Prenatal exposure to DiEthylStilbestrol and sexual orientation in men and women

2011 Study Abstracts

Introduction

Both sexual orientation and sex-typical childhood behaviors, such as toy, playmate and activity preferences, show substantial sex differences, as well as substantial variability within each sex. In other species, behaviors that show sex differences are typically influenced by exposure to gonadal steroids, particularly testosterone and its metabolites, during early development (prenatally or neonatally).

Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior, National Institutes of Health, Front Neuroendocrinol; 32(2): 170–182, NCBI PubMed PMC3296090, 2011 Apr.

This article reviews the evidence regarding prenatal influences of gonadal steroids on human sexual orientation, as well as sex-typed childhood behaviors that predict subsequent sexual orientation. The evidence supports a role for prenatal testosterone exposure in the development of sex-typed interests in childhood, as well as in sexual orientation in later life, at least for some individuals. It appears, however, that other factors, in addition to hormones, play an important role in determining sexual orientation. These factors have not been well-characterized, but possibilities include direct genetic effects, and effects of maternal factors during pregnancy. Although a role for hormones during early development has been established, it also appears that there may be multiple pathways to a given sexual orientation outcome and some of these pathways may not involve hormones.

PRENATAL EXPOSURE TO DES AND SEXUAL ORIENTATION IN MEN

The possibility that exposure to ovarian hormones before birth influences sexual orientation in males also has been investigated. These studies have produced largely negative results. One study compared two groups of men exposed to the synthetic estrogen, DES, prenatally to matched controls. One group included 17 men exposed to DES alone and the second included 21 men exposed to DES along with natural progesterone. The study also included 10 men exposed prenatally to natural progesterone alone and 13 men exposed prenatally to synthetic progestins alone. Each of these groups was compared to matched controls. None of the four groups of hormone-exposed men differed from their respective controls in sexual orientation in fantasy or behavior. In addition, for all four samples combined, non-heterosexual orientation was reported by 8 of the 61 hormone-exposed men (13%), and by 8 of the 60 control men (13%). Two other research teams also have looked at sexual orientation in men exposed to DES prenatally, and have found no evidence of reduced heterosexual orientation. One studied 46 men exposed to DES and 29 unexposed controls. Men exposed to DES had somewhat more heterosexual coital experience than did controls, but did not differ in the number of heterosexual or homosexual coital partners. The second compared 1,342 DES-exposed men to 1,342 unexposed men, and found no difference in the numbers reporting sexual experience with a partner of the same sex, although, as noted above, this study used a relatively insensitive procedure for assessing sexual orientation. Nevertheless, the findings overall suggest that prenatal exposure to estrogen does not feminize sexual orientation in developing males, and this conclusion is consistent with predictions from results of experimental studies in other species, where early exposure of male animals to estrogen does not promote the development of female-typical behavior.

Prenatal exposure to DES and sexual orientation in women

One research team has studied three samples of women exposed prenatally to DES. The first sample included 30 women exposed to DES, 30 unexposed women recruited from the same gynaecological clinic and 12 unexposed sisters of the DES-exposed women. All of the participants had abnormal PAP smear findings. (Although DES rarely, if ever, causes genital virilization, prenatal exposure is often associated with abnormal PAP smears). Sexual orientation was assessed by interview and rated using Kinsey scale scores, and a global rating for lifelong sexual responsiveness (behavior and fantasy combined) was reported for 29 of the DES-exposed women and 30 of the controls. DES exposure was associated with reduced heterosexual orientation. Although 76% of the DES-exposed women were exclusively or almost exclusively heterosexual for lifetime scores, 24% were not. The comparable figure for the matched controls with abnormal PAP smear findings was 0%. The subset of 12 sister pairs showed a similar pattern with 42% of the DES-exposed sisters being not exclusively or almost exclusively heterosexual for their lifetime in terms of fantasy or behavior, compared to 8% of their unexposed sisters. Among the total group of DES-exposed women, five had experienced homosexual activities involving genital contact and two were living with a female partner. The same research team later reported data from this initial study along with data from two more samples of women exposed to DES prenatally. The first additional sample included 30 DES-exposed women, 30 demographically matched controls, with no history of DES-exposure or abnormal PAP smears, and 8 unexposed sisters. In this sample, a global Kinsey rating for lifelong sexual responsiveness was reported for 29 of the DES-exposed women and 30 of the matched controls. For the exposed group, 35% were not exclusively or almost exclusively heterosexual, whereas for the control group the comparable figure was 13%. Among the 20 sister pairs in the first and second samples, 40% of the DES-exposed group, compared to 5% of their sisters, were not exclusively or almost exclusively heterosexual. The second additional sample included 37 DES-exposed women whose mothers’ obstetrical files indicated prescription of at least 1000 mg of DES during the pregnancy, and age-matched daughters of women from the same obstetrical practice, whose mothers’ files showed that no DES was prescribed. For these women, 16% of the DES-exposed group and 5% of the unexposed group were not exclusively or almost exclusively heterosexual. For all three samples combined, 24% of the DES-exposed women, and 6% of the control women were not exclusively or almost exclusively heterosexual.

