DES Sons and Cryptorchidism, Testicular Hypoplasia, Semen Abnormalities

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities

1979 Study Abstract

Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls.

Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent).

Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism.

Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent.

Although none of our Diekmann’s lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid.

A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.

Sources

  • Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities, The Journal of urology, NCBI PubMed, PMID: 37351, 1979 Jul.
  • Featured image credit Ian Espinosa.
DES DIETHYLSTILBESTROL RESOURCES

Follow-up study of male and female offspring of DES-treated mothers, 1975

Bibbo’s 1975 study revealed anatomic abnormalities such as epididymal cysts, undescended and hypoplastic testis in males exposed to DES in utero

Abstract

This is a follow-up study of male and female offspring of mothers who were part of a double-blind placebo controlled investigation during the years 1951-1952, originally aimed at determining the usefulness of DES administration in maintaining pregnancy. So far, 84 DES-exposed females, 43 female controls, 42 DES-exposed males and 37 male controls have been examined.

Circumferential ridges of the vagina and cervix were seen in 39% of the DES-exposed females but in none of the controls. Colposcopy revealed vaginal epitheleal changes in 78% of the DES-exposed females 2% of the female controls. Cytology proved to be reliable as a screening test for vaginal epithelial changes in the DES-exposed female. Urine cytology was negative for tumor cells in all patients.

The main abnormal finding in the DES-exposed males was that cysts in the epididymis were detected in 10%. No cases of cancer were observed in either the male or female offspring.

Population Information Program

The original study conducted 22 years earlier at the Chicago Lying-in Hospital attempted to determine the value of diethylstilbestrol (DES) in maintaining pregnancy. The number completing the course of therapy was 840 in the DES group; there were 860 in a control group. Increasing doses were given beginning during the 7th week of pregnancy. The present study was to determine the level of risk of cancer and other anomalies in the female and male offspring of mothers who participated in the study. So far, 84 DES-exposed females, 43 female controls, 43 DES-exposed males, and 37 male controls have been examined.

No cases of cancer have been found. The average age was 22 years. For female patients the medical history, a general physical examination, a gynecological examination, a colposcopic study, and laboratory tests were made. Laboratory tests consisted of cervical, endocervical, and 4 vaginal wall Pap smears, urine cytology, and follicle stimulating hormone and luteinizing hormone determinations. Biopsies were performed when indicated. Progesterone and total estrogens were determined only in patients with irregular menstrual cycles. In male patients, a general physical examination, urologic studies, and laboratory work-up were done. Medical records of all the newborn infants were surveyed and pediatric records examined. No cases of congenital malformations were recorded. Minor differences in menstrual histories and in ability to conceive were noted.

The differences appeared mainly at vaginal examinations. Circumferential ridges in the vagina and cervix were seen in 39% of the exposed females but in none of the controls. Erythroplakia of the cervix was seen in 67% of the exposed and in 53% of the controls. Colposcopic findings in the vagina revealed vaginal epithelial changes in 78% of the DES-exposed females and 2% of female controls. Iodine negative areas in the vagina were noted in 78% of the exposed females compared with 2% of the unexposed females. Iodine negative areas on the cervix were seen in 74% of the exposed and 58% of the unexposed. All dysplastic lesions were confirmed by histology. The cytology was negative in all.

In the males abnormal findings were noted mainly in the DES-exposed group. An undersized penis was noted in 2, small testes in 2, varicocele in 1, and epididymal cysts in 4. Urine cy tology and prostatic fluid cytology did not reveal unusual findings. A more detailed analysis of findings will follow when material is larger and older.

Sources

  • Follow-up study of male and female offspring of DES-treated mothers a preliminary report, The Journal of reproductive medicine, NCBI PubMed, PMID: 1171234, 1975 Jul.
  • Featured image credit Oli Metcalfe.
DES DIETHYLSTILBESTROL RESOURCES

Transplacental effects of diethylstilbestrol in mice

Lower reproductive capacities observed in both females and males

Abstract

The effect of prenatal exposure to DES on the postnatal development of male and female genital tract function was studied. We investigated the placental transfer of [3H]- or [14C]-radiolabeled DES in pregnant mice.

DES-associated radioactivity in the fetal plasma approximated maternal plasma one-half hour after iv administration of [3H]DES; [3H]-acitivity associated with DES in the fetal genital tract was about threefold higher.

The decrease in reproductive capacity of female offspring from mice treated with DES during gestation was dose related; a low incidence (10% or less) of cancer of the vagina, cervix, and/or uterus was also observed in these mice.

