Part 4 Male Gender Identity in an Individual With Complete Androgen Insensitivity Syndrome

What I learned during summer workation –
(as opposed to vacation, which it wasn’t):

1.  Some intersex people really don’t like it when trans people claim to be intersex because they’re trans.

2.  Some trans people really don’t like it when they’re told they’re not intersex just because they’re trans.

3.  No one seems to care if I write about the biological basis of gender identity and cite research studies involving intersex people.  Well, if they do, they sure didn’t tell me. (And that includes the Accord Alliance, who never replied to my query on the subject.)

Now I didn’t learn all this from reading comments to my blog posts.  There are plenty of people out there in our communities who talk and write about this issue, and I’ve seen it pop up on the lists as well.  Although this is an important subject that would likely benefit from open dialog, that’s not the focus of what we’re doing here at ATM, at least not at the moment.

So what does it all mean?

It means I’m finally going to finish the topic I started in June and make this fourth and final post in the series on the biological basis of gender and male gender identity in an individual with Complete Androgen Insensitivity Syndrome.

Woo…


So where were we?

In Part 1 of this series, we learned about O.J. Simpson.  Oh, and also about the androgen receptor.  We learned about its structure, what it does and how it is mutated, at least what we know at this point.  (And prior to Part 1, I posted a  link to a primer on Androgen Insensitivity Syndrome.)

In Part 2, the case was presented about a person who was born with unremarkable female genitalia and was raised female but who reported a male gender identity in adulthood (T’Sjoen et al., 2010).  No big deal, right?   This description could be about me and plenty of other guys.  The significance is that this person is a chromosomal male with a mutated androgen receptor gene and so has Complete Androgen Insensitivity Syndrome (CAIS). In other words, his body cannot recognize or respond to the testosterone that his internalized testes produce.

This case of an individual with CAIS goes against the theory that testosterone masculinizes the brain during fetal development to result in male gender identity.  According to the theory, without a functional androgen receptor, a person should not be able to have a male gender identity, no matter what their chromosomal makeup.

And that led us to Part 3, where we talked about  gender-typical behavior and gender identity of chromosomal females with the intersex condition of Congenital Adrenal Hyperplasia.  CAH is typified by excess androgen production during fetal development due to genetic mutations affecting the steroidogenic pathways of the adrenal glands.

In discussing 46,XX individuals with CAH, the reasoning was that if excess androgens such as testosterone were present in sufficient quantity to virilize the developing genitalia, then the masculinization of the brain should also have occurred.  The studies we discussed were designed to test the assumption that masculinization of the genitalia in 46,XX individuals with CAH was correlated with masculinization of the brain, as evidenced by masculine-typical behavior and male gender identity.  The problem with this reasoning was, as we learned, that there is no proof that the degree of genital virilization in individuals with CAH correlates with the amount of testosterone present.

So if we can’t understand male gender identity by considering individuals with excess testosterone during fetal development, such as chromosomal females with CAH, let’s consider the reverse situation. What happens in chromosomal males with Androgen Insensitivity Syndrome (AIS) whose bodies see less testosterone during fetal development?

Androgen Insensitivity Syndrome

Mutations of the gene for the androgen receptor can result in 46,XY individuals who are either completely or partially insensitive to the actions of testosterone and dihydrotestosterone (DHT).  There are variations in the mutations of the androgen receptor gene and thereby in the phenotypes (i.e. physical manifestations) of the mutations.  Whereas 46,XX individuals with CAH have varying degrees of masculinization of the external genitalia, 46,XY individuals with AIS have varying degrees of under-masculinization of the external genitalia.  When some masculinization occurs, the individual has Partial Androgen Insensitivity (PAIS) whereas unremarkable female genitalia and lack of pubic or axial hair are hallmarks of CAIS.

From Rajender et al., 2007; Figure 2

Some clinicians will include a classification for MAIS, or Mild Androgen Insensitivity Syndrome, which has two forms characterized by gynecomastia, high-pitched voice with or without fertility (Galani et al., 2008; Rajender et al., 2007).

Similar to the question we asked regarding 46,XX individuals with CAH, we can ask whether there is any indication about testosterone’s role in forming male gender identity by regarding gender identity in 46,XY individuals with PAIS.

In doing so, however, we’re up against the same issues — in studies involving children, how much of the gender-typical behavior they exhibited was due to their gender identities and how much was due to influence by the parents, relatives and peers based on their gender of rearing? As we know, gender behavior does not equal gender identity.  But let’s look at the studies.

Jürgensen and coworkers (2007) examined the gender role behavior of 33 intersex children (ages 2-12) with an XY karyotype, 21 that had been reared as girls and 12 as boys.  All of these children were not necessarily classified as having AIS, but also had other types of intersex conditions that resulted in very low androgen levels (i.e. hypoandrogenization).  This group was divided additionally into sub-groups of individuals with complete or partial hypoandrogenization.  They found that all children with complete hypoandrogenization were reared as girls and exhibited female-typical behavior whereas the children with partial hypoandrogenization, whether raised as boys or girls, exhibited more masculine-typical behavior.  Their conclusion was that the gender-typical behavior of the children was correlated with prenatal androgen exposure (based on the level of genital masculinization).

For the flip side, let’s take a look at Mazur’s review of the literature (2005).  He reported that of 99 individuals who had been diagnosed with PAIS (only 26 of which showed an actual mutation in the androgen receptor gene), 41 were reared as females, 25 were reared as males and 3 were not assigned a gender at birth but lived as females as adults.  Of those 99 individuals, 9 of them changed gender from their gender of rearing, 3 FTM and 6 MTF.  Mazur’s conclusion for individuals with PAIS?

“Thus, self-initiated gender reassignment was rare. Gender dysphoria also appears to be a rare occurrance.”

What?  A rare occurrence?  That’s 9 percent who changed their gender!  And that doesn’t count the 3 who were unassigned at birth and the 5 who were reassigned by physicians between 1 and 6 years of age.  Still, can you imagine what the world would be like if 9% of the population went around changing their gender? (I’d bet that SRS would be covered by insurance companies!)

Nevertheless, let’s consider the data.  In PAIS, gender assignment at birth is based on the level of under-virilization of the genitalia, and yet, there were 6 individuals in the Mazur review who transitioned from male-to-female.

If we assume that they were assigned male at birth based on external genitalia that was more “male-like,” (not necessarily a correct assumption but let’s go with it) then would we not also assume that those individuals would have relatively greater masculnization of the brain than those who were assigned female at birth?  And yet, they had female gender identities, going against the assumptions.

Well, then let’s go back to CAIS, where, as mentioned previously in this series, 46,XY individuals with CAIS are almost always raised as females and most reports show that they have female gender identity (Boehmer et al., 2001; Hines et al., 2003; Jürgensen et al., 2007; Mazur, 2005; Wisniewski et al., 2000).  However, even before the publication of the case study that started this entire series (T’Sjoen et al., 2010), there was evidence in the literature that masculine behavior or male gender identity could occur in 46,XY individuals with CAIS (Kulshreshtha et al., 2009; Meyer-Bahlburg, 2009, 2010).

So what gives here?  After all this information and discussion about the data, it seems we are right back where we started.  If testosterone is the factor that masculinizes the brain to result in male gender identity, then why don’t more 46,XX individuals with CAH who have masculinized genitalia also have male gender identities?  Likewise, how could any 46,XY individual with CAIS have a male gender identity?  Let’s take those two questions separately.

Why Don’t More Chromosomal Females with CAH Have Male Gender Identities?  — Considering Morphogen Gradients

Right, why don’t they?  If testosterone is a brain masculinizing factor and individuals with CAH have an over-production of androgens, enough to virilize the genitals, then why doesn’t the brain become masculinized as well?

