Reproductive performance of DES-exposed-female progeny

Consequences of diethylstilbestrol in women whose mothers ingested the substance during pregnancy

Abstract

Between October 1973-October 1979, 613 women who had been exposed to diethylstilbestrol (DES) in utero were observed at the Brookdale Medical Center;

106 of these patients were observed for problems related to pregnancy. Most patients were between 17-27 years of age, and 39% were unmarried; 70 were in their 1st pregnancy.

Results of the 1st pregnancy were

  • 52 induced abortions,
  • 3 pregnancies still ongoing at the time of the study;

of the remaining 51 pregnancies,

  • 32 terminated in delivery;
  • there was a 37% of fetal wastage, mostly due to early delivery.

36 of the original 106 patients had a 2nd pregnancy;

  • in this group there were 7 abortions
  • and only 22 deliveries.

11 patients had a 3rd pregnancy, and 5 a 4th pregnancythese patients were able to bring their pregnancy to term.

In total there were 159 pregnancies, and a high percentage of fetal loss, mostly between the 13th and 28th week of pregnancy.

It is well known that many women who have been exposed to DES in utero present modifications of the aspect, shape, and size of the uterine cavity, which causes difficulties in bringing a pregnancy to term.

The article reviews the published literature on the subject.

Sources

  • Reproductive performance of DES-exposed-female progeny. Consequences of diethylstilbestrol in women whose mothers ingested the substance during pregnancy, Contraception, fertilite, sexualite, NCBI PubMed, PMID: 12338184, 1982 May.
  • Image credit watermark.silverchair.
DES DIETHYLSTILBESTROL RESOURCES

Genetic variation in sensitivity to DES and breast cancer risk

Extent of variation in responses to DES among strains of rodents

2018 Study Abstract

Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens).

This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling.

Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in five different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol.

Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density.

The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.

Responses to DES among strains of rodents

…”Long-term exposure to diethylstilbestrol (DES) increased ductal branching to a similar extent in wild type BALB/cJ and 129/SvEv female mice but no mammary tumors were observed in either strain.” …

…”ACI rats also developed mammary tumors with chronic exposure to 17β-estradiol or DES.”…

…”While estrogen agonists induce proliferative responses in mammary, uterine and pituitary, they cause regression in other tissues. DES induced thymic regression in both C57BL/6 and BALB/c strains. Although the strains differed in initial thymus weights, both exhibited similar ~1.5 g decreases following DES treatment. In rats, the F433 strain was most responsive in pituitary and uterine tissues, but DES-induced thymic regression was greatest in the SD strain compared to F344 and BN.”…

… “In contrast, ACI rats have a persistent proliferative response to DES in mammary epithelium without a compensatory increase in apoptosis and was associated with extensive hyperplasia. Thus, strains of rodents appear to have adopted different strategies to achieve tissue homeostasis. The ability to attenuate signaling also appears to differ among tissues. An example is the formation of neoplastic lesions in the uterus of 129/SvEv mice treated with DES, but no lesions developed in the mammary glands of these mice.”…

Genetic variants determining responses to DES

…”When pituitary weight was used as a phenotypic indicator of estrogen stimulated lactotroph proliferation, five QTL were identified upon characterization of DES treated female F2 progeny generated in an intercross between F344 and BN rats. One additional QTL was mapped during characterization of backcross progeny generated using these same strains. When ACI rats were utilized as the sensitive strain, six QTL were mapped upon characterization of DES treated male F2 progeny generated in reciprocal intercrosses between ACI and COP rats…”

…”A second QTL, Eutr2 was mapped to the same region of chromosome 5 through characterization of DES treated congenic rats in which BN alleles across proximal chromosome 5 were introgressed onto the F344 genetic background.”…

…”Treatment with DES identified QTL influencing repression on chromosome 10 (Esta1) and chromosome 2 (Esta2 and Esta3) in a study using male F2 progeny from a BN x ACI intercross. QTL associated with regression of testes induced by DES were identified on chromosomes 1 and 7 in recombinant inbred male rats.”…

Sources

  • Full study (free access) : Genetic variation in sensitivity to estrogens and breast cancer risk, Mammalian genome : official journal of the International Mammalian Genome Society, NCBI PubMed PMC5936622, 2018 Feb 29.
  • Positions of QTL regulated responses to estrogens in 5 tissues in rats featured image credit figure/F1.
DES DIETHYLSTILBESTROL RESOURCES

Postcoital contraception

DES used as an emergency contraception, The Netherlands, 1981

Abstract

Some form of postcoital contraception for protection against unwanted pregnancy is indispensable today especially in cases of rape, failed mechanical contraception, or 1st sexual contact without contraception.