Male offspring exposed prenatally to the highest dose (100 micrograms/kg) of DES in this study also had lower reproductive capacities. Lesions in the genital tract of these mice included epididymal cysts, inflammation, cryptorchidism, and nodular masses in the seminal vesicles and/or prostate gland. Such lesions and sterility were not observed at the lower DES doses.

Histologic studies with neonatal mice raise the possibility that müllerian duct tissue may represent a site for the transplacental toxicity of DES in both the male and female fetus.

Sources

  • Transplacental effects of diethylstilbestrol in mice, National Cancer Institute monograph, NCBI PubMed, PMID: 481582, 1979 May.
DES DIETHYLSTILBESTROL RESOURCES

Health effects : pregnancy use of diethylstilbestrol

The Journal of the Indiana State Medical Association, 1979

Abstract

The use of DES (diethylstilbestrol) to prevent pregnancy complications and miscarriages has shown effects in women who took DES and their offspring.

A University of Chicago follow-up study indicated that women who had used DES had more breast and gynecological cancers than a control group, although the results were statistically insignificant.

DES daughters have a higher occurrence of a rare malignant vaginal cancer, clear cell adenocarcinoma,

and DES-exposed males showed a history of cryptorchidism, hypoplastic testes, epididymal cysts, and low sperm counts.

A DES Task Force formed by the Office of the Assistant Secretary for Health in 1978 recommends that all persons exposed to DES be informed of health risks and that DES daughters be carefully monitored by using Pap smears, iodine staining, and colposcopy when necessary.

In addition, the Task Force recommends

  • that DES women not use estrogens,
  • that postmenopausal replacement estrogens be prescribed prudently,
  • that DES not be given to suppress lactation,
  • and that women given DES for postcoital contraception be informed of the possible health risks.

Sources

  • Health effects: pregnancy use of diethylstilbestrol, The Journal of the Indiana State Medical Association, NCBI PubMed, PMID: 458172, 1979 May.
DES DIETHYLSTILBESTROL RESOURCES

Physician advisory : health effects of the pregnancy use of diethylstilbestrol

Clinical toxicology, 1979

Abstract

A DES (diethylstilbestrol) Task Force formed in February by the Office of the Assistant Secretary for Health, examined the health effects of DES in pregnancy. This report is an outline of the Task Force’s recommendations.

Physicians should advise women to whom they prescribe the drugs of their exposure and of the need for follow-up medical care for themselves and their offspring. Physicians are also to provide patients inquiring of possible past DES exposure, complete and accurate information whenever possible, and such information should be provided free of charge.

The incidence of clear cell adenocarcinoma for DES-exposed daughters is between 1.4/100 to 1.4/10,000. Periodic examination, rather than active therapeutic intervention (e.g., surgery) is recommended for patients with adenosis. For asymptomatic DES daughters, periodic screening examinations should start at age 14 or at menarche; vaginal bleeding/discharge should be promptly evaluated. Hystersosalpingography should not be used as a routine screening procedure in DES daughters but should be reserved for cases of repeated pregnancy loss or infertility.

Asymptomatic DES mothers should have routine screening (e.g., annual pelvic exam including bimanual palpation and Pap smear; breast exam) appropriate for women with no prior estrogen exposure.

DES exposed males have been known to have:

  1. history of cryptochirdism;
  2. hypoplastic testes;
  3. epididymal cysts;
  4. and sperm abnormalities (low sperm counts, decreased motility).
    DES males should have physical examination, appropriate medical follow-up or corrective measures, as the case may be.

Use of DES postcoital contraception should be limited to situations where the fully informed patient or her physician deems that there is no alternative.

Sources

  • Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy, Clinical toxicology, NCBI PubMed, PMID: 37020, 1979 Mar.
  • Features image Michael Marusin
DES DIETHYLSTILBESTROL RESOURCES

Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy

American Association for Cancer Research, 1977

Study Abstract

Pregnant mice were given a single dose (10 mug/g body weight) of diethylstilbestrol (DES) on Days 7 to 19, which correspond to the first to fifth lunar months in humans, after the authors, using a 14C-labeled compound, confirmed easy placental penetration by DES.

  • Treatment with DES on Days 15 to 19 resulted in the induction of persistent urogenital sinus (15.8 to 92.5%) and hypertrophy of the portio vaginalis (11.8 to 73.3%) in female offspring,
  • and treatment on Days 17 and 19 resulted in the induction of undescended testes and their hypogenesis (70.4 to 73.3%) in male offspring, although treatment with DES at other stages of pregnancy and after birth did not cause these alterations.

