A Discussion on the Relationship Between Gender Identity And Prenatal Exposure to Diethylstilbestrol (DES) in 46XY Individuals 

   Research

 

 

 

From - The Dictionary of Organic Compounds, Sixth Edition Volume 3, Diethylstilbestrol page 2175 2176 Publishing info  Cover

”Causes male impotence and transsexual changes particularly in offspring exposed in utero."

 

From - The Endocrine Society


"When synthetic compounds function as hormonal "mimics," they also bind to the receptor. Some foreign chemicals interact with the estrogen receptor and produce estrogen-like effects on the development of the brain, male and female reproductive organs, and breasts, causing a variety of disorders, including: overgrowth of the vaginal lining, premature breast development, and infertility feminization of male offspring."


Note : The Endocrine Society claims to be the world's largest and most active professional organization of endocrinologists. The above document includes DES as an example. This fact sheet no longer exists online which isn't surprising since many of the Endocrine Societies supporters are pharmaceutical companies however I do have a copy of the original. What they now have is this.5)


"Based on our knowledge of the effects of certain synthetic chemicals, such as DDT, diethylstilbestrol and PCBs, and the increasing evidence that reproductive function in wildlife and humans is changing, scientists are now examining a broad range of chemical effects.

EEDs can affect people and animals in many ways:

  • disrupted sexual development

  • decreased fertility

  • birth defects

  • decreased hatching in animals

  • reduced immune response

  • neurological and behavioral changes, including reduced stress tolerance"

 

From - the National Toxicology Programs information sheet on DES. (This page is also no longer online but I have the original safely saved)


"It can cause male impotence and trans-sexual changes [029]. It may also cause congenital malformation in the fetus [269]. Human reproductive effects by ingestion include abnormal spermatogenesis, changes in the testes, epididymis and sperm duct; menstrual cycle changes or disorders, changes in female fertility, developmental abnormalities of the fetal urogenital system, germ cell effects in offspring and delayed effects in the newborn."


 

From - The role of the androgen receptor in CNS masculinization 287)

 

"The medial posterior region of the bed nucleus of the stria terminalis (BSTMP) and the locus coeruleus (LC) show opposite patterns of sexual dimorphism. The BSTMP in males is greater in volume and number of neurons than in females (male > female) while in the LC, the opposite is true (female > male). To investigate the possible role of the androgen receptor (AR) in the masculinization of these two structures, males with the testicular feminization mutation (Tfm) were compared to their control littermate males. No differences were seen in the number of neurons of the BSTMP between Tfm and their control littermate males, while in the LC, Tfm males have a greater number of neurons than their control littermate males. These results show that the AR is involved in the control of neuron number in the LC but not in the BSTMP. Results based on the LC suggest that when females have a larger brain area than males, masculinization in males may be achieved through the AR, with androgens perhaps decreasing cell survival"

 

Note: testicular feminization is older term. Androgen Insensitivity syndrome is more often used today.

 

 

From - Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats 288)

 

"In control animals, LC volume is greater in females than in males. Animals treated with BPA at both low and high doses and with DES all showed a reversal of this normal sexual dimorphism"

 

In relation to DES and high dosages of BPA, (test dependent) the following observations were made

"Sex difference eliminated (males behave like control females)"

 

"BPA had no effect on the size of the SDN-POA"

 

 

From - Brain masculinization requires androgen receptor function 289)

 

"Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal brain masculinization underlying the expression of male-typical behaviors remains unclear because of the conversion of testosterone into estrogen in the brain. Here, we report a null AR mutation in mice generated by the Cre-loxP system. The AR-null mutation in males (ARL-/Y) resulted in the ablation of male-typical sexual and aggressive behaviors, whereas female AR-null homozygote (ARL-/L-) mice exhibited normal female sexual behaviors. Treatment with nonaromatizable androgen (5{alpha}-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in ARL-/Y mice. Impaired male-typical behaviors in ER{alpha}-/- mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in ARL-/L- mice. Perinatal DHT treatment of females led to adult females sensitive to both 17{beta}-estradiol and DHT in the induction of male-typical behaviors. However, this female brain masculinization was abolished by AR inactivation. Our results suggested that perinatal brain masculinization requires AR function and that expression of male-typical behaviors in adults is mediated by both AR-dependent and -independent androgen signaling. "

 

Why is this article important? Numerous theories have been put forward as to how the male brain is masculinized. Some indicate that a process of converting testosterone to estrogen by the aromatase molecule is the sole cause of brain masculinization. This article adds to that indicating that the androgen receptor is critical to brain masculinization. Without androgens the brain does not masculinize and DES inhibits testosterone production.

