Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis, 1999
One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM).
One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy.
The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.
Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis, Breast cancer research and treatment, NCBI PubMed PMID: 10424402, 1999 Mar.
Side effects of estrogen administration to prostatic cancer patients: clinical and statistical survey of 109 prostatic cancer cases of Kyoto University Hospital, 1993
Since the introduction of hormonal treatment for prostatic cancer by Huggins and Hodges in 1941, severe side effects of synthetic estrogen, which have overcome its benefit, have been reported in the U.S.A. and in European countries.
However, in Japan the adverse effects of estrogen have been reported to be milder than in western countries, and estrogen still has an important role in the treatment of prostatic cancer in Japan.
In this communication, the side-effects of synthetic estrogen administered to 109 prostatic cancer patients, who were admitted to Kyoto University Hospital between 1980-1990 are reported.
Fifty-three (48.6%) of the 109 patients suffered adverse side effects of the estrogen, specifically cardiac disease (20.2%), fluid retention (14.7%) and hypertension (13.8%). Five of these patients died. Among the risk factors analyzed, daily dose, past history of cardio-vascular disease and ECG abnormalities were significantly correlated with the appearance of adverse effects. The reasons why the frequency of lethal side-effects is lower in our cases compared to findings reported by the Veterans Administration group may be the lower daily dose and cessation of estrogen administration when mild adverse effects appear and some other unknown factors, although the background of the patients and method of analysis are not comparable among them.
The overall frequency of side-effects in prostatic cancer patients administered estrogen in our cases is not necessarily lower than in western countries, but the severity of the side effects was milder in our cases. We must be a ware of the potential adverse effects of estrogen.
Side effects of estrogen administration to prostatic cancer patients: clinical and statistical survey of 109 prostatic cancer cases of Kyoto University Hospital, Hinyokika kiyo. Acta urologica Japonica, NCBI PubMed PMID: 8460581, 1993 Jan.
Diethylstilbestrol revisited in advanced breast cancer management, 1990
Prior to the introduction of tamoxifen, diethylstilbestrol (DES) was widely used as the first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Since randomized trials reported that tamoxifen has a similar response rate but fewer side effects than DES, its use has declined markedly.
We administered DES in a dose of 10-20 mg daily to 11 postmenopausal women with advanced breast cancer, all of whom had received previous endocrine and some cytotoxic therapy also.
Four women showed tumour responses to DES (1 complete and 3 partial), 5 had stable disease, and 2 progressive disease. Amongst the patients who responded, 2 had previously been unresponsive to other endocrine treatments. Of the women with stable disease, 3 had prolonged relief of symptoms. No withdrawal responses were noted. The major side effects were nausea (severe in 2 patients, mild in 1) and cardiac failure (2 patients).
We conclude that DES remains a useful, active agent in the management of advanced breast cancer in postmenopausal women, even in patients with tumours unresponsive to other endocrine therapy.
Diethylstilbestrol revisited in advanced breast cancer management, Medical and pediatric oncology, NCBI PubMed PMID: 2355892, 1990.
IN AGREEMENT WITH ITS extragovernmental physician-advisers, FDA has approved, under restricted conditions, postcoital (contraceptive) use of diethylstilbestrol (DES), a synthetic estrogen.
Adequate evidence to support the use of any other estrogen for this purpose is not presently available.
The Agency considers the use of DES for this purpose to be safe only as an emergency measure (in situations such as rape, incest, or where, in the physician’s judgment, the patient’s physical or mental well-being is in jeopardy) and explicitly warns against its routine or frequent use as a contraceptive.
Physicians are urged, prior to prescribing DES for this purpose, to inform patients (or guardians) fully of the possible side effects of the drug, and of alternative measures available and their hazards, so that the patient may participate in an informed way in the decision to use the drug. Pregnancy should be ruled out by appropriate tests prior to instituting therapy, so that no unnecessary exposure of a fetus to DES occurs.
The efficacy of DES in preventing pregnancy depends upon the time-lapse after coitus and dosage of the drug. The currently recommended dosage is 25 mg twice a day for 5 continuous days beginning, preferably, within 24 hours and not later than 72 hours after exposure. When this dosage is given within the specified time interval after sexual intercourse, DES is highly effective in preventing conception. But the patient must be warned to take the full course of the drug in spite of the nausea which commonly occurs, if it is to be effective.
