Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility, Lancet (London, England), NCBI PubMed PMID 15500896, 2004 Oct.
Treatment with oestrogen to reduce the adult height of tall girls has been available since the 1950s. We undertook a retrospective cohort study to assess the long-term effects of this treatment on fertility.
Eligible participants were identified from the records of Australian paediatric endocrinologists who assessed tall girls from 1959 to 1993, and from self-referrals. Individuals included girls who had received oestrogen treatment (diethylstilboestrol or ethinyl oestradiol) (treated group) and those who were assessed but not treated (untreated group). Information about reproductive history was sought by telephone interview.
1432 eligible individuals were identified, of whom 1243 (87%) could be traced. Of these, 780 (63%) completed interviews: 651 were identified from endocrinologists’ records, 129 were self-referred. Treated (n=371) and untreated (n=409) women were similar in socioeconomic and other characteristics. After adjustment for age, treated women
were more likely to have ever tried for 12 months or more to become pregnant without success (relative risk [RR] 1.80, 95% CI 1.40-2.30);
more likely to have seen a doctor because they were having difficulty becoming pregnant (RR 1.80, 1.39-2.32);
and more likely to have ever taken fertility drugs (RR 2.05, 1.39-3.04).
Time to first pregnancy analysis showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse (age-adjusted fecundability ratio 0.59, 95% CI 0.46-0.76). These associations persisted when self-referred women were excluded.
High-dose oestrogen treatment in adolescence seems to reduce female fertility in later life. This finding has implications for current treatment practices and for our understanding of reproductive biology.
Exposure to Diethylstilbestrol during Sensitive Life Stages: A legacy of heritable health effects, National Institutes of Health, NCBI PubMed PMCID: PMC3817964, 2013 June.
Although women were prescribed DES to improve the outcomes of their given pregnancy, the results of a double-blind clinical trial of over 1500 women at the University of Chicago by Dieckmann and coworkers in 1953 demonstrated that DES did not reduce the incidence of spontaneous abortion, prematurity or postmaturity, and the study suggested that DES enhanced premature labor. However, it continued to be used for another nearly 20 years.
DES Pregnancy: DES Daughthers
Hoover determined that DES daughters have an increased risk for many pregnancy-related issues including spontaneous abortion (<14 weeks gestation), ectopic pregnancy, loss of pregnancy in the second trimester (14–27 weeks), preeclampsia, preterm delivery (<37 weeks), stillbirth (at >27 weeks), and neonatal death within the first month of life. Many of these outcomes including ectopic pregnancy, miscarriage, and premature delivery have been reported in more than one study, and appear to be exacerbated effects for which DES was prescribed to prevent.
The effects of prenatal DES exposure on the ability to reproduce are substantial. The risk for infertility (defined as ≥ 12 months of trying to conceive) among DES daughters is reported to be 33% compared to 14% in unexposed women (p<0.001), and full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64.1% of DES exposed women (RR=0.76, 95% CI, 0.72–0.80). The Dutch DES cohort reports that 33% of DES daughters are nulliparous at the age of ≥ 40 yr, compared with only 17% in the Dutch population. Kaufman and co-workers also reported that that once pregnant, 20% of DES daughters experience preterm delivery (versus 8% of unexposed population (RR=2.93; 95% CI, 2.23–3.86)), their risk of ectopic pregnancy was 3 to 5 times higher than unexposed women (RR=3.84; 95% CI, 2.26–6.54), and 20% of the DES-exposed group had a miscarriage during the first pregnancy (versus 10% unexposed (RR=2.00; 95% CI, 1.54–2.60). These adverse pregnancy-related outcomes in DES daughters are also experienced by unexposed women, but the excess risk in those outcomes (not stillbirth) owing to in utero DES exposure was significant. Also, there are strong data suggesting that the presence of vaginal epithelial changes at cohort entry examination adds to the cumulative risk for DES-induced infertility, spontaneous abortion, preterm delivery, and ectopic pregnancy.
