Basic Statistics and Findings on DES Sons

DES Sons International Network 5-Year Summary Statistics: First Findings on DES Sons Participating in the DES Sons International Network Between 1999 and 2004

Scott Kerlin, 5-Year Research Summary Update, October 2004

  1. In the five years since formation of the DES Sons Network in July 1999, approximately 600 individuals have requested more information or support through e-mail follow-up requests and/or requests to join the Network. This is over and above all information that is freely available for visitors to the Network’s website which provides substantial information and resources on DES without subscription. Because the DES Sons International Network does not maintain statistics on total Internet traffic to its website, there is no accurate method to gauge how many other affected individuals may be utilizing this information.
  2. Of those 600 individuals who have sought further DES information, approximately 500 are 46XY males who indicated at the time of my initial Network subscription screening that they had either strong suspicions (based on evidence from family members) or actual confirmation (from mother, or direct access to medical records) that they had been exposed to DES in utero. These 500 individuals with confirmed or likely prenatal DES exposure have been members of the network sometime between 1999 and 2004. For this reason I consider our study’s base sample size to have attained a total of 500 DES sons as of spring 2004.
  3. The vast majority of individuals whom I have allowed to join the Network had either “confirmed” (i.e. directly through medical records access or indirectly through personal conversation with mother) or “strongly suspected” (i.e. all evidence points in that direction, but medical records access and/or contact with mother not possible) prenatal DES exposure. However, a few (less than 50 altogether since the Network was formed) who had no way of confirming their exposure also were permitted to join in order to assist them with unanswered questions.
  4. Based on responses between 1999 and 2004 to Network surveys, responses from individual online or telephone interviews, and follow-up discussions with DES sons members, the three areas of greatest health concern among DES sons in the DES sons’ network appear to be
    1. hormonal/endocrine health issues;
    2. gender identity and sexual health issues;
    3. and psychological/mental health issues including anxiety and depression.
  5. Somewhat lower proportions of members indicated concerns regarding autoimmune disorders, infertility, reproductive tract abnormalities, ambiguous or underdeveloped genitalia, epididymal cysts, testicular cancer, and erectile dysfunction. Because not every individual member has necessarily disclosed the full range of health issues or medical concerns by which he or she has been affected, the relative significance of reported health concerns among DES sons in this research study is an approximation, based on rigorous qualitative analysis of information which has freely volunteered by network members.
  6. Despite exhaustive efforts to clarify the history of health issues experienced by DES sons, it appears that only a small number of DES sons contacting our Network have suffered from any type of cancer-related health problems (primarily testicular cancer during younger years). The Network continues to raise awareness among members regarding potential cancer risks. These efforts include participation in the annual prostate cancer awareness month activities of the National Cancer Institute and membership subscription to monthly online alerts from the International Society for Men’s Health and Gender (ISMH). Despite my numerous inquiries, no case of prostate cancer has been disclosed by network members as of July 2004.
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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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Gender-identity, body-experience, sexuality, and the wish for having children in women exposed prenatally to diethylstilbestrol

US National Library of Medicine National Institutes of Health, 1996

Study Abstract

The main focus of the present study is to examine the impact of being a DES-daughter upon gender-identity, body-experience, body-acceptance, sexual satisfaction, and the wish for having children.

Gender-identity, body-experience, sexuality, and the wish for having children in DES-daughters, Women’s Health, NCBI PubMed PMID: 8948086, 1996.

Pink & Blue image credit Janet McKnight.

Subjects were DES-daughters (N = 206) and age-matched controls (N = 121) who were not prenatally exposed to DES.

All subjects completed a battery of measures including Bem’s Sex Role Inventory (1977), a written gynecological anamnesis, and questionnaires concerning body-experience, sexuality, and the wish for having children.

  1. First, it was expected that DES-daughters would be more masculinized in their self-concepts than non-exposed control subjects.
  2. Our second hypothesis was that DES-daughters would be lower in body-acceptance and sexual satisfaction, and would have stronger wishes and more emotionality concerning reproduction.

Contrary to expectations, DES-daughters were not more ‘masculinized’ than controls. Instead, they tended to have higher scores on femininity.