There is at present no positive evidence that the restricted postcoital use of DES carries a significant carcinogenic risk either to the mother or fetus. However, because existing data support the possibility of delayed appearance of carcinoma in females whose mothers have been given DES later in pregnancy, and because teratogenic and other adverse effects on the fetus with the very early administration recommended are ill understood, failure of postcoital treatment with DES deserves serious consideration of voluntary termination of pregnancy.
Before prescribing, the physician should be familiar with the complete FDA-approved labeling on products intended for this use.
More Information – Abstract from WikiVisually
In May 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive to emergency situations such as rape, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES. (In February 1975, the FDA Commissioner testified that the only error in the May 1973 FDA Drug Bulletin was that the FDA had not approved postcoital contraceptive use of DES.)
In September 1973, the FDA published a proposed rule specifying patient labeling and special packaging requirements for any manufacturer seeking FDA approval to market DES as a postcoital contraceptive, inviting manufacturers to submit abbreviated new drug applications (ANDAs) for that indication, and notifying manufacturers that the FDA intended to order the withdrawal of DES 25 mg tablets (which were being used off-label as postcoital contraceptives).
In February 1975, the FDA said it had not yet approved DES as a postcoital contraceptive, but would after March 8, 1975 permit marketing of DES for that indication in emergency situations such as rape or incest if a manufacturer obtained an approved ANDA that provided patient labeling and special packaging as set out in a FDA final rule published in February 1975. To discourage off-label use of DES as a postcoital contraceptive, in February 1975 the FDA ordered DES 25 mg (and higher) tablets removed from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications be changed to state: “THIS DRUG PRODUCT SHOULD NOT BE USED AS A POSTCOITAL CONTRACEPTIVE” in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label.
In March 1978, a FDA Drug Bulletin was sent to all U.S. physicians and pharmacists which said: “FDA has not yet given approval for any manufacturer to market DES as a postcoital contraceptive. The Agency, however, will approve this indication for emergency situations such as rape or incest if a manufacturer provides patient labeling and special packaging. To discourage ‘morning after’ use of DES without patient labeling, FDA has removed from the market the 25 mg tablets of DES, formerly used for this purpose“.
Selected Items, from the FDA Drug Bulletin, California Medicine, NCBI PubMed PMC1455105, May 1973.
…”In spite of evidence that success in the macaque should be paralleled by success in man, initial human experimentation was undertaken with some trepidation.
The first cases were rape cases. All of the subjects received 50 mg. of stilbestrol for 4 to 6 days after exposure. The chance of pregnancy following rape is uncertain for many obvious reasons. Sometimes no sperm could be found in the cervix or vagina. In a few instances, temperature charts were started; if no rise occurred, no drug was given. In most of the cases accepted for treatment, exposure occurred near midcycle and fern crystallization of cervical mucus as well as presence of sperm were demonstrated. In this small series of patients, none has become pregnant so far. The subsequent menstruation was generally unremarkable, although in some instances it was either scantier or more profuse or prolonged than usual. Side effects, when they occurred, were those usually associated with administration of estrogen; they consisted of nausea and breast soreness, which ceased shortly after medication was stopped.
A limited number of courageous volunteers furnished an opportunity for further and more adequate observation. Coitus took place at midcycle near the time of the temperature rise. Fern crystallization and Huhner tests with motile sperm were obtained in most instances.
The apparent effect of 5 to 50 mg. of stilbestrol or 0.5 mg. of ethinyl estradiol on the biphasic temperature curve chart is to counteract the thermogenic effect of progesterone or to shorten the luteal phase.
From these charts it was anticipated that the secretory changes in the endometrium might be altered. However, instead of a proliferative or hyperplastic endometrium, endometrial biopsies taken on postovulation days 5 to 7 and 10 to 12 showed a progestational effect with secretion in some instances on both sides of the nucleus, occasionally almost suggestive of an Arias-Stella reaction. The stroma was dense in some areas, markedly edematous in others. Basal vacuolization often persisted up to menstruation, sometirnes giving an early secretory appearance late in the cycle.
