Hypospadias in DES Sons

Latrogenic legacy from diethylstilbestrol exposure

2002 Study Abstract

Hypospadias, characterised by the emergence of the urethral orifice on the ventral surface of the penis or on the perineum rather than at the tip of the glans, is one of the most common birth defects in boys. Although there is no increased mortality associated with hypospadias, there is substantial morbidity, including surgical operations and the psychosocial consequences of having a genital abnormality.

Little is known about the causes of hypospadias. However, since fusion of the urethral groove is mainly under the control of androgens originating in the fetal testis, it has been suggested that agents with antiandrogenic or oestrogenic activities might increase the risk.

Diethylstilbestrol also seems to affect sons exposed in utero, leading to higher risks of structural urogenital anomalies, including cryptorchidism, testicular hypoplasia, microphallus, abnormalities of the penile urethra, hypospadias, and epididymal cysts. Similar disorders were induced in mice exposed to diethylstilbestrol in utero.

In males, fusion of the urethral folds brings the urogenital meatus from the perineal region to the tip of the phallus between the 8th and 14th week of gestation, and genital malformations were more frequent among males exposed to diethylstilbestrol before the 11th week than among those exposed later.

Sources

  • Latrogenic legacy from diethylstilbestrol exposure, NCBI PubMed PMID: 11943252, 2002 Mar.
  • Featured image credit mcgill.ca.
DES DIETHYLSTILBESTROL RESOURCES

How DES prescribed during gestation can alter foetal sex differentiation in men

Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation

2001 Study Abstract

The effects of diethylstilbestrol (DES) provide an unfortunate model of how a potent estrogenic chemical prescribed during gestation can alter foetal sex differentiation in human. The occurrence of genital abnormalities in the sons of women exposed to DES during pregnancy is noteworthy:

  • 20.8% of the males exposed to DES in utero had epididymal cysts (vs 4.9% in controls),
  • 4.4% had hypospadias (vs 1.1% in controls),
  • 11.4% presented with cryptorchidism and hypoplastic testes (vs 2.1% in controls),
  • and 1.5% had micropenis (vs 0% in controls).

This set of data emphasizes the sensitivity of foetal external genitalia to excess synthetic estrogen exposure.

The adverse effects of DES have been extensively studied in experimental animals. After DES exposure in pregnant mice, male offspring exhibited micropenis, hypospadias, and cryptorchidism along with underdevelopment of the vas deferens, epididymis, and seminal vesicles.

These defects are similar to those of DES-exposed human male foetus.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Effects in Men of Intra-Uterine Exposure to DES

1998 Study Abstract

The reasons for increased incidence of cryptorchidism, hypospadias and testicular cancer are unknown, but experimental data demonstrating the important role of sex steroids in the physiology of testicular descent and urethral development point to the possibility that environmental factors could cause the problem by interfering with the sex steroids. The best example of such an influence is diethylstilbestrol (DES), which has been studied extensively in both humans and experimental animals.

Millions of pregnant women in the USA and Europe were treated with DES between the late 1940s and early 1970s to prevent abortion, pre-eclampsia and other complications of pregnancy. Doubleblind, placebo-controlled trials had already demonstrated in the 1950s that the treatment was not efficacious, but despite that it was used until the 1970s when the US Food and Drug Administration banned its use during pregnancy after it had become evident that the daughters of DES-treated women had an increased risk of developing clear cell adenocarcinoma of the vagina.