A tablet form of postcoital contraceptive would be acceptable if 100% certainty is assured and it doesn’t involve adverse effects.

Postcoitally administered high-dose estrogens proved effective in Macaca mulatta.

Diethylstilbestrol in variable dosages with or without ethinylestradiol was used in various studies and with variable results.

Pregnancy rates depended on time of coitus in cycle, contraceptive dosage, and time of administration after coitus (within 72 hours).

Conjugated estrogens and various progestagens or combinations of both have been tried with variable success.

Another form of postcoital contraception is IUD insertion within 7 days following unprotected coitus. Advantages of this method are the time factors and absence of adverse effects of hormonal contraceptives.

Postcoital hormonal contraceptives cause changes in the endometrium which prevent blastocyst implantation. They alter tubal function affecting zygote movement towards the uterus. They have an antiovulatory effect and may be luteolytic. Estrogens have more severe side effects than progestagens.

Nausea, vomiting, mastodynia, fluid retention, and vaginal bleeding can result from estrogens. Progestagens can cause irregular bleeding. Combination of both can cause menstrual irregularity.

Postcoital hormonal contraceptives are contraindicated in heart and liver diseases, thrombosis, and pregnancy (teratogenic and carcinogenic effects on offspring).

Pregnancy despite postcoital contraception results in extrauterine pregnancy in 10% of patients. The most important reservations in evaluating publications on this subject are:

  1. lack of control group;
  2. estimation of pregnancy probability is not reliable because of study population used;
  3. patient fertility cannot be ascertained;
  4. and reliability of information provided by patient.

Conclusion from literature studies is that postcoital hormonal contraception is of value but effectiveness is not proven. More research is needed and indications are that other less radical drugs may be found in near future.

Sources

  • Postcoital contraception, Nederlands tijdschrift voor geneeskunde, NCBI PubMed, PMID: 7254397, 1981 Jul 11.
  • Image credit Helen Keen.
DES DIETHYLSTILBESTROL RESOURCES

Breast Cysts and Lesions following Estrogen Replacement Therapy in the DES-Exposed

Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats

2017 Study Abstract

The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer.

Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland.

Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone.

In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.

Sources

  • Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats, Hormones & Cancer, NCBI PubMed PMID: 28078498, 2017 Apr.
  • Featured image credit everydayhealth.
DES DIETHYLSTILBESTROL RESOURCES

Estrogens and postcoital contraception

DES prescribed despite known teratogenic and potentially carcinogenic effects

1981 Study Abstract

The contraceptive effect of large doses of estrogens administered postcoitally is not fully understood, although numerous reports have described the use of a 4 to 6 day course of high dose oral diethylstilbestrol (DES), ethinyl estradiol, conjugated estrogens, and combinations of estrogen and progestogen.

Because estrogens are effective postovulatory rather than postcoital contraceptives, it is necessary to know the exact time of unprotected intercouse in relation to a woman’s menstrual cycle. Depending on the frequency and timing of intercouse, a 5-day course of postcoital estrogen, introduced within 72 hours, yields a pregancy rate of .03-.3%. Failures are usually due to inadequate doses of estrogen, errors in timing, or multiple exposures.

A lowering of basal body temperature after postovulatory administration of high doses of estrogen indicates successful intervention. Existence of various conditions such as hypertension and migraine contraindicate the use of postcoital estrogens. DES and possibly other estrogens are associated with teratogenic and potentially carcinogenic effects. 70 to 80% of women taking postcoital estrogens report side effects such as nausea, weight gain and headache.

No randomized studies have compared the efficacy, side effects, or safety of the available estrogens. The use of informed coinsent procedures is advised because of the potency of high dose estrogens.

Sources

  • Estrogens and postcoital contraception, Female patient, NCBI PubMed, PMID: 12278953, 1981 Jul.
  • Image credit your-life.
DES DIETHYLSTILBESTROL RESOURCES

Third generation offspring – granddaughters and grandsons

Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring

Highlights

  • Diethylstilbestrol (DES) is a synthetic, non-steroidal estrogen of the stilbestrol group acting as an endocrine disruptor.
  • Adverse pregnancy outcomes, infertility, cancer, and early menopause have been identified in women exposed to DES, their offspring, and subsequent generations.
  • DES is one of the major disasters in medicine and it is mandatory to tackle and promote programs of DES-related cancer prevention.