My response to this question is more of an hypothesis than an answer, because I have no way to prove it and because I haven’t seen a study in the literature that tries to address it. That doesn’t mean the data aren’t out there, it just means I haven’t seen it. This hypothesis could be tested in a fancy experiment with genetically engineered mice, but we don’t have that luxury at the moment.  (Bet you didn’t know that genetically engineered mice would even be considered a ‘luxury’.)

During embryonic and fetal development, the patterning of different cellular relationships and anatomical structures are dependent upon morphogens.  These are factors that direct the genetic pathways and differentiation of cells so they ‘know’ what they’re supposed to become, what their cellular fate is.  For example, morphogens might tell a cell in the embryo that it’s supposed become a bone cell rather than a muscle cell.

Morphogens are produced by a “source cell” and act upon “target cells” to direct their differentiation, and they act upon the target cells in a concentration-dependent fashion.  For example, if morphogens that tell cells to become a finger were at the same concentration at all parts of the developing hand, how would the cells know that they were supposed to be the tip of the finger rather than the knuckle?

So in our example, if the “finger morphogens” were secreted by the cells in the center of the hand (the source cells) and diffused away from there, then the cells closest to the center of the hand would be exposed to a higher concentration of the finger morphogens and would know to become the base of the finger whereas the cells further away from the center of the hand would be exposed to a lower concentration of the finger morphogens and would know to become the tip of the finger.  That’s a grossly over-simplified explanation, but you get the picture.  (I hope.)

Based on that example, we would know, then, that morphogens can’t just be dumped out there in the developing embryo to float around and wreak havoc, directing cells hither and yon to develop in a willy-nilly fashion.  Morphogens must be present at the right place in the right concentration, in a “morphogen gradient.”  There is evidence in the literature, both experimental and theoretical, for the existence and function of morphogen gradients during development (Wartlick et al., 2009; Yan & Lin, 2009).

Figure 1 from Wartlick et al., 2009

Proper morphogen gradients are dependent not only on concentration and location, but also on time.  As I mentioned in Part 3 when talking about development of the sex organs and genitalia, timing is everything.  Embryonic and fetal development rely on a precisely orchestrated set of events that occur in a critical spatio-temporal fashion.  The signals must be there in the right place, in the right concentration, at the right time (Kutejova et al., 2009).

So now with that in mind, let’s consider development of the brain.  We know that the brain develops in a sexually dimorphic way, meaning that some anatomical structures, nerve tracts and circuitry are different between males and females.  We also know that the majority of these differences are a result of hormonal (i.e. testosterone) and genetic differences between the sexes (Morris et al., 2004; Sato et al., 2004; Tobet et al., 2009; Zuloga et al., 2008).  Because testosterone induces these sexually dimorphic brain differences during development, that would make testosterone a morphogen!

Right.  Now, we take that information and go back to CAH and the over-production of progestins by the adrenal glands, with the progestins being metabolized into androgens.  The adrenal glands are located on top of the kidneys, at the anterior end (i.e. the end pointing toward the head) and they begin producing steroids during Weeks 8 to 9 of fetal development, a time that we know is critical for development of the gonads and external genitalia (see Part 3).  We also know that the level of virilization of the genitalia does not correlate with gender-typical behavior or gender identity in 46,XX individuals with CAH.

Are you with me so far?  Let’s review then:

→  To review our question, if testosterone is the factor that causes masculinization of the brain, resulting in male gender identity, then why don’t more 46,XX individuals with CAH experience masculinization of their brains along with the virilization of their genitalia?

→  To review our knowledge of morphogens, they must be present during development in the right place, in the right concentration at the right time.

Now, let’s bring it all home!

The developing adrenal glands in individuals with CAH produce excess progestins that are metabolized into androgens, known morphogens, during the same time as the development and differentiation of the gonads and external genitalia.  The level of virilization of the external genitalia would be dependent upon the efficiency of:

  • the steroidogenic pathway in the adrenal glands and production of progestins,
  • the metabolism of the progestins into androgens (i.e. testosterone, mainly),
  • the metabolism of the testosterone into dihydrotestosterone (DHT) at the genitalia.

The efficiency of all of those steps would set up the morphogen concentration gradient of androgens at the proper time and at the proper place to affect the development of the internal organs and external genitalia.  The final factor would be the genetic response to the morphogens (i.e. androgens) that would add to the extent of the virilization of the external genitalia in 46,XX individuals with CAH.

Okay, take that one step further to the brain. We don’t know when masculinization of the brain occurs, so we don’t know the timing in relation to masculinization of the genitalia.  What we do know is that the adrenal glands are located anatomically closer to the genitalia than to the brain.  What if the morphogenic gradient of the steroids from the adrenal glands to the brain during development is at a threshold concentration, so that in some cases but not in others, full masculinization occurs?

If we put all of that together, then only some individuals who have virilized genitalia would also have a fully masculinized brain and a male gender identity.

In support of this theory, I take you back to the monkey studies.  When pregnant female rhesus monkeys were treated with testosterone earlier in gestation, the female offspring had virilized genitalia but not masculinized behavior, but when they were treated with testosterone later in gestation, the female offspring exhibited masculinized behavior with no effects on their genitalia.  (See Part 3.)

What I didn’t tell you was about another study where a lower dose of testosterone was administered to the pregnant female rhesus monkeys.  When administered early in gestation, this lower dose of testosterone did not result in virilized genitalia.  When administered late in gestation, the lower dose of testosterone did not result in masculinized behavior (reviewed in Wallen & Hassett, 2009).

Whoa, sounds good right?  It all makes sense and points to the importance of timing and concentration of the exposure of the brain to the androgens.  Well, not so fast — I’m going to throw a monkey wrench in my own theory.  (Haha, get it?  Monkey wrench? Rhesus monkeys?  Um, yeah, okay, I’ll stick to science rather than comedy.)

In pregnant women carrying fetuses with CAH, the elevated progestins produced by the fetal adrenal glands can be measured in the amniotic fluid (Hines et al., 2002).  Well, if they’re at such a high concentration that they can be measured in the mother, then wouldn’t that mean that there would be more than enough androgens metabolized from those progestins needed to masculinize the fetal brain?  Well, maybe. Perhaps.  Hard to say.  Intuitively, we would think so, but again, we have the limitations that we can’t measure how much androgen is metabolized in the fetus from the excess progestins (White & Speiser, 2000), so that’s a fly in our theoretical ointment.

Okay, now onto our second question:

How could any 46,XY individual with CAIS have a male gender identity? — Considering Activity of the Mutated Androgen Receptor

Exactly!  How could an chromosomal male with CAIS have a male gender identity if testosterone is the factor that masculinizes the brain?  It should be impossible, right?  Well, this is all dependent upon the androgen receptor, which is tricky.  Let’s talk about that.

In Part 1 of this series, I described the androgen receptor (AR), it’s structure and how it works.  To review, the AR has a domain the binds the ligand, i.e. androgens such as testosterone and DHT, it has a domain that binds to DNA and it has a domain that interacts with other proteins.  In a nutshell, when the receptor is bound by one of its ligands, it joins up with other proteins and then sits down onto DNA and turns on genes.

If the gene for the AR is mutated, as is the case in PAIS and CAIS, the result can be an AR that does not bind androgens, does not bind DNA, does not bind other proteins, or even does not exist at all.  Any of those issues should either decrease the functionality of the AR or obliterate it completely, resulting in either PAIS or CAIS, respectively.

We would therefore assume, intuitively, that the functionality of the AR would depend on the specific mutation, right?  And we would assume, intuitively, that all of the people with the same mutation of the AR would exhibit the same phentype (i.e. physical manifestation) of that specific mutation.  For example, if Mutation X resulted in a PAIS score of 3 in one individual, we would assume that Mutation X would result in a PAIS score of 3 in all individuals who carry that mutation, right?  Well, Nature’s biological variation doesn’t adhere to logic like that.

