Feminization in males exposed prenatally to DES

What Do Animal Research Findings Reveal About Future DES Health Effects?

This excerpt is from a teleconference with Dr. John McLachlan, a long time researcher on the effects of DES exposure, and Scott P. Kerlin, Ph.D., DES Sons International Network,

CDC’s DES Update – TELECONFERENCE TRANSCRIPT

Abstract (pages 17 to 20)

Dr. McLachlan, it’s Scott Kerlin from the DES Sons Network. Good to make a connection with you here. I appreciate your presentation on many different levels, but I’ll try to be fairly specific on my own topic question. Our network in the past year did a poll to try to find out what were the leading concerns of DES sons and, as you’ve pointed out and other’s have, there’s a lot less research that has documented the effects on DES sons than on daughters.

We learned quite a bit though from network members that: endocrine system problems, gender identity problems, and mental health problems seem to be among the top three areas, closely followed by cancer. I wonder if you could just briefly comment from your own long-term research about two somewhat questionable or controversial topics; one being feminization in males, and the other being various endocrine disorders in males, particularly hypogonadism, and whether you’ve seen linkages in your research over the years in animal research that might point to a significant predominance of hypogonadatropic hypogonadism, I guess is what it would be called.

Dr. McLachlan : Right. Hypogonadatropic hypogonadism, is a low level of pituitary hormone telling the testicle, the gonad, to make testosterone and sperm. It is something that has been seen occupationally in men who have acute exposure to DES. So if an adult male takes estrogen or is exposed to estrogen, the obvious results will be gynecomastia (enlarged breasts),, and hypogonadotropic hypogonadism, (small testicles, low libido).

I haven’t seen the same kind of thing reported from prenatal exposure to DES. Mice that get treated with DES prenatally have a smaller than normal testicular size and a lower than normal sperm count that’s dose related. Testosterone levels in these mice are pretty much normal, although estrogen levels are higher than normal. I don’t know of any comparable studies that have been done in humans, but you might know.

Scott Kerlin : I’ve been looking hard.

Dr. McLachlan : The other issue you mentioned was feminization. All mammals – mice, rats, and humans – as fetuses start out as bisexed beings. We have a gonad that’s going to be either a testis or an ovary, depending on the genetics. Once that happens that little organ secretes some things that do one of two things.

In the case of a genetic male, the testis will start making testosterone, which keeps the male reproductive system intact during fetal life. They also make another protein called Mullerian inhibiting substance, which is specifically set to wipe out the female reproductive system that the fetus has at this time.

If there is no genetically determined male gonad that makes androgen to keep the male tract alive, and then makes this other inhibitor to kill the female tract, invariably you end up with a female. There are genetic disorders or genetic syndromes where those things can change resulting in a genetic male that may have a complete functioning cervix or uterus. This could happen, it seems in mice or humans exposed to DES, though it hasn’t been shown clearly in many human cases. In a mouse whose mother is given DES, you feminize the reproductive system such that a genetically born male, has testis, is usually not making as many sperm as normal, has slightly lower androgen levels, and has higher estrogen levels. That male mouse will have a prostate seminal vesicle, all the other plumbing to get the sperm from the gonad out, but it will also literally have a functioning set of fallopian tubes, uterus, cervix, and an upper portion of the vagina.

The penis of this mouse is also feminized to the extent that there is a higher prevalence of a condition called hypospadias, which is a congenital defect wherein the penis doesn’t totally close in the right way. There is an opening that might be along the shaft of the penis or is often at the end of the penis where there’s almost another kind of — I hate to use the term because it’s not scientific — quasi-vaginal like orifice. It means that estrogen has prevented the total masculinization of what could just as easily end up being the clitoral structure and vaginal structure.

Scott Kerlin : Right.

Dr. McLachlan : We also know that femininization can even happen inside a cell, and from a molecular level there’s a kind of feminization that we and others have shown in mice.

