Advice for the genetically disadvantaged

Discussion in 'Steroid Forum' started by Structure, Nov 19, 2010.

  1. Structure

    Structure Member

    I had long suspected that I was "disadvantaged" genetically, but I recently have had this confirmed genetically: I have mild androgen insensitivity syndrome (MAIS). I have chosen to post in the steroid forum because I am already on HRT, and am considering moving up to a cycle. I need advice. Here are the details:

    By outside appearances, I'm a normal man: my dick and balls are normal and are normally sized (no hypospadias, micropenis, etc.). My doctors never suspected anything. The only signs that something was not right was that I have sparse body hair and very slight gynocomastia (barely perceptible). These things are well in the range of normal, so when I was a teenager and asked my doctors about these things, they just said "don't worry about it." After all, I had otherwise went through puberty just fine, etc.

    I always had a hard time with putting on muscle, and grew up really skinny. In my early 20s, I was well over 6' and weighed 140 lbs. I never thought much of it, or of the fact that I didn't need to shave. By the time I was 30, I though I should ask my doctor about this. He just said some people don't need to, but for the fuck of it, he would check my hormone levels. My testosterone was around 1200. While this was well out of range, he just said not to worry, since all the important things were working right (sex was good, and I was healthy).

    I decided to look into it on my own, and came across AIS on the internet. I went to see a geneticist, and had to practically force him to give me the test. It came back positive.

    I decided that I wasn't going to let this mutant gene stop me from reaching my potential, so I started reading up on diet and exercise. I figured, if I do everything right, maybe I can get *some* results. I started working out 50 mins a day, every other day, and ate around 3400 calories per day, including around 180g protein. After a few years of this, I was up to 180 lbs, although my body fat was around 17%. I've stayed at this level for the last 3 years, and have seen very little progress.

    I went to see a specialist about HRT. He mentioned that it probably wouldn't do anything for me in small doses, but was willing to try it. He was only partially right. I started on Androderm. The testosterone that these patches provided (exogenously) did not change much; rather, it just eased the burden on my body so that I didn't need to produce as much endogenously. I kept increasing the number of patches until I was using 3 patches per day. Finally, at this level, my pituitary stopped producing LH, and I started getting ball shrinkage. Not to mention, this was fucking expensive.

    I figure that if I was going about this the wrong way --- If I want to make up for my mutant AR gene, supplementing with HRT is not going to change anything; it will just mean that my body will not need to produce as much by itself. If I want to have supraphysiological levels of T, then I'm going to have to go on a cycle. This is where my knowledge ends --- I don't know anything about how to do a cycle, and I need some expert advice.

    What I can tell you is this: I don't have to worry about androgenic side effects like going bald or prostatic hypertrophy. I'll grow a beard before either of those things happens, so I'll see it coming long in advance. However, I still have to worry about LH production / pituitary shutdown. Just like everyone else, my pituitary has its own opinion about how much T should be in my body, and will shrink down my balls if it thinks I have too much.

    Any ideas regarding what kind of cycle I should try are welcome. You guys are the experts. I'm sure with some planning, my doc would even be on board. Thanks.
  2. Excallibro

    Excallibro Member

    I wonder what your total T. is now, or have you had yourself checked lately? Is it increasing steadily with age, or no? What about your DHEA levels?

    You're basically in the same boat as men who have been abusing steroids for so long, that their bodies have desensitized. Interesting case for a younger doctor, fresh out of school. You might want to shop around a little, and find someone much more interested in your dilemma, than the average doc. in a box.

    My guess is that you are probably more sensitive to some androgens, than others. Finding out what those are, could be helpful.

    I would read up on the opposite side of your problem. Do some research on dwarfism, and adrenal cancer. Finding the right doc., might require some driving, but you're a special case and deserve someone who is real interested in you as an individual. I've found that most doctors are gifted in a narrow band of expertise, regardless of what's written on their shingle. If you're not careful, you could further desensitize your body. I'm not that familiar with your genetic makeup, but if it has anything to do with the number of receptors, WATCH OUT.
  3. Structure

    Structure Member

    The last time my T was checked was about 6 months ago. It is routinely in the range of 1200 to 1400. DHEA and DHEAS have always been in the normal range. The number of androgen receptors is normal, they just don't work as efficiently. According to Wikipedia, this can be because of poor binding or a number of other factors. With high enough levels of T, they can be made to work normal.
  4. Millard Baker

    Millard Baker Member

    What is the typical medical treatment for mild AIS?
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Last edited: Nov 19, 2010
  6. Structure

    Structure Member

    Typically, there is no treatment. Occasionally, testosterone is prescribed when secondary sexual characteristics are delayed or absent (i.e. when puberty is incomplete), or for infertility. From the stuff I've read, they use some pretty high doses of testosterone (cyp), though the articles I've read don't mention what they do to prevent / correct the resulting testicular shrinkage.
  7. Structure

    Structure Member

    Testing included LH, FSH, T, DHT, SHBG, and E. However, the diagnosis was made from AR gene sequencing (I have a mutation in exon 1 that is associated with MAIS). LH, FSH, SHBG and E were normal, DHT was low normal (and thus my T : DHT ratio reveals poor conversion). However, 5-ARD is negative (fertility testing was normal, and as I mentioned before, so is my junk). If it is meaningful, I can get the exact values.
  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Are you infertile? Did they tell you the single point mutation? Do you have the results of the actual genetic testing? The T dose used in the study was not all that high - 250 mg/week - but was long. There is no danger for HPTA shutdown if the proper treatment is provided.