 

 

 

From - Development of the Cerebral Cortex: XV. Sexual Differentiation of the Central Nervous System Roger A. Gorski, Ph.D. 8)

 

"Hormones are also required for the proper development and sculpting of key areas of our brains. Hormones also lead to sexual differentiation of the CNS. It is clear that in laboratory animals, the CNS is inherently female unless exposed to testicular hormones."

 

 

From - The Role of Estrogen in Sexual Differentiation Elaine Bonleon de Castro . 12) 

 

"Male rats have a larger absolute cross-sectional callosal area than females in absolute and relative measurements, and the neonatal removal of ovarian hormones leads to callosal enlargement; these effects can be countered by the administration of estrogen. These experimental data strongly suggest that ovarian hormones, especially estrogen, contribute to the sexual differentiation process in ways comparable to testosterones masculinization effects."


 

From - Genome and Hormones: Gender Differences in Physiology, Estrogens effects on the brain: multiple sites and molecular mechanisms. Bruce S. McEwen  122) 

 

"Recent research is showing that the brain is more widely responsive to gonadal hormones than previously thought. That is, not only is the hypothalamus affected by circulating estrogens and androgens but also structures like the hippocampus, which undergo sexual differentiation and are hormone responsive in maturity. Even the cerebellum is sensitive to estrogens."

 

 

From - Gender-specific steroid metabolism in neural differentiation. JB Hutchison  137)

" Both the neuroendocrine system and the brain mechanisms underlying gender-specific behavior are known to be organized by steroid sex hormones, androgen and estrogen, during specific sensitive phases of early fetal and perinatal development. The factors that control these phasic effects of the hormones on brain development are still not understood."


 

From - Ontogeny of Region-Specific Sex Differences in Androgen Receptor Messenger Ribonucleic Acid Expression in the Rat Forebrain. Michael D. McAbee and Lydia L. DonCarlos 28) 

 

"SEXUAL differentiation of the brain is dependent upon exposure to the gonadal hormone testosterone during the perinatal period (1). In the absence of circulating testosterone, the mammalian brain develops an essentially female phenotype. "


 

From - Fitch, Roslyn Holly and Denenberg, Victor H. (1995) A Role for Ovarian Hormones in Sexual Differentiation of the Brain, Psycoloquy : 6,#5 Sex Brain (1)  34)

"The bulk of findings in this field support the notion that mammalian sexual differentiation is primarily mediated by androgens of testicular origin and that the presence of these androgens in early life produces a "male" brain. In contrast, the female brain is thought to develop via a hormonal default mechanism, in the absence of androgen. Findings are reviewed which show that ovarian hormones also play a significant role in sexual differentiation, and that the process of ovarian feminization has a considerably later sensitive period than androgen-mediated masculinization."


 

From - McCarthy, Margaret M. (1995) How About Sexually Differentiating Factors Other Than Estrogen?, Psycoloquy: 6,#32 Sex Brain (7) 36)


" Whereas the evidence of estrogen-mediated sexual differentiation is irrefutable, the strength of this evidence may have inadvertently prejudiced researchers against looking to other factors in the differentiation process."


 

From - Sex Differences in Progesterone Receptor Expression: A Potential Mechanism for Estradiol-Mediated Sexual Differentiation. Princy S. Quadros, Jennifer L. Pfau, Ann Y. N. Goldstein, Geert J. De Vries and Christine K. Wagner  49)

"The differential exposure of males and females to testosterone (T) and its metabolite estradiol (E) contributes to the development of sex differences in the brain."

