Adverse health effects in children of women exposed in utero to diethylstilbestrol

2016 study results confirmed a transgenerational transmission of defects in male genital tract

Abstract

OBJECTIVE
Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to further assess the health effects in children of prenatally exposed women.

Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES), US National Library of Medicine, NCBI pubmed/27203157, 2016 Feb 5.

Russian doll beauty and the beast, rawdonfox.

METHODS
In a retrospective cohort study, the reports of women exposed to DES in utero on their 4409 children were compared with those of unexposed women on their 6203 children. Comparisons used odd ratios (OR) between children of exposed and unexposed women and standardized incidence rate (SIR) with the general population. These cohorts were recruited on a voluntary basis to answer questionnaires.

RESULTS
There was a global increase of defects in children born to exposed women when compared with those born to unexposed (OR 2.29, 95% CI: 1.80-2.79, P<0.001) and with the general population (SIR 2.39, 95% CI: 2.11-2.68). Increased defects were observed in male genital tract, esophagus, lip or palate, musculoskeletal and circulatory systems. For female genital tract anomalies, there was no significant increase. However, this cohort being relatively young, further follow-up is needed. An increase of cerebral palsy was revealed. The incidence of cancers was not increased, in particular for breast, uterus and ovary.

CONCLUSION
Our results confirmed a transgenerational transmission of defects in male genital tract. With caution due to possible bias associated with this method, our data suggest an increase of defects for esophagus, lip or palate, musculoskeletal and circulatory system in children of exposed women.

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Low-dose and combined effects of oral exposure to BPA and DES on the male reproductive system

Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population

Abstract

Study of the joint action of xenobiotics is important to fully explore their toxicity and complete risk analysis. In this study, we investigated the effects of low-dose and combined exposure of Bisphenol-A (BPA) and diethylstilbestrol (DES) on the reproductive system in adult male rats.

The results showed that the sperm motility decreased in the BPA/DES and combined groups. Sperm deformity ratios and histological lesions of the testes were significantly higher and more significant, respectively, in the combined group compared with the single treated groups. No dose-effect relationship or significant additive effect on serum hormone levels was observed after combined exposure to BPA/DES. Ultrastructural results showed lesions of the Sertoli and Leydig cells, mainly in the endoplasmic reticulum (ER), in all treated groups. ER stress molecular sensor IRE1 was phosphorylated and activated after BPA and DES treatment in this study.

Low-dose and combined effects of oral exposure to bisphenol A and diethylstilbestrol on the male reproductive system in adult Sprague-Dawley rats, NCBI pubmed/26970683, doi: 10.1016/j.etap.2016.02.014, 2016 Feb 24.

The protein levels of ES stress molecular marker CHOP were significantly up-regulated after exposure to BPA, DES, and BPA and DES combined.

These findings indicate that ER stress is important in BPA/DES-induced damage in rat testes. Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population.

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In-utero DES exposure and cardiac structure/function alteration

Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

Abstract

Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs.

Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart.

Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5-14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart.

Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny, article/pii/S0041008X12004607, 1 January 2013.

Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged.

We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males.

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Gender-related Disorders resulting from DES Exposure in Males

PRENATAL EXPOSURE TO DIETHYLSTILBESTROL IN MALES AND GENDER-RELATED DISORDERS: RESULTS FROM A 5-YEAR STUDY

Important research on DES exposure in males.

For many years, researchers and public health specialists have been assessing the human health impact of prenatal exposure to the estrogenic anti-miscarriage drug, diethylstilbestrol (commonly known as DES or “stilbestrol”). The scope of adverse effects in females exposed to DES (often called “DES daughters“) has been more substantially documented than the effects in males (“DES sons“).

This paper contributes three areas of important research on DES exposure in males:

  1. an overview of published literature discussing the confirmed and suspected adverse effects of prenatal exposure in DES sons;
  2. preliminary results from a 5-year online study of DES sons involving 500 individuals with confirmed (60% of sample) and suspected prenatal DES exposure;
  3. documentation of the presence of gender identity disorders and male-to-female transsexualism reported by more than 100 participants in the study.
Sources and related posts
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DES exposure and the aging woman: mothers, sons and daughters

Increased risk of cancers for the DES-exposed

image of holding hands
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

2002 Study Abstract

Diethylstilbestrol (DES), the first orally active artificial estrogen ever developed, was prescribed to several million pregnant women during the 1940s through the 1960s in the mistaken belief that it reduced the risk of miscarriage.

In 1971, the US Food and Drug Administration contraindicated its use in pregnancy when DES was associated with the development of vaginal clear cell adenocarcinoma (CCA) in daughters exposed in utero.

In daughters whose mothers took DES during pregnancy, the drug has been associated with congenital malformations of the reproductive tract, fertility problems, a possible increased risk of cervical carcinoma in situ, and a presumed lifetime risk of vaginal and cervical CCA.

DES mothers have an increased risk of breast cancer (RR = 1.3).

DES sons have an increased prevalence of urogenital anomalies, and a possible increased risk of testicular cancer.

