Impact of prenatal exposure to DES on psychological outcome

A national survey of DES daughters and unexposed controls

2017 STUDY ABSTRACT

Impact of prenatal exposure to diethylstilbestrol (DES) on psychological outcome: a national survey of DES daughters and unexposed controls, US National Library of Medicine National Institutes of Health, Archives of women’s mental health, NCBI PubMed PMID: 28064340, 2017 Jan 7.

Image credit Maciej Kraus.

To explore whether prenatal exposure to diethylstilbestrol (DES) is associated with increased risk of poor psychological outcome independently of the occurrence of major somatic complications related to DES exposure. Data on health outcome were collected in women prenatally exposed to DES (n = 2566) and unexposed women (n = 2967) recruited in a French national survey.

Women prenatally exposed to DES were 1.7 times more likely to have consulted a mental health specialist compared to unexposed women (adjusted odds ratio = 1.69, 95% confidence interval 1.47-1.96), independently of demographic characteristics, poor gynecological or obstetrical outcome, or history of cancer.

Frequency of consultation with a mental health specialist in persons with a history of gynecological complications or cancer was comparable in women prenatally exposed to DES and unexposed women.

Findings regarding psychological outcome obtained in the high-risk group of women prenatally exposed to DES may contribute to improving identification of psychological needs of all women presenting with gynecological abnormalities.

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Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood

Evidence from a French cohort of 1002 prenatally exposed children

2016 STUDY ABSTRACT

Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children, US National Library of Medicine National Institutes of Health, The official journal of the International Society of Gynecological Endocrinology, NCBI PubMed PMID: 26172930, 2016 Sep.

Image credit JustCallMe_Bethy.

In utero diethylstibestrol (DES) exposure has been demonstrated to be associated with somatic abnormalities in adult men and women. Conversely, the data are contradictory regarding the association with psychological or psychiatric disorders during adolescence and adulthood. This work was designed to determine whether prenatal exposure to DES affects brain development and whether it is associated with psychiatric disorders in male and female adolescents and young adults.

HHORAGES Association, a national patient support group, has assembled a cohort of 1280 women who took DES during pregnancy. We obtained questionnaire responses from 529 families, corresponding to 1182 children divided into three groups:

  1. Group 1 (n=180): firstborn children without DES treatment,
  2. Group 2 (n=740): exposed children,
  3. and Group 3 (n=262): children born after a previous pregnancy treated by DES.

No psychiatric disorders were reported in Group 1.
In Group 2, the incidence of disorders was drastically elevated (83.8%),
and in Group 3, the incidence was still elevated (6.1%) compared with the general population.

This work demonstrates that prenatal exposure to DES is associated with a high risk of psychiatric disorders in adolescence and adulthood.

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DES and the risk of psychiatric disorders

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A critical review and new insights

2012 Study Abstract

Diethylstilbestrol and risk of psychiatric disorders: a critical review and new insights, US National Library of Medicine National Institutes of Health, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, NCBI PubMed PMID: 21428730, 2012 Feb.

Image credit Karina Lamontagne.

OBJECTIVES
We explored whether in utero DES exposure has produced consistent findings with regard to an increased risk of psychiatric disorders.

METHODS
We reviewed systematically the epidemiological studies investigating a possible association between prenatal DES exposure and risk of psychiatric disorders.

RESULTS
We identified 10 relevant studies reporting the psychiatric outcome of offspring with a history of in utero DES exposure compared to a control group.

We classified them into four categories:

  1. a mail survey in a sample from a randomized double-blind controlled trial of prophylactic DES for first pregnancy in the early 1950s reported that depression and anxiety were twice as frequent in the exposed group compared to the placebo group;
  2. five small clinical samples with inconclusive results;
  3. two large cohorts of DES-exposed participants:
    1. the first study reported a higher lifetime history of weight loss related to anorexia nervosa
    2. the second did not found any significant difference;
  4. two subsamples from general population cohorts:
    1. the first study did not found any significant difference
    2. the second reported that exposed women showed a higher rate of incident depression than non-exposed women.

CONCLUSIONS
The role of prenatal exposure to DES as an environmental risk factor for psychiatric disorders requires more evidence before any conclusions can be drawn. If confirmed, several explanations could be proposed: gene × environment interaction and epigenetic mechanisms, although phenocopy and gene-environment aggregation are plausible.

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Prenatal estrogens and the development of homosexual orientation

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DES Daughters more likely to be rated as bisexual or homosexual

1995 Study Abstract

In psychobiological research on sexual orientation, the prenatal hormone theory has a central position.

Prenatal estrogens and the development of homosexual orientation, Developmental Psychology, ResearchGate, January 1995.

Image credit torbakhopper.

This article examines the hypothesis that prenatal estrogens contribute to the development of human sexual orientation.

Several groups of women with a history of prenatal exposure to diethylstilbestrol (DES), a nonsteroidal synthetic estrogen, were compared with several samples of control women in the context of a comprehensive study of the psychiatric and psychologic effects of prenatal DES.

Various aspects of sexual orientation were assessed by systematic interview.

Consistently across samples, more DES-exposed women than controls were rated as bisexual or homosexual (scores 2–6 on Kinsey-format scales ranging from 0 to 6).

The data are compatible with the hypothesis that prenatal estrogens may play a role in the development of human sexual orientation.

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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.

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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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