 

 

From - Emerging science on the impacts of endocrine disruptors on intelligence and behavior. (Our Stolen Future : New Science Brain and Behavior ). 66)

"The sex steroids (testosterone, estrogen, etc.) contribute to, among other things, sexual differentiation of brain centers, and thereby, to the development of sexual identity and sexual behaviors."


 

From - GONADAL STEROID HORMONE RECEPTORS IN THE HIPPOCAMPUS: IMPLICATIONS FOR DEVELOPMENT AND DIFFERENTIATION. Robert J. Handa*1,2, Wendy A. Pouliot 1,2, Derek Solum1,2, Richard H. Price Jr.1,2, Michael D. McAbee 1 Lydia D. DonCarlos 1, Sheryl G. Beck 1. 135)

"These studies support the hypothesis that androgen and estrogen act to sculpt the actions of the hippocampus by both organizational and activational mechanisms. The two steroids appear to influence hippocampal function by different, but perhaps overlapping mechanisms. The interactions of these two steroids with both glutamatergic and GABA-ergic systems illustrate a complex regulatory system which has only begun to be teased apart."

 

From - Environmental Signaling: What Embryos and Evolution Teach Us About Endocrine Disrupting Chemicals. John A. McLachlan 29) 

 

"While retention of the female genital anlage, the Müllerian duct, was a prominent feature in DES-exposed male mice, no report from similarly exposed men has addressed this issue."

Chemicals which affect androgen levels and interfere with MIS, which is responsible for the regression of the Mullerian ducts in the 46XY fetus, are the chemical equivalent of a natural condition called Gonadal Dysgenesis, which is discussed on the observations page.

 

 

 From - Organizational effects of diethylstilbestrol on brain vasotocin and sexual behavior in male quail Carla Viglietti-Panzica, , Barbara Montoncello, Elena Mura, Marzia Pessatti and GianCarlo Panzica Laboratory of Neuroendocrinology, Rita Levi Montalcini Center for Brain Repair, Department of Anatomy, Pharmacology, and Forensic Medicine, University of Torino, Corso M. D’Azeglio 52, I-10126 Torino, Italy 269)

"In Japanese quail, we previously described a sexual dimorphism of the parvocellular vasotocin system of the limbic regions that, as the reproductive behavior, is steroid-sensitive and is organized during embryonic life by the exposure to estradiol. We verified in this study whether diethylstilbestrol, a chemical xenoestrogen, has analogous organizational effects on vasotocin innervation of limbic regions and on copulatory behavior of male Japanese quail. We injected in the yolk sac of 3 day-old quail embryos diethylstilbestrol or estradiol benzoate (a treatment which suppresses male copulatory behavior in adulthood and reduces vasotocin innervation), or sesame oil (control). No further hormonal manipulations were performed after hatching. Sexual behavior was recorded in males at the age of 6 weeks. Estradiol- and diethylstilbestrol-treated males exhibited a total suppression of copulatory behavior. After behavioral tests, all males were sacrificed and brain sections processed for vasotocin immunocytochemistry. Significant decrease in the density of vasotocin immunoreactivity was detected in the medial preoptic nucleus, and in the bed nucleus of stria terminalis and lateral septum of diethylstilbestrol-treated males. The magnocellular vasotocin neurons were, in contrast, not affected. In conclusion, the present data demonstrate that embryonic treatment with diethylstilbestrol induces a full sex reversal behavioral phenotype as well as a significant decrease of vasotocin expression in the preoptic-limbic region in male Japanese quail. Therefore, the parvocellular vasotocin system could represent an optimal model to investigate the effects of pollutants on neural circuits controlling reproductive functions.
"

 

Scientific American Article: Sex Differences in the Brain Men and women display patterns of behavioral and cognitive differences that reflect varying hormonal influences on brain development 203)

" If a rodent with functional male genitals is deprived of androgens immediately after birth (either by castration or by the administration of a compound that blocks androgens), male sexual behavior, such as mounting, will be reduced, and more female sexual behavior, such as lordosis (arching of the back when receptive to coitus), will be expressed. Likewise, if androgens are administered to a female directly after birth, she will display more male sexual behavior and less female behavior in adulthood. These lifelong effects of early exposure to sex hormones are characterized as 'organizational' because they appear to alter brain function permanently during a critical period in prenatal or early postnatal development. Administering the same sex hormones at later stages or in the adult has no similar effect.