Furthermore, no differences between DES-daughters and controls appeared in body-acceptance and sexual satisfaction. However, the DES-daughters reported a stronger wish for having children and expressed more emotionality concerning the subject.

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Gender-related behavior in women prenatally exposed to DES

Diethylstilbestrol exposures influence brain development and the differentiation of the central nervous system

1993 Study Abstract

Accumulating evidence in experimental animals over the past three decades suggests that mammalian brain development and differentiation of the central nervous system are influenced by perinatal exposure to sex hormones.

Gender-related behavior in women exposed prenatally to diethylstilbestrol, US National Library of Medicine National Institutes of Health, Environmental health perspectives, NCBI PubMed PMID: 8404755, 1993 Aug.

Dancing statues image credit Oiluj Samall Zeid.

Hence, changes in human behavioral patterns may be associated with prenatal exposure to estrogenic substances such as diethylstilbestrol (DES).

This paper reviews relevant studies from a series of laboratories and finds that no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior, although the physical and psychological impact of the problems associated with exposure to DES are well documented.

If both prenatal and postnatal influences such as social, economic, and environmental factors are taken into consideration, individual variation is more apparent than differences in gender-related behavior between unexposed and DES-exposed women.

In summary, gender-related behavior is determined by a complex array of interacting factors, and prenatal influences are only one of many developmental events. More studies are needed using larger populations with carefully controlled selection criteria to suggest a direct role of prenatal DES exposure on subsequent gender-related behavior.

Download (free access) the full PDF on NCBI.

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Female gene expression in the seminal vesicle after prenatal exposure to DES

Feminization of the male mouse reproductive tract after prenatal exposure to Diethylstilbestrol

1989 Study Abstract

Previous studies from our laboratory on the feminization of the male mouse reproductive tract after prenatal exposure to diethylstilbestrol (DES) showed that the mRNA for the major estrogen-inducible uterine secretory protein, lactoferrin (LF), was constitutively expressed in the seminal vesicle of male mice exposed prenatally to DES, but not in the seminal vesicle of control mice.

Female gene expression in the seminal vesicle of mice after prenatal exposure to diethylstilbestrol, US National Library of Medicine National Institutes of Health, Endocrinology, NCBI PubMed PMID: 2707167, 1989 May.

Lactoferrin image credit wikipedia.

After castration, treatment with 17 beta-estradiol (20 micrograms/kg.day) for 3 days induced the LF mRNA in the seminal vesicle of both control and prenatally DES-exposed mice; however, the levels in DES-treated tissues were approximately 6-fold higher than those in control tissue.

This report describes the presence of LF in seminal vesicle tissues and secretions of prenatally DES-exposed mice, as determined by immunohistochemistry and Western blot analysis.

Further, these data are correlated with immunolocalization of the estrogen receptor in the seminal vesicle tissue.

We conclude that the seminal vesicle of prenatally DES-exposed male mice has acquired two key characteristics of female tissues, namely LF production/regulation and estrogen receptor localization/distribution similar to that in uterine tissues.

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Prenatal exposure to DES alter the expression of the lactotransferrin gene in seminal vesicles

Feminization of the male mouse reproductive tract after prenatal exposure to DES

1988 Study Abstract

We have previously isolated an estrogen-inducible secretory protein, lactotransferrin (LTF), and a cDNA to its messenger RNA from the uterus of mice.

Prenatal exposure of male mice to diethylstilbestrol alter the expression of the lactotransferrin gene in seminal vesicles, US National Library of Medicine National Institutes of Health, Molecular endocrinology (Baltimore, Md.), NCBI PubMed PMID: 3216864, 1988 Dec.

Image credit research gate.

In this report we determined that the level of LTF mRNA is minimal in the seminal vesicles of normal mice.

In contrast, expression of LTF mRNA in the seminal vesicles of developmentally estrogenized males was both constitutive and estrogen inducible.

The mRNA for the major estrogen-inducible uterine secretory protein, lactoferrin (LF), was constitutively expressed in the seminal vesicle of male mice exposed prenatally to DES, but not in the seminal vesicle of control mice. The results suggested that this alteration may be an example of atypical gene expression after hormonal manipulation early in development.

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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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