testicular neoplasia in mice. A rare form of testicular cancer, rete testis carcinoma, was observed in five percent of male mice treated in utero with DES. We also demonstrated altered regulation of an estrogen responsive gene, lactotransferrin (LTF) in the seminal vesicles of treated mice, but not the controls. Likewise, LTF was irreversibly altered in the uteri of developmentally treated females; at the molecular level altered methylation of the gene appears to be involved, thus, providing a potential marker for hormonal effects during development.

The induction of permanent or “imprinted” responses during the development of a relatively estrogen-free reproductive tract cell suggests that undifferentiated targets for estrogen action may be sites for subsequent growth and differentiation defects associated with neoplasia.

References

  • Are estrogens carcinogenic during development of the testes?, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed, PMID: 9524585, 1998.
  • Steroidogenic cells featured image Zoe Johnston, eurekalert.
DES DIETHYLSTILBESTROL RESOURCES

DES Incidence of Testicular Cancer : Not Enough Evidence Yet

Do Environmental Estrogens Contribute to the Decline in Male Reproductive Health ? 1995

Selected Abstracts

Testicular cancer is now the most common malignancy of young men in many countries; although it is still rare compared with the malignant diseases most prevalent in old age, the lifetime risk of developing testicular cancer now approaches 1% in Denmark. The incidence of testicular cancer has been increasing for several decades. On the basis of data from several cancer registries, increases in incidence are evident in England and Wales, Scotland, the Nordic and Baltic countries, Australia, New Zealand, and the US. The observed increase has been 2-4% per annum in men younger than age 50 and has occurred in those between ages 20 and 45 years, in whom the incidence of testicular cancer is highest. Marked differences in race and in geographical areas exist; e.g., the incidence in Denmark is fourfold higher than in Finland, and whites are three fold more susceptible to this disease than are blacks in the US. We do not know the etiology of testicular cancer and therefore cannot prevent the disease.

The structural abnormalities of the reproductive organs more frequently reported in males exposed to DES than in controls include meatal stenosis, hypospadias, epididymal cysts, and testicular abnormalities.

Not enough evidence exists to indicate an increased risk of testicular cancer in men exposed to DES, but the case-control studies thus far performed include major design problems.

  • Hormone treatment may have been initiated at variable times during pregnancy; therefore, the presumed critical period when adverse effects of estrogens might occur may have been missed in some of these studies.
  • Furthermore, the exact prescribed hormone and the dose are often not remembered and therefore some women may have been treated with only progesterone.
  • Also, the number of cases has been too small to determine whether a substantial difference truly exists, and recall bias may also be present.

References

  • Full study (free access) Do environmental estrogens contribute to the decline in male reproductive health?, Clinical chemistry, NCBI PubMed, PMID: 7497651, 1995.
  • Trends in age-standardized (world standard population) incidence rates of testicular cancer featured image aaccjnls.
DES DIETHYLSTILBESTROL RESOURCES

DES and tumors in the area of the rete testis

Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens, 1995

Abstracts

Studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. (DES-linked) abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males.

Testis Cancer

The identification of tumors in the area of the rete testis is exceptionally rare; in fact, rete testis tumors have been reported infrequently in the clinical literature and in experimental animals. It is interesting that treatment of pregnant CD-1 mice with DES (100 pg/kg) resulted in rete testis adenocarcinoma in 5% of their male offspring. The high incidence of retained testis in mice (92%) following prenatal DES exposure and the occurrence of the rare rete testis adenocarcinoma raise the possibility of an association between prenatal DES exposure and the incidence of cryptorchidism and rete testis cancer.

Although cryptorchidism resulted in decreased or lack of spermatogenesis in male mice, inactivity alone could not account for the higher prevalence of rete cancer because several of the mice with the tumor had spermatogenesis occurring in the same testis. In addition to rete cancer, increased incidence of lesions of the corpus testis and Mullerian duct remnants were also seen. Since these lesions were observed in high-dose DES males, males receiving lower DES doses are being followed for increased cancer risk, although their fertility was not significantly affected.