A separate investigation of women exposed to DES prenatally concluded that this exposure did not influence their sexual orientation. This study included 3,946 women exposed prenatally to DES and 1,740 women not exposed to DES. The DES-exposed women were somewhat less likely than the unexposed women to have had sex with a female partner. The DES-exposed women also were more likely than the unexposed women to have ever married, and for those who had had sexual intercourse with a man, were less likely to have had sexual intercourse before age 17 or to have had more than one sexual partner. These last differences raise questions about the comparability of the exposed and unexposed groups, and, although the large sample is impressive, the assessment of sexual orientation, in terms of a single question regarding sexual behavior, is relatively insensitive.

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Handedness and other laterality indices in women prenatally exposed to DES

image of left wrist.

Many DES Daughters more likely to be left handed

1995 Study Abstract

A group of 175 women who had been exposed to diethylstilbestrol (DES) prenatally were compared with 219 unexposed control subjects on four laterality indices: handedness, footedness, eyedness, and earedness.

Handedness and other laterality indices in women prenatally exposed to DES, US National Library of Medicine National Institutes of Health, Journal of clinical and experimental neuropsychology, PubMed PMID: 8557813, 1995 Oct.

Left hand image credit katie.

It was found that there was a higher incidence of left-handedness among the DES-exposed subjects than among the controls.

It was concluded that intrauterine exposure to the synthetic estrogen DES disturbs the normal process of cerebral lateralization.

The mechanism by which this takes place is still unknown.

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Psychological consequences of DES exposure in utero

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DES-exposed persons in utero have an increased risk of experiencing psychological disorders and should be monitored accordingly

2011 Study Abstract

Between the 1950s and the late 1970s, millions of women worldwide took diethylstilbestrol (DES) during pregnancy. It was claimed that DES prevented miscarriage, even though a clinical trial was interrupted in 1953 when an interim analysis showed no beneficial effect in the prevention of miscarriage.

Psychological consequences of DES exposure in utero, US National Library of Medicine National Institutes of Health, Neuropsychologia, Prescrire International, PubMed PMID: 22066313, 2011 Nov.

Image credit Dave C.

In 1971, it emerged that DES exposure in utero was associated with somatic effects in adulthood, including female genital abnormalities with obstetric consequences, vaginal cancer, and male urogenital disorders.

This article examines the psychological effects of exposure to DES in utero, based on a review of the literature using the standard Prescrire methodology.

  • In two experimental studies, mice exposed to DES during gestation were found to be more aggressive than unexposed mice.
  • A randomised clinical trial and epidemiological studies have pointed to a risk of psychological disorders during adolescence and adulthood after DES exposure in utero.
  • A placebo-controlled randomised trial of DES was conducted in London in the 1950s but was never published.
  • In the 1980s, a research team recovered some of the original data and obtained information on the adult health status of the persons exposed in utero. Compared to the placebo group, psychological disorders were twice as frequent in the adults who were likely to have been exposed to DES in utero.
  • Three large epidemiological studies were also conducted.
    • One study showed that major depressive episodes were about 1.5 times more frequent in women exposed to DES in utero than in unexposed women;
    • the second showed that exposed women had an episode of major weight loss more often than unexposed women;
    • while the third showed no significant difference between the groups in terms of depressive episodes.
  • Smaller studies also suggest that depressive episodes tend to be more frequent after DES exposure in utero.

In practice, these data suggest that persons exposed to DES in utero have an increased risk of experiencing psychological disorders and should be monitored accordingly.

More DES DiEthylStilbestrol Resources

Handedness in women with intrauterine exposure to DES

Many DES Daughters more likely to be left handed

1994 Study Abstract

Completed forms containing the Edinburgh handedness inventory were received from 77 women exposed to diethylstilbestrol (DES) in utero.