Effects of exposure period and dose of diethylstilbestrol on pregnancy in rats, The Journal of veterinary medical science / the Japanese Society of Veterinary Science, NCBI PubMed PMID: 19887736, 2009 Oct. Full text: J-Stage, Laboratory Animal Science, 71/10/71_001309, August 2009.
The aim of this study was to investigate the effect of exposure period and dose of diethylstilbestrol (DES), which has strong estrogenic activity, on pregnancy in rats.
All rats with observed vaginal plugs or sperm in vaginal smear tests after mating were divided into 3 groups:
those fed a normal diet,
a diet mixed with DES throughout pregnancy
and a diet mixed with DES from day 13 of pregnancy.
DES was mixed into the diet at 0.1, 1, 10 and 100 ppm.
All bred rats fed the normal diet and 0.1 ppm DES from day 13 of pregnancy delivered pups, while none of the rats treated with 1-100 ppm DES during pregnancy and 100 ppm DES from day 13 of pregnancy delivered any pups. The number of male and female pups born decreased in rats treated with 10 ppm DES from day 13 of pregnancy.
These results suggest that DES could affect pregnancy and that the exposure period and dose may result in
Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies: Volume I, Institute of Medicine (US) Committee on Ethical and Legal Issues Relating to the Inclusion of Women in Clinical Studies, NCBI PubMed NBK236538, 1994.
Diethylstilbestrol (DES), synthetic estrogen, was first produced in London in 1938. The earliest studies of DES in pregnant women in the United States were conducted at Harvard University in the late 1940s. Although the studies were criticized because they were conducted without the use of controls, the physicians directing the studies concluded that “DES was effective against a variety of pregnancy complications and resulted in a healthier maternal environment“. In 1947 the FDA approved new drug applications (NDAs) to market DES for the purpose of preventing miscarriages.
In the 1950s, however, controlled studies of DES in pregnant women yielded different results. At Tulane University, researchers found that more of the DES-treated women had miscarriages and premature births, while the controls had bigger, healthier babies.
At the University of Chicago, every pregnant woman at the University’s Lying-In Hospital (1,646) was a test subject for a DES experiment without their knowledge or consent, and became part of a clinical trial: one-half were randomized to receive DES and the other half received placebos. None of the women were told they were part of a study, nor were they told what drug they were taking. The study found that twice as many of the DES-treated mothers had miscarriages, premature births, small babies, thereby confirming the finding of a Tulane study that contradicted the original uncontrolled Harvard study which extoled high doses of DES effectiveness against pregnancy complications.
In 1951 the FDA concluded that DES was safe for use during pregnancy and stopped requiring manufacturers to complete NDAs prior to marketing the drug as a preventive against miscarriage.
Despite growing evidence that DES was ineffective and the confirmatory findings of harm, physicians continued prescribing DES for 20 years resulting in numerous birth complications and exposing the unborn daughters and sons of their patients to serious risk of cancers.
Informed Consent: the women in this study did not know that the study was taking place and did not know about the study.
Voluntary Participation: these women did not choose to participate in the study.
Failure to prevent unnecessary harm: the Tulane University study should have been considered before proceeding with this case and ultimately leading to harm.
Self-determination: the women did not have the choice to participate or decline participation in the study.
Declaration of Helsinki Violations
The risk and benefits were not weighed in this study.
The loyalty of the doctor did not lie with the women, but to research and the general population.
The women did not have self-determination prior to or during the study.
The University’s Lying-In Hospital experiment should not have been conducted.
That study violated the Hippocratic Oath, the Nuremberg Code, and the Declaration of Helsinki.
The data results from this study should have been published and used.
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, The Cochrane database of systematic reviews, NCBI PubMed PMID: 12918007, 2003. Full text: The Cochrane Collaboration, doi/10.1002/14651858.CD004353, 26 APR 2003.
Effect of stilbestrol on pregnancy compared to the effect of a placebo, American journal of obstetrics and gynecology, Volume 65, Issue 3, Pages 592–601 0002-9378(83)90615-4, March 1953.
