I think this is a great thread in that it may finally once and for all demonstrate that NO ONE HERE IS SUFFERING FROM THIS......
Not exactly...
I have genetically confirmed MAIS. I received the genetic test a few years back, and it was positive for a mutation known to cause MAIS.
My dick and balls are normal. Everyone with MAIS has normal junk. When your genitalia has issues, then you're categorized differently:
CAIS: This is complete androgen insensitivity. Your body is that of a normal female (i.e. tits and a pussy), despite being having an XY karyotype. You grow up thinking you're a normal woman, but when you hit puberty, you find out something's wrong because you don't ever get your period (this is because there is no uterus, despite everything looking like a normal woman on the outside). Incidence is about 1:60,000 XY births. These people do not look masculine at all (see image below).
PAIS: This is partial androgen insensitivity. These poor bastards really have a hard time fitting in because their genitalia is only
partially masculinized. The genitalia can be anywhere in between looking like a penis or a vagina. There's a scale that's used to grade various points in this spectrum called the Quigley scale. Incidence is about 1:100,000. These people can look masculine OR feminine, OR somewhere in between... (See image below).
MAIS: This is mild androgen insensitivity. Your body is that of a normal male. You have a normal penis and balls. Incidence is unknown. You do not look feminine. (See image below). The primary manifestation is infertility, which is common in men with MAIS, although there are exceptions.
You might ask why the category of MAIS exists at all if the body looks normal. It's because there are manifestations in the blood work. Specifically, since the androgen receptor does not work as well, the body's HPT naturally raises its own T levels to whatever it needs to in order to achieve the normal results.
There is a limit to how high the body can raise its own T to. If your T maxes out before the body is able to do what it needs to do, that's when you might get the ambiguous genitalia. But in that case, you are classified as PAIS, not MAIS.
In the last 20 years, a lot has been learned about how the same mutations can result in such drastically different body types. Here's the basic idea behind how that works:
- Genes are sequences in DNA that encode how to synthesize a protein. As we all learned in school, these genetic sequences are made up of the nucleotides A, C, T and G.
- There is more than one kind of mutation: when a nucleotide is changed, that is called a "point mutation." When one or more nucleotides are added in a sequence, that is called an "insertion mutation." When some are missing, that is a "deletion mutation."
- The cell interprets these A's C's T's and G's in groups of 3. Every three nucletides tells the cell how to create a single amino acid. These groups of 3 are called "codons." The resultant amino acids come together to make the final protein encoded by the gene.
- The cell knows when to stop making amino acids when it encounters the "stop" codon. The stop codon is just three nucleotides just like any other codon, except it tells the cell to "stop" making amino acids. The protein synthesis is finished as soon as the stop codon is encountered.
- For those that are curious, there are exactly three stop codons: TAG, TAA, and TGA.
- Obviously, if you insert or delete a large portion of a gene, the resulting protein is going to be all fucked up, and probably won't work at all. For the androgen receptor, this means that you will have a nonfunctional androgen receptor, so no amount of testosterone will work for you. You will have CAIS.
- However, even if you have a single nucleotide change (i.e. a point mutation), very drastic things can happen. Suppose that in your androgen receptor you have a single point mutation that changed the triplet "TCG" to "TAG". This is only one letter different, the middle C is now an A. However, the cell interprets TCG as the amino acid serine, while it interprets TAG as "stop". This means that the cell immediately stops synthesizing the protein as soon as this "TAG" is encountered, even if the mutation happens at the very beginning of the gene. All the genetic code that occurs after this mutation is discarded. This too likely results in a non-functional androgen receptor.
- When a point mutation results in a stop codon like this, it is called a "premature stop codon" and results in a "nonsense mutation".
- If you have a single point mutation, and the resulting triplet encodes another amino acid, then you do not have this premature stop, but you will have created a slightly different protein in the end. These subtle mutations are more likely to result in a functional androgen receptor, but it just may not work as well. These mutations can result in MAIS or PAIS.
- Depending on where in the androgen recpetor the mutation occurs, different things will happen. This is because different parts of the androgen receptor protein do different things. These different parts are called "functional domains." One functional domain is called the "ligand binding domain." It is the part of the androgen receptor that actually binds to the hormones testosterone and dihydrotestosterone. A point mutation in this area can dramatically impair the ability of the androgen receptor to bind to hormone, and thus can also result in extreme insensitivity to androgens (CAIS).
- A deletion of only one or two nucleotides is actually worse than a deletion of three nucleotides. This is because the cell interprets these A C T and G's in groups of three. If you delete only one or two, you change not only the way that the cell will interpret that triplet, but all triplets that come after it, since the groupings will be "frame-shifted". This is called a "frameshift" mutation. In these cases, the cell may continue to synthesize amino acids long after the intended stop codon, since everything is off by one or two nucleotides. However, in practice, the frameshifted sequence often produces a stop codon early on. In any case, a frameshift is a complete reinterpretation of the genetic sequence, and thus results in a non-functional androgen receptor (CAIS).
So as you see, there are all kinds of interesting things that can happen on the genetic level. Depending on what is going on, you will have more or less insensitivity to androgens.
I have a single (point) mutation that
did not result in a premature stop (these point mutations are called "missense mutations" as opposed to "nonsense mutations"). It is located in the transactivation domain (the first functional domain). This domain regulates transcription. In other words, my androgen receptors bind to T and DHT just fine, but they do not "work" so well once bound. As a result, my hypothalamus and pituitary "see" less T, and demand that my testes make more; I typically have T in the 1200s, but it has been as high as 1400.
I grew up normally. I went through puberty normally, and as I said earlier, my dick and balls are normal. I've had fertility testing and a testicular ultrasound: my sperm count is actually on the high end of normal --- the last count was 930 million (normal is considered over 40 million). And my testicular volume is right around 50 mL. I do have puffy nipples though --- the high testosterone I've been living gets aromatized just like everyone else. I don't have legitimate gynecomastia though (i.e. I'm not one of those guys that goes swimming with his shirt on).
The only signs that something wasn't quite right was the fact that I had a hard time putting on muscle and I didn't have much facial hair (I didn't need to shave except once every few days, and the facial hair I had was mostly at the mustache). Decreased facial hair is an uncommon finding with MAIS, so it didn't raise any suspicion with my doctors. They just figured it was normal male variation. MAIS was particularly
not suspected since I am fertile. As we know, statistics are helpful, but not so much when your case is uncommon.
I feel bad for Sade since I pretty much was dismissed by all of my doctors too, until I did the research myself and insisted upon getting the genetic test.
It's true that there's always the possibility that he doesn't have MAIS until he gets genetic confirmation, but his blood work does support the diagnosis.
I would guess that a lot of the back-and-forth that these threads have seen are less related to the possibility of him having MAIS, and are more related to his pissed-off drunken posts...
Be that as it may, I'm making the point MAIS is so subtle that you can have it without even knowing that you do (i.e. looking feminine is not part of the equation). After all, its primary manifestation is in the blood. If you have high T and high LH, but don't have signs of hyperandrogenism, then you quite possibly have it, and should get the genetic test.