Sources and more information
  • DES exposure and the aging woman: mothers and daughters, Current women’s health reports, NCBI PMID: 12215312, 2002 Oct;2(5):390-3..
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Gender Dysphoria, Transsexualism, and Disorders of Sexual Differentiation in DES Sons

DES Sons International Network slideshow presentation, 2004

by Scott P. Kerlin, Ph.D.

DES Sons International Network

The Presence of Gender Dysphoria, Transsexualism, and Disorders of Sexual Differentiation in Males Prenatally Exposed to Diethylstilbestrol: Initial Evidence from a 5-Year Study.

Sources:

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Prenatal exposure to progesterone suppresses reproduction in male mice

P. Sreenivasula Reddy, Harini Challa, Sainath S.B, Sep 2011

Prenatal-exposure-to-proges
DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

Partial recovery of reproduction by testosterone

The role of androgens in development of male reproductive organs is well documented. The role of estrogens in the development of male reproductive organs remains largely unknown; although both estrogen receptors and aromatase enzyme have been identified in the developing penis of a number of species, including humans.

Male offspring of women exposed to diethylstilbestrol during pregnancy have higher incidences of epididymal cysts, cryptorchidism, hypospadiasis, and smaller testes.

Since female hormones were routinely prescribed to treat threatened pregnancy and considering the potential implications of female hormones during prenatal period on the development of male reproductive system, the present book describes the effect of prenatal exposure to progesterone on adult male reproduction.

Significant deterioration in reproduction was observed in mice exposed to progesterone during embryonic development which includes reduction in steroidogenesis and spermatogenesis. Testosterone supplementation during post-natal period partially restored the suppressed reproduction.

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The Riddle of Gender: Science, Activism, and Transgender Rights

What it means to be a man, a woman, and a human being

The_Riddle_of_Gender_cover_
What it means to be a man, a woman, and a human being..

How do nature and nurture interact to produce a persistent awareness of one’s identity as male or as female?
How does understanding the psychology of transgendered people illuminate gender psychology?

When Deborah Rudacille learned that a close friend had decided to transition from female to male, she felt compelled to understand why.

Coming at the controversial subject of transsexualism from several angles–historical, sociological, psychological, medical–Rudacille discovered that gender variance is anything but new, that changing one’s gender has been met with both acceptance and hostility through the years, and that gender identity, like sexual orientation, appears to be inborn, not learned, though in some people the sex of the body does not match the sex of the brain.

Informed not only by meticulous research, but also by the author’s interviews with prominent members of the transgender community, The Riddle of Gender is a sympathetic and wise look at a sexual revolution that calls into question many of our most deeply held assumptions about what it means to be a man, a woman, and a human being.

More information

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Psychopathology and social functioning in men prenatally exposed to diethylstilbestrol

Previous research has suggested increased psychopathology in prenatally DES-exposed persons

Split-of-Personality image
In this 1993 study, DES-exposed men had almost twice the prevalence of at least one episode of MDD and had significantly more recurrent episodes. Split of Personality image by Derrick Tyson.

1993 Study Abstract

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

Sources and more information
  • Psychopathology and social functioning in men prenatally exposed to diethylstilbestrol, Pillard RC, Rosen LR, Meyer-Bahlburg H, Weinrich JD, Feldman JF, Gruen R, Ehrhardt AA., Psychosom Med. 1993 Nov-Dec;55(6):485-91, NCBI PMID: 8310108, 1993.
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Hormonal contributions to sexually dimorphic behavioral development in humans

DES-exposed male subjects appeared to be feminized and/or demasculinized

image of dancing-statues
This 1991 study confirms that DES-exposed male subjects appeared to be feminized and/or demasculinized, and there is some evidence that exposed female subjects were masculinized. Dancing statues image by Dixie Lawrence.

1991 Study Abstract

Nineteen studies on the behavioral effects of prenatal exposure to hormones administered for the treatment of at-risk human pregnancy are reviewed. Because the role of prenatal exposure to hormones in the development of human behavioral sex differences is potentially confounded by society’s differential treatment of the sexes, comparisons between exposed and unexposed subjects were evaluated and summarized separately for male and female subjects.

Therefore, this review focuses on data for individuals whose prenatal hormone environments were atypical relative to what is normal for their own sex. Overall, it appears that prenatal exposure to androgen-based synthetic progestin exerted a masculinizing and/or defeminizing influence on human behavioral development, whereas prenatal exposure to natural progesterone and progesterone-based synthetic progestin had a feminizing and/or demasculinizing influence, particularly among female subjects.

The data on prenatal exposure to synthetic estrogen derive primarily from subjects exposed to diethylstibestrol (DES). DES-exposed male subjects appeared to be feminized and/or demasculinized, and there is some evidence that exposed female subjects were masculinized. These findings are discussed in the context of prenatal hormonal contributions to sexually dimorphic behavioral development both within and between the sexes. Recommendations for the conduct of future research in developmental behavioral endocrinology are presented.

Sources and more information
  • Hormonal contributions to sexually dimorphic behavioral development in humans, Reinisch JM1, Ziemba-Davis M, Sanders SA, Psychoneuroendocrinology. 1991;16(1-3):213-78., NCBI PMID: 1961841, 1991.
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