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

   Intersex and DES

 

 

 

Is there a connection between DES exposure in utero and Intersexed conditions in genetic males? To reiterate the ISNA definition of Intersex "Simply put, intersexuality is a set of medical conditions that features "congenital anomaly of the reproductive and sexual system." That is, a person with an  intersex condition is born with sex chromosomes, external genitalia, or an internal reproductive system that is not considered "standard" for either male or female."  It is a well known fact that abnormal hormone levels or the inability to react to those hormones can cause the fetus to be intersexed. Some of those conditions are discussed on this page. One of my goals is to show that at the cellular level, 2 of those intersexed conditions are very similar to the effects of DES.  Another goal is to show that some people with intersexed conditions have gender identity issues. Hence if DES can cause intersexed conditions then is it not reasonable to postulate that DES can also cause gender identity issues?

The definitions of 2 natural Intersex conditions, Androgen Insensitivity Syndrome and Gonadal Dysgenesis are central to this discussion.

From - Syndromes of Abnormal Sex Differentiation: A guide for patients and their families (a Johns Hopkins document, see specific syndromes of sex differentiation):

"Androgen Insensitivity Syndrome (AIS)
Androgen Insensitivity Syndrome occurs when an individual, due to a mutation of the androgen receptor gene, is incapable of responding to androgens. Two forms of AIS exist, Complete AIS (CAIS) and Partial AIS (PAIS)."

"Gonadal Dysgenesis
Unlike AIS in which affected individuals possess functioning testes but can not respond to the androgens their testes produce, patients with Gonadal Dysgenesis can respond to androgens but develop abnormal testes which are incapable of producing androgens. Like AIS, two forms of Gonadal Dysgenesis exist (Complete and Partial)."

Clicking on the links below will bring up discussions on the various topics listed.


Table 1 compares the physical effects of DES to Gonadal Dysgenesis and AIS.
Table 2 compares DES at the cellular level to gonadal dysgenesis and AIS.
Table 3 looks at Gender identity issues associated with people who have intersexed conditions.

 

Mice are often used by researchers as a means to discover how chemicals may affect humans. This excerpt is from a teleconference with Dr. John McLachlan, a long time researcher on the effects of DES exposure. The Centers for Disease Control is very careful about what they say in relation to DES , the fact that this transcript is posted on their website indicates the high quality of Dr. McLachlan's research .

From - CDC’s DES Update, DES & Findings of Animal Research March 26, 2003

"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."

"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."

 

 

Another article which discusses the link between gender identity and prenatal hormone levels.

From - Emedicine : Sexuality: Gender Identity. Author: Shuvo Ghosh, MD, Fellow, Developmental/Behavioural Pediatrics, Department of Pediatrics, McGill University Health Centre/Montreal Children's Hospital Coauthor(s): Leslie Walker, MD, Head, Section of Adolescent Medicine, Assistant Professor, Department of Pediatrics, Georgetown University Medical Center 202).

"This rudimentary gender identity, although incomplete, is an important determinant in gender development. The dimorphism of the brain itself suggests this. Nevertheless, variations may occur when endogenous or exogenous factors create a fetal environment where hormone levels do not follow the genetically determined pattern. The gender bias of these infants may be tilted away from one that correlates with the genotype. Such variations are discussed below."

"Conditions resulting from genetic or hormonal influences to the usual process of fetal development cause a number of differences in the resulting fetus. When levels of prenatal hormones are altered, phenotypic progression is altered as well. The inherent brain bias towards one sex may be discordant with the genetic makeup of a fetus, or even with its external anatomic presentation. Other variations lead to psychologic stressors in later development but have their origin in the prenatal stage. A number of such conditions exist that may ultimately affect a child’s gender identity."

 

 

From - Consequences of disturbed sex-hormone action in the central nervous system: behavioral, anatomical and functional changes: Kula K, Slowikowska-Hilczer J.

"Experimental studies revealed that transient action of sex steroids during perinatal period is crucial for the development of male sexual behavior and sexually dimorphic brain anatomy. Meanwhile, the lack of gonadal steroids in female foetus and estrogen effects at puberty determine female behavior together with female type of anatomical brain structures and of endocrine functions. In men psychic sex consists of gender identity (self-estimation), gender role (objective estimation of sex behavior). In addition, a sexual psycho-orientation (hetero-, bi- or homosexual) has been distinguished. Although it is believed that gender depends on the socio-environmental influences such as rearing, learning and individual choice, the biological factors are considered to be most important. This concept arises from recent study on patients with gender dysphoria syndrome (transsexualism). In intersexualism, in genetic men with disturbances of sexual differentiation of external genitalia because of the lack of testoterone production or action in peripheral tissues (male pseudohermaphroditism) or in genetic women with ambiguous genitalia because of the presence and action of androgens (female pseudohermaphroditism), a discordance between the formal sex (assigned after the birth) and the psychic gender may appear. In these individuals the legal sex established according to somatic and/or genetic sex at birth may be incompatible with their actual gender identity and role. The knowledge about gender identity is necessary at the decision of eventual (!) surgical correction of sex organs in patients with ambiguous genitalia. This decision should depend not on the expected, but on the actual gender identity of the individual patient. Meantime, early bilateral gonadectomy in patients with gonadal dysgenesis and male pseudohermaphroditism is an indication for life because of the highest risk of germ cell carcinoma. "

