A case report is presented of the failure of diethylstilbestrol to prevent an ectopic pregnancy.
A 29-year-old physician’s wife, gravida 4, para 2, abortuses 2, received 25 mg diethylstilbestrol twice daily for 5 days beginning on Day 14 of the menstrual cycle after condom accident during intercourse the prior night. Withdrawal bleeding did not occur. The patient’s menstrual period before the condom accident had begun on August 25, 1971.
In mid-October she returned to the doctor feeling pregnant. The pregnancy test was positive on October 18, 1971, and physical examination revealed a soft uterus of about 7 weeks’ gestation.
Because of the fear of congenital defects in the fetus from diethylstilbestrol, suction curettage was carried out on October 27, 1971.
On October 31, 1971, the patient experienced great pain in the lower left quadrant. Her abdomen was tender and distended, and pelvic examination revealed a bulging cul-de-sac from which culdocentesis revealed nonclotting blood. Laparotomy revealed a ruptured tubal pregnancy on the left side. A left salpingectomy was carried out which pathologically confirmed a tubal pregnancy.
The question of whether diethylstilbestrol prevents implantation in the uterus but not in extrauterine sites is examined. A report by Morris is noted in which the only 3 pregnancies which followed diethylstilbestrol failure were ectopic. It is recommended that others with similar cases report them in order to better understand what occurs.
Ectopic pregnancy after postcoital diethylstilbestrol, American journal of obstetrics and gynecology, PMID: 1115139, 1975 Jan.
According to the International Agency for Research on Cancer (IARC), in-utero exposure to diethylstilbestrol, i.e., when a pregnant woman uses the drug, increases a female child’s risk of developing breast cancer.
The knowledge on the etiology of breast cancer has advanced substantially in recent years, and several etiological factors are now firmly established. However, very few new discoveries have been made in relation to occupational risk factors. The International Agency for Research on Cancer has evaluated over 900 different exposures or agents to-date to determine whether they are carcinogenic to humans. These evaluations are published as a series of Monographs.
For breast cancer the following substances have been classified as “carcinogenic to humans” (Group 1): alcoholic beverages, exposure to diethylstilbestrol, estrogen-progestogen contraceptives, estrogen-progestogen hormone replacement therapy and exposure to X-radiation and gamma-radiation (in special populations such as atomic bomb survivors, medical patients, and in-utero exposure). Ethylene oxide is also classified as a Group 1 carcinogen, although the evidence for carcinogenicity in epidemiologic studies, and specifically for the human breast, is limited.
The classification “probably carcinogenic to humans” (Group 2A) includes estrogen hormone replacement therapy, tobacco smoking, and shift work involving circadian disruption, including work as a flight attendant. If the association between shift work and breast cancer, the most common female cancer, is confirmed, shift work could become the leading cause of occupational cancer in women.
Full study (free access) : Risk Factors for Breast Cancer, Including Occupational Exposures, Saf Health Work, NCBI PubMed PMC3431884, 2011 Mar.
The Population Planning Department School of Public Health University of Michigan
This paper represents an updating of a study done at the University of Michigan Health Service from the fall of 1967 through April, 1971.
Of the 1410 women of child bearing age who received the morning-after pill, diethylstilbestrol, 1298 have received follow-up, or a total of 92.1%.
Of the 1217 patients who met the criteria of having had one unprotected or inadequately protected sexual exposure since the last normal menstrual period, who came in for therapy within 72 hours of the fact, and completed the course of 25 mg of DES twice daily for five days, there were no pregnancies, or 100% effectiveness.
One would have to conclude, with a follow-up of 90%+ that this therapy is highly efficacious.
Influence of high-dose estrogen exposure during adolescence on mammographic density for age in adulthood
2010 Study Abstract
High-dose estrogen exposure during adolescence has been hypothesized to increase a woman’s breast cancer risk, possibly mediated through an increase in mammographic density, a well-established breast cancer risk factor.
In 2006 to 2007, we conducted a retrospective study of women assessed for tall stature as an adolescent between 1959 and 1993. Eligible participants were ages > or =40 years and treated during adolescence with 3 mg diethylstilbestrol or 150 microg ethinyl estradiol daily or untreated. Mammograms from 167 treated and 142 untreated women were digitized.
Total breast area, dense area, nondense area, and percent density were measured using a computer thresholding technique. Data on potential determinants were collected from medical records and telephone interview.
Treated women had, on average, 17% lower dense area (P = 0.032). Means (95% confidence intervals) adjusted for age and body mass index for treated and untreated women were 24.5 cm(2) (21.8-27.2) and 29.1 cm(2) (26.0-32.4), respectively. There was no difference in adjusted means (95% confidence intervals) between treated and untreated women for nondense area [71.7 cm(2) (66.2-77.7) versus 70.5 cm(2) (64.7-76.9); P = 0.78], percent dense area [24.8% (22.4-27.4) versus 27.7% (24.8-30.7); P = 0.16], or total area [105.6 cm(2) (100.1-111.4) versus 109.3 cm(2) (103.1-115.8); P = 0.41], respectively.
