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.
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.
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).
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).
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…)
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??
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
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)
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
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)
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)
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)
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
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)
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
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)
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)