The incidence of various tumors (lung adenoma, granulosa cell tumor, etc.) increased significantly (31.0 to 37.9%) when DES was given on Days 15 and 17, which correspond to the stage sensitive to other carcinogens. However, adenosis and adenocarcinoma of the vagina were not observed in the offspring.

Sources

  • Induction of urogenital anomalies and some tumors in the progeny of mice receiving diethylstilbestrol during pregnancy, Department of Histology and Embryology, Cancer Research, content/37/4/1099, April 1977.
DES DIETHYLSTILBESTROL RESOURCES

In utero exposure to both high and low dose diethylstilbestrol disrupts mouse genital tubercle development

image of female-mice

The resulting hypospadias phenotypes in male and female mice prenatally exposed to DES

2018 Study Abstract

Exposure to estrogenic endocrine disrupting chemicals (EDCs) during in utero development has been linked to the increasing incidence of disorders of sexual development (DSDs).

Hypospadias, the ectopic placement of the urethra on the ventral aspect of the penis, is one of the most common DSDs affecting men, and can also affect women by resulting in the misplacement of the urethra.

This study aimed to comprehensively assess the resulting hypospadias phenotypes in male and female mice exposed in utero from embryonic day 9.5 to 19.5 to the potent estrogenic endocrine disruptor, diethylstilbestrol (DES), at a high, clinically relevant dose, and a low, previously untested dose, administered via water.

  • The anogenital distance of male pups was significantly reduced and hypospadias was observed in males at a high frequency.
  • Females exhibited hypospadias and urethral-vaginal fistula.

These results demonstrate the ability of an estrogen receptor agonist to disrupt sexual development in both male and female mice, even at a low dose, administered via drinking water.

Sources

  • In utero exposure to both high and low dose diethylstilbestrol disrupts mouse genital tubercle development, NCBI PubMed PMID: 29931162, 2018 Jun 21.
  • Featured image credit Steph Hillier.
DES DIETHYLSTILBESTROL RESOURCES

Hypospadias can be transmitted to the DES-exposed third-generation

Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

2014 Study Abstract

Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES.

Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal.

Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.

Sources

  • Full text (free access) : Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains, NCBI PubMed PMC4254634, 2014 Oct.
  • Featured image credit figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

Environmental factors in genitourinary development

In utero exposure to DES has been shown to increase the testicular dysgenesis syndrome risk

2010 Study Abstract

PURPOSE
In the last century the world has experienced an increase in the use of industrial chemicals as well as possible increases in the prevalence of hypospadias and cryptorchidism. Because hormones regulate the fetal development of many organs, numerous investigations have explored the role of environmental factors in genitourinary growth. We summarize the data regarding endocrine disruptors in human genitourinary development..

MATERIALS AND METHODS
A PubMed literature search was performed for human studies from 2004 to 2009.

RESULTS
Few data exist on environmental influences on the kidneys, ureters or bladder. Studies on the influence of pesticides, vegetarian diets, diethylstilbestrol, oral contraceptives and corticosteroids on hypospadias have yielded varied conclusions.

Phthalates appear to increase the odds of hypospadias and anogenital distance.

The testicular dysgenesis syndrome postulates that cryptorchidism, hypospadias, poor semen quality and testicular cancer share a common environmental origin. In utero exposure to diethylstilbestrol has been shown to increase the risk of testicular dysgenesis syndrome.

However, to our knowledge no other environmental factor has been shown to cause testicular dysgenesis syndrome. Some industrial chemicals as well as the pesticide dichloro-diphenyl-trichloroethane have detrimental effects on semen quality. In cases of documented industrial accidents, chemical exposure has also decreased the male-to-female birth ratio.

CONCLUSIONS
Data on chemical exposure are largely mixed and inconclusive. Studies of populations with high exposure rates due to industrial accidents or in utero exposure to diethylstilbestrol suggest that endocrine disruptors adversely affect genitourinary development.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis

Some extreme positive risk ratios were reported after what is commonly referred to as “third-generation exposure” to DES

2008 Study Abstract

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)-alpha-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.

Sources

  • Full study (free access) : Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis, NCBI PubMed PMC2235228, 2008 Feb.
  • Featured image credit Arthur Osipyan.
DES DIETHYLSTILBESTROL RESOURCES