High-dose estrogen exposure during adolescence appears to curtail growth of mammographically dense tissue and therefore is unlikely to increase breast cancer risk through mechanisms related to mammographic density.
Full study (free access) : Influence of high-dose estrogen exposure during adolescence on mammographic density for age in adulthood, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, cebp.aacrjournals DOI: 10.1158/1055-9965, January 2010.
Diethylstilbestrol usage as an effective postcoital contraceptive has been lauded
During the past 5 years much emphasis has been placed on the development of an effective postcoital contraceptive (an intraceptive, or “morning-after” pill). Much of the impetus toward this goal has come from college health services and from rape cases. The idea is not new. In 1926, Smith and Parkes and Bellerby demonstrated that administration of estrogen could inhibit pregnancy in laboratory animals. The mechanism of this action was considered to be either a change (increase or decrease) in tubal transport or an effect on the endometrium. Within a few months after the synthesis of DES, Parkes et al. reported a similar DES effect in rabbits. Interestingly, in 1969 Dodds remarked that the possible human implications of this work had not occurred to them in 1939, and so development of oral contraceptives had been delayed many years.
It was the mid 1960’s before DES was again studied actively as a postcoital agent. Primarily through the work of Morris and van Wagenen in primates, DES was shown to be very effective. Kuchera reported the first large series in humans, noting no pregnancies among 1,000 exposures, wherein 20 to 40 pregnancies would have been expected. Morris commented in February 1972 that of “several thousand” midcycle exposures treated with DES, only three failures were known.
The results of these trials prompted the FDA to approve DES for use as a postcoital antifertility agent. The present dosage recommended is 25 mg twice daily for 5 days, beginning within 72 hours of exposure. Because failure can occur (though it is unlikely), the patient must be warned of the possibility of a late effect-Le., development of genital adenocarcinoma-in female offspring. And if pregnancy does ensue, therapeutic abortion should be considered.
The mechanism by which DES prevents pregnancy in humans is not clear. Large doses of most estrogens prevent pregnancy. Ethinyl estradiol has been studied extensively in this regard and is effective. But since a small amount of estrogen is known to be necessary for implantation in most species, including man, small doses of estrogens may promote rather than prevent gestation. Various antiestrogenic drugs also have been shown to prevent pregnancy in some species, but the “results are various and not confirmed in humans. A recent study has confirmed the suspected decrease of plasma progesterone in women receiving DES postovulation and has suggested that this may be the primary reason for inhibition ofimplantation. Endometrial biopsies do not show a persistent proliferative phase; rather, secretory endometrium appears early and persists unchanged throughout the luteal phase. Another postulated explanation of the inhibition of implantation is that the decrease of progesterone causes a change in the concentration of carbonic anhydrase in the endometrium.
Diethylstilbestrol Usage: Its Interesting Past, Important Present, and Questionable Future, Medical Clinics of North America, sciencedirect, July 1974.
The influence of endocrine disrupting chemicals on the proliferation of ERalpha knockdown-human breast cancer cell line MCF-7; new attempts by RNAi technology
2009 Study Abstract
Bisphenol A (BPA) is a monomer use in manufacturing a wide range of chemical products which include epoxy resins and polycarbonate.
It has been reported that BPA increases the cell proliferation activity of human breast cancer MCF-7 cells as well as 17-β estradiol (E2) and diethylstilbestrol (DES). However, BPA induces target genes through ER-dependent and ER-independent manners which are different from the actions induced by E2. Therefore, BPA may be unique in estrogen-dependent cell proliferation compared to other endocrine disrupting chemicals (EDCs).
In the present study, to test whether ERα is essential to the BPA-induced proliferation on MCF-7 cells, we suppressed the ERα expression of MCF-7 cells by RNA interference (RNAi).
Proliferation effects in the presence of E2, DES and BPA were not observed in ERα-knockdown MCF-7 cells in comparison with control MCF-7. In addition, a marker of proliferative potential, MIB-1 labeling index (LI), showed no change in BPA-treated groups compared with vehicle-treated groups on ERα-knockdown MCF-7 cells.
In conclusion, we demonstrated that ERα has a role in BPA-induced cell proliferation as well as E2 and DES. Moreover, this study indicated that the direct knockdown of ERα using RNAi serves as an additional tool to evaluate, in parallel with MCF-7 cell proliferation assay, for potential EDCs.
Full study (free access) : The influence of endocrine disrupting chemicals on the proliferation of ERalpha knockdown-human breast cancer cell line MCF-7; new attempts by RNAi technology, Acta Histochem Cytochem, NCBI PubMed PMC2685020, 2009 Apr 28.
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.
Do oestrogens induce chromosome specific aneuploidy in vitro, similar to the pattern of aneuploidy seen in breast cancer?, Mutation research, NCBI PubMed PMID: 18162433, 2008 Mar.
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.
Possibility of postconception control of fertility using medicamentous nidation inhibitors, Zentralblatt fur Gynakologie, PMID: 4131008, 1973 Dec.
Systematic review and meta-analysis of current evidence, 2007
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.
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.