Not only does the same mutation in the AR gene result in different phenotypes of the external genitalia in different people with AIS (Deeb et al., 2005; Hellwinkel et al., 2000; Werner et al., 2008; Zenteno et al., 2002; Zuccarello et al., 2008), but even of people within the same family who carry the same AR mutation can have quite variable comparative phenotypes (Evans et al., 1997; Holterhus et al., 2000; Rodien et al., 1996).

How does that apply to people with CAIS?  If there is some minimal activity in a mutated AR that results in unremarkable female genitalia in a 46,XY individual, but just enough to cause brain masculinization, then a male gender identity in a person with CAIS is theoretically possible.  What a coincidence! There is evidence of such a mutated AR!

Hannema and coworkers (2004) performed a study where they closely examined the testes that had been removed from 33 individuals with CAIS and compared the histological analysis with mutational analysis of the AR genes from the same individuals.  (Individuals with AIS have internalized testes that are usually removed after puberty because of the risk of testicular cancer.  The testes produce testosterone which is aromatized to estrogen and contributes to the secondary feminine characteristics of these individuals at puberty.  Sometimes, the testes are removed at a  younger age if they are located in the labia or the inguinal canal.)

Remarkably, 14 of these individuals (42%) with CAIS in Hannema’s study had developed epididymides and/or vas deferentia.  Why is this remarkable?  Because these structures are derived from the Wolffian ducts (see Part 3) and the Wolffian ducts require the action of testosterone to differentiate.  With a completely non-functional AR, the Wolffian ducts in these individuals should not have been able to recognize or react to testosterone and therefore should not have differentiated!

The authors of the study concluded:

The finding of epididymides and vasa deferentia in patients diagnosed with CAIS pose a problem with the classification of AIS.  Because there is evidence of AR activity in vivo, it is incorrect to say that these patients are completely insensitive to androgens. However, the term partial androgen insensitivity is historically associated with partial masculinization of the external genitalia.  We therefore suggest using the term severe androgen insensitivity syndrome to describe patients with normal female external genitalia but male internal genitalia.

In two follow-up studies, Cheikhelard et al. (2008) and Hannema et al. (2006) examined the testes of 29 and 44 individuals with CAIS, and found 14 (48%) and 16 (36%) that had differentiated epididymides and/or vas deferentia, respectively.

What does that mean?  That means that the AR in these individuals with CAIS must have had a tiny bit of activity, even though there was no evidence of that based on the completely under-masculinized, unremarkably female external genitalia.  Well, if there can be some small amount of AR functionality at the level of the Wolffian ducts during development, perhaps there can be a small amount of AR functionality at the level of the brain.

Going back to the case study of male identity in the individual with CAIS (T’Sjoen et al., 2010), a histological examination of that person’s removed testes would provide the evidence.  If epididymides or vas deferentia were present, then that would have indicated the possibility for a low level of AR activity.

Well, we don’t have that information, but what we do have is the genetic mutation of this individual’s AR gene, which was 2660delT, meaning that there was a premature stop codon in the gene transcript.  This mutation has been found in other cases of CAIS and was reported in two of the individuals studied by Hannema et al. (2004).  In those two individuals with that same AR mutation, there was no evidence of epididymides or vas deferentia.  In addition, all of the individuals in the study by Cheikhelard and coworkers (2008) reported a female gender identity, regardless of the presence or absence of epididymides or vas deferentia.  In other words, this theory appears to be a dead end in the case of the individual with CAIS and a male gender identity.  (Yes, I’m disappointed too.)

Considering Ligand Selectivity of Mutated Androgen Receptors

Don’t let that dead end get you down, ’cause we’re not licked yet, by golly!
(The following possibility was raised by Kulshreshtha et al., 2009.)

Regarding the family of steroid nuclear receptors, just as the steroids themselves have some similarities in structure, so too do their receptors.  Of all of the steroid receptors — androgen receptor, glucocorticoid receptor, progesterone receptor, mineralocorticoid receptor and estrogen receptors α and β — the two closest in structure are the androgen and glucocorticoid receptors (McEwan et al., 2007).  Because the ligands and the receptors are so similar, it’s no surprise that sometimes a point mutation in the ligand binding domain of the androgen receptor will change it just enough to allow a different steroid to bind and activate it.

These types of selectivity mutations have been documented in metastatic prostate cancer (Rajender et al., 2007), but also in instances of CAIS, where the AR mutation in the ligand binding domain allowed it to bind to 17-β-estradiol (Thin et al., 2003).  However, in the case study by T’Sjoen et al. (2010) of the individual with CAIS and a male gender identity, the AR mutation conferred a premature stop codon rather than a point mutation in the ligand binding domain, making it unlikely that this individual’s AR would be capable of binding any steroids.

Considering Non-Genomic Activities of Androgen Receptors

(The following possibility was raised by Meyer-Bahlsburg, 2010.)
As we have learned, testosterone and other androgens exert their actions by binding to the AR which is located in the nucleus.  Upon ligand binding, the AR associates with other proteins and binds to DNA, initiating transcription of genes.  This is a classical view of androgen activity, but more recent data have pointed to non-genomic activities of androgens.  Some of these non-genomic and rapid activities involve the nuclear AR but some do not.  A membrane-bound androgen receptor has been hypothesized based on the ability of androgens to bind at level of the outer membrane of a number of cell types, including neurons in the brain (reviewed in Foradori et al., 2008, Michels & Hoppe, 2008), but until the membrane receptor is identified, we cannot know whether it is involved in brain masculinization by androgens.

Considering Somatic Mosaicism

(The following possibility was raised by T’Sjoen et al., 2010.)
When genetic analyses are performed with the families of individuals with PAIS/CAIS, approximately 70% of the AR mutations are found in relatives of the affected individual and are therefore known to be inherited, whereas roughly 30% are consistently found not to be present in any relatives of the individual with AIS.  This means that the AR genes in these individuals were mutated de novo, or, were new, spontaneous mutations (Galani et al., 2008; Hiort et al., 1998; Rajender et al., 2007).

The multi-colored patchwork markings of the calico cat are due to somatic mosaicism. Click the kitty cat to see an informative video about mutations arising to form somatic mosaicism.

These de novo mutations could have arisen in the mothers’ eggs that were fertilized to become the individuals with PAIS/CAIS, or could have arisen in the affected individuals themselves when they were embryos.  In the latter situation, de novo (spontaneous) mutation of the AR gene in the developing embryo leads to somatic mosaicism so that some of the cells of the individual carry the wild-type (non-muted) AR gene whereas others carry the mutated AR gene.

Now, hypothetically, somatic mosaicism in a 46,XY individual with CAIS could result in the cells of the genitalia harboring the mutated form of the AR gene whereas those in the brain, or even just some of them in the brain, could harbor the wild-type AR gene.  In that theoretical case, which is not likely but also not impossible, and assuming that testosterone is the factor that masculinizes the brain, the individual would have under-virilized (female) genitalia but a masculinized brain and, therefore, a male gender identity.

For us FTM transsexuals, however, this situation wouldn’t work.  We need a functional AR in the brain if testosterone is the masculinizing factor in that organ, and we need functional ARs throughout the body if testosterone therapy is to work during medical transition.  In addition, we have two copies of the AR gene, one on each of our X-chromosomes, so the likelihood of spontaneous mutations occurring in both copies of the gene is slim.

On the other hand, somatic mosaicism could account for female gender identity in MTFs. Trans women, being 46,XY, only have one copy of the AR gene that would need to be spontaneously mutated in cells of the brain but not in the rest of the body during embryonic development.  A mutated AR in cells of the brain would not allow the brain to be masculinized by testosterone, and voilà, a feminized brain in a masculinized body.  Probably not very likely, but not impossible either.

But ladies, before you run out and ask for sequencing of your AR gene to look for somatic mosaicism and the basis of your transsexualism, remember that if the de novo mutation of the AR gene arose in the cells that were destined to be neurons of the brain, it might not be detectable in the cells of the blood or fibroblasts of the genital skin, which are the cells usually tested in these types of genetic analyses.