 

From - A NEW CONCEPT FOR BRAIN AROMATASE IN SEXUAL DIFFERENTIATION. Koh Shinoda 136)

"Taken together, brain aromatase, especially in the mPOAM arc, is thought to indirectly regulate the expressions of EsR and AnR by controlling the levels of androgen and estrogen, playing a crucial role in determination of the direction of brain sexual differentiation."

 "

 

 

 

 

From - Androgens and male behavior. LJ Gooren and FP Kruijver December 30, 2002 170)

"Sexual differentiation into a male or a female includes sexual differentiation of the brain. The paradigm of mammalian sexual differentiation is that in the presence of androgens (normally produced by the fetal testis) a male brain differentiation occurs, while in the absence of androgens (normal in females) a female brain differentiation follows. In the human there is a sex-dimorphism in gender identity/role, sexual orientation, sexual functioning, and in non-sexual functions, such as spatial ability, and verbal fluency. Inasmuch these properties can be studied in other mammals the effects of androgens are solidly demonstrable. In the human the evidence for androgen effects is equally plausible, evident from observations in subjects with errors in the process of sexual differentiation and in morphological studies of brain structures presumably related to these properties. But clinical observations show compellingly that other, largely unidentified, factors may modulate, or even override the effects of androgens."



From - Postnatal influence of diethylstilbestrol on the differentiation of the sexually dimorphic nucleus in the rat is as effective as perinatal treatment.
234)

"The volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the male rat brain is larger than that of the female. In the female rat, treatment with diethylstilbestrol (DES), either perinatally (from day 16 of gestation to postnatal day 10), or postnatally (birth to day 10) was equally effective in increasing the volume of SDN-POA compared to controls. Prenatal treatment (day 16 of gestation to birth) with DES also increased the volume of the SDN-POA but this increase was significantly smaller than that achieved with the other treatments. These results confirm the effectiveness of DES in increasing the volume of the SDN-POA in the female rat brain, and prove that the differentiating SDN-POA is very receptive to hormone influences in the early postnatal period."


 From - Pre- and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats. 235)

"The volume of the sexually dimorphic nucleus in the preoptic area (SDN-POA) of the rat brain is several fold larger in males than in females. When female rats were treated pre- and postnatally with testosterone propionate (TP) or with diethylstilbestrol (DES) they became anovulatory and their SDN-POA developed equivalent in size to that of normal males. Identical treatment of male rats resulted in deficient testicular development, but had no influence on SDN-POA volume. The results indicate that the gross morphological sex difference in SDN-POA volume can exclusively be controlled by the hormonal environment during the critical period of sexual brain differentiation, and that non-steroidal estrogens are just as effective as convertible androgens in stimulating SDN-POA differentiation."

 

Chemicals which affect the Androgen receptor offer an important parallel with a genetic condition called Androgen Insensitivity Syndrome (AIS), which is discussed on the observation page. Androgen insensitivity syndrome is caused by a genetic impairment of the cell’s androgen receptor to bind with testosterone. For a comprehensive list of androgen receptor gene mutations, see 171). 

 

From - Reproductive Malformation of the Male Offspring Following Maternal Exposure to Estrogenic Chemicals. Chanda Gupta 16) 

 

" We report that these chemicals permanently affected male sexual differentiation by increasing anogenital distance, inducing prostate growth and its AR binding activity, and reducing epididymal weight. At high dosage, on the other hand, DES produced an opposite effect, inducing hypospadias and inhibiting prostate growth and AR binding activity." 

 

Note : This reports confirms that the effects of DES are Non-monotonic 185) 17). AR stands for androgen receptor, which is the cellular structure androgen molecules bind to in order to activate the portion of the genetic code dependant upon androgen activation. If DES inhibits androgen receptor binding then testosterone can't activate the cell’s RNA and the effects of testosterone on the cell are diminished. Hypospadias is a male genital developmental anomaly whereby the urethra opens somewhere along the underside of the penis rather than at the end 22). Hypospadias is a known side effect of DES in humans 94).


