Age at menarche among diethylstilbestrol granddaughters

Age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal DES exposure

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In this 1995 study, age at menarche for DES granddaughters seemed to be unaffected by mother’s prenatal diethylstilbestrol exposure. However the 2011 study showed DES-exposed girls were somewhat more likely to have begun menstruating at age 10 or younger.

1995 Study Abstract

American journal of obstetrics and gynecology, NCBI PMID: 7573253, 1995 Sep.

We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women’s daughters. A total of 123 daughters were > or = 10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother’s prenatal diethylstilbestrol exposure.

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Cellular and molecular effects of developmental exposure to DES: implications for other environmental estrogens

Exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism

This 1995 study found that low doses of DES demonstrate alterations in both male and female exposed offspring

1995 Study Abstract

Concerns have been raised regarding the role of environmental and dietary estrogens as possible contributors to an increased incidence of various abnormalities in estrogen-target tissues of both sexes. These abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males. Whether these concerns are valid remains to be determined; however, studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES has potent estrogenic activity, it may be used as a model compound to study the effects of weaker environmental estrogens, many of which may fit into the category of endocrine disruptors.

Conclusions

There are many possible cellular and molecular mechanisms that may be involved in the toxic response to DES and other environmental estrogens if an organism is exposed during critical stages of development. Several mechanisms have been discussed in this report. Studies with the developmentally DES-exposed murine model have duplicated and predicted many of the lesions seen in similarly DES-exposed humans and in the wildlife population. Currently, there is increased interest in the effects of other environmental estrogens and antiandrogens on reproductive tract differentiation and development. Whether these compounds have effects similar to DES is uncertain, but since low doses of DES demonstrate alterations in both male and female exposed offspring, the possibility of adverse effects from other compounds with estrogenic and/or antiandrogenic activity must be considered.

Sources and Full Study
  • Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens, Newbold R, Environ Health Perspect. 1995 Oct;103 Suppl 7:83-7. PMID: 8593881.
  • Full study, Environ Health Perspect. 1995 Oct; 103(Suppl 7): 83–87, PMC1518878, 1995 Oct.
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Fertility in Men exposed prenatally to DiEthylStilbestrol

DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced

Abstract

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In that 1995 study, DES sons with genital malformations were nonetheless as fertile as other men.

BACKGROUND:
Prenatal exposure to diethylstilbestrol causes infertility in male mice and has been associated with malformations of the genital tract in men. However, little is known about the fertility of men who have been exposed prenatally to diethylstilbestrol.
METHODS:
In 1950 through 1952, 1646 pregnant women were enrolled in a randomized, placebo-controlled clinical trial of diethylstilbestrol at Chicago Lying-in Hospital. We interviewed men who were born to the women during that study about their fertility.
RESULTS:
Four decades after their birth, we were able to trace 548 of the surviving sons (68 percent). Ninety percent consented to be interviewed (253 who had been exposed to diethylstilbestrol in utero and 241 who had not been exposed). Congenital malformations of the genitalia were reported three times as often by the diethylstilbestrol-exposed men as by the sons of the women in the placebo group. Within the exposed group, malformations were reported twice as often among those exposed to diethylstilbestrol before the 11th week of gestation as among those exposed later (P = 0.05). Men with genital malformations were nonetheless as fertile as other men. The diethylstilbestrol-exposed men (with or without genital malformations) had no impairment of fertility by any measure, including whether they had ever impregnated a women, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception in the most recent pregnancy of the female partner. Finally, diethylstilbestrol-exposed men had no impairment of sexual function, as indicated, for example, by the frequency of intercourse or reported episodes of decreased libido.
CONCLUSIONS:
High doses of diethylstilbestrol did not lead to impairment of fertility or sexual function in adult men who had been exposed to the drug in utero.

Sources

  • Fertility in men exposed prenatally to diethylstilbestrol, NCBI, PMID: 7723797, ;332(21):1411-6, 1995 May 25.
  • Full text – New England Journal of Medicine 1995; 332:1411-1416, DOI: 10.1056/NEJM199505253322104, May 25, 1995.
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Multi-generational Carcinogenesis from DiEthylStilbestrol investigated by Blastocyst Transfers in Mice

DES usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced

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DiEthylStilbestrol DES also has a multi-generational effect transmitted through the blastocyst.

Previous studies have shown that a carcinogenic effect can be transmitted from female mice exposed prenatally to diethylstilboestrol (DES) to their female offspring. Furthermore, male mice exposed pre-natally to DES can transmit a carcinogenic effect to their offspring through their germ cells.

To study how multi-generational carcinogenesis is transmitted through females exposed pre-natally to DES, the technique of blastocyst transfer was utilized. Blastocysts from strain CD-1 mice exposed pre-natally to vehicle were transferred to mice exposed pre-natally to DES. Among 143 offspring from these transfers, there were 10 ovarian adenomas and 10 uterine adenocarcinomas. Among 92 offspring from blastocyst transfers between mice exposed pre-natally to vehicle only, there was 1 ovarian adenoma and 1 uterine adenocarcinoma. Thus the pre-natal exposure of the host to DES produced a maternal environment which increased the incidence of ovarian and uterine tumors.