Handedness in women with intrauterine exposure to diethylstilbestrol, US National Library of Medicine National Institutes of Health,  Neuropsychologia, PubMed PMID: 8084419, 1994 May.

Left hand image credit Sor Cyress.

Laterality scores (LSs; range: -100 to +100) were calculated for each respondent based on the handedness inventory and were compared with LSs from 514 female controls.

The handedness distribution in the DES daughters was significantly shifted away from strong righthandedness compared with the handedness distribution in the controls (chi-square = 22.0, P < 0.0001).

Possible explanations for the association between handedness and DES exposure are presented, and aspects of handedness measurement are discussed.

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Diethylstilbestrol Exposure in Utero and Depression in Women

DES Daughters have a higher risk of depressive symptoms and use of antidepressants

2010 Study Abstract

Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor.

Diethylstilbestrol Exposure in Utero and Depression in Women, Oxford University Press, American Journal of Epidemiology, , doi.org/10.1093/aje/kwq023, 23 March 2010.

Image credit Hartwig HKD.

The association between in utero DES exposure and depression was assessed among participants in the Nurses’ Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995–2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004).

These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects.

Summary

We found that women who were exposed to DES in utero had a higher risk of depressive symptoms and use of antidepressants, and that this increase in risk extended into their middle age. Although the possibility that some women became depressed because of awareness of their exposure status cannot be ruled out, these results are consistent with the hypothesis that the physiologic effects of in utero exposure to DES lead to higher rates of depression during adult life. It remains to be established whether prenatal exposures to ubiquitous environmental chemicals that are structurally similar to DES and have similar estrogenic effects also increase the risk of depression.

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Play behavior affected by early administration of diethylstilbestrol during development

EDCs are able to influence the development of the brain during a critical period, resulting in long-term effects on behavior

2005 Study Abstract

Play behavior is affected by alteration of the hormonal environment during development. In fact, congenital adrenal hyperplasia or early administration of diethylstilbestrol are able to modify female play behavior in mammals.

Early exposure to a low dose of bisphenol A affects socio-sexual behavior of juvenile female rats, US National Library of Medicine National Institutes of Health, Brain research bulletin, NCBI PubMed, PMID: 15811590, 2005 Apr.

Image credit Philippa Willitts.

In this research, play behavior of female rats was used to explore the effects of perinatal exposure to low, environmentally relevant dose of bisphenol A (BPA), a xenoestrogen widely diffused in the environment.

We used 18 females born to mothers exposed to 40 microg/kg/day BPA during pregnancy and lactation, and 18 control females. The subjects were observed in a heterosexual social situation from 35 to 55 days of age.

Six main behaviors were identified by principal component analysis (PCA): exploration, defensive behavior to males, play behavior with males, play behavior with females, low-intensity mating behavior, social grooming. Early administration of BPA was responsible for a significant increase of exploration (including social investigation) (p<0.001), as well as a decrease of play with males (p<0.02) and social grooming (p<0.01) at 45 days of age, indicating a general decrease of playful interactions.

In general our results suggest that BPA does not induce a clear masculinization of female behavior, but is able however to defeminize some aspects of female behavior. This result is compatible with the estrogenic properties of BPA, and suggests caution in the use of a chemical that, in the range of human exposure, is able to influence the development of the brain during a critical period, resulting in long-term effects on behavior.

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Psychosexual characteristics of men and women exposed prenatally to DES

DES Follow-up Study

Animal studies suggest that estrogen affects the developing brain, including the part that governs sexual behavior and right and left dominance. We examined the potential impact of prenatal DES exposure on these characteristics in 2,684 men and 5,686 women participating in the NCI DES Follow-up Study.

DES Follow-up Study, National Cancer Institute, bibliography_Psychosexual_summary, 2003.

Image credit neilcraver.

Information on marital status, sexual behavior, and handedness was reported by subjects on a questionnaire. Responses indicated that DES neither influenced sexual behavior nor resulted in an increased likelihood of homosexual contact. In sons, DES was unrelated to the likelihood of ever having been married or of having a same-sex sexual partner in adulthood, age at first intercourse and number of sexual partners. DES Daughters were slightly more likely than unexposed women to have ever been married but were less likely to report having had a same-sex sexual partner, having had their first sexual intercourse before age 17 and to having had more than one sexual partner.

