DiEthylStilbestrol, a Gender Bender

Excerpted and condensed from It’s My Ovaries, Stupid, pgs. 83 – 107, Scribner, 2003

Abstract

Diethylstilbestrol, or DES, is a case in point. DES is a highly potent estrogenic compound that was first synthesized in Britain in 1938. Believing that it would prevent miscarriages, doctors subsequently prescribed DES to over 5 million women in the United States, Europe, and Latin America.

Later, DES was even more widely used, with the idea that it would create healthier pregnancies and stronger, healthier babies. Its application was further expanded to :

  • include emergency “morning after” contraception,
  • to suppress milk production in women who did not want to nurse,
  • for treatment of menopausal symptoms like hot flashes,
  • it even became a way to stop growth in teenage girls who were becoming “too tall !”
  • DES was added to animal feed to fatten livestock and given to chickens speed their development.

Human ingenuity compiled an absolutely staggering list of uses for DES.

Some Health Consequences of DES

DES Daughters

  • Deformed uteruses, fallopian tubes, and ovaries
  • Lowered egg production
  • Higher rates of infertility, ectopic pregnancies, miscarriages, and premature babies
  • Higher rates of endometriosis, uterine tumors, breast tumors, and pituitary tumors
  • Increased frequency of ovarian cysts and abnormal follicles Immune system problems
  • Abnormal glucose tolerance and glucose utilization
  • Abnormal development of gender-specific sexual behavior in DES offspring (feminized males and masculinized females), suggesting that DES caused abnormal sex differentiation during fetal development

DES Sons

  • Increased genital defects, undescended testicles, and stunted testicles and penises
  • Low sperm counts, abnormal sperm, and reduced fertility
  • Higher rates of testicular cancer at earlier ages
  • Immune system problems
  • Abnormal glucose tolerance and glucose utilization
  • Abnormal development of male sexual behavior

Clearly DES, and more broadly all POPs, can cause a wide range of serious health problems. But it is their specific ability to interfere with sexual development and gender-specific behavioral function that has earned them the dubious distinction of being called “gender benders.”

  • Read the full paper by Elizabeth Lee Vliet, MD, Gender Benders & Endocrine Disruptors around You, herplace, 24 Oct 2004.
  • Image credit Gender Bender.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal exposure to DES linked to intersexed development in males

Did Diethylstilbestrol cause intersexed development in the DES Sons by blocking testicular testosterone production ?

This blog post was  originally a comment made by a DES Son

“My own opinion is that DES caused intersexed development in the DES sons by blocking testicular testosterone production. DES is a potent chemical castration agent that for many years the treatment of choice for hormone-sensitive prostate cancer. Just 3mg of DES per day is enough to fully chemically castrate an adult man; the starting dose as a miscarriage treatment was 5mg per day (and often went much higher during the later stages of the pregnancy). It’s a not widely appreciated fact, but male development isn’t driven directly by genes, but instead by hormones (primarily testosterone) produced in the testicles of a male fetus. Given the ability DES has to block testosterone production, it’s no surprise that many DES sons are physically and/or psychologically intersexed. The surprising thing is that there’s so little public awareness of it!

If the problem is just one of testosterone production being suppressed during the critical time sexual development was taking place, then I don’t see any reason for there to be any long term genetic effect or 3rd generation effects. However, one thought that’s occured to me is that DES daughters often have a great deal of difficulty getting pregnant and carrying the pregnancy to term, which puts them at vastly increased risk of medical intervention – and potentially being given hormonal medication during the pregnancy. If one of these hormonal treatments for miscarriage (DES) can cause problems with intersexed development, then the likelihood is that others can too. There’s one drug in particular called hydroxyprogesterone caproate, which is in widespread current use to prevent miscarriages and premature births, and is being given in doses which I’m sure would have some serious gender-bending effects if you were to give the same dose to an adult man.

In short, although DES was phased out 40 years ago, there’s plenty of other sex hormone derivatives still finding their way inside pregnant women and potentially causing many of the same problems. That’s why I’ve been trying so hard to get people to take me seriously, and see whether there’s a link between exposure to these drugs before birth and endocrine and intersex-related problems later in life!”

Hugh Easton, 28/04/2013.

