Gender Identity, Sexual Orientation, and Sexual Diversity of DES Sons

January 2002 Poll of DES Sons Network Members

Background:
The following question was posted as a “poll” for network members on December 22, 2001 and respondents were allowed until January 13, 2002 to respond:

If you were talking with your closest friend who likes you “just as you are,” what term would you use to represent how you define yourself at the present time? (choose one)

The responses were as follows:

January 2002 Poll of DES Sons Network Members.

* TOTAL: 63 Individual Responses from 102 network subscribers. Response rate approximately 65-70% based on an estimated 90-95 active list participants receiving the survey in January 2002; estimated 10 additional members received survey but were not accessing their computers during the survey period of December 22, 2001 and January 13, 2002.

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DES Sons and Gender Dysphoria, Transsexualism, Disorders of Sexual Differentiation

Initial Evidence from a 5-Year Study
by Scott P. Kerlin, Ph.D.

DES Sons International Network, 2004.

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Effect of prenatal exposure to DES on Müllerian duct development

Prenatal DES exposure may lead to persistence of Müllerian duct remnants in male

1998 Study Abstract

The clinical use of diethylstilbestrol (DES) by pregnant women has resulted in an increased incidence of genital carcinoma in the daughters born from these pregnancies. Also, in the so-called DES-sons abnormalities were found, mainly, the presence of Müllerian duct remnants, which indicates that fetal exposure to DES may have an effect on male sex differentiation.

Effect of prenatal exposure to diethylstilbestrol on Müllerian duct development in fetal male mice, US National Library of Medicine National Institutes of Health, Endocrinology, NCBI PubMed PMID: 9751506, 1998 Oct.

Image credit nature genetics.

Fetal regression of the Müllerian ducts is under testicular control through anti-Müllerian hormone (AMH). In male mice, treated in utero with DES, the Müllerian ducts do not regress completely, although DES-exposed testes do produce AMH. We hypothesized that incomplete regression in DES-exposed males is caused by a diminished sensitivity of the Müllerian ducts to AMH. Therefore, the effect of DES on temporal aspects of Müllerian duct regression and AMH type II receptor (AMHRII) messenger RNA (mRNA) expression in male mouse fetuses was studied.

It was observed that Müllerian duct regression was incomplete at E19 (19 days post coitum), upon DES administration during pregnancy from E9 through E16. Furthermore, analysis of earlier time points of fetal development revealed that the DES treatment had clearly delayed the onset of Müllerian duct formation by approximately 2 days; in untreated fetuses, Müllerian duct formation was complete by E13, whereas fully formed Müllerian ducts were not observed in DES-treated male fetuses until E15. Using in situ hybridization, no change in the localization of AMH and AMHRII mRNA expression was observed in DES-exposed male fetuses. The mRNA expression was quantified using ribonuclease protection assay, showing an increased expression level of AMH and AMHRII mRNAs at E 13 in DES-exposed male fetuses. Furthermore, the mRNA expression levels of Hoxa 11 and steroidogenic factor-1 (SF-1) were determined as a marker for fetal development. Prenatal DES exposure had no effect on Hoxa 11 mRNA expression, indicating that DES did not exert an overall effect on the rate of fetal development. In DES-exposed male fetuses, SF-1 showed a similar increase in mRNA expression as AMH, in agreement with the observations that the AMH gene promoter requires an intact SF-1 DNA binding site for time- and cell-specific expression, although an effect of DES on SF-1 expression in other tissues, such as the adrenal and pituitary gland, cannot be excluded. However, the increased expression levels of AMH and AMHRII mRNAs do not directly explain the decreased sensitivity of the Müllerian ducts to AMH.

Therefore, it is concluded that prenatal DES exposure of male mice delays the onset of Müllerian duct development, which may result in an asynchrony in the timing of Müllerian duct formation, with respect to the critical period of Müllerian duct regression, leading to persistence of Müllerian duct remnants in male mice.

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Endocrine disruptors and psychiatric disorders in children exposed in utero

Evidence from a French cohort of 1002 prenatally exposed children and the example of diethylstilbestrol (DES) as a model for PE study

2016 Study Abstract

Aim of the work In utero diethylstilbestrol (DES) exposure has been demonstrated to be associated with somatic abnormalities in adult men and women as well as shown for its trangenerationnal effect.

Endocrine disruptors and psychiatric disorders in children exposed in utero: evidence from a French cohort of 1002 prenatally exposed children and the example of diethylstilbestrol (DES) as a model for PE study, Conference Paper, Research Gate, publication/293333931, January 2016.

Researchers Marie-Odile Soyer-Gobillard and Charles Sultan, image credit lamarseillaise.

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 and/or Ethinyloestradiol affects brain development and whether it is associated with psychiatric disorders in male and female adolescents and young adults.

Methods
HHORAGES Association, a national patient support group, has assembled a cohort of 1280 women (spontaneous testimonies communicated after various informations) who took DES and/or EE during pregnancy. We obtained responses to detailed questionnaire 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 and/or EE.

