In 1971, the US Food and Drug Administration contraindicated its use in pregnancy when DES was associated with the development of vaginal clear cell adenocarcinoma (CCA) in daughters exposed in utero.
In daughters whose mothers took DES during pregnancy, the drug has been associated with congenital malformations of the reproductive tract, fertility problems, a possible increased risk of cervical carcinoma in situ, and a presumed lifetime risk of vaginal and cervical CCA.
DES mothers have an increased risk of breast cancer (RR = 1.3).
DES sons have an increased prevalence of urogenital anomalies, and a possible increased risk of testicular cancer.
DES exposure and the aging woman: mothers and daughters, Current women’s health reports, NCBI PubMed PMID: 12215312, 2002 Oct.
In utero DES exposure increases the risk of testicular dysgenesis syndrome ; linked to cryptorchidism, hypospadias, poor semen quality and testicular cancer
2012 Study Abstract
Prospective clinical studies have suggested that the rate of congenital cryptorchidism has increased since the 1950s. It has been hypothesized that this may be related to environmental factors.
Testicular descent occurs in two phases controlled by Leydig cell-derived hormones insulin-like peptide 3 (INSL3) and testosterone. Disorders in fetal androgen production/action or suppression of Insl3 are mechanisms causing cryptorchidism in rodents.
Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study
BACKGROUND Diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women during the 1940s70s, has been shown to cause reproductive problems in the daughters. Studies of prenatally-exposed males have yielded conflicting results.
METHODS In data from a collaborative follow-up of three U.S. cohorts of DES-exposed sons, we examined the relation of prenatal DES exposure to occurrence of male urogenital abnormalities. Exposure status was determined through review of prenatal records. Mailed questionnaires (1994, 1997, 2001) asked about specified abnormalities of the urogenital tract. Risk ratios (RR) were estimated by Cox regression with constant time at risk and control for year of birth.
RESULTS Prenatal DES exposure was not associated with varicocele, structural abnormalities of the penis, urethral stenosis, benign prostatic hypertrophy, or inflammation/infection of the prostate, urethra, or epididymus. However, RRs were 1.9 (95% confidence interval 1.13.4) for cryptorchidism, 2.5 (1.54.3) for epididymal cyst, and 2.4 (1.54.4) for testicular inflammation/infection. Stronger associations were observed for DES exposure that began before the 11th week of pregnancy: RRs were 2.9 (1.65.2) for cryptorchidism, 3.5 (2.06.0) for epididymal cyst, and 3.0 (1.75.4) for inflammation/infection of testes.
CONCLUSION These results indicate that prenatal exposure to DES increases risk of male urogenital abnormalities and that the association is strongest for exposure that occurs early in gestation. The findings support the hypothesis that endocrine disrupting chemicals may be a cause of the increased prevalence of cryptorchidism that has been seen in recent years.
Full study (free access) : Urogenital abnormalities in men exposed to diethylstilbestrol in utero: a cohort study, Environmental health : a global access science source, NCBI PubMed, PMC2739506, 2009 Aug.
Prenatal exposure to diaethylstilbestrol in the rat inhibits transabdominal testicular descent with involvement of the INSL3/LGR8 system and HOXA10
2009 Study Abstract
BACKGROUND Prenatal exposure to diaethylstilbestrol (DES) has been found to lead to intra-abdominal cryptorchidism, but the mechanism is still not completely clear. This study investigated the roles of the INSL3/LGR8 system and HOXA10 in DES-induced intra-abdominal cryptorchidism (DIIAC). The effect of DES on steroidogenic factor-1 (SF-1), that has been reported to control transcription of insulin-like factor 3 (INSL3), was also investigated.
METHODS Fifty pregnant female SD rats at embryonic day 13.5 (E13.5) were randomly assigned to five groups that received a subcutaneous injections of dimethyl sulfoxide (control), 2.5 mg/kg, 5 mg/kg, 10 mg/kg, or 20 mg/kg of DES. Male offspring were sacrificed at E19.5, and fetal mortality and the degree of transabdominal testicular ascent (DTA) were determined under a stereomicroscope. The mRNA expression of INSL3 and SF-1 in the testis and leucine rich repeat-containing G protein-coupled receptors 8 (LGR8) and homeobox-A10 (HOXA10) in the gubernaculum were determined by RT-PCR. The expression of INSL3 protein was determined by Western blotting.
