Adenocarcinoma of the rete testis

Diethylstilbestrol-induced lesions of the mouse rete testis, 1986


The induction of a lesion resembling carcinoma in the rete testis of male mice provides a useful model for study of the pathogenesis of hormonally induced lesions of the testis and possibly other developmental neoplasms.

The model should be of further use in alerting the clinician to the possibility of rete testis changes in the DES-exposed patient. Also, the extreme rarity of this lesion in both experimental animals and humans has made study of the general cytologic features of this neoplasm difficult; studies of the pathogenesis of the lesion are unknown.

The relatively large number of hyperplasias and adenocarcinomas of the rete testes in DES-treated mice provides new possibilities for such investigations.

While no reports of rete hyperplasia or adenocarcinoma in humans have been attributed to prenatal exposure to DES, three cases of seminoma have been described in prenatally DES-exposed men, suggesting an association of prenatal DES treatment with subsequent development of testicular tumors (1979 study and 1983 study).

A recent report states that rete adenocarcinoma can be misdiagnosed as seminoma, and seminoma must be ruled out before a diagnosis of rete adenocarcinoma can be made. Thus, caution should be taken in diagnosing any testicular lesions associated with prenatal DES exposure.


  • Adenocarcinoma of the rete testis. Diethylstilbestrol-induced lesions of the mouse rete testis, The American journal of pathology, NCBI PubMed PMC1888460, 1986 Dec.
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Testicular cancer case in a DES Son

Seminoma and Epididymal Cysts in a Young Man With Known Diethylstilbestrol Exposure In Utero, 1983


Exposure of women to diethylstilbestrol in utero has been linked to the development of adenosis and clear cell adenocarcinoma of the vagina.

A variety of male genital tract abnormalities, including epididymal cysts, maldescended testes, hypoplastic testes, varicoceles, and spermatozoal defects, occur with increased incidence in men exposed to diethylstilbestrol in utero.

Testicular tumors occur in adult mice given diethylstilbestrol, and preneoplastic testicular changes have been described in mice exposed prenatally to diethylstilbestrol. The possibility of carcinogenesis has been suggested in diethylstilbestrol-exposed males, but, to our knowledge, until now no case of testicular cancer has been documented in a person exposed in utero to diethylstilbestrol.

We report a seminoma and ipsilateral epididymal cysts in a 28-year-old man with known diethylstilbestrol exposure.



Reproductive tract lesions in male mice exposed prenatally to DES

DES Sons should be further evaluated for latent alterations of the genital tract, 1975


Sixty percent of the male offspring from pregnant mice treated with diethylstilbestrol during gestation were sterile. The affected animals had gonadal changes which included intra-abdominal or fibrotic testes, or both. Additionally, nodular masses in the ampullary region of the reproductive tract were observed in 6 of 24 animals; one of these appeared to be preneoplastic.

… “Eight animals had epididymal cysts; six of these also had testicular lesions.” …

… “In light of these results in rodents, the incidence of cryptorchidism in young boys whose mothers had been treated with DES during gestation may be of clinical importance. Obviously, these offspring should be further evaluated for latent alterations of the genital tract, since changes in the adult male human reproductive tract similar to those we observed in the mouse might be dismissed as secondary to inflammation. Some of these lesions could be important causes of infertility even when viable sperm are produced.” …


  • Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol, Science, NCBI PubMed, PMID: 242076, 1975 Dec 5.
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Prenatal DES treatment and subsequent development of testicular tumors

Lesions of the rete testis in mice exposed prenatally to diethylstilbestrol, 1985


Adenocarcinoma of the rete testis is an exceptionally rare and malignant testicular neoplasm.

Although treatment of pregnant women with diethylstilbestrol (DES) results in reproductive tract abnormalities in their male offspring, increased incidence of testicular tumors has not been verified. However, recently three cases of seminoma have been described in men prenatally exposed to DES, suggesting an association of prenatal DES treatment and the subsequent development of testicular tumors.

This report describes the treatment of outbred pregnant CD-1 mice with DES (100 micrograms/kg) on Days 9 through 16 of gestation and its effects on their male offspring.