The reverse type of transfer was also performed, in which blastocysts from female mice exposed pre-natally to DES were transferred into mice exposed to vehicle only pre-natally. Among 99 offspring derived from DES-exposed germ cells, 6 developed ovarian adenomas and 16 developed uterine adenocarcinomas.

Thus DES also has a multi-generational effect transmitted through the blastocyst, which is consistent with fetal germ cell mutation from DES.

Sources:
  • Multi-generational carcinogenesis from diethylstilbestrol investigated by blastocyst transfers in miceNCBI, PMID: 7705955, Int J Cancer. 1995 Apr 10;61(2):249-52.
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Effect of DiEthylStilboestrol on Gonad Development

Gonadal feminization and feminization of the quail following DES exposure

1st Abstract – 1979

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The effect of diethylstilboestrol on gonad development in quail embryos has been quantitatively analysed.

Early treatment of Quail eggs by DES promotes a transient feminization of the gonads in genetic males and a strong stimulation of the Müllerian ducts. The left ovotestis results from the juxtaposition of a testicular medulla and an induced female-type cortex, which develops follicles and a characteristic 17 beta-HSD activity. The right testis is reduced but keeps a consistent structure. The medulla of the treated gonads shows, in both sexes, an inhibition of delta 5-3 beta HSD activity during embryonic development. After hatching, this specific enzyme then develops in the steroidogenic cells. These results are compared with others obtained with estradiol and also in chick. The discussion deals also with the effects of these estrogens on the endogenous abilities and specific responses of the gonads in relation to sex differentiation factors.

2nd Abstract – 1995

The effect of diethylstilboestrol on gonad development in quail embryos has been quantitatively analysed. Quail embryos at 4 days of incubation were treated with diethylstilboestrol (DES), using the egg dipping method. At 10 days of incubation, embryos were removed and killed by decapitation. Tissues were prepared for chromosome analysis, and the parts of the abdomen containing the gonads were prepared for serial sectioning and quantitative assessment. Left gonads of DES-treated male embryos resembled ovaries histologically, while their right gonads were markedly reduced in size. Right gonads of DES-treated female embryos were also further reduced by treatment with DES. There was no statistically significant effect by DES treatment on the size of left gonads, although the ratio of left compared with right gonadal volumes was highly significant. Since, in birds, the left embryonic gonad has ambisexual potential, while the potential of the right gonad is exclusively masculine, these results exemplify the adverse effect exerted by oestrogen on male sexual development in vertebrates.

Sources
  • Feminization of the quail by early diethylstilbestrol treatment: histoenzymological investigations on steroid dehydrogenases in the gonadsNCBI, PMID: 294849, 1979;68(2):85-98.
  • A quantitative investigation of gonadal feminization by diethylstilboestrol of genetically male embryos of the quail Coturnix coturnix japonicaNCBI, PMID: 7616493, 1995 Mar;103(2):223-6.
  • Full text: Journal of Reproduction and Fertility, doi: 10.1530/jrf.0.1030223
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Alterations in Estrogen Levels during Development affects the Skeleton: use of an Animal Model

Diethylstilbestrol DES side-effects on bones

Alterations in estrogen levels during development affects the skeleton: use of an animal model
DES side-effects on bones

Exposure to estrogens during various stages of development has been shown to irreversibly influence responsive target organs. The recent finding of the presence of estrogen receptor in both osteoblasts and osteoclasts has suggested a direct role of steroid hormones on bone tissue. Furthermore, estrogens have important effects on bone turnover in both humans and experimental animal models. Thus, this tissue is now regarded as a specific estrogen target tissue. To investigate whether a short-term developmental exposure to estrogens can influence bone tissue, we have injected female mice with diethylstilbestrol (DES) from day 1 through day 5 of life. Additionally, a group of pregnant female mice were injected with different doses of DES from day 9 through 16 of pregnancy. Mice were then weaned at 21 days of age, and effects on bone tissue of the female mice were evaluated in adulthood (7-12 months of age). These short-term treatments did not affect body weight of exposed mice. However, a dose-dependent increase in bone mass, both in the trabecular and compact compartments, was observed in the DES-exposed female offspring. Furthermore, femurs from DES-exposed females were shorter than femurs from controls. A normal skeletal mineralization accompanied these changes in the bone tissue. In fact, a parallel increase in total calcium content of the skeleton was found in concomitance with the increase in bone mass. Estrogen treatment induced an increase in the amount of mineralized skeleton when compared to untreated controls. In summary, this report shows that alterations of estrogen levels during development can influence the early phases of bone tissue development inducing permanent changes in the skeleton. These changes appear to be related to bone cell programming in early phases of life. ”

Abstract, NCBI Endocrinology, October 1995  – Full text here

Related post: Alterations of maternal Estrogen Levels during Gestation affect the Skeleton of Female Offspring, May 1996.

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