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

DES is the best documented compound

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 It was implicated in urogenital abnormalities in children exposed in utero and was withdrawn from the market.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.

Sources

  • 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.
  • Featured image Jamie Street.
DES DIETHYLSTILBESTROL RESOURCES

DES responsibility in the testicular feminization syndrome

Ingestion of diethylstilbestrol during pregnancy, 1990 Report

Abstract

We report the cases of two women who had testicular feminization with remnants of Müllerian ducts and whose mothers had received diethylstilbestrol (DES) during the first trimester of pregnancy.

At laparotomy, masses were removed which had the microscopic appearances of testes and Fallopian tubes, and were confirmed as such at histology.

There were three possible explanations for these genetic abnormalities:

  1. deficient antimüllerian hormone (AMH) secretion (or lack of sensitivity of Müllerian ducts to AMH);
  2. early testicular descent with regression of Müllerian ducts beyond the efficacy margin of AMH;
  3. exposure to DES in utero during the first trimester of pregnancy.

In these two women, the most likely explanation seems to be the last one.

Sources

  • Ingestion of diethylstilbestrol during pregnancy. Its responsibility in the testicular feminization syndrome, Presse medicale (Paris, France : 1983), NCBI PubMed, PMID: 2146621, 1990 Sep.
  • Featured image credit Anna Sullivan.
DES DIETHYLSTILBESTROL RESOURCES

Follow-up study of male and female offspring of DES-exposed mothers

This follow-up study presents the effects of DES on the genital tract of male and female offspring of mothers who were part of a double-blind, placebo-controlled investigation during 1951 and 1952 aimed at determining the effect of DES on pregnancy

1977 Study Abstract

Epididymal cysts, hypotrophic testes, and capsular induration were the more common genital lesions found in 25% of 163 DES-exposed males as compared to 6% in 168 control males. Semen analysis data on 39 subjects of the DES-exposed group and 25 subjects of the control group showed that 26% of the DES-exposed group produced an ejaculate volume under 1.5 ml; no such cases were observed in the control group. The average values for sperm density ant total motile spermatozoa per ejaculate, although in the normal range, were more than two times lower in the DES-exposed group as compared to the controls. A quality score of greater than 10 (“severely pathologic semen”) was found in 28% of the DES-exposed group as compared to 0 in the control group. An association of pathologic semen quality with physical abnormalities was found only in the DES-exposed group. Two cases of azoospermia, one without genital abnormalities on physical examination and one with bilateral hypotrophic testes were observed so far in the DES-exposed group.

Eighteen percent of 229 DES-exposed female patients had irregular menstrual cycles (oligomenorrhea) as compared to 10% of 136 controls. The history of pregnancy revealed a lower incidence of pregnancy in the DES-exposed group (18%) than in the control group (33%). Circumferential ridges of the vagina and cervix were seen in 40% of 229 DES-exposed females but in none of 136 controls. Colposcopic findings in the vagina revealed adenosis in 66.8% of the DES-exposed females and in 3.6% of the control group. Dysplastic lesions were more prevalent in the vagina and cervix of the DES-exposed subjects.

No cases of cancer were observed in either the male or female offspring.

Sources

  • Follow-up study of male and female offspring of DES-exposed mothers, Obstetrics and gynecology, NCBI PubMed, PMID: 318736, 1977 Jan.
  • Features image credit Isaac Cabezas.
DES DIETHYLSTILBESTROL RESOURCES

DES Exposure and Offspring Reproductive Health, 1982 Review

In utero exposure to diethylstilbestrol: Adverse effects on the reproductive tract and reproductive performance in male and female offspring

1982 Study Abstract

Exposure to diethylstilbestrol (DES) in utero is associated with adverse effects on the reproductive tract in male and female progeny.

These effects include epididymal cysts, microphallus, cryptorchidism, and testicular hypoplasia in male subjects and adenosis, clear cell adenocarcinoma, and structural defects of the cervix, vagina, uterus, and fallopian tubes in female subjects.

As these offspring have reached reproductive age, reports of adverse reproductive performance have been published, including still controversial reports of menstrual dysfunction and infertility.

More well established are increased rates of spontaneous abortion, ectopic pregnancy, premature deliveries, and perinatal deaths, all contributing to an increase in overall adverse pregnancy outcome.

Often there is correlation between the DES-associated anatomic abnormalities in the reproductive tract and the adverse reproductive performance. Altered male reproductive capacity is also suggested by diminished semen analyses and sperm penetration assays. A detailed review of these effects of in utero DES exposure is presented.

Sources

  • In utero exposure to diethylstilbestrol: Adverse effects on the reproductive tract and reproductive performance in male and female offspring, American journal of obstetrics and gynecology, NCBI PubMed, PMID: 6121486, 1982 Apr.
  • Featured image credit Callie Gibson.
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