In addition to nonmalignant abnormalities such as retained testes which have been reported in men exposed prenatally to DES, lesions resembling adenocarcinoma of the rete testis were seen in prenatally DES-treated mice at 10 to 18 mo of age (11 of 233; 5%). No comparable lesions were seen in 96 age-matched control male mice.

These results suggest an association of prenatal DES exposure and the subsequent development of testicular lesions in the rete testis of mice.


  • Lesions of the rete testis in mice exposed prenatally to diethylstilbestrol, Cancer research, NCBI PubMed PMID: 4027990, 1985 Oct.
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Testicular dysgenesis syndrome

Possible role of endocrine disrupters, 2006


The testicular dysgenesis syndrome (TDS) hypothesis proposes that the four conditions cryptorchidism, hypospadias, impaired spermatogenesis and testis cancer may all be manifestations of disturbed prenatal testicular development. The TDS hypothesis is based on epidemiological, clinical and molecular studies, all suggestive of an interrelation between the different symptoms. The aetiology of TDS is suspected to be related to genetic and/or environmental factors, including endocrine disrupters.

…Important insight into the effect of in utero exposure to compounds with oestrogenic activity in humans comes from the former widespread use of diethylstilboestrol (DES), a synthetic oestrogen. …
… The effect of DES on sperm concentration and risk of development of testis cancer is unclear, as some studies have found a reduced sperm concentration in men exposed to DES in utero, whereas others have not. For testis cancer, only a slight increase in risk has been cautiously suggested (1996), (2001). …

Few human studies have found associations/correlations between endocrine disrupters, including phthalates, and the different TDS components. However, for ethical reasons, evidence of a causal relationship between prenatal exposure and TDS is inherently difficult to establish in human studies, rendering the recently developed animal TDS model an important tool for investigating the pathogenesis of TDS. Clinically, the most common manifestation of TDS is probably a reduced sperm concentration, whereas the more severe form may include a high risk of testis cancer. Clinicians should be aware of the interconnection between the different features of TDS, and inclusion of a programme for early detection of testis cancer in the management of infertile men with poor semen quality is recommended.


  • Testicular dysgenesis syndrome: possible role of endocrine disrupters, Best practice & research. Clinical endocrinology & metabolism, NCBI PubMed PMID: 16522521, 2006 Mar.

Cancer risk in men exposed in utero to diethylstilbestrol

DES Sons’ (increased) cancer risk, 2001


An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up.

A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided.

Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation.

To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.


  • Cancer risk in men exposed in utero to diethylstilbestrol, Journal of the National Cancer Institute, NCBI PubMed PMID: 11287449, 2001 Apr.
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DES-induced Testis Cancer

Male reproductive health and environmental xenoestrogens, 1996


Incidence of Testicular Cancer

Testicular cancer is now the most common malignancy of young men in many countries; and although it is still rare compared to the malignant diseases most prevalent in old age, the lifetime risk of developing testicular cancer now approaches 1% in a country such as Denmark. The incidence of testicular cancer has increased for several decades.

Risk factors for testicular cancer have been analyzed in several case-control studies. Estrogen treatment of mothers whose sons have developed testicular cancer has remained an equivocal risk factor. It is unfortunate that there are no prospective studies yet concerning the testicular cancer risk among males exposed to DES.

The effect of DES on risk of development of testis cancer seems to be unclear; only a slight increase in risk has been cautiously suggested.

Occurrence of Abnormalities in the Reproductive System of the Sons of Women Exposed to Diethylstilbestrol during Pregnancy


Exposure to DES during pregnancy results in an increased risk for several male reproductive disorders, such as cryptorchidism, urethral abnormalities, epididymal cysts, and testicular hypoplasia. In addition, the semen quality of DES sons is worse than that of controls. Incidence of testicular cancer is approximately doubled among DES sons compared to the general population, but whether this represents a true increase of the cancer risk is equivocal.

Effects of Synthetic Estrogens on the Testis in Animal Models


Diethylstilbestrol treatment of experimental animals in utero results in increased incidence of cryptorchidism; urethral abnormalities; testicular hypoplasia; poor semen quality; and infertility, abnormalities in accessory sex organs, rete testis adenocarcinoma, interstitial cell hyperplasia, and tumors. Thus, the outcome of DES exposure of experimental animals is highly analogous to the findings in humans.