Considering Other Possibilities

Studies involving genetic analyses in people with intersex conditions sometimes reveal 46,XY individuals with clinical manifestations of AIS that have no mutations in the AR gene or other genes of the steroidogenic pathway (Deeb et al., 2005).  That means that there are other events occurring that are not related to the AR gene itself that result in the diagnosis of AIS, and any one of them could be a factor that induces brain masculinization.

Something other than AR that can be linked to gender formation would help to explain people who feel that they have a dual gender, or are a-gender, or experience some gender outside of the binary or somewhere in between.  What factors are responsible for these different permutations of gender identity?  There are plenty of possibilities that we don’t know enough about to be able to rule them out at the moment.

Take, for example, the proteins that interact with the AR — there were 169 proposed co-regulators of the AR known in 2007 (Heemers & Tindall) and there might be even more now in 2010.  We can probably safely assume that mutations or dysfunction of some of those co-regulators could contribute to improper signaling by the AR, even if the AR itself is not mutated.

Other possibilities are newly discovered genes and proteins that come along and add complexity to the story.  Take, for instance Steroidogenic Factor-1 (SF1), a nuclear receptor, similar to the steroid receptors.  SF1 is encoded by the gene NR5A1 on chromosome 9, is involved with development and function of the adrenal glands and the gonads and is also expressed in the developing brain and pituitary gland (Lin & Achermann, 2008).  The kicker?  Although it has a ligand binding domain, no one has yet identified a ligand for SF1. In other words, no one knows what binds to it!  (It’s mysterious…)

Figure 1, from Lin & Achermann, 2008, originally from Krylova et al., 2005

What we do know is that mutations of only a single copy of NR5A1, the gene for SF1, result in intersex conditions in 46,XY individuals with a range of phenotypes, including dysfunctional androgen steroidogenesis, female (external and/or internal) or ambiguous external genitalia with internalized testes or gonadal streaks, micropenis and vanishing testis syndrome (Köhler et al., 2008; Lin et al., 2007; Philibert et al., 2007).  Of the 10 individuals in these case studies carrying mutations of NR5A1, 8 were raised as females and 2 as males based on external genitalia, but there was no information about gender behavior or identity in these individuals.

Because NR5A1 is known to be expressed in the brain, time will tell whether SF1 is  involved in brain masculinization and/or gender formation.  What about our topic and the individual with CAIS who has male gender identity.  Is it possible that he has, along with a mutated AR, a mutation in NR5A1 with a mild phenotype?  It’s hard to say because NR5A1 wasn’t sequenced for this individual.  Although I have seen in the literature at least one case where two mutations in one family contributed to both CAH and AIS (Giwercman et al., 2002), I’m not sure that multiple mutations are very common, but it is possible.

Back to the Future

So here we are, six weeks, four posts (directly looking at this topic) and a gajillion references after mentioning a case of male gender identity in an individual with Complete Androgen Insensitivity Syndrome.  Are we any closer to answering the question as to how this person managed to have a male gender identity?  Is testosterone the masculinizing factor for the brain?

Well, after all this discussion, we can certainly make some good guesses.  I know mine.  What are yours??

–ATM

I would like to thank Jamison Green for kindly procuring and providing some of the references cited in this series of posts.

References Cited in This Really Long Post

Boehmer, Brüggenwirth, Assendelft, Otten et al., 2001.  Genotype versus phenotype in families with androgen insensitivity syndrome.  J Clin Endocrinol Metab 86:4151-4160

Cheikhelard, Morel, Thibaud et al., 2008.  Long-term followup and comparison between genotype and phentype in 29 cases of complete androgen insensitivity syndrome.  J Urol 180:1496-1501

Deeb, Mason, Lee, Hughes, 2005.  Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome.  Clin Endocrinol (Oxf) 63:56-62

Evans, Hughes, Bevan, Patterson, Gregory, 1997.  Phenotypic diversity in siblings with partial androgen insensitivity syndrome.  Arch Dis Child 76: 529–531 (free article)

Foradori, Weiser, Handa, 2008.  Non-genomic actions of androgens.  Front Neuroendocrinol 29:169-181 (free article)

Galani, Kitsiou-Tzeli, Sofokleous et al, 2008.  Androgen insensitivity syndrome: clinical features and molecular defects.  Hormones 7:217-229 (free article)

Giwercman, Nordenskjöld, Ritzén, Nilsson, Ivarsson et al., 2002.  An androgen receptor gene mutation (E653K) in a family with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency as well as in partial androgen insensitivity.  J Clin Endocrinol Metab 87:2623-2628 (free article)

Hannema, Scott, Hodapp et al., 2004.  Residual activity of mutant androgen receptors explains Wolffian duct development in the complete androgen insensitivity syndrome.  J Clin Endocrinol Metab 89:5815-5822 (free article)

Hannema, Scott, Rajpert-De Meyts, et al., 2006.  Testicular development in the complete androgen insensitivity syndrome. J Pathol 208:518-527

Heemers & Tindall, 2007.   Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28:778-808

Hellwinkel, Bassler, Hiort, 2000, Transcription of androgen receptor and 5alpha-reductase II in genital fibroblasts from patients with androgen insensitivity syndrome.  J Steroid Biochem Mol Biol 75:213-218

Hines, Golombok, Rust et al., 2002.  Testosterone during pregnancy and gender role behavior of preschool children: a longitudinal, population study.  Child Dev 73:1678-1687

Hines, Ahmed & Hughes, 2003.  Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch Sex Behav 32:93-101

Hiort, Sinnecker, Holterhus, Nitsche, Kruse, 1998.  Inherited and de novo androgen receptor gene mutations: investigation of single-case families.  J Pediatr 132:939-943

Holterhus, Sinnecker, Hiort, 2000.  Phenotypic Diversity and Testosterone-Induced Normalization of Mutant L712F Androgen Receptor Function in a Kindred with Androgen Insensitivity.  J Clin Endocrinol Metab 85:3245-3250 (free article)

Jurgensen, Hiort, Holterhus, Thyen, 2007.  Gender role behavior in children with XY karyotype and disorders of sex development.  Horm Behav 51:443-453 (free article)

Köhler, Lin, Ferraz-de-Souza, 2008. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency.  Hum Mutat 29: 59–64 (free article)

Krylova, Sablin, Moore, Xu, Waitt et al., 2005.  Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1.  Cell 120:343-355

Kulshreshtha, Philibert, Eunice, Khandelwal, Mehta et al., 2009.  Apparent male gender identity in a patient with complete androgen insensitivity syndrome.  Arch Sex Behav 38:873-875

Kutejova, Briscoe, Kicheva, 2009.  Temporal dynamics of patterning by morphogen gradients.   Curr Opin Genet Dev 19:315-322

Lin & Achermann, 2008.  Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development. Sex Dev 2:200-209 (free article)

Lin L, Philibert P, Ferraz-de-Souza et al., 2007.  Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.  J Clin Endocrinol Metab 92:991-999 (free article)

Mazur, 2005.  Gender dysphoria and gender change in androgen insensitivity or micropenis.  Arch Sex Behav 34:411-421

McEwan, Lavery, Fischer, Watt, 2007.  Natural disordered sequences in the amino terminal domain of nuclear receptors: lessons from the androgen and glucocorticoid receptors.  NRS 5:1-6 (free article)

Meyer-Bahlburg, 2009.  Concerns regarding gender change to male in a 46,XY child with complete androgen insensitivity syndrome: comment on Kulshreshtha et al., (2009).  Arch Sex Behav 38:876-877

Meyer-Bahlburg, 2010.  Gender outcome in 46,XY complete androgen insensitivity syndrome: comment on T’Sjoen et al. (2010).  Arch Sex Behav Jun 15. [Epub ahead of print]

Michels & Hoppe, 2008.  Rapid actions of androgens.  Front Neuroendocrinol 29:182-198