Thereafter, several studies on the effects of DES on the children of exposed mothers were published. Many of the papers are based on the socalled Dieckmann cohort comprising more than 1600 pregnant women who were treated with increasing doses of DES or placebo from gestational weeks 7-20 to week 35 . The use of the medication was verified by a dye indicator in the urine. Children from these pregnancies have been followed since the 1970s, and a large number of structural and functional abnormalities in their reproductive organs have been found. For example, 20.8% of 308 men exposed to DES in utero had epididymal cysts, compared with 4.9% of 307 placebo-exposed controls. There were other structural anomalies in reproductive organs that were more frequent in DES-exposed male subjects than in controls, for example meatal stenosis (12.9% versus 1.8%), hypospadias (4.4% versus 0%), testicular abnormalities, including hypoplastic testis, cryptorchidism and capsular induration (11.4% versus 2.9%), and microphallus (4 cases versus 0 cases). The frequency of anomalies was dependent on the timing of exposure, so that the men who were exposed to DES before week 11 of gestation had a significantly higher prevalence of anomalies than those who were exposed only later, emphasizing the sensitivity of organogenesis to external disturbance. In these cohort studies, cryptorchidism was significantly more frequent in DES-exposed men than in controls, but in retrospective case-control studies, maternal oestrogen exposure was not associated with an increased incidence of cryptorchidism in the offspring. The strength of a retrospective case-control study, however, is not as good as that of a prospective cohort study, and DES can therefore be considered to be a risk factor for cryptorchidism. In a metaanalysis of 14 studies, no association was found between first-trimester exposure to sex hormones other than DES, and external genital abnormalities.

Several reports have demonstrated that the semen quality of men exposed to DES in utero is significantly worse than in placebo-exposed controls. However, the sperm concentrations of most of the DES-exposed men were well above the limit at which subfertility occurs, and it is therefore not surprising that the fertility of these men was reported to be normal.

The risk of testicular cancer among men exposed to DES in utero has been a controversial issue, and one can often read in the literature claims that the risk is not increased. This does not seem to be true. On the basis of a meta-analysis of six case-control studies, Mantel-Haenszel estimate of the odds ratio was 2.6, with 95% confidence limits of 1.1-6.1. However, more direct evidence would be necessary to assess the risk. Thus far, no data have been available for testicular cancer in the known DES-exposed cohorts.

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DES DIETHYLSTILBESTROL RESOURCES

Estrogen fetal exposure and male reproductive health alterations

Do environmental estrogens contribute to the decline in male reproductive health?

1995 Study Abstract

Several observations suggest that male reproductive health has been declining since World War II in many countries.

The incidence of testicular cancer, hypospadias, and cryptorchidism has been increasing and semen quality has been decreasing, and these may have a common etiology.

Treatment of several million pregnant women with the synthetic estrogen diethylstilbestrol led to an increase in these conditions among the sons of these women. These abnormalities probably arise during fetal development.

The similarity between these effects and the adverse change in male reproductive development and function raised the question of whether the adverse changes are attributable to altered exposures to estrogenic and other endocrine-disrupting agents during fetal development.

We speculate that alteration in exposure to estrogen in the past half-century may have caused the changes in male reproductive health.

Sources

  • Do environmental estrogens contribute to the decline in male reproductive health?, NCBI PubMed PMID: 7497651, 1995 Dec.
  • Featured image credit John Jason.
DES DIETHYLSTILBESTROL RESOURCES

Fertility disorders attributable to the use of diethylstilbestrol during intrauterine life

Women treated with distilbene during pregnancy : it seems that the increased number of miscarriages, extra-uterine pregnancies and perinatal deaths are probably due to the maternal treatment which is also responsible for semen abnormalities

1984 Study Abstract

In the early 1970s, the elevated rate of abnormalities in children of the 2-3 million US women and 260,000 French women treated with diethylstilbestrol (DES) during pregnancy began to be recognized.

Four kinds of cervicovaginal anomalies have been observed in women exposed to DES in utero:

  1. 22-58% have been estimated to have morphologic anomalies with the timing of exposure to DES more important than the total dose
  2. a high proportion has an insufficient cervical mucus not corrected by exogenous administration of estrogen
  3. a high proportion develop cervical stenosis after cryosurgery, electrocoagulation, or conization
  4. and the increased incidence of prematurity in infants of DES-exposed mothers has been attributed to cervical incompetence.