  • Full study (free access) : Male reproductive health and environmental xenoestrogens, Environmental Health Perspectives, NCBI PubMed PMC1469672, 1996 Aug.
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DES immunotoxicity

The comparative immunotoxicity of five selected compounds following developmental or adult exposure, 2006

Study Abstract

It is well established that human diseases associated with abnormal immune function, including some common infectious diseases and asthma, are considerably more prevalent at younger ages. Although not established absolutely, it is generally believed that development constitutes a period of increased immune system susceptibility to xenobiotics, since adverse effects may occur at lower doses and/or immunomodulation may be more persistent, thus increasing the relative risk of xenobiotic exposure to the immunologically immature organism.

To address this issue, a brief overview of immune maturation in humans is provided to demonstrate that functional immaturity alone predisposes the young to infection. Age-dependent differences in the immunotoxic effects of five diverse compounds, diethylstilbestrol (DES), diazepam (DZP), lead (Pb), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and tributyltin oxide (TBTO), which have undergone adult and developmental immunotoxicity testing in rodents, are then reviewed, as are human data when available. For all five chemicals, the developing immune system was found to be at greater risk than that of the adult, either because lower doses produced immunotoxicity, adverse effects were more persistent, or both.

Diethylstilbestrol immunotoxicity


Between 5 and 10 million pregnant women were given diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen, between 1938 and 1971 to prevent premature delivery or pregnancy loss. Its use was terminated when a rare form of reproductive system cancer was found in female offspring of DES-exposed mothers. Male and female reproductive systems malformations have been reported in children of treated women, as has anecdotal evidence of immune system dysfunction. DES was also used to increase weight gain in livestock, although this use is no longer permitted in most countries.

Effects on the Immune System in Humans

Both female and male children of DES-exposed mothers report a higher incidence of autoimmune diseases and asthma (Baird et al., 1996). In general, these diseases are considered to be the result of inappropriate immune system responses, or possible loss of homeostatic control, instead of immune system suppression.

Effects on the Immune System in Rodents

In utero exposure
Luster et al. (1978b) reported that a single injection of 0.1 mg DES/kg body weight on gestational day (GD) 16 did not affect the antibody response to the T-cell-dependent antigen, sheep red blood cells (SRBC), when evaluated in 7-wk-old male and female offspring of Swiss-Webster mice. The T-independent IgM response of female offspring to bacterial lipopolysaccharide (LPS) was suppressed by DES, but was similar to control responses when females were
immunized for a second time. In marked contrast, the male offspring response to LPS immunization was enhanced after both first and second immunizations, an effect attributed to the stimulating effect of estrogen on the antibody response to LPS. Delayed-type hypersensitivity responses (DTH) were suppressed in female, but not in male, offspring, even though thymus weights and T-cell responses to polyclonal stimulation were suppressed in both genders (Luster et al., 1979). Further studies suggest that DES targets early precursors of T lymphocytes in the fetal liver, accounting for thymic atrophy and suppression of DTH (Holladay et al., 1993), but not for defects in T-independent responses to LPS of female offspring.

