DES causative role in breast cancer through inducing aneuploidy

image of chromosome aberrations

Do oestrogens induce chromosome specific aneuploidy in vitro, similar to the pattern of aneuploidy seen in breast cancer ?

2008 Study Abstract

The study was concerned with investigating the specific effects of non-DNA reactive oestrogens at low “biologically relevant” doses and the causative role they may play in breast cancer through inducing aneuploidy.

A review of previous studies identified a non-random pattern of aneuploidy seen in breast cancers. This information was used to select those chromosomes that undergo copy number changes in breast cancer and chromosomes that appear stable.

A panel of centromeric specific probes were selected and centromeric specific fluorescence in situ hybridisation (FISH) was carried out on the human lymphoblastoid cell line, AHH-1, which had been pre-treated with the chemical aneugens 17-beta oestradiol, diethylstilbestrol (DES) and bisphenol-A (BP-A).

The results suggest that oestrogens may play a causative role in breast cancer by inducing a specific pattern of aneuploidy similar to that seen in breast carcinomas. 17-beta oestradiol appears to induce changes most similar to those seen in breast tumours, BPA induces the same pattern but at a lower frequency and DES appears to be less chromosome specific in its act.

Sources

DES DIETHYLSTILBESTROL RESOURCES

DES as postconception fertility control

Possibility of postconception control of fertility using medicamentous nidation inhibitors

1973 Study Abstract

Clinical aspects of postconception fertility control are reviewed. Estrogens (ethinyl estradiol and diethylstilbestrol) have been used for this purpose. In addition to their undesirable side effects, they must be administered within a strictly defined time period.

Several progestagens have been used as postcoital contraceptives, but they too are effective only when administered a few days after ovulation.

A number of nonsteroidal substances appear promising, as inhibitors of implantation and as abortifacient agents.

Prostaglandins also appear promising because of similar properties. Oral administration is not feasible, but vaginal administration is an attractive possibility. But the high incidence of side effects and somewhat unreliable effects are problems. The mechanisms of action of all these substances have not been explained.

Sources

  • Possibility of postconception control of fertility using medicamentous nidation inhibitors, Zentralblatt fur Gynakologie, PMID: 4131008, 1973 Dec.
DES DIETHYLSTILBESTROL RESOURCES

Intrauterine factors and risk of breast cancer

Systematic review and meta-analysis of current evidence, 2007

Abstract

BACKGROUND
Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer. Potential underlying mechanisms include variation in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer.

METHODS
We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer. We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors.

FINDINGS
We identified 57 studies published between Oct 1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight (relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13 [1.02-1.25]), and paternal age (1.12 [1.05-1.19]). Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]). No association was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) or maternal diethylstilbestrol treatment (1.40 [0.86-2.28]).

INTERPRETATION
The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanisms responsible for such predisposition need to be elucidated.

Sources

  • Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence, The Lancet Oncology, NCBI PubMed PMID: 18054879, 2007 Dec.
  • Image credit swissfetus.
DES DIETHYLSTILBESTROL RESOURCES

DES contraceptive effects

On the mechanism of the contraceptive action of oestrogens administered after ovulation

1973 Study Abstract

The antifertility effects of estrogens in animals has long been known, but it was not until 1966 that the effects of estrogen in man became known as well.

The estrogen effects during the time of the transport of the egg through the fallopian tubes to the uterine cavity was studied. 50 mg of diethylstilbestrol (DES) was administered daily during the 5-day postovulatory period.

The results were

  • a shortening of the cycle,
  • a lowering of plasmic progesterone,
  • and a decrease in the secretion of pregnanediol.
  • The development of the endometrium stopped.

These results indicate that DES, when given at this time, shortens the function of yellow corpuscles and affects the further development of the endometrium. Either of these mechanisms could explain the contraceptive effects of the estrogen.

Sources

  • On the mechanism of the contraceptive action of oestrogens administered after ovulation , Ceskoslovenska gynekologie, PMID: 4765140, 1973 Sep.
  • Image credit The Roaming Platypus.
DES DIETHYLSTILBESTROL RESOURCES

Intrauterine factors and breast cancer risk

Breast cancer increased risk in DES offspring

Abstracts

“Suggestions that risk of breast cancer in human beings might be affected by early-life exposures, or even intrauterine events and conditions, have been reported in published studies in the past four decades, …

… More direct evidence in support of a role of pregnancy oestrogens has been provided by the results from a unique cohort of women in utero exposed to diethylstilbestrol, a synthetic oestrogen. These women were found to be at increased risk for breast cancer after the age of 40 years, when familial breast cancer becomes rare.”

Sources

DES DIETHYLSTILBESTROL RESOURCES

Postcoital antifertility agents

Diethylstilbestrol as a “morning after” pill

1972 Study Abstract

Investigators have studied a variety of agents to determine their usefulness in postcoital antifertility.

To determine the mechanism of action of postcoitally administered estrogen, 2 groups of regularly ovulating volunteers were given 25mg of diethylstilbestrol for 5 days, beginning on Day 1 of basal temperature rise.

Blood samples were taken from 1 group every 1-3 days to measure the levels of plasma progesterone. The other group had endometrial biopsies on the fifth day after the basal temperature rise about the time implantantion would obcur.

Preliminary results showed lowered levels of plasma progesterone, and biopsy on cycle Day 20 showed endometrium resembling that expected on Day 16. Decreasing levels of circulating progesterone prevent the usual rise in endometrial carwonic anhydrase, inhibiting blastocyst implantation.