DES DIETHYLSTILBESTROL RESOURCES

Estrogen receptor-α mediates DES-induced feminization of the seminal vesicle in male

These 2012 data suggest that DES-induced SV toxicity and feminization are primarily mediated by ERα; however, some aspects of androgen response may require the action of ERβ

Study Abstract

Background
Studies have shown that perinatal exposure to the synthetic estrogen diethylstilbestrol (DES) leads to feminization of the seminal vesicle (SV) in male mice, as illustrated by tissue hyperplasia, ectopic expression of the major estrogen-inducible uterine secretory protein lactoferrin (LF), and reduced expression of SV secretory protein IV (SVS IV).

Estrogen receptor-α mediates diethylstilbestrol-induced feminization of the seminal vesicle in male mice, US National Library of Medicine National Institutes of Health, Environmental health perspectives, NCBI PubMed PMID: 22275727, 2012 Apr.

Image credit NCBI PMC3339448 figure/f2.

Objectives
The present study was designed to evaluate the role of the estrogen receptor (ER) in this action by using ER-knockout (ERKO) mice.

Methods
Wild-type (WT), ERα-null (αERKO), and ERβ-null (βERKO) male mice were treated with either vehicle or DES (2 μg/day) on neonatal days 1–5. These mice were divided into two groups: In the first group, intact mice were sacrificed at 10 weeks of age; in the second group, mice were castrated at 10 weeks of age, allowed to recover for 10 days, treated with dihydrotestosterone (DHT) or placebo, and sacrificed 2 weeks later. Body weights and SV weights were recorded, and mRNA expression levels of Ltf (lactoferrin), Svs4, and androgen receptor (Ar) were assessed.

Results
In DES-treated intact mice, SV weights were reduced in WT and βERKO mice but not in αERKO mice. DES-treated WT and βERKO males, but not αERKO males, exhibited ectopic expression of LF in the SV. DES treatment resulted in decreased SVS IV protein and mRNA expression in WT males, but no effect was seen in αERKO mice. In addition, DES-treated βERKO mice exhibited reduced Svs4 mRNA expression but maintained control levels of SVS IV protein. In DES-treated castrated mice, DHT implants restored SV weights to normal levels in αERKO mice but not in WT mice, suggesting full androgen responsiveness in αERKO mice.

Conclusions
The data presented here demonstrate that ERα plays a role in the developmental effects resulting from DES toxicity in the SV. ERα is involved in the lack of androgen responsiveness determined by increases in SV weight after DHT treatment and by SVS IV protein and Svs4 gene expression, but this does not appear to be due to down-regulation of the AR itself. Therefore, other factors that control androgen signaling must be affected. In addition, this study definitively shows that ERα is necessary for the molecular feminization of the SV after neonatal exposure to DES, because we did not observe aberrant LF expression in αERKO mice.

Irrespective of the underlying mechanisms, the toxicological effects of DES that lead to androgen resistance and feminization in the SV are dependent on functional ERα. Furthermore, this is clearly a toxicological effect of aberrant stimulation of ERα signaling in the SV during development, as unexposed αERKO males invariably exhibited overly well-maintained SVs, thus indicating that normal development and function of the tissue are not dependent on functional ERα.

  • Read/download (free access) the full study via the ncbi.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal exposure to progesterone suppresses reproduction in male mice

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.

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

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.

DES DIETHYLSTILBESTROL RESOURCES

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

In the event of ambiguous sex at birth, the sex appearance of the genitals may not reflect the sexual orientation of the brain

Summary

During the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge.

Sexual differentiation of the human brain in relation to gender identity and sexual orientation, The Netherlands Institute for Neuroscience, Amsterdam, The Netherlands, cic/389_XXIV_1/3373, 2010.

Image credit Samat Jain.

In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed into our brain structures when we are still in the womb.

However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality.

This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain.

There is no proof that social environment after birth has an effect on gender identity or sexual orientation.

Abstract

On the “antijen website” they claim that transsexuality occurs in 35.5% and a gender problem in 14% of the DES (diethylstilbestrol, an estrogen-like substance) cases. This is alarming, but needs, of course, to be confirmed in a formal study.

DES DIETHYLSTILBESTROL RESOURCES

Atypical Gender Development – A Review

image of rainbow

DES may have the potential to impact on the sex-differentiation of the central nervous system

From an international research group chaired by Dr. Milton Diamond, and organized by the Gender Identity Research and Education Society (GIRES), this exhaustive review of leading research into causes of “atypical” gender identity development included documentation of prenatal DES exposure.

Summary

Atypical Gender Development – A Review, Gender Identity Research and Education Society (GIRES), International Journal of Transgenderism, 9 (1): Pages 29-44, Volume 9, 2006 – Issue 1.