2017 Review Abstracts

Diethylstilbestrol (DES) was an orally active estrogen prescribed to the pregnant women to prevent miscarriages. DES is known as a ‘biological time bomb’ and long-term effects of DES have been recorded in the mothers exposed to DES and their offspring (DES-daughters and DES-sons). Adverse pregnancy outcomes, infertility, cancer, and early menopause have been discovered in women exposed to DES, and some events occur in their offspring and subsequent generations. An increased risk of breast cancer is not limited to the DES-exposed daughters.

We were told that it “could take over 50 years” to detect the effects of DES exposure in future generations, due to the length of time required for diseases to manifest. It is predicted that cross-generational responses to the exposure of DES are possible due to epigenetic changes in the DNA.

The studies on the cohort of grandchildren (grandsons and granddaughters) whose mothers were exposed to DES prenatally (i.e., grandchildren had no direct DES exposure) are limited as they have just reached the age when relevant health problems could be studied.

It seems that the DES 3rd generation has also an increased risk for cancer. The epigenetic effects of DES could be manifested in this generation. DES could affect daughters of the exposed mothers as their oocytes might be developing at the critical stage, but transgenerational effect of DES, i.e., children of sons or daughters of DES mothers, may have an epigenetic basis.

In opposition to developmental epigenetics transgenerational epigenetics implies an absence of resetting of epigenetic states between generations. In fact,the exposure to endocrine disruptor chemical compounds is associated with abnormal DNA methylation and other epigenetic modifications, as well as altered expression of genes important for development and function of reproductive tissues as recently observed by Ho et al.

In a multi-center study, an increase of congenital disabilities in the sons and daughters of the 3rd generation was observed. Currently, there are no large human studies that show adverse events of DES for granddaughters. Kaufman et al. conducted a small cohort study on 28 DES granddaughters and found neither CCA nor abnormalities of the lower genital tract. On the other hand, granddaughters may have more menstrual problems and higher infertility rate compared to non-exposed granddaughters. Direct maternal DES exposure during pregnancy can cause not only an alteration to the reproductive capacity of the woman, but also this alteration may be passed on to next generation, a phenomenon that is called ‘DES granddaughter effect’ and DES granddaughters may also harbor a higher risk of ovarian cancer rather than breast cancer. In DES grandsons, the incidence of hypospadia is 20 times higher than unexposed grandsons, but the risk of developing such anomaly seems to be low.

There is an urgent need to find ways to stop the inheritance cycle of DES and prevent adverse effects of DES in the future generations. The present article reviews the health implications of DES exposure and screening exams currently recommended to DES daughters and their offspring.

Sources

  • Current perspective of diethylstilbestrol (DES) exposure in mothers
    and offspring
    , NCBI PubMed, 28461243, August 2017.
  • Image credit gstatic.
DES DIETHYLSTILBESTROL RESOURCES

Diethylstilboestrol – A long-term legacy

Transgenerational effect of DES, i.e., children of sons or daughters of DES mothers, may have an epigenetic basis

2012 Study Abstract

Diethylstilboestrol (DES) is an endocrine disrupter which causes cancer in rodents.

It was prescribed in large amounts to treat women with gynaecological problems; some of the daughters of these women subsequently developed a rare cancer (vaginal clear cell adenocarcinoma) while genital abnormalities were found in some of the sons.

It was used for decades in livestock feed and this may have contaminated the food chain leading to the exposure of the more general population.

DES appears to cause epigenetic effects in animals and there is some evidence that this also occurs in man.

The mechanisms of carcinogenesis are complex and the effects are difficult to prove due to the background of dietary and environmental phyto- and xenooestrogens.

It has been suggested that, like other endocrine disrupters, DES may have acted as an obesogen in the human population.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Ovral touted as morning-after pill

Contraceptive technology, 1980

Abstract

Studies by A. Albert Yuzpe, MD, and Lee H. Schilling, MD, have shown Ovral to be an effective contraceptive after unprotected intercourse at any time in the menstrual cycle, not just in midcycle.

As a morning after pill, Ovral is taken in 2 doses: 2 tablets within 72 hours after coitus; 2 tablets 12 hours later, a total of 200 mcg ethinyl estradiol and 2 mg di-norgestrel. Risk of pregnancy from a single act of unprotected midcycle coitus averages 20-30% while the risk from unprotected intercourse at other times in the cycle averages 2-4%. Young, nulliparoous, women would be the prime target for the morning after pill. 98.5% of the women in Yuzpe’s study bled within 21 days. The 1.5% who do not bleed within the expected time will either be pregnant or have a delayed period. Ovral can be administered from a pack in the doctor’s office.