 

 


From - Androgens, androgen receptors, and male gender role behavior.Wilson JD:

"Studies of genetic males with single gene mutations that impair testosterone formation or action and consequently prevent development of the normal male phenotype provide unique insight into the control of gender role behavior. 46XY individuals with either of two autosomal recessive mutations [17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency or steroid 5 alpha-reductase 2 (5 alpha-R2) deficiency] have a female phenotype at birth and are raised as females but frequently change gender role behavior to male after the expected time of puberty. In contrast, genetic males with mutations that impair profoundly the function of the androgen receptor are also raised as females and have consistent female behavior as adults. Furthermore, the rare men with mutations that impair estrogen synthesis or the estrogen receptor have male gender role behavior. These findings indicate that androgens are important determinants of gender role behavior (and probably of gender identity) and that this action is mediated by the androgen receptor and not the result of conversion of androgen to estrogen. The fact that all genetic males with 17 beta-HSD3 or 5 alpha-R2 deficiency do not change gender role behavior indicates that other factors are also important determinants of this process. Copyright 2001 Academic Press."

See also Estrogen: Consequences and Implications of Human Mutations in Synthesis and Action 189):   

"Psychosexual Development and the Central Nervous System (CNS)":

"The role of estrogens on psychosexual development in the human in contrast to other mammals is poorly understood. The men and women with aromatase deficiency owing to a mutation in CYP19 and the man with estrogen resistance due to a homozygous mutation in the estrogen -receptor had sex-appropriate gender identities (6, 8, 9). Taken as a whole, these observations suggest that despite the diffuse distribution of estrogen receptors and the enzyme aromatase in the pre- and postnatal CNS (160, 161, 162), and despite well-documented sex differences in human brain functioning, estrogen in the human does not have the critical effect on male gender behavior described in non-primate mammals (13, 163, 164, 165, 166, 167, 168, 169) and supports restraint in extrapolating concepts in this active field from studies in animals to the human (8, 14, 170). "

 

 

One more intersexed condition to consider in relation to gender identity is 5-alpha reductase.


From - Syndromes of Abnormal Sex Differentiation, A guide for patients and their families (a Johns Hopkins document, see specific syndromes of sex differentiation):

"5-alpha reductase deficiency affects 46XY individuals. During fetal development, the gonads differentiate into normal testes, secrete appropriate amounts of testosterone, and patients are able to respond to this testosterone. However, affected individuals are unable to convert testosterone to dihydrotestosterone (DHT), and DHT is necessary for the external genitalia to masculinize normally. The result is a newborn baby with functioning testes, normally developed Wolffian ducts, no Mullerian ducts, a penis resembling a clitoris, and a scrotum resembling labia majora."

 From - Steroid 5a-Reductase 2 Deficiency* JEAN D. WILSON, JAMES E. GRIFFIN, AND DAVID W. RUSSELL  173):

"Reversal of Gender Role Behavior Imperato-McGinley et al. (45, 85) reported that 18 of 19 individuals from the Dominican Republic cluster were initially raised as females but subsequently changed gender role behavior to male at the time of expected puberty."

Like people with cloacal extrophy these 46XY children have a normal prenatal hormone environment with the exception that their bodies cannot convert testosterone into DHT which is required for the development of the external male genitals. As such at birth they are often assigned as female. However, their brains are subjected to normal testosterone levels and they have nothing wrong with their androgen receptors. Just as the people in the cloacal extrophy study they often change gender as they mature.  

 
 

From - Sex-Typed Toy Play Behavior Correlates with the Degree of Prenatal Androgen Exposure Assessed by CYP21 Genotype in Girls with Congenital Adrenal Hyperplasia. Anna Nordenström, Anna Servin, Gunilla Bohlin, Agne Larsson and Anna Wedell. 2002:

"Previous studies have shown that girls with congenital adrenal hyperplasia (CAH), a syndrome resulting in overproduction of adrenal androgens from early fetal life, are behaviorally masculinized."

"Our results support the view that prenatal androgen exposure has a direct organizational effect on the human brain to determine certain aspects of sex-typed behavior."

 


From - Gender change from female to male in classical congenital adrenal hyperplasia. HF Meyer-Bahlburg, RS Gruen, MI New, JJ Bell, A Morishima, M Shimshi, Y Bueno, I Vargas, and SW Baker:

"In regard to childhood gender-role behavior, the four gender-change patients tended to be more masculine or less feminine than (behaviorally masculinized) CAH-SW controls."

 


 From - What is Gender and Who is Transgendered? by Carl W. Bushong, PhD, LMFT.

This informative article is posted on the Transgendercare.com website which discusses the various aspects of gender. About half way down the page are two photos, the first is of the genitals of a XX person with Congenital Adrenal Hyperplasia (CAH), the second is a full body shot of an XY individual with Androgen Insensitivity Syndrome (AIS). Both photos are extremely graphic. They serve to prove just how powerful the effects of prenatal hormones are on the physiological development of the fetus.

 

 

 

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