69% of 267 women studied had hysterographically demonstrated uterotubal malformations. A characteristic aspect was a T-shaped uterus but other anomalies were noted. Hysterographic anomalies were correlated with cervico-isthmic anatomic anomalies, anomalies of the vaginal epithelium, and with the date of 1st exposure to DES in utero. The total dose of DES did not affect the frequency of genital anomalies. Possible tubal anomalies have not been well studied, although 1 author has observed short and narrow tubes and other abnormalities.

The number of extrauterine pregnancies is known to be elevated in women exposed to DES in utero. The possibility of an increased incidence of menstrual irregularity, dysmenorrhea, or oligomenorrhea in DES-exposed women has been suggested but remains controversial.

The responsibility of DES exposure in utero for later reduced fertility is also in dispute. Higher rates of spontaneous abortion, extrauterine pregnancy, prematurity, and perinatal death have been reported in DES-exposed women.

Increased incidence of stenosis of the meatus, hypospadias, epididymal cysts, testicular hypoplasia and other anomalies, cryptorchidism, microphallus, and varicocele have been reported in men exposed to DES in utero. Reduced sperm counts and anomalies in the volume of the ejaculate, percentage of sperm mobile, and sperm morphology have been reported in exposed men. Sperm anomalies may be responsible for reduced fertility in exposed men, but the exact extent is unknown.

Sources

  • Fertility disorders attributable to the use of diethylstilbestrol during intrauterine life, NCBI PubMed PMID: 6397835, 1984 Apr.
  • Featured image credit Edward Cisneros.
DES DIETHYLSTILBESTROL RESOURCES

Urogenital tract abnormalities in DES sons

DES-exposed male offspring urogenital tract abnormalities, 1976

Study Abstract

Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices.

The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).

Remark : a DES-induced abnormality of the male urethra is embryologically consistent with DES-induced abnormalities of the vagina whether the latter are of Mullerian or urethral fold origin.

The findings suggest that more detailed historical and clinical examination of such boys is warranted.

Sources

  • Urogenital tract abnormalities in sons of women treated with diethylstilbestrol, NCBI PubMed PMID: 972792, 1976.
  • SELECTED MEDICAL HISTORIES IN DES-EXPOSED AND DES-UNEXPOSED MALES featured image credit PMID: 972792.
DES DIETHYLSTILBESTROL RESOURCES

Birth Defects in DES Grandsons

Birth defects in children of men exposed in utero to diethylstilbestrol (DES)

2018 Study Abstract

OBJECTIVE
Prenatal exposure to diethylstilbestrol (DES) is associated with adverse effects, including genital anomalies and cancers in men and women. Animal studies showed birth defects and tumors in the offspring of mice prenatally exposed to DES. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to assess the birth defects in children of prenatally exposed men.

METHODS
In a retrospective study conceived by a patients’ association (Réseau DES France), the reports of men prenatally exposed to DES on adverse health effects in their children were compared with those of unexposed controls and general population.

RESULTS
An increased incidence of two genital anomalies, cryptorchidism (OR=5.72; 95% CI 1.51-21.71), and hypoplasia of the penis (OR=22.92; 95% CI 3.81-137.90), was observed in the 209 sons of prenatally exposed men compared with controls, but hypospadias incidence was not increased in comparison with either the controls or the general population. No increase of genital anomalies was observed in daughters.

CONCLUSION
With caution due to the methods and to the small numbers of defects observed, this work suggests an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES. This transgenerational effect, already observed in animals and in the offspring of women prenatally exposed to DES, could be the result of epigenetic changes transmitted to the subsequent generation through men.

Sources

  • Birth defects in children of men exposed in utero to diethylstilbestrol (DES), Therapie, NCBI PubMed PMID: 29609831, 2018 Mar 3.
  • Featured image credit Danielle MacInnes.
DES DIETHYLSTILBESTROL RESOURCES

Epigenetics and transgenerational effects of DES

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals

Selected Abstracts

Prenatal exposure to DES caused hypermethylation of the Hoxa10 gene in the uterus of mice and was linked to uterine hyperplasia and neoplasia later in life. Beyond the effects of prenatal exposure to DES on the daughters exposed in utero are suggestions that this leads to transgenerational effects of the chemical on the reproductive system, although whether this is linked to DNA methylation changes in humans is unknown.

