Endocrine disruptor compounds and their role in the developmental programming of the reproductive axis

DES sons show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality

2007 Study Abstract

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 It was implicated in urogenital abnormalities in children exposed in utero and was withdrawn from the market.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, NCBI PubMed PMID: 17569302, 2007 Jan-Feb.
  • Featured image credit Fabian Grohs.

Risk factors for hypospadias

The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias

2007 Study Abstract

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents.

Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias.

A strong indication for an increased risk of hypospadias was found among boys whose mothers were exposed to DES in utero – ‘DES-daughters’ – an association reported in a previous article by our group. In 2002, Klip et al. reported the prevalence ratio for hypospadias in sons of DES-daughters to be 21.3 (95%CI: 6.5–70.1), which was the first suggestion of a transgenerational effect of DES in humans. However, the association between intrauterine DES exposure and hypospadias was assessed in a cohort of women with fertility problems, who do not reflect DES-daughters in general. According to our findings, the excess risk of hypospadias appears to be of a much smaller magnitude. This may be explained by the differences in study design, and in the study population in particular, and probably results in a more valid risk estimate that is concordant with findings from a recent study in France. It is possible that DES-related pathology of reproductive structures in DES-daughters interferes with normal fetal development during pregnancy, but other explanations have been suggested as well.

We found no indication that DES-sons ‘transmit’ a predisposition to hypospadias to their sons. Our results also point towards an association between paternal subfertility and hypospadias.



Update on cryptorchidism : endocrine, environmental and therapeutic aspects

Journal of Endocrinological Investigation, June 2003


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 suspected 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.


  • Update on cryptorchidism: endocrine, environmental and therapeutic aspects NCBI PubMed PMID: 12952375, 2003 Jun.
  • Featured image credit Ehowcdn.com.

    Environmental Estrogens Linked to Reproductive Abnormalities, Cancer

    DES as a model, 1994


    … Endocrinologists regard the effects of DES on human offspring as a model for the problems that other estrogen mimics might cause in humans. … … Loved A. Jones, director of experimental gynecology and endocrinology at the University of Texas M.D. Anderson Cancer Center, tells C&EN,

    “we are jut starting to begin to realize the additional problems the offspring of the women who took DES face.”

    The incidence of abnormalities in the reproductive tracts of the daughters and sons of DES-treated women is much greater than the incidence of cancer.

    • The female offspring have high rates of T-shaped uteri and of other structural abnormalities in the reproductive tract that tend to make them sterile.
    • The male offspring show increased incidence of abnormalities in the scrotum, increased incidence of undescended testicles and malformed urethras, and decreased sperm counts, and they also may have an increased risk of testicular cancer and prostate problems.


    • Read Bette Hileman‘s full paper Environmental Estrogens Linked to Reproductive Abnormalities, Cancer on infohouse, JANUARY 31,1994.
    • Estrogenic chemicals eh%it a variety of molecular structures, featured image credit Bette Hileman, C&EN.

    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.


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

    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.



    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.



    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.


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

    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.


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

    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.


    • Urogenital tract abnormalities in sons of women treated with diethylstilbestrol, NCBI PubMed PMID: 972792, 1976.