Neonatal exposure
Nonspecific T- and B-cell proliferation was reported to be suppressed in 6-wk-old female NMRI mice given 5 μg DES/d (roughly 2.2 mg DES/kg/d) over postnatal days (PND) 1–5 (Kalland et al., 1979); suppression was still evident at 17 mo of age (normal life span ~24 mo). It is noteworthy that neither estradiol nor corticosterone exposure over PND 1–5 produced long-term suppression, and that lymphocyte proliferation was comparable to control values at 6 wk of age in females exposed to DES over PND 6–10. Lower doses (approximately 4.4, 44, or 440 μg/kg/ d) had no effect on proliferative response. The 5-μg DES/d exposure regimen also decreased NK cell activity in 6- to 8-wk-old female inbred C57Bl/6 (75%↓) and BALB/c (53%↓) mice and in outbred NMRI (28%↓) mice (Kalland, 1980a). NMRI or AKR/J female mice, exposed to 5 μg DES/d over PND 1–5, were also more likely to develop tumors after low dose injection of a known carcinogen (Kalland & Forsberg, 1981). A subsequent paper (Kalland, 1984) reported that, on a per cell basis, NK cells from DES mice were as active as cells from the control group, but that exposure reduced the number of NK cell precursors in the bone marrow. In other words, NK cells from experimental animals were as efficient as those from controls, but a deficiency in NK cell precursors produced functional suppression of NK activity at the whole animal level. The same postnatal exposure regimen (Kalland, 1980a) reduced the T-lymphocyte-dependent antibody response to SRBC by ~60%, and the T-independent response to bacterial LPS by ~40% when examined in 16- to 18-wk-old NMRI mice. Suppression of the T-dependent response was reportedly due to a defect in T-helper cells. DTH responses were likewise suppressed in 6- and 9-mo-old NMRI females exposed to approximately 2.2 mg/kg/d over PND 1–5 (Kalland & Forsberg, 1978). Kalland (1980b) also reported a persistent (at least 6.5 mo postpartum) decrease in the proportion of T cells in the spleens of DES-exposed mice.

Adult exposure
Luster et al. (1980) reported suppression of the antibody response to SRBC or LPS, and the DTH to keyhole limpet hemocyanin (KLH), in adult female mice exposed to 2 or 8 mg DES/kg/d × 5 d. The DTH was decreased in mice dosed with DES after, but not before, sensitization with KLH, suggesting that the suppressive effects of DES on DTH were not persistent. Using the same exposure regimen, resistance to bacterial or parasite infection was decreased and tumor incidence in animals challenged with tumor cells was increased at ≥2 mg DES/kg/d (Dean et al., 1980). T-cell-mediated resistance to a nematode infection was suppressed by 5 d of exposure to 0.2 mg DES/kg/d if exposure began on the day of infection; if exposure commenced 5 d before or 3 or 8 d after infection, decreased resistance was only observed at the highest dose (8 mg/kg/d) (Luebke et al., 1984).

Mode(s) of Action

DES is a potent estrogen, and likely affects immune function via the estrogen receptor (ER). Evidence includes similar effects of known estrogens (17β-estradiol) on the immune system of adult and neonatal rodents, blockade of certain immunotoxic effects by pharmacologic antagonism of the ER (Luster et al., 1984), and antagonism of estrogen-mediated immune system effects in mice lacking ERα (Staples et al., 1999). DES appears to target precursor cells in the bone marrow (adults and neonates) and fetal liver (neonates), producing a long-lasting or perhaps permanent reduction in numbers of precursor cells. This defect explains a significant portion of long-lived immunosuppressive effects (e.g., Kalland’s 1984 paper on suppressed NK activity), although the effects of adult exposure also includes damage to the thymic epithelium (Luster et al., 1984). The underlying mechanism of long-term suppression following exposure of the developing immune system to DES is not known, but the default assumption is that a critical cell population is lost to developmental exposure; either this purported population is refractory to estrogen-mediated ablation in adults or repair and recovery mechanisms are present in adults that are lacking in the developing immune system.

Data Gaps

There has been no systematic evaluation of persistent DES-mediated immunosuppression in adult animals. Dose-response data are not available for many of the of the developmental exposure studies that revealed persistent effects.


In utero exposure to 0.1 mg DES/kg during the last trimester of pregnancy suppressed T-cell- and B-cell-mediated responses only in female offspring. The gender dependence of effects was remarkable in that T-independent responses in male offspring were enhanced, yet suppressed in females. Exposure during gestation produced effects that persisted into the equivalent of young adulthood. In neonates there appears to be a critical developmental window during PND 1–5, during which exposure to DES produces persistent immune system defects that last well into adulthood or persist for most of the normal life span of the mouse. These effects are among the most persistent reported for any chemical. In adults, immunosuppression occurs at doses similar to those that produce immunotoxicity in developing animals. However, the immune system-related endpoints that have been evaluated over time in exposed adult animals (bone marrow cellularity, thymus weights) recover relatively quickly (Forsberg, 1984). In adults, recovery may occur so quickly that suppression of cell function or resistance to infection may require ongoing exposure to maintain suppression.