References

  • Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens, Environmental health perspectives, NCBI PubMed, PMC1518878, 1995.
  • Featured image pexels.
DES DIETHYLSTILBESTROL RESOURCES

A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy

Long-term follow-up of mothers and their offspring, 1983

Abstract

In the early 1950s, a randomized, double-blind, controlled trial of the value of prophylactic stilboestrol therapy given antenatally to reduce the incidence of late pregnancy toxaemia and to improve perinatal mortality was conducted at University College Hospital, London.

Women expecting their first baby were allocated to one or other of two groups. Those in the stilboestrol group started treatment at the 12th week of pregnancy on average and received a mean dose of about 11.5 g of the drug while those in the control group received placebo tablets.

In spite of the fact that the original trial documentation was lost, it was possible to be fairly certain which was the treated group and follow-up data from 650 mothers and 660 offspring were obtained from death certificates, cancer registrations and questionnaires sent to general practitioners.

We found no indication of any harmful long-term effect of stilboestrol exposure during pregnancy on the mothers–in particular 10 out of 331 women in the untreated group and 9 out of 319 women in the treated group were found to have developed breast cancer.

Amongst the daughters, those in the treated group suffered an excess of minor benign lesions of the cervix uteri and an excess (not statistically significant) of unfavourable pregnancy outcomes. None of the daughters had developed clear cell adenocarcinoma of the vagina or cervix uteri.

Amongst the sons, we discovered no evidence of any significant excess of genital tract disorders or of impaired reproductive performance in the treated group but one son developed a (fatal) teratoma of the testis.

Unexpectedly, psychiatric disease (especially depression and anxiety) was reported by general practitioners about twice as often in the treated group offspring (sons and daughters) as in the untreated group. This result cannot be due to bias, and is unlikely to be due to confounding or chance, and may thus represent an adverse effect of exposure to stilboestrol in utero.

References

  • A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring, British journal of obstetrics and gynaecology, NCBI PubMed, PMID: 6357269, 1983.
  • University College Hospital, London featured image wellcomecollection.
DES DIETHYLSTILBESTROL RESOURCES

Testicular cancer development in DES Sons

Diethylstilbestrol revisited: a review of the long-term health effects, 1995

Abstract

The association between in utero DES exposure and the development of testicular cancer is controversial.

An increased risk for testicular tumors was observed in studies of mice exposed to DES, and an increased incidence of cryptorchidism, a strong risk factor for testicular cancer, has been observed in DES sons.

Several cases of testicular cancer in men exposed to DES have been reported , and two cohort studies have each reported one case of testicular teratoma.

The findings from six case-control studies that have examined the association between DES exposure in utero (or exposure to any exogenous hormone) and testicular cancer have been mixed.

On the basis of interviews with mothers of 79 men with testicular cancer that was diagnosed between 1972 and 1974 and interviews with 79 matched controls, Henderson and associates found a relative risk of 5.0 (P = 0.11; CI not given) for any hormone use during the pregnancy.

Schottenfeld and colleagues reported that drug use was associated with a relative risk of 1.96 (CI, 0.8 to 4.3) for bleeding, spotting, or threatened miscarriage during the pregnancy; however, 45% of case mothers and 63% of control mothers could not recall the specific drug taken.

In a study of 108 cases diagnosed in California between 1973 and 1979 and 108 matched controls, Depue and coworkers found that any exogenous hormone use during the first trimester was associated with an eightfold increased relative risk for testicular cancer; however, only two case mothers reported receiving DES.

In contrast to these suggestive studies, three studies have found no effects of DES exposure on the risk for testicular cancer.

Moss and colleagues reported an odds ratio of 0.9 for use of exogenous hormones during pregnancy; DES exposure, reported by four case mothers and two control mothers, resulted in a nonsignificant odds ratio of 2.0.

Similarly, Brown and associates found an odds ratio of 0.8 for hormone use, and Gershman and Stolley) reported an odds ratio of 0.8 for the receipt of drugs used to prevent miscarriage.

Problems common to these studies include the lack of documentation to confirm exposure and the difficulty of maternal recall of exposures during pregnancy. The relatively young age of the cohort at the time of study could also have precluded detection of an increased risk for testicular cancer, which in the general population peaks in the fourth decade of life.