DES Daughters were just as likely as unexposed women to be left-handed. DES Sons were slightly more likely to be left-handed than unexposed men. Overall, about 17% of women reported a mental illness, but we found no evidence that it was more frequent in the exposed than the unexposed women. Mental illness was not assessed in the men.

2003 Study Abstract

Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol, US National Library of Medicine, Epidemiology, NCBI PubMed PMID: 12606880, 2003 Mar.

BACKGROUND
Between 1939 and the 1960s, the synthetic estrogen diethylstilbestrol (DES) was given to millions of pregnant women to prevent pregnancy complications and losses. The adverse effects of prenatal exposure on the genitourinary tract in men and the reproductive tract in women are well established, but the possible effects on psychosexual characteristics remain largely unknown.

METHODS
We evaluated DES exposure in relation to psychosexual outcomes in a cohort of 2,684 men and 5,686 women with documented exposure status.

RESULTS
In men, DES was unrelated to the likelihood of ever having been married, age at first intercourse, number of sexual partners, and having had a same-sex sexual partner in adulthood. DES-exposed women, compared with the unexposed, were slightly more likely to have ever married (odds ratio [OR] = 1.1; confidence interval [CI] = 1.0-1.4) and less likely to report having had a same-sex sexual partner (OR = 0.7; CI = 0.5-1.0). The DES-exposed women were less likely to have had first sexual intercourse before age 17 (OR = 0.7; CI = 0.6-0.9) or to have had more than one sexual partner (OR = 0.8; CI = 0.7-0.9). There was an excess of left-handedness in DES-exposed men (OR = 1.4; CI = 1.1-1.7) but not in DES-exposed women. DES exposure was unrelated to self-reported history of mental illness in women.

CONCLUSIONS
Overall, our findings provide little support for the hypothesis that prenatal exposure to DES influences the psychosexual characteristics of adult men and women.

More DES DiEthylStilbestrol Resources

DES exposure : implications for health care providers

Why did DES Daughters develop an enduring distrust of the medical profession?

2000 Study Abstract

A focus group study of women exposed to diethylstilbestrol (DES) in utero (DES daughters) was conducted to gain understanding about exposure to this drug from a patient perspective.

A focus group study of DES daughters: implications for health care providers, US National Library of Medicine, Psycho-oncology, NCBI PubMed PMID: 11038482, 2000 Sep-Oct.

Image credit chinagrrrl.

Focus group participants reported that learning about their DES exposure was devastating; they experienced strains in their family relationships, emotional shock, a feeling that their health concerns were not appreciated by others and, to some degree, a sense of social isolation.

Although many were aware of the need for special gynecological exams and high-risk prenatal care, they were frustrated by what they felt was a lack of reliable and clear information about the effects of DES exposure.

Most expressed questions and anxiety about their health.

Many found their communication with physicians about their DES exposure unsatisfying. They felt that physicians lacked information about the long-term health effects of DES exposure and as a result did not give them accurate information. Furthermore, they felt that physicians were dismissive of their concerns and often gave what they felt to be false reassurances. Consequently, the women developed an enduring distrust of the medical profession.

The results of the study suggest implications for the delivery of health care to DES daughters.

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Language lateralization and handedness in DES-exposed women

Many DES Daughters more likely to be left handed for writing

2000 Study Abstract

Hand preferences and language lateralization were assessed in women exposed prenatally to the synthetic estrogen, diethylstilbestrol (DES), and in their unexposed sisters.

Language lateralization and handedness in women prenatally exposed to diethylstilbestrol (DES), US National Library of Medicine, Psychoneuroendocrinology, NCBI PubMed PMID: 10818283, 2000 Jul.

Image credit amymememe.

The DES-exposed women showed an increased degree of hand preference (regardless of direction) and were more likely to be left handed for writing. However, the groups did not differ significantly on a dichotic listening measure of language lateralization.

Perhaps as a result of the alterations in hand preferences, the typical relationship between hand preferences and language lateralization was disrupted in the DES-exposed group. Also, within the DES-exposed group, exposure early in gestation correlated with left handedness whereas exposure late in gestation correlated with reduced left ear (right hemisphere) scores on the verbal dichotic task.

Results are discussed in terms of theoretical perspectives predicting hormonal influences on sexual differentiation of hemispheric asymmetry and in terms of separate critical periods for hormonal effects on individual sexually differentiated characteristics.

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