The major complaint about DES was nausea and vomiting. Only 24% of the women taking Ovral reported nausea. The episodes were mild and controlled with an antiemetic.

Both doctors and patients are wary of DES because of public concern about teratogenesis. Many doctors recommend termination of pregnancy if it was conceived while the woman was using DES. Ovral use does not usually indicate abortion.

The postcoital IUD insertion studies have included small numbers of patients, but the difficulties are that bleeding following insertion may suggest pregnancy, and the potential for pelvic infection is increased. Ovral should not be given to women who have contraindications to oral contraceptives, and benefits and risks should be weighed.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Estrogen Use in Children and Adolescents: A Survey

Pediatrics, VOLUME 62 / ISSUE 6, December 1978

Article Abstract

Members of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society of Pediatric Endocrinology (ESPE) were mailed a questionnaire to survey their views and practices with respect to the use of estrogens in children and adolescents. The purpose of this survey was to ascertain the prevalence of estrogen therapy in children and adolescents, as well as the estrogen preparation used, dose, benefits, and observed complications.

Seventy-four of 213 LWPES members or groups and 29 of 106 ESPE members or groups returned the survey. The lack of rapid retrieval systems in many clinics and the necessity for return of the survey data within a ten-week period precluded many respondents from the exhaustive, careful chart reviews necessary to answer many of the questions posed. Accordingly, data generated in this survey must be interpreted in this light.

Estrogens are used primarily in children and adolescents for

  1. the treatment of tall stature,
  2. replacement therapy in hypogonadal adolescents,
  3. and as a component of contraceptive pills given to sexually active teenagers.

ESTROGEN TREATMENT OF TALL GIRLS

The treatment of “excessively” tall adolescent girls with pharmacologic doses of estrogen, in an attempt to decrease mature height, has been a subject of controversy since its inception by Goldzieher in 1956; 50% of the LWPES and 17% of the ESPE respondents indicated that they never treat “tall” girls with pharmacologic doses of estrogen, basing their decision primarily on the fact that the long-term side effects of such doses of estrogens are unknown. In addition, the risk-benefit ratio and the fact that tall stature is not a disease were other important reasons for not treating these girls.

Sources

DES DIETHYLSTILBESTROL RESOURCES

Reproductive and hormone-related outcomes in DES third generation women

Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study

2019 Study Highlights

  • Studies of mice indicate intergenerational effects of DES exposure; i.e., effects in the offspring of prenatally DES-exposed animals.
  • We assessed DES exposure in relation to outcomes in a cohort of third generation women whose mothers were prenatally DES-exposed and unexposed.
  • Results suggested DES-exposed third generation women have increased risks of menstrual aberrations, preterm birth, and possibly ectopic pregnancy.
  • The data did not indicate an increase in same-sex orientation in DES-exposed third generation women.
  • Menstrual aberration and preterm birth in the DES-exposed third generation suggest intergenerational effects of endocrine disrupting chemicals in humans.

Abstract

Background
Animal studies suggest that prenatal exposure to diethylstilbestrol (DES) causes epigenetic alterations in primordial germ cells that affect the next generation, but human studies are sparse.

Methods
We assessed hormonally mediated outcomes in third generation women whose mothers were prenatally DES-exposed and unexposed.

Results
Compared to the unexposed, DES-exposed third generation women had an increased risk of irregular menses and amenorrhea; the respective prevalence ratios and 95% confidence intervals (CI) in follow-up data were 1.32 (95% CI: 1.10, 1.60) and 1.26 (95% CI: 1.06, 1.49); associations were more apparent in third generation women whose prenatally DES-exposed mothers were affected by vaginal epithelial changes. The follow-up data also indicated an association with preterm delivery (relative risk (RR): 1.54; 95% CI: 1.35, 1.75).

Conclusion
DES third generation women may have an increased risk of irregular menstrual cycles, amenorrhea, and preterm delivery, consistent with inter-generational effects of endocrine disrupting chemical exposure in humans.

Sources

  • Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study, ScienceDirect doi.org/10.1016/j.reprotox.2018.12.008, Reproductive Toxicology Volume 84, March 2019, Pages 32-38.
  • Featured image credit ars.els-cdn.
DES DIETHYLSTILBESTROL RESOURCES