Reports of adenocarcinoma in female offspring of mothers who have taken diethylstilbestrol in early pregnancy lead authors to suggest use of ethinyl estradiol 2 to 3mg daily starting within 48 hours of coitus when postcoital contraception is desired. However, side effects of nausea and vomiting restrict its use to isolated instances and it should not be used routinely.

Sources

  • Postcoital antifertility agents, Southern Medical Journal, popline, 1972 Nov.
  • Image credit Curtis Potvin.
DES DIETHYLSTILBESTROL RESOURCES

Breast cancer risk in DES offspring

Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?

2006 Study Abstracts

Since 1990, when a hypothesis on intrauterine influences on breast cancer risk was published, several studies have provided supportive, indirect evidence by documenting associations of birth weight and other correlates of the prenatal environment with breast cancer risk in offspring. Recent results from a unique cohort of women with documented exposure to diethylstilbestrol in utero have provided direct evidence in support of a potential role of pregnancy oestrogens on breast cancer risk in offspring.

Since 1992, all US cohorts of DES-exposed persons for whom there was an appropriate comparison group of unexposed persons and for whom there was medical record documentation of exposure (or not) to this substance are being followed in a study supported by the US National Cancer Institute. Slightly more than 4800 women exposed in utero to DES and approximately 2070 unexposed women are included in this cohort. Results concerning breast cancer in offspring have been reported in three reports. The risk for developing breast cancer in the earliest report, when women exposed to DES in utero were still very young (38 years on the average), was barely 18% higher in exposed to nonexposed women. However, the increase became progressively greater with longer follow up.

In the most recent report, for breast cancer occurring at age 40 years or older the risk was significantly higher, by 91%, in women exposed to DES in utero than in those who were not exposed. For breast cancer at age 50 years or older the corresponding excess was 200%, which again was significant but with a wide confidence interval. The overall pattern does not come as a surprise because breast cancer among young women is known frequently to have genetic roots, so an excess risk on account of intrauterine exposure to oestrogens is likely to become more evident with advancing age.

Sources

  • Full paper (free access) : Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?, Breast Cancer Research, NCBI PubMed PMC1797035, 2006.
  • Image credit boram kim.
DES DIETHYLSTILBESTROL RESOURCES

How Soon Will We Have the “Ideal” Contraceptive ?

” If we wait for vastly new advanced techniques, instead of making better use of what we now have, it may be too late for the ideal method to help solve our population problems ! “

Abstract

… “The closest to a morning after pill has been the three-day use of large doses of diethylstilbestrol (75 mg) after exposure to pregnancy.

This approach has been utilized by gynecologists for many years, although its effectiveness has not been conclusively demonstrated.

It is by no means a new method, despite current magazine articles to the contrary.” …

Sources

DES DIETHYLSTILBESTROL RESOURCES

Garlic consumption : useful for the prevention of DES-related breast cancer

Diallyl sulfide inhibits diethylstilbestrol-induced lipid peroxidation in breast tissue of female ACI rats: implications in breast cancer prevention

2003 Study Abstract

Diallyl sulfide (DAS) is a component of garlic and prevents cancer in several animal models in various organs. The chemopreventive effects of DAS are attributed to modulation of enzymes to alter the bioactivation of xenobiotics.

Diethylstilbestrol (DES) is a synthetic estrogen that causes breast cancer in female ACI rats subsequent to metabolism with concurrent free radical production.

This study assessed the effect of DAS on DES-induced reactive oxygen species (ROS) using lipid peroxidation as an empirical endpoint.

We have demonstrated that acute exposure to DES results in a significant increase in lipid hydroperoxides (LPH) in breast tissue and DAS attenuated DES-induced LPH concentrations. Two-week exposure to DES caused significant increases in LPH concentrations in breast and liver tissues. DES-induced LPH concentrations were decreased by coadministration of DAS at this time point. There were no statistical differences in the concentrations of LPH in breast and liver tissues of rats treated for 4/6 weeks with DAS/DES. These results demonstrate that DAS inhibits the production of ROS which suggests that DAS effectively inhibits DES bioactivation in female ACI rats which may have implications for chemopreventive intervention strategies.

Our results suggest that garlic consumption might be useful for the prevention of human breast cancers.

Sources

  • Diallyl sulfide inhibits diethylstilbestrol-induced lipid peroxidation in breast tissue of female ACI rats: implications in breast cancer prevention, Oncology reports, NCBI PubMed PMID: 12684652, 2003 May-Jun.
  • Image credit Mike Kenneally.
DES DIETHYLSTILBESTROL RESOURCES

Post-coital contraception, first-aid use, 1972

…”Though the area of post-coital contraception seems to offer one of the most likely advances in fertility control, the morning-after pill is probably best restricted to first-aid use.”…

Abstracts

…”In 1938 two oestrogenic compounds were found to be active when taken by mouth-diethylstilbcestrol 11 and ethinyloestradiol; both prevented implantation in rabbits.’…

…”Until lately, oestrogens were used post-coitally in women only as a first-aid measure: DODDS found them useful after rape, but was uncertain of their reliability; …” …

…” KucHERA, in 1971, reported her experience using 50 mg. daily of diethylstilboestrol for 5 days in 1000 women of childbearing age exposed to unprotected intercourse. … … No pregnancies were recorded after this treatment.”…

…” HASPELS, this year,described post-coital treatment with both ethinyloestradiol and diethylstilboestrol in 2000 women. … …. There were no pregnancies after 5 mg of ethinyloestradiol for 5 days or 50 mg of stilboestrol for 6 days. ” …

Sources

DES DIETHYLSTILBESTROL RESOURCES