One hundred ninety pregnant women received increasing doses of stilbestrol. Treatment was begun by at least the twentieth week of pregnancy and continued through the thirty-fifth week of pregnancy, unless the patient delivered or aborted while on the treatment. The dose of stilbestrol began with 6.3 mg. to 50 mg. a day and ended with 137.5 mg. a day.
Two hundred three similar women received an indistinguishable placebo and provided a fair comparison.
The stilbestrol had no effect on :
fetal weight and survival,
or the size of the placenta.
The importance of adequate controls is discussed.
All interventions need objective evidence of effectiveness and possible placebo effect should not be ignored. Antenatal oestrogen (stilbestrol) was not shown to be of benefit in preventing adverse fetal outcome. The miscarriage rate, preterm labour, birthweight, stillbirth or neonatal death were not positively influenced by the intervention as compared to the control group.
Another researcher presented his prospective placebo controlled trial in an annual meeting of the American Gynecological Society in 1953, the result of which contradicts Smith’s 1948 theory. The DES tragedy 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 for consumption.
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Library, DOI: 10.1002/14651858.CD004353, 26 APR 2003.
Laboratory evidence in the 1940s was proposed to support the concept that reduced placental hormone production was associated with a variety of adverse pregnancy outcomes such as miscarriage, preterm labour and hypertension in pregnancy. Animal models suggested that diethylstilbestrol, a synthetic oestrogen, was a suitable therapeutic agent. Diethylstilbestrol was thought to cause an increase in placental progesterone secretion because of its stimulatory effects on human chorionic gonadotrophin secretion without responding to negative inhibition by progesterone. On the basis of this, a rationale for providing hormone therapy to women in pregnancy, particularly those at risk of miscarriages, was advanced. Synthetic oestrogens were administered to women, often at an incremental dosage, throughout pregnancy.
1948 Study Abstract (Smith OW)
Diethylstilbestrol in the prevention and treatment of complications of pregnancy, American journal of obstetrics and gynecology, Volume 56, Issue 5, Pages 821–834, AJOG 0002-9378(48)90440-2, November 1948.
” The basis for the use of stilbestrol in pregnancy is briefly reviewed, together with the indications and the dosage schedule recommended. Complete case reports on 632 pregnant women, to whom diethylstilbestrol was given largely for the indications and in the amounts recommended by us, have been analyzed. They have been divided according to the indications for therapy, i.e., threatened abortion (219 cases), abortion prophylaxis (272 cases) and prophylaxis against late pregnancy toxemia, intrauterine death, and premature delivery (98 cases). Although we have not recommended stilbestrol as a definitive measure in later pregnancy, 24 patients were so treated and are considered separetely. Nineteen cases that fell into none of these categories are omitted.
Seventy-eight per cent of the patients who were treated for bleeding between the sixth and twenty-first weeks carried to twenty-eight weeks, and 72 per cent had living and well babies. The highest spontaneous cure rate reported in the literature is 50 per cent. Eighty-three per cent of the patients who were given stilbestrol prophylactically against abortion carried to twenty-eight weeks, and 78 per cent had living and well babies. In the 127 cases who had two to five consecutive abortions prior to the one in which stilbestrol was given, the fetal salvage 77 per cent. In each group it was very significantly higher than the spontaneous cure rate as established by Malpas and Eastman. In the total 491 cases treated for abortion the incidence of abortion and of later pregnancy complications was higher when the dosage schedule was not followed than it was in the group as a whole.
In many of the patients treated prophylactically for late pregnancy complications it was impossible to evaluate the effect of stilbestrol therapy, and this part of our report must be considered preliminary. Twenty-two of them, however, had had three or more previous obstetric abnormalities, 27 had had two or more premature deliveries, 17 had known essential hypertension with bad obstetric histories, and nine had diabetes, six of these with bad obstetric histories. Considering the past obstetric histories of these patients, the course and outcome on stilbestrol gave good indication that the administration of this drug as a preventive measure may be expected to reduce the incidence of those complications of later pregnancy associated with a premature deficiency of the placental steroid hormones, estrogen and progesterone. There was even stronger evidence that the onset of thse complications would be postponed and the fetal mortality reduced. The results of the use of stilbestrol as a definitive measure in later pregnancy were not promising. ”
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes, Cochrane Library, DOI: 10.1002/14651858.CD004353, 26 APR 2003.