DES caused histone deacetylation in the promoter region of the cytochrome P450 side chain cleavage (P450scc) gene.

Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members, caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells and increased the incidence of cystic glands in rats.

Studies in mice showed that DES induced vaginal adenosis by down-regulating RUNX1, which inhibits the BMP4/activin A-regulated vaginal cell fate decision; induced epithelial cell proliferation and inhibited stromal cell proliferation; and caused persistent down-regulation of basic-helix-loop-helix transcription factor expression (Hes1, Hey1, Heyl) in the vagina, leading to estrogen-independent epithelial cell proliferation. Neonatal exposure to DES caused persistent changes in expression of IGF-1 and its downstream signaling factors in mouse vaginas. It also up-regulated Wnt4, a factor correlated with the stratification of epithelial cells, in mouse vaginas. Interestingly, the simultaneous administration of vitamin D attenuated the ability of DES to cause hyperplasia of the vagina in neonatal mice.

In mice treated prenatally with DES there was a significant increase in enhancer of Zeste homolog 2 (EZH2) protein and EZH2 activity (measured by increased mammary histone H3 trimethylation)—a histone methyltransferase that may be linked to breast cancer risk and epigenetic regulation of tumorigenesis, as well as an increase in adult mammary gland EZH2.

EDC exposures to pregnant animals have been shown to cause multigenerational or transgenerational effects on a number of disease endpoints, particularly reproduction, neurobehavior, and adiposity. This work needs much more follow-up to better determine the underlying mechanisms, which are likely to include epigenetic molecular programming changes. Moreover, research is needed in human populations. Some work has been conducted in grandchildren of DES-exposed women who took this estrogenic pharmaceutical during pregnancy. The consequences on the offspring (F1 generation) are well-studied, and research is beginning to be published on the grandchildren (F2 generation). For environmental chemicals, several ongoing projects need continued funding.

Sources

  • Full study (free access) : EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, NCBI PubMed PMC4702494, 2015 Nov 6.
  • Featured image credit Craig Whitehead.
DES DIETHYLSTILBESTROL RESOURCES

Alterations of Immune Function in the DES Exposed

Diethylstilbestrol Revisited: A Review of the Long-Term Health Effects

1995 Research Abstract

Alterations of Immune Function

Speculation that prenatal exposure to DES may lead to an altered immune status is based on observations that mice exposed perinatally to DES show reversible thymic and splenic atrophy, decreased T-helper cell subpopulations, and impaired natural killer-cell activity. Interestingly, two small case series have shown altered T-cell and natural killer-cell function in women exposed to DES in utero.

In reviewing data from the DESAD cohort, Noller and associates observed that reporting of a lifetime history of autoimmune diseases was increased among persons exposed to DES in utero compared with unexposed controls. Overall, the rate of any autoimmune disease was 28.6 cases per 1000 persons among the exposed daughters and 16.9 cases per 1000 persons among the unexposed women, resulting in a relative prevalence rate of 1.8 cases per 1000 persons (CI, 0.99 to 3.1). Although no individual autoimmune disease was significantly associated with exposure, Hashimoto thyroiditis was reported by 10 of the 1711 women exposed to DES compared with 1 of 922 controls. No other clinical manifestations of immune dysfunction have been established. On the basis of the results of animal studies, however, Blair has hypothesized that immune dysfunction in exposed offspring may only become clinically manifest with aging.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Reductions in fertility in DES sons and daughters