RESULTS Higher fetal mortality and DTA were induced by DES in a dose-dependent manner (P < 0.01). Compared with the control group, the expression of INSL3 and SF-1 mRNA were down-regulated in a dose-dependent manner (P < 0.01), as was INSL3 protein; HOXA10 in the 2.5 mg/kg group and LGR8 mRNA in the 2.5 mg/kg and 5 mg/kg groups were not significantly different (P > 0.05); HOXA10 mRNA in groups C, D, and E decreased significantly and LGR8 mRNA levels in groups D and E increased significantly (P < 0.05, P < 0.01, respectively).
CONCLUSIONS DES can inhibit transabdominal testicular descent in a dose-dependent manner via down-regulating the expression of INSL3, which is induced by down-regulating the expression of SF-1. HOXA10 may not be involved in DES induced intra-abdominal cryptorchidism at 2.5 mg/kg, but is involved at 5, 10 and 20 mg/kg. LGR8 may not be responsible for DES-induced transabdominal testicular maldescent.
Full study (free access) : Prenatal exposure to diaethylstilbestrol in the rat inhibits transabdominal testicular descent with involvement of the INSL3/LGR8 system and HOXA10, Chinese medical journal, NCBI PubMed, PMID: 19493424, 2009 Apr.
Background Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive.
Objectives We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored.
Results We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer.
Conclusions The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.
Full study (free access) : Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis, Environmental Health Perspectives, PMC2235228, 2008 Feb.
Different perturbations during fetal and postnatal development unleash endocrine adaptations that permanently alter metabolism, increasing the susceptibility to develop later disease, process known as “developmental programming.”
Endocrine disruptor compounds (EDC) are widely spread in the environment and display estrogenic, anti-estrogenic or anti-androgenic activity; they are lipophilic and stored for long periods in the adipose tissue. Maternal exposure to EDC during pregnancy and lactation produces the exposure of the fetus and neonate through placenta and breast milk. Epidemiological and experimental studies have demonstrated reproductive alterations as a consequence of intrauterine and/or neonatal exposure to EDC.
Diethystilbestrol (DES) is the best documented compound, this synthetic estrogen was administered to pregnant women in the 1950s and 1960s to prevent miscarriage. It was implicated in urogenital abnormalities in children exposed in utero and was withdrawn from the market.
The “DES daughters” are women with high incidence of vaginal hypoplasia, spontaneous abortion, premature delivery, uterine malformation, menstrual abnormalities and low fertility.
The “DES sons” show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality.
This entity is also associated wtih fetal exposure to anti-androgens as flutamide.
The effects on the reproductive axis depend on the stage of development and the window of exposure, as well as the dose and the compound.
The wide distribution of EDC into the environment affects both human health and ecosystems in general, the study of their mechanisms of action is extremely important currently.
Endocrine disruptor compounds and their role in the developmental programming of the reproductive axis, Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, NCBI PubMed, PMID: 17569302, 2007 Jan-Feb.
Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies. Reports of an increase in male reproductive disorders in several countries led to the hypothesis that estrogens during fetal life may cause reduced sperm counts, cryptorchidism, hypospadias and testicular cancer. So far the hypothesis is based on animal studies and reports from the wild life.
We systematically searched the epidemiological literature for evidence linking indicators of prenatal serum levels of maternal estrogens with sperm density, hypospadias, cryptorchidism and testicular cancer in humans. Indicators of fetal estrogen exposure included direct measurements, recorded intake of hormones (diethylstilbestrol (DES), oral contraceptives (OCs) and estrogens), pregnancy conditions with known deviant estrogen level as for instance twin pregnancies and some environmental exposures.
We identified four studies focussing on estrogens given prenatally, mainly DES studies.
Physical examination of men from Dieckman’s cohort revealed a higher number of men with hypoplastic testes among exposed [OR = 4.36 (1.9–11.4) calculated by the author] and cryptorchidism was more prevalent among exposed men with hypoplastic testes, but data on the occurrence of cryptorchidism among all men are not given.
Vessey et al. found an equal frequency of cryptorchidism in the DES and the placebo group among offspring from Sweyer and Law’s DES cohort from 1954. Selection bias in this study is less likely since information was obtained from GP’s, blinded for exposure status. The time of entry and the total dose of DES were similar in these two DES studies (11.6 and 11.5 g, respectively).
Two case-referent studies using data on estrogen prescription from medical records found increased risk of cryptorchidism [RR 1.9 (95%CI: 0.5–6.6)  and 2.8 (95% CI: 0.9–8.8)…
Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies, Reproductive toxicology, NCBI PubMed, PMID: 16005180, 2006 Jan.