Image credit Chainless Photography.

In 2003, the Gender Identity Research and Education Society (GIRES) ran a small symposium in London, assisted by a Trans Group, founded in 1993, with the aim of moving transsexualism from its current categorisation, in the International Classification of Diseases (ICD 10), as a psychiatric disorder. GIRES was awarded additional funding for this project from the King’s Fund-an eminent charity providing funds for medical and scientific work.

The members of the symposium included physicians and specialists in the different areas pertinent to the understanding and the treatment of transsexualism, and also the Member of Parliament who chairs the Parliamentary Forum for Transsexualism. Transsexual people were represented within this group. Members came from the United Kingdom, The Netherlands, Belgium, Japan and the United States of America.

Professor Milton Diamond (USA) chaired the group who collaborated in producing the following paper. The team endeavoured to provide a balanced and comprehensive review of what is currently understood, in the scientific field, regarding atypical gender development and transsexualism.

Abstract

Evidence of a mechanism that can alter the fetal endocrine milieu is reported by Dessens et al. (1999). They found a raised incidence of transsexualism in children of mothers exposed to anti-epileptic medication during pregnancy. In laboratory conditions, diethylstilbœstrol (DES) has been shown to affect sex differentiation in mice and rats, producing effects such as hypospadias, hypogonadism and cryptorchidism.

Findings that the human fetus is similarly affected by chemicals crossing the placenta are inconclusive, however there is some evidence of this. DES is described as an ‘endocrine disrupter’ (Gorski, 1998, McLachlan 2001; McLachlan et al., 2001), having anti-androgenic and possibly estrogenic effects, which are capable of altering the human fetal environment when administered to a pregnant mother (Toppari and Skakkebaek, 1998; Berkson, 2000). Beyer explains that it crosses the placental and blood-brain barriers, bypassing the feedback system which would normally suppress the body’s production of estrogen (Beyer, 2003; Gorski, 1998).

DES, therefore, may have the potential to impact on the sex-differentiation of the central nervous system. It was widely administered to pregnant women from the 1950s through to the 1980s to prevent miscarriage. A number of defects of sex differentiation occurred in the children born of these pregnancies (Klip et al., 2001) According to self-reports, there appears to be a raised incidence of gender dysphoria experienced by the sons in this group (DES Sons’ International Research Network). It is thus thought that there may possibly be a link between this condition and the prenatal exposure to DES of those sons. This remains a plausible, but unproven hypothesis.

  • Read/download (free access) the full study via gires.
DES DIETHYLSTILBESTROL RESOURCES

Transsexualism : An Unacknowledged Endpoint of Developmental Endocrine Disruption?

Thesis for the Master of Environmental Studies Degree, Christine Johnson, 2004

Johnson is interviewed in Deborah Rudacille’s book The Riddle of Gender. She was born a DES son but transitioned to female (m to f) in her 20s. Scott Kerlin served on her Master’s degree thesis committee at Evergreen State University in Washington and this thesis contained extensive evidence of prenatal exposure to DES, DDT, PCBs, and other endocrine disrupting substances on gender identity and gender development.

Abstracts

In recent years, evidence has accumulated demonstrating that endocrine disrupting chemicals (EDCs) have the potential to alter sexual development at the organizational and functional level in many species, including humans, indicating that this class of chemicals may play a role in the etiology of transsexualism. Although transsexualism has historically been attributed to social or psychological causes, little data exists to support these claims, thus requiring a closer examination of the evidence regarding changes in sexual development due to EDCs. Toward that end, this thesis considers data from studies examining hormonal signaling mechanisms and changes in sexual development observed in wildlife, laboratory animals, and humans exposed to EDCs, all providing a consistent picture that sex hormones and their receptors are highly conserved evolutionarily, finding similar effects of disruption in many species.

Transsexualism: An Unacknowledged Endpoint of
Developmental Endocrine Disruption? by Christine Johnson, A Thesis: Essay of Distinction Submitted in partial fulfillment of the requirements for the degree, Master of Environmental Studies, The Evergreen State College, antijen.org, June 22 2004.

Image credit Penn State.