Diethylstilbestrol Revisited: A Review of the Long-Term Health Effects

1995 Research Abstract

DES Sons

Some investigators have reported abnormalities of the urogenital system in DES sons, whereas others have found no increase in such abnormalities compared with men who were not exposed to DES. Gill and coworkers examined 308 men exposed to DES and 307 men receiving placebo who were traced from Dieckmann and colleagues’ cohort and found that the prevalence of epididymal cysts and hypotrophic testes was four times greater among exposed men. In men with testicular hypoplasia, cryptorchidism was observed in 65% (17 of 26) of men exposed to DES compared with 17% (1 of 6) of controls. No significant differences were found in mean circulating follicle-stimulating hormone, luteinizing hormone, or testosterone levels in the two groups. Spermatozoa were analyzed in 134 men (44%) exposed to DES and in 84 men (27%) who received placebo. The average sperm density of the group exposed to DES was lower than that of the placebo group (91 sperm cells X 106 /mL compared with 115 sperm cells X 106 /mL; P = 0.05). Semen quality was compared using the average Eliasson score, a scoring system that assesses sperm concentration, percentage of motile sperm, motility, and morphology. A score of 1 is classified as normal; a score of 5 to 10 is classified as pathologic; and a score of greater than 10 is classified as severely pathologic. The average Eliasson score was higher in the group exposed to DES than in the group exposed to placebo (4.9 compared with 2.5; P = 0.01); more men exposed to DES than controls had severe semen pathologic disorders (an Eliasson score > 10) (24 of 134 men exposed to DES [18%] compared with 7 of 87 controls [8%]; P = 0.05). In contrast, a study done by the Mayo Clinic found no significant differences between men who were and were not exposed to DES in the proportion of testicular or penile anomalies, sperm density or Eliasson score, or the number of pregnancies attained by their wives. These conflicting results may be related to differences in the maternal DES dose levels, heterogeneous hormone (non-DES) exposures, or different methods of recruiting study participants in the reported studies.

DES Daughters

Developmental abnormalities in the female reproductive tract frequently occur after DES exposure. Among DESAD participants at the Baylor College of Medicine who were exposed to DES, 50 of 282 (18%) were found to have gross anatomical changes of the cervix (absent pars vaginalis, coxcomb, hypoplastic cervix collar, or pseudopolyp). Among a subgroup of DESAD participants recruited for a fertility study, 154 of 293 (53%) were found to have abnormal hysterosalpingograms. These abnormalities included T-shaped and hypoplastic uteri; constriction of the upper, middle, or cornual regions; and irregular uterine margins. Data from the Dieckmann and colleagues’ cohort have consistently shown reductions in fertility in DES daughters. On the basis of data analyzed until 1986, 33% of the exposed women compared with 14% of the unexposed women reported primary infertility. Secondary infertility was also reported significantly more often among the exposed women. Vaginal epithelial changes and cervicovaginal ridges were found more often among the exposed women with primary infertility. In contrast, an early analysis of data from the DESAD cohort found that exposed and unexposed daughters were similar in the number achieving pregnancy, the total number of pregnancies, and age at first pregnancy. However, these women may have been studied too early in their reproductive life span to detect major differences in fertility. Kaufman and associates found no difference in the proportion of women with normal and abnormal hysterosalpingograms who had difficulty with conception, suggesting that structural abnormalities of the uterus alone did not account for failure to conceive. Some clinical studies and case reports have suggested that hormonal changes in DES daughters occur, including elevated testosterone and prolactin levels. However, a prospective cohort study suggested that although in utero DES exposure was related to a reduction in the duration and amount of menstrual bleeding, exposure did not affect cycle length and variability of cycle length. This suggests that gross endocrine function was not disturbed. Failure of implantation and alterations in ovarian steroidogenesis have also been postulated as possible causes of infertility in these women. Once pregnancy is achieved, DES daughters are at high risk for an unfavorable pregnancy outcome. In a review of English-language articles, Swan estimated that, overall, DES daughters are 8.6 times more likely to have an ectopic pregnancy, 1.8 times more likely to have a miscarriage, and 4.7 times more likely to have a premature birth than unexposed women. Among women with an abnormality of the cervix, vagina, or uterus, the relative risks for ectopic pregnancy, miscarriage, and premature birth are even higher (13.5, 2.6, and 9.6, respectively).

Sources

DES DIETHYLSTILBESTROL RESOURCES