Cryptorchidism is the most frequent developmental abnormality in boys, present in more than 1% of infants above three months of age. It is associated with an increased risk of infertility and testicular cancer. The etiological quest is often disappointing, except in bilateral cases or associated malformations. Recent focus is on genetic and environmental aspects. Animal models have revealed the role of genes encoding for proteins implicated in testicular migration (InsI3, Hoxa 10), but in humans results are less convincing. While some degree of endogenous hormonal abnormality is suspeeted in some patients, the endocrine disruptor hypothesis is also tested. It is unclear whether the incidence of cryptorchidism has really increased, or whether there is only a better screening for this condition. However, other male reproductive problems, such as subfertility, hypospadias and testicular cancer seem on the rise. This secular trend suggests the possible in utero impact of hormonally active environmental factors, such as pesticides with estrogenic or antiandrogenic effect, and is consistent with the increased risk of cryptorchidism observed in the sons of mothers exposed to diethylstilbestrol during pregnancy. From a therapeutic point of view, there is an agreement that the correction of cryptorchidism is needed, but there is controversy on the best medical and/or surgical approach and on the optimal timing. There is a recent trend in proposing early therapeutic intervention, before 1 yr of age, in the hope of improving fertility; however, there is no proof that such a strategy can reduce the risk of testicular cancer.
2003 Study Abstract
” …Prenatal exposure to diethylstilbestrol (DES) is a well known factor causing cryptorchidism in different animal models and in man. In addition, 100 g/kg/day of DES given to pregnant mice from day 9 to 17 prevent normal gubernaculum development and is associated with a three-fold decrease in Insl3 mRNA expression, with no change in steroidogenic factor 1 (SF1) expression. These results are similar to those obtained with β-estradiol, α-estradiol and DES also in mice. …
… In an American case-control study, the relative risk of cryptorchidism was 2.8 in boys whose mothers were treated with estrogens (DES, estradiol, or a contraceptive pill) during pregnancy. Regarding the risk linked to DES, results vary from one study to another; Gill reports a frequency of 8% compared to 1% in controls. …”
Update on cryptorchidism: endocrine, environmental and therapeutic aspects, Journal of endocrinological investigation, NCBI PubMed, PMID: 12952375, 2003 Jun.
For three decades, we have known that estrogens alter the development of the mammalian reproductive system in predictable ways.
In mice exposed prenatally to diethylstilbestrol (DES) or other estrogens, the male offspring exhibit structural malformations including cryptorchidism, epididymal cysts and retained Mullerian ducts.
The estrogen-associated alterations in the genital tract phenotype can be usefully considered as a model called Developmental Estrogenization Syndrome. While estrogen treatment during critical periods of morphogenesis of the male reproductive system has been associated with these changes, the mechanisms at the molecular level are still being discovered. Parallel findings on the hormones involved in Mullerian duct regression and testicular descent have helped guide research on the mechanisms of developmental estrogenization of the male.
Cellular localization of molecular signals associated with key steps in genital tract development, use of mice with gene disruption, and knowledge of the mechanisms underlying persistent changes in gene expression are beginning to provide a blue print for both the physiological role and pathological effects of estrogens in reproductive tract development.
Since many of the same biological principles underlie genital tract morphogenesis in mammals, one may expect some of the same changes in males of other species exposed to estrogen during the appropriate developmental periods.
From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed, PMID: 11469497, 2001 Apr.
About DES Sons, European Beckman Conference, Clinical chemistry, 1995
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.
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. McLachlan reported similar abnormalities in the male offspring of mice exposed to DES. Dieckmann et al. performed a double-blind placebo-controlled study in the 1950s. DES was given to 840 women between the 7th and 35th gestation week. Of the offspring of these mothers, 308 men were exposed to DES and 307 men were exposed to placebo; 31.5% and 7.8%, respectively, had abnormal reproductive tracts. Whitehead and Leiter reported genital abnormalities in 29 of 48 DES-exposed men. These data are convincing and cannot be explained by differences in confounding factors.
Gill et al. studied semen samples from 88 men exposed to DES and 85 men exposed to placebo who were offspring of the Dieckmann cohort. Sperm concentration was much lower among men exposed to DES. There was no difference in semen volume, whereas the total sperm count, the sperm motility grade, the total number of motile sperm, the percentage of sperm with normal morphology, and the quality score were all statistically lower in men exposed to DES. In a later study of the same men, only semen concentration differed in the two groups. Similar findings were reported in another study including 17 men exposed to DES and 12 controlsubjects.
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.
Read the full text (free access) : Do environmental estrogens contribute to the decline in male reproductive health?, Clinical chemistry, NCBI PubMed, PMID: 7497651, 1995.