Morris, Jordan, Breedlove, 2004.  Sexual differentiation of the vertebrate nervous system.  Nat Neurosci 7:1034-1039 (free article)

Philibert, Zenaty, Lin et al., 2007.  Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study.  Hum Reprod 22:3255-3261 (free article)

Rajender, Singh, Thangaraj, 2007.  Phenotypic heterogeneity of mutations in androgen receptor gene.  Asian J Androl 9:147-179 (free article)

Rodien, Mebarki, Mowszowicz et al., 1996.  Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene.  J Clin Endocrinol Metab 8:2994-2998

Sato, Matsumoto, Kawano et al. 2004.  Brain masculinization requires androgen receptor function.  PNAS 101:1673-1678 (free article)

Thin, Wang, Kim, Collins, Basavappa, Chang, 2003.  Isolation and characterization of androgen receptor mutant, AR(M749L), with hypersensitivity to 17-beta estradiol treatment. J Biol Chem 278:7699-7708 (free article)

Tobet, Knoll, Hartshorn, Aurand, Stratton, et al., 2009.  Brain sex differences and hormone influences: a moving experience?  J Neuroendocrinol 21:387-392

T’Sjoen, De Cuypere, Monstrey et al., 2010.  Male gender identity in complete androgen insensitivity syndrome.  Arch Sex Behav Apr 1. [Epub ahead of print]

Wallen & Hassett, 2009.  Sexual differentiation of behavior in monkeys: role of prenatal hormones.  J Neuroendocrinol 21:421-426 (free article)

Wartlick, Kicheva, González-Gaitán, 2009. Morphogen gradient formation.  Cold Spring Harb Perspect Biol  1:a001255
(free article)

Werner, Zhan, Gesing, Struve, Hiort, 2008, In-vitro characterization of androgen receptor mutations associated with complete androgen insensitivity syndrome reveals distinct functional deficits.  Sex Dev 2:73-83

White & Speiser, 2000.  Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Endocr Rev 21:245-291 (free article)

Wisniewski, Migeon, Meyer-Bahlburg, Gearhart, Berkovitz et al., 2000.  Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome.  J Clin Endocrinol Metab 85:2664-2669 (free article)

Yan & Lin, 2009.  Shaping morphogen gradients by proteoglycans. Cold Spring Harb Perspect Biol 1:a002493 (free article)

Zenteno, Chavez, Vilchis, Kofman-Alfaro, 2002.  Phenotypic heterogeneity associated with identical mutations in residue 870 of the androgen receptor.  Horm Res 573:90-93

Zuccarello, Ferlin, Vinanzi et al., 2008.  Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility.  Clin Endocrinol (Oxf) 68:580-588

Zuloago, Puts, Jordan, Breedlove, 2008.  The role of androgen receptors in the masculinization of brain and behavior: what we’ve learned from the testicular feminization mutation.  Horm Behav 53:613-626 (free article)

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50 Responses to Part 4 Male Gender Identity in an Individual With Complete Androgen Insensitivity Syndrome

  1. j says:

    Very thought provoking, and this is my first reading of it. I’ll have to read it more times to have an opinion. So thank you for writing this very detailed post. It’s very amazing how much effort you’ve put into it. I’m sorry if this is a bit off topic… but there are those who don’t totally identify with either gender for long enough. They’re like gender identity pendulums. Does this throw a monkey wrench into your theory? I wonder.

    • Thanks. Maybe I should have broken this one up — there’s a lot of of information there. I just wanted to finish this topic and move one. But I did mention different permutations of gender, toward the bottom under “Other Considerations” and a fluid gender would fall into that category, although I admit I didn’t specifically spell out that one.

  2. j says:

    All the same, well done. This will help lots of people. Trust you got my mail about the calcium project I worked on. I sent it from my real name email.

  3. A says:

    Wow thanks for what must have been a hell of a lot of work!
    I read somewhere that there was a study that suggested that there were actually two stages in gender development not one, one *very* early “mental” one and a (slightly) later physical one, and at two different times rather than all at once (I wish I remembered where it was but it had to do with the SRY part of the Y chromosome and how if it was missing or inactivated a male karotype could still become female, anyways maybe part of the mystery is that it’s not “just” testosterone?
    I’m with J I’m going to have to read this a couple more times lol
    As for fluidity, maybe it’s more a scale, it’s not what’s expected but I know some very “feminine” guys that are defenitely happy to be a guy and some very masculine women that are all woman all the same and wouldn’t consider transitioning.. never heard of someone going back and forth but it’s something to think about..

    • You’re welcome A.

      The two stages of gender development you mentioned are indeed in the literature. I referred to that briefly in one of my comments to Part 3 but I didn’t really talk about it in the posts themselves because I was focused on the events during fetal development. The theory is that steroid hormones increase two times in an individual’s life, during fetal development to establish gender and then during puberty to “actualize” it. However, actualization is dependent upon the establishment. I think this is more clear in animals — the waters are muddier with humans. That’s something I can write about later, and perhaps incorporate information about other intersex conditions as well as sexual orientation.

      As far as “fluidity” I am speaking about what you referred to — someone whose feelings of gender identity shift and change on a regular basis, say from day to day, as opposed to men who are more feminine in their gender or woman who are more masculine but both of whom are fairly constant with those feelings. J will have to comment what exactly she was referring to, but I have met people who feel that their gender is fluid and does not stay fixed.

  4. j says:

    Hello A, Hi ATM,
    I meant those people who go through periods of time feeling they are one gender and then they reverse it and say they are another gender. And they seem to seesaw back and forth, never identifying with one gender for more than a few years. I hope I have been able to clarify what I meant.

  5. A says:

    wow didn’t know that exists, learn something new every day, thanks for that.

    The two spikes, no I meant two spikes during fetal development (then at puberty later as I guess a third time) but it’s been a while since I read that so I might have misread it.. hmm let me try and find that article 🙂

  6. A says:

    ok didn’t find my original article back but I was reading over this article and it speaks of two peaks as well (one before birth and one at or close to birth)
    http://www.reproduction-online.org/cgi/content/full/133/2/331

    The testis synthesize testosterone in Leydig cells from E15 in the rat (El-Gehani et al. 1998a) and 12–17 weeks of pregnancy in humans (Diez d’Aux & Pearson Murphy 1974). Low levels of testosterone are synthesized by Leydig cells in the foetal rat testis on E15 and its intratesticular concentration rises slowly over E16–17. Testicular testosterone levels then rise sharply on E18, to peak at E19 and then decline over E20–21 (Bentvelsen et al. 1995). Circulating levels of testosterone are first detectable on E16 or 17, peak at E18 and fall on E20 (Weisz & Ward 1980, Ward et al. 2003), followed by a second surge on the day of birth (Rhoda et al. 1984). Androgen receptor immunoreactivity (AR-ir) first appears in the rat urogenital tract on E14, with equal densities in males and females (Bentvelsen et al. 1995). Testicular androgens increase AR density in males over the ensuing prenatal period, resulting in a greater expression in males compared with females (Bentvelsen et al. 1995).

    I’ll keep looking..

    • Hi A. Thanks for the reference.

      Please note in the paragraph you posted that, other than the mention of testosterone production at 12-17 weeks of gestation in humans, all of the rest of it is about what happens in the rat, including the T surge at birth. There are some differences between rat and human.

  7. j says:

    :-)) A , you and ATM will get along really well. You are both on the same wavelength. LOL. This is too technical for me. I’m still on the ABC’s of endo. But I make an attempt to understand.

  8. A says:

    LOL I was worried about being able to drive (not the greatest hand eye coordination ever) then I realized something.. most people are bad drivers!
    The more I read, the more I feel we’re all still at the ABCs 😉
    I can’t tell you how amazing it is to find some people willing to think and talk about this stuff, way cool

  9. j says:

    Hi A, I’m so delighted you like this site. ATM takes a lot of pains to write all this and I’m happy he has you to discuss all these issues. In fact I’m going to leave you two to discuss the rest of the topic alone without me butting in. Do you know this is one of the only sites that actually tackles endo issues with a trans perspective? You are right, A, the more I talk to endos and doctors, the more I suspect that the endo system is a mystery. Anyway, great to meet you and hope to keep seeing you here!!!