Coming back to one of the earlier questions about hormonal changes in the brain and how this might relate to gender identity. That’s been a really tough one for a lot of people. In the mouse and rat you can certainly do prenatal or neonatal treatment with estrogens or androgens to feminize or masculinize behavior. But in humans it’s very controversial and unknown as to whether this can happen at all. It seems as if the network is hardwired in a different way. Having said that, I’m not sure if anybody is really dealing directly with this.

Scott Kerlin : I will let go at this point so everyone else can ask their questions, but one of the documents that we have actually posted to our Sons Network home page is from the National Toxicology Program fact sheet on DES. I was intrigued when I read the list of symptoms from physical exposure taken by adults. It says right in the text, not only can it cause male impotence, but it can cause transsexual changes, and it indicates it can cause gynecomastia.

Dr. McLachlan : This is in adults though, right?

Scott Kerlin : I think so as best as I can tell. My understanding was that if one time DES was used for male to female transsexuals who were transitioning.

Dr. McLachlan : It is actually

Scott Kerlin : Is it? Okay.

Dr. McLachlan : Yes.

Scott Kerlin : But the prenatal exposure and transsexual effects, that has never been clear to me exactly how that works.

Dr. McLachlan : Yes. We are talking about, in both humans and mice, a feminization of structures. An example in terms of the genital tract is that with undescended testicles the male gonads stay right where they were when they were both male and female. But again, even though animal studies suggest that you can feminize male rats or mice with developmental exposure to estrogens or androgens, this is not clearly the same case, and I think is pretty much considered impossible, with humans. I don’t think that has really been tested in all of the kinds of subtlety that would be required when one considers the complexity of an issue like gender identity.

Scott Kerlin : Yes, that would concur. Thank you so much. “

DES DIETHYLSTILBESTROL RESOURCES

Male Pseudohermaphrodism

Report of a Case, with Observations on Pathogenesis

“Here is a case report from 1959, of a male baby that was heavily feminized by DES.

The doses used in this instance were quite a bit higher than under the standard “Smith and Smith” regimen, starting with 50mg per day and quickly ramped up until a dose of 200mg per day was reached 8 weeks after conception, where it stayed for the remainder of the pregnancy.”

Hugh Easton.

Captain Norman M. Kaplan, MC, USAF,
Endocrinology Service,
Department of Medicine,
United States Air Force Hospital, 1959.

The pathogenesis of male pseudohermaphrodism has not been definitely elucidated.

Although this anomaly has been induced in the newborn of numerous laboratory animals by the administration of estrogens during pregnancy, no human counterpart of this experimental form of intersexuality has been reported.

The patient described below is a male pseudohermaphrodite whose mother had received large doses of estrogens during the critical period of fetal sexual differentiation.

Although the administration of estrogen to the mother and the occurrence of feminization of the external genitalia in the fetus may have been coincidental, a cause- and-effect relation is suggested. “…

… Continue reading on the New England Journal of Medicine DOI: 10.1056/NEJM195909242611303, September 24, 1959.

DES DIETHYLSTILBESTROL RESOURCES

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

Gender-related behavior development in females exposed to DES in utero: an attempted replication

Can prenatal exposure to Diethylstilbestrol masculinize the gender-role behavior of girls and women?

1991 Study Abstract

This report concerns the role of prenatal hormones in normal and abnormal psychosexual differentiation.

Gender-related behavior development in females exposed to diethylstilbestrol (DES) in utero: an attempted replication, US National Library of Medicine National Institutes of Health, Journal of the American Academy of Child and Adolescent Psychiatry, NCBI PubMed PMID: 2005061, 1991 Jan.

Image credit RAZ Zarate.

Several studies indicate that perinatal treatment of infrahuman female mammals with diethylstilbestrol (DES) masculinizes certain features of their brain and behavior.

Accordingly, the authors have hypothesized that prenatal exposure to DES may also masculinize the gender-role behavior of girls and women.

A previous study suggested that prenatally DES-exposed women show decreased interest in parenting.

The authors failed to replicate these findings in a different sample despite the use of similar methodology.

Post-hoc analysis shows that the assessment devices would have detected masculinization if it were present.

The implications of these findings for an understanding of psychosexual development are discussed.

DES DIETHYLSTILBESTROL RESOURCES