 

From - Estrogen, But Not Androgens, Regulates Androgen Receptor Messenger Ribonucleic Acid Expression in the Developing Male Rat Forebrain. Michael D. McAbee and Lydia L. DonCarlos  47)

"The importance of perinatal testosterone exposure in the masculinization of the rat central nervous system is well established (1). Circulating testosterone acts to organize the structure of neural substrates that underlie numerous sexually differentiated behaviors and neuroendocrine functions including reproduction, play, feeding, learning and memory, aggression, sleep/wake cycles, and GH secretion."
"The importance of postnatal testosterone in the production of sex differences in AR mRNA content during development has been demonstrated by our previous finding that elimination of circulating testosterone on either PND-0 or PND-5 decreases AR mRNA expression in the BSTpr and MPO of PND-10 males to female-typical levels (15)."

In this report (see Exp 1) the dosage used by these researchers confirms that DES can increase androgen receptor binding in the rat forebrain, confirming a link with the above report which uses the prostate as an example. Different dosages can have very different effects.


 

Another report which indicates that high dosages of DES can affect androgen receptors:

From - Induction of Reproductive Tract Developmental Abnormalities in the Male Rat by Lowering Androgen Production or Action in Combination with a Low Dose of Diethylstilbestrol: Evidence for Importance of the Androgen-Estrogen Balance 150)

"The induction of major abnormalities in rats treated with DES (10 µg) was coincident with loss of androgen receptor immunoexpression in affected tissues. Reduced androgen receptor immunoexpression was also induced by combined treatment with DES (0.1 µg) plus GnRHa or flutamide, whereas treatment with any of these compounds alone had no or only minor effects. These findings suggest that reduced androgen action sensitizes the reproductive tract to estrogens, demonstrating that the balance in action between androgens and estrogens, rather than their absolute levels, may be of fundamental importance in determining normal or abnormal development of some regions of the male reproductive tract."

DDT also affects androgen receptors: "Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist 152).”


 

From - Suppression of androgen action and the induction of gross abnormalities of the reproductive tract in male rats treated neonatally with diethylstilbestrol 153):

"In DES-treated rats, androgen receptor (AR) immunoexpression was virtually absent from all affected tissues and the testis, whereas AR expression in controls was intense in epithelial and stromal cells. The DES-induced change in AR immunoexpression was confirmed by Western analysis for the testis"


 

From - Neonatal coadministration of testosterone with diethylstilbestrol prevents diethylstilbestrol induction of most reproductive tract abnormalities in male rats 233):

 

"The primary purpose of this study was to evaluate whether the coadministration of testosterone (TE; 200 micro g) with 10 micro g of diethylstilbestrol (DES) between days 2 and 12 postnatally could prevent the adverse gross reproductive tract changes and associated loss of androgen receptor (AR) expression induced by DES treatment alone. Various endpoints (rete testis area, efferent duct lumen area, epithelial cell height of efferent ducts, and vas deferens) were quantified to check for the abnormal changes that have been shown to occur after neonatal treatment with a high dose (10 micro g) of DES. Additionally, DES induction of an aberrant pattern of estrogen receptor alpha (ER-alpha) immunoexpression in the vas deferens and seminal vesicles was evaluated. The coadministration of DES with TE prevented the induction of all but one of the abnormalities induced by DES treatment on its own, coincident with the restoration of normal/supranormal TE levels and normal immunoexpression of the AR and ER-alpha in the tissues studied. The exception was DES-induced lumenal distension of the efferent ducts, which was only partially prevented by the coadministration of DES with TE"


These next 2 reports concern PCB's and DDT: 

 

From - Human Studies - Reproductive and Sexual Effects of PCBs, (19 General studies, 9 Human studies ) 69)

" Effects Cited in Study Reviews / Behavioral Changes

-changed sexual differentiation (3 reviews)
-sex reversal
-altered reproductive behavior, abnormal sexual behavior
-feminization
-demasculinization
-delays in sexual maturation
-some chemical effects show only after puberty
-reduced fertility by affecting breeding performance "

"The incidence of disorders of development of the male reproductive tract has more than doubled in the past 30-50 years while sperm counts have declined by about half. Similar abnormalities occur in the sons of women exposed to diethylstilbestrol (DES) during pregnancy and can be induced in animals by brief exposure to exogenous oestrogen/DES during pregnancy."



