Diethylstilbestrol prenatal exposure affects later personality in humans
1977 Study Abstract
Seventy-one offspring of mothers administered combinations of synthetic progestins and estrogen for the maintenance of at-risk pregnancy were evaluated for their performance on IQ and personality tests. Siblings born of untreated pregnancies acted as controls. Hormone-exposed subjects were partitioned into three treatment subgroups dependent on the ratio of progestin to estrogen administered to their mothers during pregnancy.
Prenatal exposure to synthetic progestins and estrogens: Effects on human development, Springer International Publishing AG, Part of Springer Nature, Archives of Sexual Behavior, Volume 6, Issue 4, pp 257–2881977, DOI: 10.1007/BF01541201, July 1977.
Image credit Eva Rinaldi.
No difference in IQ was obtained among the three treatment subgroups even when scores were adjusted for sibling score and prenatal and perinatal complications. Responses to the personality questionnaire provided significant differences among the three groups. The group exposed to the progestin regime (progestin alone or in combination with very low doses of estrogen) and the estrogen regime (higher doses of estrogen than progestin) were most dissimilar. Progestin regime exposed subjects were characterized as more independent, sensitive, self-assured, individualistic, and self-sufficient. In contrast, the subjects exposed to the estrogen regime were more group oriented and group dependent. Analysis of difference scores generated by subtracting the score of an unexposed sibling from that of the exposed cosibling provided similar results.
A general discussion is presented on the efficacy of hormone treatment for pregnancy maintenance, augmented fetal wastage of males, birth order and treatment, maternal knowledge of treatment and its possible postnatal effects on the offspring, and drug effects on the fetus.
Of all the estrogens used for pregnancy maintenance, the synthetic diethylstilbestrol (DES) was perhaps the most widely administered, in part because of its inexpensiveness, its activity when given in oral form, and its potency: “five times that of estradiol if administered orally and only slightly less active if injected” (Noller and Fish, 1974). When the action of DES was compared to that of the natural estrogens, their effects were found to be similar, and therefore
In 1948 Smith recommended that DES be given for some of the complications of pregnancy, begining with 5 mg per day as early in gestation as possible, and that the dose be increased by 5 mg per day every 2 weeks and then every week up to 125 mg daily, and discontinued at the 35 th week. The 1950 Physician’s Desk Reference recommended this same dosage for threatened abortion, and as late as 1967 the Physician’s Desk Reference recommended large amounts of stilbestrol for complications of pregnancy. (Lanier et al., 1973)
It has been established that in the decade from 1945 to 1955 between 500,000 and 3 million women received DES (Noller and Fish, 1974), and Heinonen (1973) calculated that between 1960 and 1970 each year 33,000- 100,000 children were exposed. Combining the estimates for 1945-1971 in the United States alone, approximately 980,000 to 4.5 million boys and girls were born of pregnancies treated with DES. In 1971 the Federal Drug Administration removed DES from the market because of the possible relationship between prenatal exposure and clear-cell adenocarcinoma of the cervix and vagina (Lanier et al., !973).
Given the large number of exposed individuals in the United States, it is curious that only one study of the possible psychological effects of prenatal DES and estradiol has been carried out (Yalom et al., 1973). This investigation evaluated nondiabetic male offspring of diabetic mothers who received estrogen or DES in combination with progestin during pregnancy at the Joslyn Clinic in Boston. The two experimental groups included twenty 16-year-olds whose mothers received a combination of DES and hydroxyprogesterone acetate, and twenty 6-year-olds whose mothers were treated with estradiol and hydroxyprogesterone acetate. Both experimental groups were also divided by dosage and timing of estrogenic treatment. The control groups consisted of eight 16-year-old sons of diabetic mothers who had not received hormone treatment plus fourteen 16-year-olds of nondiabetic mothers matched for age and socioeconomic status. The contrast groups for the 6-year-old was made up of 17 subjects matched for age and socioeconomic status.
The results revealed that
16-year-old sons of hormone-treated diabetic mothers were less aggressive, less assertive, had less athletic skill and grace, and performed less well on the embedded figure task. Six year old experimental subjects were rated by their teachers as less assertive and poorer athletically than the normal contrast subject sample.
Interestingly, in most cases it was the non-exposed 16-year-old sons of diabetic mothers who were significantly more masculine than the DES-exposed 16-year olds rather than the sons of untreated non-diabetic mothers. The authors suggested, albeit tentatively, that this finding indicated “it is not the diabetes but the hormone administration which influenced the psychosocial development to move in the direction we have described.” Analysis of the data on the DES-exposed older subjects showed a trend toward “low dose, late initiation Of hormone to be related to ‘feminine’ behavior.” There was no relationship between behavior and timing in the 6-year-olds, and the dosage/behavior relationship was in the opposite direction. The authors offered no explanation for these results.
There are a number of problems with this study:
- The relationship among dosage, timing, and behavior could also have been interpreted as high dosage-early administration resulting in more masculine behavior.
- The authors did not take into account the progestin administered because they suggested it did not represent any considerable increment in the amount of progesterone normally available to the fetus. However, it has not been ascertained how much of an increment is sufficient to produce an effect.
- Most importantly, Yalom et al. stated:
A major uncontrolled variable in the study was the state of health of the mothers in the experimental and contrast groups. The mothers of all the experimentals suffered from a chronic illness requiring daily attention. Only eight of the 37 contrast mothers were also diabetic, and the severity of their diabetes was less. It is possible that chronic illness in the mother induces overprotection of offspring or greater anxiety over health in offspring so as to interfere with aggressive masculine development./t could also be that some endocrine disorder in diabetic women, irrespective of exogenous hormone administration, may have affected the fetal development of the boys. (Italics added.)
Although certainty of interpretation cannot be assured from these data, the evidence on chronic serious diabetes renders the second hypothesis most parsimonious. For example, Jost (1973) described some of the effects on the fetus of maternal diabetes. This condition
results in hyperglycemia, ketosis, and other maternal plasma changes. Hyperglycemia is reflected in the fetus and might be responsible for the fetal hyperinsulinism. Moreover, antibodies to insulin, when present in the maternal plasma, reach the fetus and inactivate fetal insulin.
Further, Forfar and Nelson (1973), in a paper discussing the efficacy of drugs during pregnancy, suggested that when evaluating the effect of a maternal drug treatment on the fetus one must consider that
An association between the consumption of a drug during pregnancy and an adverse effect on the fetus does not necessarily imply causation. For instance, where illness in a pregnant mother has been treated with drugs, it may be impossible to differentiate a possible effect of illness on the fetus as opposed to a drug used to treat the illness.
Despite the above reservations, the finding of a relationship between “feminized” behavior and prenatal treatment with estrogen in human males is interesting in that it parallels the results of the investigations with animals.
Download the full study on germline exposures.