In order to place the data in context, a number of historical threads are examined, including: the use of chemicals in agriculture, the use of the pesticide DDT and the pharmaceutical drug diethylstilbestrol (DES), the intertwined relationship between chemical manufacturers and the military, and the history of transsexualism since 1950. The operation and function of the endocrine system is reviewed in order to provide the background to properly interpret findings from endocrine disruptor studies, focusing particularly on the hypothalamic-pituitary-gonadal (HPG) axis. Recent physiological data regarding the vomeronasal organ (VNO) is reviewed, demonstrating that the VNO is the organ responsible for detecting pheromones, or sexually-relevant chemically-based cues, and that exposure of the VNO to extremely low levels of putative sex hormones causes numerous autonomic system responses, including alterations in endocrine function in males. It is therefore suggested that the VNO plays a central role in the circuitry involving sexual development, and a hypothetical framework for testing this concept is provided.

Using this framework, a mechanism for the development of gender identity is proposed, suggesting that gender identity is determined via pheromones by comparing the self with others at an unconscious level. One consequence of this mechanism is that messages conveyed by pheromones can be regarded as signals that can be in contradiction from messages from society, leading to a paradoxical double bind, or a logical contradiction between messages that exist on different logical levels. Another consequence is that there may exist a class of chemicals, pheromone disruptors, that could interfere with pheromones in a manner analogous to endocrine disruptors. Further research must be performed to test this hypothesis since little data exists on pheromones in humans, but early data suggests chemicals may be found that interfere with normal pheromone function.

The prevalence of transsexualism is examined, finding that prevalence differences reported in various countries are not well explained by social factors. Also, it is observed that existing studies have reported the prevalence of transsexuals seeking treatment over a specific time period, but this reporting method is not a measure of the number of transsexuals for each country, which is what the term implies to most people. Several recent epidemiological studies that address sexual changes from endocrine disruption are critiqued, finding that they are plagued with methodological weaknesses and contain a number of errors in interpretation. It is argued that instead of using epidemiological techniques, a more useful approach would be to perform demographic studies that map the birthplace of transsexuals in space and time to determine any patterns that may be related to environmental conditions. The lack of detailed data on transsexual demographics, especially in the United States where such data are completely lacking, has left a void where a lack of data has been interpreted incorrectly as a lack of effect.

The fundamental assumptions used in risk analysis and toxicology are reviewed in the context of recent findings that the effects of a chemical may be larger at low doses than at high doses and that thresholds for the endocrine system must be determined empirically, rather than by assumption of a dose-response curve and extrapolation from an observed toxicological endpoint. The use of invalid techniques by toxicologists has thus invalidated claims of chemical safety, and indicates that public policy based on these techniques are insufficiently protective of public health. Because few things are more important to the continuity of cultures than sexuality and social relations, a number of areas requiring further research are identified, and the need for education of the public is emphasized. I conclude that the existing evidence points towards chemical causes of transsexuality rather than social or psychological causes, requiring a shift in research priorities away from psychosocial studies towards physiological studies of transsexuals.

Hormones, Sexual Development, and Transsexualism

… “this observation raises questions about the validity of existing methods of assessment for studying questions of gender identity development in general. This problem is particularly relevant for offspring of mothers prescribed DES during their pregnancy, since no studies have been performed that specifically asked about changes in gender identity due to these known prenatal exposures to an estrogenic substance.”…

… “The first study was a cohort study of men and women exposed in utero to DES; the study collected demographic data including: age, education, and ethnicity, and psychosexual characteristics including: handedness, sex partner choice, marital status, age at first intercourse, and number of partners.

Interestingly, one finding that reached statistical significance was that DES sons had a higher frequency of left-handedness, which the authors associated with complications during pregnancy; other authors have found that transsexuals also have a higher frequency of left-handedness, suggesting that questions explicitly asking about gender identity status would be appropriate to add to all future studies examining these relations.

However, there are several problems with the study. The format of the study was a survey questionnaire mailed to exposed and unexposed groups, but ultimately, 49% of men and 50% of women from the cohort could not be located, were dead, or chose not to participate in the survey. Consequently, sampling may be biased to an unknown degree because there is no method of determining if those responding are representative of the whole group. Other problems are that all children exposed to DES in utero are assumed to be similarly affected, but because the endocrine disruption thesis suggests that dose and timing is important with regard to outcomes, it is necessary to distinguish when and in what amounts the DES was present in the fetus during critical stages of sexual development. Because the study lacks empirical data regarding prenatal DES exposure, this dramatically weakens the ability of the study to detect differences. Because sexual development proceeds in a number of stages, the timing of the dose is critically important to detecting differences statistically. By considering all those exposed to DES as a homogenous group, effects deriving from exposures during critical periods are obscured, because those exposed outside of these critical windows do not show effects, and therefore they dilute the statistical power of the study. This could be repaired by stratifying the groups by ‘period of exposure’.