  10. A says:

    c’mon don’t leave 🙂 butt in by all means..

    I left a reply (that first one) and figured I wouldn’t get very personal but well here I am anyway lol I am an FtM with kids (yeah didn’t expect that one either) I’m not sure if I’ll ever change that F into an M on my ID, but I’m trying to find some peace with myself, be that soul searching and/or medical stuff, whatever I am trying to unite what I look like with who I know I am.. My son is intersex. He’s too young right now to have a whole lot of questions but I know they’ll come when he gets older. Many of the same ones I ask myself. People don’t like talking about different points of view when it took people so much to define themselves.

    ATM mentioned more than a few intersex people don’t like including trans people as intersex.. small wonder though, isn’t it? I’m not saying I agree with them (I don’t) but I can see why they knee jerk, they’ve had to spend a lot of their energy and soul searching to define themselves as normal dispite looking “different”, most of us “look” normal but feel different.
    I’m just trying to find answers, just like you 🙂

    If I say stuff that makes you “hey what did you just say!?” I might be able to define something better in plain old english and we might both learn something 😉
    Science was meant to understand the world, to make understanding it easier and more accesible, somewhere that’s become lost in the search of an elegant formula.
    Science is not cold, or clinical, or distant, not at it’s core, it comes from every child’s question of “why”? and the amazement and awe that sparks that question.. it’s poetry.

  11. j says:

    Thank you, thank you, how very kind of you … Great to meet you Sir, and Greetings and best wishes to your little boy! Thank you for sharing about you. Yes I comprehend and support your need to understand these medical issues. I’m so glad to see you are so much into it. I’m very impressed by your knowledge!!! I’m a gg, I have PCOS which hits women where it hurts the most: appearance and child bearing ability. So last year I got online and started to read up on how to cope. And I handle my health so much better now. From feeling totally helpless and desperate, I feel more empowered.

    My ex fiancé was a transman. I began reading up on trans issues in March this year as a way to understand him, the relationship and then ultimately myself. But I ended up wanting to support the trans community in whatever way I can. For me trans people are the ultimate role models achievers and survivors: people who’ve been through so much yet come out so strong. Look at you… it’s not been easy for you, and yet you are able to radiate so much warmth and think of others. Now that’s superhuman! ATM too, he’s one of the most amazing people I know, which is why my day is not complete till I interact with him through something he has written.

    Thank you for your kind encouragement. I won’t go anywhere; this is my second home! But I will butt in when I have something of value to add. I’m just waiting to see ATM and you have a discussion. It’s sure to spark of so many ideas and theories!!!! How exciting!!!

    A, it’s close to midnight here; forgive me I have to leave you and get to bed :-(( But hoping to see some great comments from you and ATM when I get up and check the site:-)) Have a wonderful day and take care of yourself.

  12. A says:

    back at you 🙂 looks like you’ve had plenty of things to deal with. A lot of people would have left the community behind as they moved on with their lives. People who care, truely give a shit, are far and few. It’s amazing to me, and very much what “human” should be 🙂 people who hurt people don’t just waste what should have been a good time for whoever they hurt, but also deny themselves that. That might sound soft but it’s a very hard reality for those that really did hurt someone. Time slows for nobody.
    As for knowledge, when it’s just me it’s less important, but when my son was born and we found out he is intersex obviously I wanted to know everything under the sun especially before making any decisions about surgery, I decided that that is for him to decide when he’s old enough. Some people wish their parents would have let them have the surgery as infants but you can’t undo surgeries such as these. I kind of feel that I don’t really have the right to make that choice for him. I just hope that is the right choice.

    ATM sorry for posting half a dozen things to your blog lol you have a way of getting people thinking 🙂

  13. j says:

    Ah thanks, A. Like you, when it was about me it was less important, when it’s about my future kid, everything’s a priority. I don’t know if I will ever have kids, but I want to ensure I do everything right if I do have kids. This includes seeing if the hormones in my PCOS body may cause my kid to become intersex or transgender.

    I totally understand your dilemma about your baby. Did you see the video link I inserted … the little adopted intersex baby? Right now wiser heads seem to say wait… let your baby decide when he is older. I’d have made the same decision as you. Get on to http://www.bodieslikeours.org/forums/ if you’ve not visited already. And there are plenty of videos on youtube and the www to help you. There are well known forums for FTMs but if you choose to leave them or get banned at a future date, they refuse to remove your posts and photos. And the whole world can then see them. So lurk if you like and if you join be careful what you say, write.
    This blogsite is to help people like you and me. Our comments demonstrate why ATM’s research is so vital.

  14. A says:

    yeah I might have posted tons on here in like 2 days but I usually lurk on sites that have anything to do with gender whatsoever, for the most part I am not out.
    The people that really know me well (and I can count those on one hand) do know this, but I’m mostly islands with just a bit of sea. Most of the time I’m okay with it and try to find ways to make me happy, other days I wonder who I’m fooling and can’t stand it (and no it’s not “fluidity” just that river in egypt thing lol)

    I don’t know if your hormones would cause changes as far as gender identity goes, but being as open as you are the baby’s sexuality/gender/gender identity/intersex condition wouldn’t be much of a problem for you I think .. I don’t know if anyone really has any real answer though. I don’t know a whole lot about your hormone/cyst condition, I’ve seen it mentioned but don’t really know much about it (so I’ve started reading up on it 😄 good way to spend a friday afternoon lol)

    I think it speaks for you and for who you are that you’re not giving up on it. Just be careful with yourself. Having kids, adopted or your own, will shift things in a way I can’t express. It’s both very powerful and empowering and honest to god terrifying. When it’s just you, it’s hard to realize just how fearless you can be, you’re a warm person that’s not hard to see, you’ve got what’s most important 🙂 so be careful with yourself, and don’t give up 😉 also you’re right, there isn’t nearly enough research..

  15. j says:

    My kids sexuality/gender/gender identity/intersex condition is never going to be a problem for me. But it may be a problem for my kid. I have to think of my child. S/he may not like being trans or intersex. I am guided by spirituality; I believe everyone is here for a reason. And everyone is someone’s guru. But try telling that to a dysphoric teenager who ‘hates’ himself. Even if I dont have genetic kids, the world and everyone in it is my child. We must love and be responsible for each other, no?
    Good to see you visit sites that teach you about you. Susans.org and crossdressers.com are informative. And forget what’s on sites and the advice all the world gives you … you be the ultimate judge of what is good for you. Your inner voice is your friend. Take it slow. And go to youtube to listen to Little Jimmy Scott sing Someone to Watch Over Me. He has Kallmann Syndrome.

    • May I say how much I’ve been enjoying reading the A & J discourse? Thanks to you both for the sharing of yourselves here.

      • A says:

        thanks for having a place for this.. as far as the study goes, yeah I know we’re not the same as rats but the study I read had to do with monkeys and that’s a lot closer.. I wish I could find that article already lol
        Anyways, I think your place is a breath of fresh air, seriously! thanks
        Question for you, were you out very early with this or were you older? I’m playing with the idea, I’m not sure if I should for so many reasons but I’d love to hear your point of view..

        • You’re welcome, and thanks for the nice comments.

          Was I out very early with this or was I older? I will assume that by “out” you mean “out to myself” and by “early” you mean “young” and by “this” you mean “trans.” I didn’t realize I was trans until about 7 weeks after my 47th birthday.
          Now if you mean “out” as in out to my family and friends, well, that came little by little, but now I am out in almost all aspects of my life.

  16. Zoe Brain says:

    Out Freaking Standing.