In these preliminary trials there have been no pregnancies. While of interest, these clinical studies are incomplete and have as yet no statistical significance.” …
Compounds interfering with ovum implantation and development. 3. The role of estrogens, American journal of obstetrics and gynecology, NCBI PubMed PMID: 4959099, 1966 Nov.
Pregnancy‐related factors and risk of B‐cell non‐Hodgkin lymphoma among women in Los Angeles
2018 Paper Abstracts
… “Pregnancy‐related factors evaluated included pregnancy history [ever (full‐term) pregnant, number of full‐term pregnancies], breast‐feeding (ever breast‐fed, duration, number of children breast‐fed), nausea during pregnancy that required treatment or hospitalization, diethylstilbestrol (DES) use during pregnancy and lactation suppressant use after full‐term pregnancy.” …
… “However, women who used DES during a pregnancy had two‐fold greater risk of B‐cell NHL overall than ever pregnant women who never used DES (OR = 2·37, 95% CI = 1·03–5·44). Notably, use of DES during pregnancy was associated with five‐fold greater risk of MZL (OR = 5·54, 95% CI = 1·76–17·45). This association is of potential interest as DES is known to alter immune function and is considered an oestrogenic endocrine disruptor.” …
… “In conclusion, our results provide evidence that increased parity, early age at first full‐term pregnancy, and breast‐feeding are associated with decreased risks of B‐cell NHL. These associations are also observed with breast cancer, and warrant further investigation to uncover whether similar anti‐carcinogenic mechanisms or specific hormone‐related immune alterations are responsible. Our report is the first suggesting the association of DES use with increased B‐cell NHL risk, particularly MZL, and warrants further investigation in collaborative efforts. Although no DES longer in use, should the association be replicated, it could provide important clues towards pinpointing biological mechanisms important for lymphomagenesis.” …
Pregnancy‐related factors and risk of B‐cell non‐Hodgkin lymphoma among women in Los Angeles, Wiley Online Library doi.org/10.1111/bjh.15699, 29 November 2018.
Diallyl sulfide inhibits diethylstilbesterol-induced DNA adducts in the breast of female ACI rats
2005 Study Abstract
Diethylstilbestrol (DES) is metabolized to reactive intermediates that produce DNA adducts and ultimately cancer. Diallyl sulfide (DAS) has been shown to inhibit the metabolism of several procarcinogens.
The ability of DES to produce DNA adducts in microsomal, mitochondrial, and nuclear in vitro metabolic systems and in the breast of female ACI rats, as well as ability of DAS to inhibit DNA adducts were investigated.
Microsomes, mitochondria, and nuclei isolated from breast tissue of female ACI rats were used to catalyze oxidation reactions. Female ACI rats were treated i.p. as follows: (1) corn oil, (2) 200mg/kg DES, (3) 200mg/kg DES/200mg/kg of DAS, (4) 200mg/kg DES/400mg/kg DAS. DES produced DNA adducts in each metabolic system. The relative adduct levels were 2.1 x 10(-4), 6.2 x 10(-6), and 2.9 x 10(-7) in microsomal, mitochondrial, and nuclear reactions, respectively. DAS inhibited DNA adducts in each metabolic system. The percent inhibition ranged from 86% in microsomes to 93% in nuclei.
DES produced DNA adducts in mtDNA and nDNA. DAS completely inhibited the DES-induced mtDNA adducts and caused a dose dependent decrease in nDNA adduct formation.
These findings suggest that DAS could inhibit DES-induced breast cancer by inhibiting its metabolism.
Diallyl sulfide inhibits diethylstilbesterol-induced DNA adducts in the breast of female ACI rats, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, NCBI PubMed PMID: 15989972, 2005 Sep.
In 1971, the US Food and Drug Administration contraindicated its use in pregnancy when DES was associated with the development of vaginal clear cell adenocarcinoma (CCA) in daughters exposed in utero.
In daughters whose mothers took DES during pregnancy, the drug has been associated with congenital malformations of the reproductive tract, fertility problems, a possible increased risk of cervical carcinoma in situ, and a presumed lifetime risk of vaginal and cervical CCA.