Although these studies probably rule out a high level of risk, they are based on fairly small numbers, which may preclude the detection of a low to moderate increase in risk associated with DES. No other cancer sites in men have been implicated.

References

  • Diethylstilbestrol revisited: a review of the long-term health effects, Annals of internal medicine, NCBI PubMed, PMID: 7717601, 1995.
  • Featured image Jordan Whitfield.
DES DIETHYLSTILBESTROL RESOURCES

Sperm-head abnormality in germ cells following DES exposure

Testicular toxicity and mutagenicity of steroidal and non-steroidal estrogens in the male mouse, 1991

Abstract

The mutagenicity and toxicity of diethylstilbestrol (DES), 17 beta-estradiol and zeranol on the male mouse germ cells were investigated with meiotic micronucleus assays in vivo and in vitro, sperm-head abnormality test and morphometry. Further, the developmental effects of DES on testicular morphology were explored.

Micronucleus induction was observed at 10(-7) M concentration of DES and 17 beta-estradiol in vitro, but other treatments yielded negative results. The micronucleus assay in vivo revealed a small number of micronuclei in early haploid spermatids 17 days after a single subcutaneous injection of DES 50 mg/kg, whereas estradiol and zeranol gave negative results. The sperm-head abnormality rates were significantly elevated 5 weeks after treatments with high doses of DES, 17 beta-estradiol and zeranol, and testicular morphometry revealed transient changes in the volume densities of testicular tissue components. Prenatal and neonatal estrogen administration resulted in permanent alterations in seminiferous epithelium and dilatation of the rete testis, but did not affect micronucleus or sperm-head abnormality rates. The mutagenicity and toxicity of hormones in the mouse testis paralleled the hormonal activity of these compounds. Early estrogenization was the most sensitive toxicity test, followed by in vitro meiotic micronucleus induction, whereas the sperm-head abnormality assay and morphological analysis did not reveal subtle changes.

References

  • Testicular toxicity and mutagenicity of steroidal and non-steroidal estrogens in the male mouse, Mutation research, NCBI PubMed, PMID: 1719410, 1991.
  • Featured image credit thegolfclub.
DES DIETHYLSTILBESTROL RESOURCES

Diethylstilboestrol exposure and testicular cancer

International Journal of Epidemiology, 1989

Abstract

The postulated association between exposure to diethylstilboestrol (DES) in utero and testicular cancer is an attractive hypothesis—especially since exposure to DES and the subsequent development of vaginal cancer has been established as cause and effect.

The cases (A case-control study of testicular cancer using Connecticut tumour registry data) were patients diagnosed between 1945 and 1980 as having testicular cancer, and born between 1945 and 1972.

As the authors acknowledged, other studies are needed to conclusively answer the question of whether DES is a causal factor in the aetiology of testicular cancer.

References

  • Diethylstilboestrol exposure and testicular cancer, International Journal of Epidemiology, NCBI PubMed, PMID: 2767864, 1989.
  • Featured image Gabriel.
DES DIETHYLSTILBESTROL RESOURCES

Azoospermia in DES-treated male progeny

Infertility in a patient with abnormal spermatogenesis and in utero DES exposure, 1988

Abstract

A young azoospermic patient is described whose spermatogenesis reflected an abnormality of meiosis.

A diagnosis of asynapsis of chromosomes during early spermatogenesis was made by cytogenetic examination of a testicular biopsy. Standard histologic examination gave no indication of this abnormality.

An incidental history of intrauterine diethylstilbesterol (DES) exposure of the patient was elicited. Attention is called to the dearth of cytogenetic studies of spermatogenesis in DES-treated male progeny and the usefulness in general of meiotic cytogenetic studies for obtaining accurate diagnoses in human infertility.

References

  • Infertility in a patient with abnormal spermatogenesis and in utero DES exposure, International journal of fertility, NCBI PubMed, PMID: 2899562, 1988.
  • Featured image credit wecareindia.
DES DIETHYLSTILBESTROL RESOURCES