This Study is from Germany:

 

From - Genetic and Epigenetic Effects on Sexual Brain Organization  Mediated by Sex Hormones. Günter Dörner, Franziska Götz, Wolfgang Rohde, Andreas Plagemann, Rolf Lindner, Hartmut Peters & Zhara Ghanaati , Berlin Germany 11). 

 

" In connection with the introduction and extensive use of the pes-ticide DDT, the following findings were obtained in subjects born before as com-pared to those born during this period:

 

1. The prevalence of patients with polycystic ovaries (PCO), idiopatic oligospermia (IO), and transsexualism (TS) increased significantly (about 3 – 4 fold)."
 

The thing about this study is the incredably low dosages used. NG stands for nanogram which is .000000001 grams.

 

From - Effects of endocrine modulators on sexual differentiation and reproductive function in male Japanese quail. Krister Halldin, Jeanette Axelsson and Bjvrn Brunstrvm Brain Research Bulletin Copyright 2004 Published by Elsevier Inc.

 

"Males and females display different behavioral patterns during sexual interaction and the copulatory sequence is only seen in males and not in intact females [1] and [4]. Differences in the hormonal milieu during differentiation explain these sex-specific behaviors.During the embryonic stage, the brain is exposed to hormones, presumably produced by the developing gonads, which organize the neural tissue to react in a specific way to hormones later in life. Treatment with antiestrogens or aromatase inhibitors have shown that estrogens produced during embryonic development demasculinize the brain of female embryos [2] and [8]. Demasculinization can also be produced in the male by exposing the brain to estrogens during differentiation, and these males will not display male sexual behavior as adults regardless of the hormonal milieu [3] and [71]."

 

"EE2 and DES were injected into the yolk of embryonated eggs. After the male birds had been raised to sexual maturity, we examined sexual behavior, plasma T concentrations, and testis morphology [31].
 
EE2 significantly depressed male sexual behavior at 6 ng/g egg, and for DES a significant decrease was observed at 19 ng/g egg (Fig. 3)."

 

"Our studies have shown that behavioral demasculinization of male quail can be induced by synthetic estrogens, such as EE2, at doses of about 1000 times lower than the doses of estradiol usually employed in neurophysiological studies (reviewed in [7]) and we obtained doseresponse relationships for the synthetic estrogens EE2 and DES. Depressed sexual behavior was the most sensitive of the variables studied and we concluded that this

 endpoint is useful for studying effects of endocrine modulating chemicals. We did not find any significant effects by BPA and TBBPA on the variables studied, whereas o,p′-DDT caused profound effects on sexual behavior, cloacal gland area, and plasma T concentration in males. In other labs, various environmental contaminants suspected of having estrogen-like effects have been administered to quail embryos during sexual differentiation. These studies have confirmed that certain pollutants can interfere in an estrogen-like manner with sexual differentiation of brain and behavior in birds [18], [21] and [42]."

 

There are at least 2 types of estrogen receptor, DES has different activational properties for each type of receptor. ERb has a number of subtypes.

 

From - Estrogen Receptor Structures & Functions 270)

 

"Binding Assays
Typical assays to gauge the binding affinities of estrogen analogs or new drugs follow a standard pattern. The receptors are infused with E2, and a binding curve is obtained based on varying concentrations of E2 present. Then, the molecule in question is added in varying concentrations, acting as a competitive inhibitor, and its ability to bind is plotted against E2's. Most of these assays are depicted using Scatchard plots. The relative binding constants of some well-studied molecules are as follows:

 

Ligand  ERa ERb
17b-Estradiol ("E2" or "EST") 100 100
Diethylstilbestrol 468 295
Tamoxifen

6

7


"

 

 

 

 

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