The dictum ‘do no harm’ is relevant to the diethylstilboestrol saga of the 1950s. It was demonstrated physiologically that oestrogens and progesterone were necessary for pregnancy continuation. Thus, it was scientifically logical to postulate that diethylstilboestrol might prevent adverse pregnancy outcome. The sound physiological reasoning and impressive results from non-randomised studies resulted in enthusiastic uptake of the treatment before it was adequately tested in controlled clinical trials.
Dieckmann presented his prospective placebo controlled trial in an annual meeting of the American Gynecological Society in 1953, the result of which contradicts the findings of Smith. During discussion time, Smith made a remark: “Our experience with the use of stilbestrol continues to be satisfactory … we are convinced that it has reduced the complications of late pregnancy and saved many babies“. He was at this time an authority in the field and the objective evidence provided by Dieckman was largely ignored. Doctors continued prescribing DES to several million women over the next 20 years. There were no known side effects, and despite lack of objective evidence of effectiveness, both doctors and women were happy with the therapy.
Biological inferences in clinical practice without properly designed clinical trials may lead to more harm than good. All interventions need objective evidence of effectiveness and possible placebo effect should not be ignored. Had the principle of ‘best evidence’ been followed, the embarrassment of diethylstilboestrol as a medical intervention, and the effects on offspring who were exposed to it before birth, would have been avoided.
Reproductive and gynecologic surgical experience in diethylstilbestrol-exposed daughters, American journal of obstetrics and gynecology, NCBI PubMed PMID: 7315913, 1981 Dec.
Information on reproductive history, gynecologic operations, and examinations was analyzed for 338 diethylstilbestrol (DES)-exposed and 298 unexposed women whose mothers participated in an evaluation of DES use in pregnancy 28 years ago.
A history of infrequent menses (less often than every 36 days) was reported more commonly by the exposed women (32%) than by the unexposed women (15%) and the mean duration of menstrual flow was also less.
A greater number of exposed women than unexposed women experienced primary infertility (53 versus 19). The reasons for these differences are not currently known.
Comparison of the outcomes of first pregnancies showed a higher proportion of premature births, spontaneous abortions, and ectopic pregnancies in the exposed women (P less than 0.001).
The difference in the occurrence of ectopic pregnancies was statistically significant (8 versus 0; P less than 0.005).
An adverse pregnancy outcome was more likely in DES-exposed women with cervicovaginal ridges.
However, when the outcome of all pregnancies were considered, 81% of the exposed women had at least one living child.
More exposed women than unexposed women had gynecologic surgical procedures, which may, in part, be due to the increased medical surveillance of the exposed group.
The spectrum of diseases at operation in both groups was similar.
Adnexal masses and pelvic inflammatory disease were more commonly reported among the exposed women while the occurrence of endometriosis in both groups was similar.
For the exposed women who had been examined at the Chicago Lying-In Hospital over a 4-year period, epithelial changes in the vagina had disappeared in 32% and cervicovaginal ridges had disappeared in 57%.
Pregnancy Outcome in 98 Women Exposed to Diethylstilbestrol In Utero, Their Mothers, and Unexposed Siblings, Obstetrics and gynecology, Volume 59 – Issue 3, July 1981.
The reproductive capability and labor complications of 98 women exposed to diethylstilbestrol (DES) in utero were compared with those of three separate control groups. The controls consisted of:
167 age-matched, normal women,
20 siblings not exposed to DES who had achieved pregnancy,
and their mothers.
Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls.
The controls also achieved a higher percentage of desired pregnancies overall; this was statistically significant (89.6 versus 75.0%, P less than .001).
When compared with their mothers, however, the DES-exposed population achieved a greater percentage of desired, viable pregnancies (75.6 versus 67.0%, P less than .001).
The unexposed siblings of the DES women achieved a higher percentage of desired, viable pregnancies than did their exposed sisters (86.9 versus 73.6%, P = .274), but less than the normal population (86.9 versus 89.6%).