DES mothers have an increased risk of breast cancer (RR = 1.3).
DES sons have an increased prevalence of urogenital anomalies, and a possible increased risk of testicular cancer.
DES exposure and the aging woman: mothers and daughters, Current women’s health reports, NCBI PubMed PMID: 12215312, 2002 Oct.
Can estrogenic radicals, generated by lactoperoxidase, be involved in the molecular mechanism of breast carcinogenesis?
2000 Study Abstract
Mutations of regulatory genes, which perturb the mechanism of cell replication resulting in abnormal cell proliferation, are the main cause of cancer.
Many endogenous and exogenous chemicals (including estrogenic hormones) are known to represent a major carcinogenic risk for humans. 2-OH- and 4-OH-derivatives of estrogenic molecules have been shown to form stable adducts with purine DNA bases and act as ‘depurinating’ agents, thus altering gene transcription.
Lactoperoxidase (LPO), which is produced by mammary glands, is likely to be involved in breast carcinogenesis, because of its ability to interact with estrogenic hormones and oxidise them through two one-electron reaction steps.
We investigated the reactivity of LPO towards five molecules:
17-beta-estradiol (a natural hormone),
diethylstilbestrol (a synthetic drug, supplied to pregnant women for preventing spontaneous abortion),
exestrol (a synthetic antigonadotropic estrogen),
and 4-OH-estradiol (catabolic products of estradiol).
Enzymatically generated radical derivatives of such molecules were stabilized by spin-trapping or by chelation of a diamagnetic metal ion and characterized with EPR spectroscopy. A kinetic study of the oxidation process was carried out using EPR and UV-visible spectroscopy.
Can estrogenic radicals, generated by lactoperoxidase, be involved in the molecular mechanism of breast carcinogenesis?, Redox report : communications in free radical research, NCBI PubMed PMID: 10994878, 2000.
DES induces in HBEC phenotypic changes indicative of cell transformation, associated with significant genomic alterations
2001 Study Abstract
Epidemiological and clinical evidences indicate that breast cancer risk is associated with prolonged ovarian function that results in elevated circulating levels of steroid hormones. Principal among these is estrogen, which is associated with two important risk factors, early onset of menarche and late menopause.
However, up to now there is no direct experimental evidence that estrogens are responsible of the initiation of human breast cancer. We postulate that if estrogens are causative agents of this disease, they should elicit in human breast epithelial cells (HBEC) genomic alterations similar to those exhibited by human breast cancers, such as DNA amplification and loss of genetic material representing tumor suppressor genes. These effects could result from binding of the hormone to its nuclear receptors (ER) or from its metabolic activation to reactive metabolites.
This hypothesis was tested by treating with the natural estrogen 17beta-estradiol (E2) and the synthetic steroid diethylstilbestrol (DES) MCF-10F cells, a HBEC line that is negative for ER. Cells treated with the chemical carcinogen benzo (a) pyrene (BP) served as a positive control of cell transformation.
BP-, E2-, and DES-treated MCF-10F cells showed increases in survival efficiency and colony efficiency in agar methocel, and loss of ductulogenic capacity in collagen gel. The largest colonies were formed by BP-treated cells, becoming progressively smaller in DES- and E2-treated cells. The loss of ductulogenic capacity was maximal in BP-, and less prominent in E2- and DES-treated cells. Genomic analysis revealed that E2- and DES-treated cells exhibited loss of heterozygosity in chromosomes 3 and 11, at 3p21, 3p21-21.2, 3p21.1-14.2, and 3p14.2 14.1, and at 11q23.3 and 11q23.1-25 regions, respectively. It is noteworthy that these loci are also affected in breast lesions, such as ductal hyperplasia, carcinoma in situ, and invasive carcinoma.
Our data are the first ones to demonstrate that estrogens induce in HBEC phenotypic changes indicative of cell transformation and that those changes are associated with significant genomic alterations that might unravel new pathways in the initiation of breast cancer.
Carcinogenicity of estrogens in human breast epithelial cells, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, NCBI PubMed PMID: 11297193, 2001 Jan.