    A seriously brilliant piece of work, Sir.

  17. j says:

    Oh we thought you’d be angry with us *said in a very small voice*. Anyway, “we missed you” *said in a very big voice*
    Hello Zoe !!! Last time you were on, I was too shaken by the debate to say hi. But today is a good day so ‘ big hello’ to you.
    A … my new friend… where are you?

    ATM can you please do a simple basic post on how FTM transitioning can be imperiled by ovarian and breast cancer. I know this young boy on a forum who has no family records bec of adoption and he wants to transition and is worried. Thanks in advance.

  18. j says:

    Good morning. Yes that is what I meant. I’ll pass this link on to him. Thanks a lot. Have a fabulous weekend, Sir.

  19. j says:

    sorry sorry…. ah thanks for wishing me for independence. I forgot to say thanks.

  20. Gwendolyn Anderson ACAS says:

    American Trans Man, thank you for the excellent course in science. Of all things that might be related to your research, I am an actuary examining gender rating in automobile insurance. Surely this is one of the most unfair rating classification methods, especially among younger people. But what is striking is the enormous disparity in fatal accidents between males and females, where death, dismemberment, disfigrement, paralysis, severe burns, etc. all come in greater number in the male population compared to female, while fender benders and non-injury accidents are spread about equally. However I would assert there must be a subcategory of males prone to severe accidents with corresponding behaviors that are outwardly noticable. Not all men are equal in risk and in my opinion should not be charged as such. So one question I am asking myself is, how many “genders” should there be in gender rating? It seems to have been already demonstrated that both gay females and gay males are better drivers than heterosexual males or females due to superior spacial perceptions, so this gender category should be charged a lower premium rate. (I suppose I should have said that after reading your articles I am left wondering what science distinguishes a gay person?) Do trans gender males also have as many layers of subcategories in automobile risk as heterosexual males? What is the scentific difference between a man who orders raspberry vinegrette and drives safely versus a man who attends football games in face paint, installs big tires on his truck and ends up dead on the highway? Are gender differences in risk all attached to the X and Y chromosomes, or not at all? Are testosterone levels implicated or is it something else like MAO? The answers to these questions could be life-saving!

    • Wow.

      Well, Ms. Anderson, this has got to be one of the most intriguing comment entries I have ever received on my blog, and I thank you for it. I read your comments and questions to my friend Jamison Green and we quickly engaged into a lively discussion about your points and queries. His advice to me was to give it some thought before answering, and so that’s what I’m going to do. I hope you don’t mind, but I’m going to sleep on it at least one night before fully responding.

      In the meantime, I will pose two questions: (1) Is “MAO” monoamine oxidase? (2) Would you mind if I posted your comments in the main body of the blog when I write my answer? I think readers would be interested in your comments and observations.

      • Well, I’m not sure if you’re still out there waiting for this reply Ms. Anderson, but here goes anyway.

        I am not familiar with the statistics that you work with to do your analyses, so I would not know whether anything I am about to write here is already known, but more than anything else, I would hesitate to link any behavior, gender identity or sexual orientation with the presence or absence of sex chromosomes, hormones or other biological characteristic. You ask what is the scientific difference between a man who orders raspberry vinaigrette and drives safely versus one who attends football games in face paint and ends up dead on the highway, and I would say there might not be any. I would even go as far to say that there might not be any correlation whatsoever between a man’s preference between salad dressing or face paint and how he drives. (I can think of at least two guys I know who put vinaigrette on their salad but drive like bats out of hell.) These seem to me to be generalizations that are not based on correlative, statistical evidence.

        But we can’t deny your point that there is a disparity in fatal accident rates between men and women. You have those data and they have been around for some time now. What I don’t know, however, is how those data break down and whether they are connected to socialization of men and women versus their biology. My first question would be — how much average time do men and women each spend behind the wheel? Do men tend to commute to work longer distances than women? Do men tend to take more of the long-distance sales jobs that require more driving than women who might take more office jobs? It seems that men take more of the long-haul trucking jobs than women. So I have to ask whether the disparity between men and women, with regard to fatal accident rates, are due to men spending more time, on average, behind the wheel than women, and so would have a higher probability of having a fatal accident. Added to that, if men, when they are behind the wheel, spend more time driving on the highways than women, thereby at a higher average rate of speed than women, wouldn’t they be more at risk for being involved in fatal accidents than women? Also, when heterosexual couples ride together in a vehicle, isn’t it the man who tends to be the one driving rather than the women, and if so, wouldn’t that also put men at more of a risk for having an accident, simply because they spend more time behind the wheel than women?

        If any of these theories hold, then it’s socialization and social norms that contribute to a higher fatality rate for men versus women, not biology.

        Now, going to your point about gay females and gay males, is it true that they are “better drivers” than their heterosexual counterparts? Who collects that kind of data? I can’t imagine that sexual orientation is part of the questionnaire for automobile insurance and statistical tracking of accidents, but perhaps it is. I’m going to go with that premise, as well as the one where you state that gay men and lesbians have superior spacial perceptions. If superior spacial perceptions result in gay men and lesbians having fewer fatal accidents than their heterosexual counterparts, then wouldn’t men in general have better driving records than women, because we have all seen the reports that men have better spacial perception than women. So in the end, these assumptions and theories don’t add up. What if it’s simply a matter of gay men and lesbians not wanting to be harassed by the police or other motorists by driving aggressively, and so they make a point to drive well and in the process, reduce their fatal accident rate?

        I have devoted more than one post in this blog to potential correlations between gender identity, sex hormones and behavior, and personally, my opinion is that causes and effects are not so easy to determine. Socialization, influences from parents, family members, teachers and peers, what a person sees in the media, their economic status, and probably other factors, all may influence a person’s behavior – and thereby their driving habits. But I’m not an expert in this field, and although the studies might be out there, I’m not going to look them up because I’m on vacation 🙂

        I hope everyone is enjoying their summer.

        PS – Thank you very much for your interest in my blog, Ms. Anderson, and for your excellent questions and comments. Makes a person think!
        PPS- A few of the points I raised in my reply above actually came from Jamison Green. He makes a person think too!

  21. Hugh Easton says:

    A very well thought out and thoroughly researched article, thanks for that, ATM!

    One thing I thought of while reading this section was what happens in cases of 5-ARD deficiency, where the enzyme that converts testosterone to DHT is absent. Genetically male people with this condition often appear female at birth, but (according to Wikipedia), usually have a male gender identity later in life despite having female genitals. What this shows is that masculinisation of the genitals is driven by DHT, whereas brain masculinisation is presumably driven primarily by testosterone itself. This may go some way towards explaining the paradox you mention, of cases of CAH where the genitals are masculinised but the gender identity is nonetheless female – the androgens produced in these instances of CAH may preferentially activate the DHT-sensitive androgen receptor subtype rather than the testosterone-sensitive one. Maybe there’s other variants of CAH or other conditions where the reverse is true too, which would result in someone who’s born looking female but likely to identify as FTM later in life.

    Regarding MTF transsexuality, there’s something you haven’t mentioned which I think is probably quite an important factor: medical treatment during pregnancy with artificial sex hormones (estrogens and progestins). In adult men, both estrogens and progestins are potent inhibitors of testicular testosterone production, and I think the same is true of a male fetus too! Most medical treatment with these drugs tends to happen after the end of the first trimester when genital development is already complete (but brain development is still ongoing), and I think the end result of a pregnancy where these drugs are used is often a normal-looking baby boy with an incompletely masculinised brain. Obviously these people are going to be at risk of being gender variant later in life!

    If you’re interested, I’ve just had an article about this published on the website Hormone Matters:
    http://www.hormonesmatter.com/hormone-treatment-pregnancy-gender-variance/

    • Hello Hugh and thank you for the comments and questions.