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

Total number of psychological/psychiatric disorders among the 982 (1002-20 stillborns) DES-exposed and post-DES children
Among the 982 DES-exposed adolescents (1002-20 stillborns) (Group 2) and post-DES adolescents (Group 3):

  • Behavioral disorders, violence, aggressiveness, obsessive-compulsive disorders (n=110) (11.2%)
  • Eating disorders (n=83) (8.4%)
  • Schizophrenia (n=171) (17.4%)
  • Depression, bipolar disorders, anxiety (n=257) (26.2%)
  • Suicides (n=33) (3.4%)
  • Suicide attempts (n=642) (65.4%)

Conclusions
This work demonstrates that prenatal exposure to DES and/or EE is associated with a high risk of psychiatric disorders in adolescence and adulthood. Molecular epigenetic mechanisms subtending these toxic effects are in progress.

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Prenatal exposure to endocrine disruptors and neurodevelopment risk

Study of siblings exposed to diethylstilbestrol

2015 Study Abstract

Many endocrine disruptors are found in our environment. They act on hormonal receptors, on their action and synthesis. They may alter neuronal transmission and neuronal formation.

Exposition prénatale aux perturbateurs endocriniens et risque sur le neurodéveloppement : étude de fratries exposées au diéthylstilbestrol, UPD5 Médecine – Université Paris Descartes – Faculté de Médecine, dumas-01213114, October 7, 2015.

Image credit open archive HAL.

A lot of neurodevelopmental diseases have a growing prevalence, raising many questions about a possible association with endocrine disruptors. One of their action mechanisms may be an effect on DNA methylation of the developing brain.

Objectives
To study neurodevelopmental characteristics and the epigenetic signature of patients exposed in utero to diethylstilbestrol. To identify differentially methylated regions in neurodevelopmental related genes, which could lead to a psychiatric vulnerability.

Materials and Methods
We recruited 75 siblings from 31 families, in which at least one member was exposed in utero to diethylstilbestrol. A psychiatric evaluation was assessed with standardized questionnaires. We used the Infinium HumanMethylation450 BeadChip and analyzed the methylation variations of 411 947 CpG loci.

Results
We found clinical differences in non-specific psychiatric symptoms and in neurological soft signs, such as lateralization, associated with the exposure. We found several biological pathways in which methylation modifications were associated to diethylstilbestrol exposure. These pathways are implicated in neurodevelopmental pathways, general metabolism and oncogenesis mostly.

Conclusion
Prenatal diethylstilbestrol exposure seems associated with non-specific psychiatric symptoms, lateralization abnormalities and methylation alterations in genes that participate to pathways known to be involved in psychiatric diseases, notably in neurotransmitters signalization.

Note
The 100 pages complete study – THÈSE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR EN MÉDECINE – is available (free access) in French language on HAL archives-ouvertes.

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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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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.

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Very High Prevalence of Major Depressive Disorder in DES Sons

DES-exposed males show high rates of lifetime depression

1993 Study Abstract

Previous research has suggested increased psychopathology in prenatally DES-exposed persons. The current study compares the psychiatric histories and social functioning of 27 men with a history of high-dose prenatal Diethylstilbestrol exposure and their unexposed brothers.

Psychopathology and social functioning in men prenatally exposed to diethylstilbestrol (DES), US National Library of Medicine, Psychosomatic medicine, NCBI PubMed PMID: 8310108, 1993 Nov-Dec.

Image credit DerrickT.

We expected DES subjects to show greater lifetime psychopathology and poorer social functioning than controls. Both groups showed high rates of lifetime depression, lifetime alcoholism, and current psychiatric symptoms in excess of community norms.

The only diagnosis on which DES subjects exceeded their unexposed brothers was Major Depressive Disorder (MDD). DES-exposed men had almost twice the prevalence of at least one episode of MDD and had significantly more recurrent episodes.

The relatively small number of subjects with concomitant lack of statistical power may have contributed to the difficulty obtaining significant effects.

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Understanding sexual differentiation of the human brain

DES exposure associated with reduced hemispheric laterality and lowered spatial ability

1992 Study Abstract

Ten males exposed to diethylstilbestrol (DES), a nonsteroidal synthetic estrogen, during gestation were compared to their matched, unexposed brothers on measures of brain hemispheric specialization for processing nonlinguistic spatial information and cognitive abilities.

Effects of prenatal exposure to diethylstilbestrol (DES) on hemispheric laterality and spatial ability in human males, US National Library of Medicine, Hormones and behavior, NCBI PubMed PMID: 1563729, 1992 Mar.

Image credit bluhousworker.

DES exposure was associated with reduced hemispheric laterality and lowered spatial ability.

These data provide direct evidence of a relationship between brain laterality, spatial cognitive ability, and prenatal exposure to hormones in human males. Further, the implications of these findings for understanding sexual differentiation of the human brain are discussed.

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