Another serious problem with the study is that there is no person in the United States that can be considered a control. As mentioned in the history section, DES was widely used for cattle, thus to a greater or lesser degree, everyone in the U.S. was exposed. Additionally, many other endocrine disrupting chemicals exist, limiting the utility of using a single marker of exposure as an independent variable for changes in sexuality. When these factors are taken into account: high non-response rate, treating all DES exposed persons as a group, and the lack of a proper control, the lack of significance should not be taken as evidence of the lack of an effect.

In a recent teleconference addressing issues of concern to DES sons, Dr. Titus Ernstoff was asked if there were any plans to study gender identity outcomes associated with DES exposure; she replied saying that their study did not have sufficient statistical power to study “rare” outcomes such as transsexuality. However, the DES Sons’ International Network, an internet based research, education, and advocacy group, has found that transsexualism is a common outcome of fetal exposure to DES among sons, indicating that studies on DES exposed persons should be examining endpoints related to altered sexual development. Of their total membership of 600 genetic males, among those who could verify their DES exposure, 52 (8.7%) consider themselves to be transsexual, 26 (4.3%) are transgendered, 9 (1.5%) are gender dysphoric, and 3 (0.5%) are intersex. When all these conditions are considered together, the total rate is 15%, indicating that for DES sons, the frequency of gender identity issues cannot be considered rare. When those who strongly suspect, but who are unable to confirm DES exposure are included, the total number of people who self-identify using one the above categories is 153, or 25% of the network membership.

If the rate of transsexuality in the U.S. is assumed to be 1 in 100,000, and if the number of DES exposed mothers ranges from 3-5 million, the number of transsexuals expected in the entire DES sons population would be 15-25, assuming that DES did not increase the probability of developing transsexualism compared to the general public. Since the DES Sons’ International Network already has double that number of transsexuals alone, this is evidence that among DES sons, the condition is not as rare as Titus-Ernstoff claims, and therefore failure to study the problem may have reasons other than a lack of statistical power – i.e. the decision not to examine the issue may be politically motivated.

Even if a much higher rate of transsexualism in the U.S. is assumed, the numbers do not change very much. For example, if the prevalence of transsexualism in the U.S. is assumed to be the same as in the Netherlands, there should be between 126 and 210 transsexuals in the U.S. due to DES exposure. Because the DES Sons International Network already has 52 transsexuals in their network, this would mean that they have found between 25 and 41% of all transsexuals whose transsexuality can be attributed to DES. Given the membership totals only 600, this seems extremely unlikely, and instead suggests that DES is capable of causing transsexualism, thus explaining the dramatic increase in the frequency of transsexualism in the DES sons group compared to the general public.”

More DES DiEthylStilbestrol Resources

Sexual differentiation of the human brain

Relevance for gender identity, transsexualism and sexual orientation

2004 Study Abstracts

Male sexual differentiation of the brain and behavior are thought, on the basis of experiments in rodents, to be caused by androgens, following conversion to estrogens.

Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, US National Library of Medicine National Institutes of Health, NCBI PubMed PMID: 15724806, 2004 Dec.

Image credit arselectronica.

However, observations in human subjects with genetic and other disorders show that direct effects of testosterone on the developing fetal brain are of major importance for the development of male gender identity and male heterosexual orientation.

Solid evidence for the importance of postnatal social factors is lacking. In the human brain, structural diferences have been described that seem to be related to gender identity and sexual orientation.

… The importance of the fetal male testosterone surge for sexual differentiation of the brain following aromatization to estrogens agrees with the observations that girls whose mothers were exposed to diethylstilbestrol (DES) during pregnancy run a higher risk of developing bi- or homosexuality. …

… Sex hormones during development also have an influence on sexual orientation, as appears from the increased proportion of bi- and homosexual girls with congenital adrenal hyperplasia. Then there is DES, a compound related to estrogens that increases the occurrence of bi- or homosexuality in girls whose mothers received DES during pregnancy to prevent miscarriage (quod non). DES was given between 1939 and the 1960s to millions of pregnant women. However, these authors could not confirm an increase in the likelihood of homosexual behavior in DES-exposed girls or boys in adulthood. The ratio of the second to fourth finger digits, a measure ascribed to the organizational actions of prenatal androgens, was significantly lower in the homosexual males and females as compared with heterosexuals. This observation suggests that homosexual males and females have been exposed to elevated levels of androgens in utero. …

More DES DiEthylStilbestrol Resources