      You asked about intersex individuals who are XY genetically but develop as females due to a mutation/deficiency in 5-alpha reductase. If I remember the literature correctly, these individuals may report a male gender identity later in life (after puberty) but my recollection is that the majority are raised as females and have a female gender identity. (I make remarks in some of my posts about Wikipedia being the most accurate source of information in the world, but those comments are tongue-in-cheek.) I do talk in a number of my posts about DHT driving development of external genitalia and testosterone driving masculinization (including, perhaps, the brain). Of course your theory could be correct, but as the DHT is derived from testosterone, the testosterone must be present for the DHT to be produced. Also, to my knowledge, there is no “DHT-sensitive androgen receptor subtype” — both DHT and testosterone (and other androgens) bind the androgen receptor. The difference is the potency of the different androgens on the receptor, with DHT having a greater binding affinity to the receptor than testosterone and so activating downstream events more than testosterone. Please let me know if I’m wrong about this. It’s been a while since I looked at the literature.

      Regarding the administration of steroids like DES to pregnant women, I left that out of my posts on purpose. Transsexuality has been documented throughout recorded time and certainly existed long before synthetic steroids were available, so although synthetic steroids administered to pregnant women might affect the gender identity of the fetus (or might not), the use of synthetic steroids does not explain the phenomenon of transsexuality. On the other hand, there are also natural steroids and some people have speculated that ingestion of them during pregnancy might alter the fetal gender identity.

      On a side note, I would not call DES or other such hormones “artificial steroids. They are all bonafide steroids that possess the basic 4-ring steroid structure and they bind to steroid receptors. They’re more “synthetic” steroids rather than “artificial” ones.

      Lastly, thank you for providing the link. I read your post and it’s very interesting.

        • Hugh I have to apologize to you (and to Wikipedia) for relying on my memory rather than going to the literature about the gender identity of individuals with deficiencies in 5-alpha-RD and 17-beta-HSD-3. Fortunately, Zoe knows the literature a lot better than I do. Please see her links above. And for what it’s worth, I recommend her well-researched blog which you can find here. (Thank you Zoe.)

      • Hugh Easton says:

        Going on what I’ve read in bodybuilding forums, there’s definitely at least 2 subtypes of androgen receptor, one of which is expressed mainly in the genitals and hair follicles and is more sensitive to DHT, the other expressed in muscle and bone and is relatively more sensitive to testosterone (in case you’re wondering, I’m not into bodybuilding myself, but bodybuilders are probably the largest single group of men who regularly take artificial sex hormones, so are a good source of information about the effects of these drugs on the male body). As far as normal male development is concerned the details of receptor subtypes don’t matter all that much, since, as you’ve mentioned, DHT is derived from testosterone, so there has to be testosterone present in order for DHT to be produced.

        It’s true, gender variance, transsexuality and intersexed people have existed throughout history. That doesn’t let DES off the hook though. I’m sure there’s been the occasional baby born with missing limbs throughout history too, does that mean that thalidomide is harmless?

        I’m not sure whether you’ve got a facebook account, but if you have, I posted a comment on my article on Hormones Matter, with some links to personal accounts of DES sons (posted on the facebook page “DES (diethylstilbestrol) Info”). Unfortunately they’re scattered all over the place, with some in the Notes section and others in the timeline (during June), but I think there’s personal stories from about 8 different DES sons in total. It’s really hard to get DES sons to talk about how they’ve been affected in an open forum, but those stories are fairly typical of the ones I’ve read elsewhere that aren’t publicly accessible. Basically, most DES sons seem to be physically and/or psychologically intersexed to at least some extent, many to the point where they fully identify as women.

        What I think happened is that doctors and the pharmaceutical companies had this exciting new drug called DES. They knew it mimicked female hormones, but apart from that nobody had the first clue about what it would do, or even what would be a reasonable dose to use for medical treatment. A couple of doctors came up with the idea of using it to prevent miscarriages, and they seem to have just plucked dosages out of the air that were in line with the sort of doses you’d use for most ordinary medicines – a starting dose of 5mg, progressively increased as the pregnancy wore on until it reached 125mg per day or more near the end of the pregnancy. No doubt that seemed reasonable to other doctors at the time too, and to the marketing people at the pharmaceutical companies (who were looking for a use for their shiny new product). None of them had ever encountered anything remotely as potent as DES before. It’s like giving this new sweetener that’s just been invented called saccharin to people who have never sweetened coffee with anything stronger than sugar. If they’re not drinking the stuff themselves, they’re likely to end up handing out cups of coffee with teaspoons full of saccharin tablets in it. That’s basically what seems to have happened with DES.

        I’ve just posted some calculations on my facebook timeline showing how high the doses of DES were that were being used for miscarriage treatment, in relation to the estrogen content of modern birth control pills. That starting dose of 5mg per day is more estrogen than you’d get from consuming 6 months supply of birth control pills, and 125mg of DES is the amount of artificial estrogen you’d be exposed to if you used contraceptive pills non stop for 15 years! The DES mothers were being given that dose every single day towards the end of their pregnancies, so it’s hardly surprising that they and their children have all sorts of health problems as a result. With the DES sons, the effects were so shocking that everyone involved (regulatory agencies, the pharmaceutical companies and the doctors who prescribed the stuff) must have taken one look at the situation and decided that their only option was to do their level best to pretend that the whole thing never happened. That’s the way I see it anyway!

  22. Pingback: What sets me apart | iamLEXY

  23. Nick says:

    I haven’t read everything yet but I just wanted to add you can be both transgender and intersex or one of the two. I’m intersex but also transgender. I have xxy gonadal dysgenesis which basically means I’m female except I have a xxy karyotype. I have female reproductive organs my hormonal profile is in range born with female genitalia went through a full puberty and am fully fertile. The only things I had off was early puberty slight hirsutism very slight (back or chest hair or facial hair so extremely slight) and when I did an ultrasound I was told my uterus was pretty small. I also think my hips never actually developed. But none of this obviously was a sign of being intersex until I took a DNA test that showed I have an xxy karyotype. My sry on my y chromosome is altered and most likely inherited from my father I should give the link

    https://www.ncbi.nlm.nih.gov/clinvar/variation/9746/

    https://www.ncbi.nlm.nih.gov/clinvar/variation/9741/

    You see I never actually started to develop as a male fetus does. My development was a lot like women with swyer syndrome. Except I developed ovaries because I have xxy karyotype instead of an xy karyotype. Therefore my hormonal profile has always been like other females.

    https://en.m.wikipedia.org/wiki/XY_gonadal_dysgenesis

    Like in the case of most people with complete androgen insensitivity syndrome, most women with gonadal dysgenesis have a female identity. Not a male identity. As they too are not exposed to androgen in utero.

    Despite that like in your case I still continuously developed a male identity even though I was for all purposes female in every sense except chromosomally and mentally. I always knew I was really a man. And I never knew how I just knew being a woman was not something I truly was instead of feeling fully female I felt like I was in a costume I felt trapped. I felt like I was really a boy and no one knew it because no paid close attention. I always knew my puberty and the way I was born felt like I was disordered. I knew all this and no I didn’t need androgen to figure it out. I just knew innately that I wasn’t like other females. I will admit maybe my initial lack of inclination towards ultra masculinity was due to a lack of androgen. But I still always knew I wasn’t really a female. I always aligned myself more with the male sex even though I function biologically like women do. But I think gender identity can be affected by a lot of thongs. And sometimes someone may not identify as the gender they’re expected to no matter what the hormonal levels are maybe because in some cases its ingrained in you to identify as one specific sex no matter what your physical outcome is. That’s how my situation panned out. Being intersex didn’t cause me to identify as male it just affected my body. And I feel like it would be no different if what happened to me happened later on in life as maybe a young child or w.e. being sex reversed would have no different effect than it has in utero for me. I still identify as a man. And even when I tried I couldn’t help but feel funny when I would try to see myself as a woman or try to say stuff implying I was a female because innately I was always ingrained to see myself as a boy.

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