Immunotoxicity has been reported at similar doses when exposure occurs during late gestation, early postpartum, or as adults. However, the distinguishing feature of developmental exposure to DES is the persistence of effects, some of which are still apparent in very old mice. In contrast, immune system-related endpoints that have been evaluated (bone marrow cellularity, thymus, weights) suggest that adults recover relatively quickly (Forsberg, 1984).


  • The comparative immunotoxicity of five selected compounds following developmental or adult exposure, Journal of toxicology and environmental health. Part B, Critical reviews, NCBI PubMed, PMID: 16393867, 2006 Jan-Feb.
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Prenatal DES exposure linked to Hashimotos thyroiditis

Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and other chronic autoimmune diseases

2006 Study Abstract

Most autoimmune diseases occur more commonly in females and many of these young women wish to become mothers. For pregnancy to proceed successfully immunomodulation and physiological changes preparing the reproductive system need to occur.

Pregnancy occurring in a chronically ill mother who requires medications in order to maintain her own health and who may have already incurred significant organ pathology gives rise to several problems and so four questions arise:

  1. What will be the effect of the pregnancy on the underlying disease?
  2. What will be the effect of the disease on the outcome of pregnancy?
  3. How to manage the disease, just prior to, throughout and immediately after the pregnancy?
  4. The long term fetal and childhood effects of maternal disease and its management.

This paper reviews the current literature pertaining to these questions in patients with systemic lupus erythematosus (SLE) and other chronic rheumatic and autoimmune diseases.


… “Other evidence suggests that the risk of autoimmune disease, particularly Hashimotos thyroiditis, is also increased in individuals exposed to DES in utero.” …


  • Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and other chronic autoimmune diseases, Lupus, NCBI PubMed, PMID: 17153855, 2006.
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DES exposure linked to laterality process disruption

Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship?, 2004


Schizophrenia is a psychiatric disease affecting around 1% of the population, the negative signs of which are correlated with inactivity of the prefrontal dorsolateral cortex, while an increased, more deeply localized, activity in the mesolimbic pathway may explain the positive signs. Several events occurring during pregnancy are likely to be involved in its genesis: hormonal supplementation by diethylstilbestrol, severe maternal denutrition, exposure to influenza virus, repeated psychological stress.

From multicentric studies and meta-analyses in the psychiatric literature, the risk of schizophrenia appears to be multiplied by two if pregnancy is complicated, mainly by diabetes, Rhesus incompatibility, bleeding, preeclampsia, premature rupture of membranes and preterm birth. When delivery is linked to an abnormal presentation or happens via a caesarean birth for acute foetal distress, the time when the first signs of psychosis appear seems to be earlier in adolescence or in early adulthood.

Cerebral imaging of schizophrenic patients shows ventriculomegaly and gray matter reduction, mainly in hippocampal volumes and in the dorsolateral prefrontal cortex. Similar alterations in the neuronal pathways have been experimentally reproduced in rats after repeated prenatal stress and perinatal hypoxia. A region on the distal portion of chromosome 1 has shown evidence for linkage to schizophrenia.

Exposure to diethylstilbestrol (DES) in the second trimester of pregnancy is likely to disrupt the laterality process, leading to an outstanding number of left-handed individuals, be they boys or girls. In the same way data from the literature suggest that people exposed to DES have a higher risk of presenting depressive signs. Nevertheless it may not be the only cause, since it is obvious that the gynecological troubles which required hormonal prescription may have affected the course of pregnancy. Katz et al. reported a higher risk of psychosis after the mother took DES about four cases: DES doses varied from 7 to 12.8 g, but two pregnant women out of four also received progestatives (total dose of 1.950 mg of medroxyprogesterone to 3.600 mg of progesterone).

Therefore, a two factor model seems to be able to explain the onset of schizophrenia in which obstetrical complications may interact with a genetic liability and in which the consequences of hypoxic events may lie on a continuum ranging from cerebral palsy in some children to subtle cognitive and behavioural disturbances in others.


  • Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship?, European journal of obstetrics, gynecology, and reproductive biology, NCBI PubMed, PMID: 15140504, 2004.
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