    Weidemann W, Peters B, Romalo G, Spindler K-D, Schweikert H-U. Response to Androgen Treatment in a Patient with Partial Androgen Insensitivity and a Mutation in the Deoxyribonucleic Acid-Binding Domain of the Androgen Receptor. J Clin Endocrinol Metab 1998;83(4):1173-6. Response to Androgen Treatment in a Patient with Partial Androgen Insensitivity and a Mutation in the Deoxyribonucleic Acid-Binding Domain of the Androgen Receptor -- Weidemann et al. 83 (4): 1173 -- Journal of Clinical Endocrinology & Metabolism

    Supplemental androgen therapy has enhanced virilization in only a few patients with partial androgen insensitivity (PAIS). We herein report on virilization in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor. At the age of 19 yr, the patient sought medical attention because of undervirilization. Endocrine findings were typical for androgen insensitivity, but 5{alpha}-reductase activity and androgen binding characteristics in fibroblasts cultured from genital skin were normal. In an attempt to improve virilization, high dose testosterone enanthate treatment (250 mg by im injection once a week) was begun. After 3.5 yr of this treatment, marked promotion of virilization was achieved, i.e. lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. In addition, serum lipid levels were not affected. To our knowledge this is the first documentation of successful treatment in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor.

    Bouvattier C, Mignot B, Lefevre H, Morel Y, Bougneres P. Impaired Sexual Activity in Male Adults with Partial Androgen Insensitivity. J Clin Endocrinol Metab 2006;91(9):3310-5. Impaired Sexual Activity in Male Adults with Partial Androgen Insensitivity -- Bouvattier et al. 91 (9): 3310 -- Journal of Clinical Endocrinology & Metabolism

    Context: Choosing the sex of rearing of an XY neonate with a major sexual ambiguity and a mutated androgen receptor remains one of the more difficult questions of neonatal endocrinology. A direct consequence of this choice is the accomplishment of sexual function in adulthood. There is very limited knowledge of the sexual performance of patients with partial androgen insensitivity syndrome.

    Objective: The objective of this study is to describe physical acts of sexuality in partial androgen insensitivity syndrome patients reared as males.

    Design: We were able to obtain factual information regarding the sexual activity of 15 adult patients who had been reared as males and followed at our institution since birth. We evaluated their sexual performance using two validated questionnaires (Golombok-Rust Inventory of Sexual Satisfaction and International Index of Erectile Dysfunction).

    Results: We documented a major impairment of all parameters of sexual activity.

    Conclusion: This long-term insight into the consequences of male sex assignment will have to be balanced by a study of the consequences of female sex assignment.

    Wang Q, Ghadessy FJ, Trounson A, et al. Azoospermia Associated with a Mutation in the Ligand-Binding Domain of an Androgen Receptor Displaying Normal Ligand Binding, but Defective Trans-Activation. J Clin Endocrinol Metab 1998;83(12):4303-9.

    Although male infertility affects a significant proportion of couples trying to conceive, the cause of defective spermatogenesis is not known in a large number of cases. Ligand binding studies indicate that a number of these subjects may have defects of the androgen receptor (AR). Genetic screening in subjects with defective spermatogenesis and in 110 fertile controls identified an azoospermic (no sperm in any ejaculates) patient with an amino acid substitution (Gln[->]Glu) in residue 798 of the AR gene. This germline mutation was pathogenic because it was not observed in fertile controls, was associated with features of minimal androgen insensitivity in our patient, has been related to more severe grades of androgen insensitivity, and caused a subtle, but significant, decrease in receptor trans-activation function in vitro that is consistent with the phenotype. Despite being located in the middle of the ligand-binding domain of the receptor, the Q798E mutation did not cause any ligand binding defect, indicating that this highly conserved residue has a trans-activation function but does not directly form part of the ligand binding pocket of the receptor. The trans-activation defect of the mutant receptor can be rectified in vitro with the androgenic drug, fluoxymesterone, but not with mesterolone or nortestosterone. Further studies are required to determine the therapeutic relevance of this finding.
    Last edited: Nov 19, 2010
  9. Structure

    Structure Member

    Thanks for looking into this. I've actually read those papers before --- pictures from the Weidemann paper are used in the Wikipedia article on partial androgen insensitivity syndrome. This guy has grade 3 PAIS, which includes micropenis, perineoscrotal (pseudovaginal) hypospadias, small testes, etc. The second paper is concerned with grade 3 PAIS also, specifically, whether to raise these people as men or women.

    The third paper is interesting, because it identifies a mutation that usually results in CAIS (complete androgen insensitivity) or PAIS, but in this instance resulted in MAIS. The subject was infertile, which was corrected with a specific androgen.

    The third paper is also interesting, because it highlights an important subject: goals of treatment. By most criteria, I do not require treatment: I have a normal sperm count and motility / morphology (i.e., I am fertile), I do not have any genital abnormalities, and I went through puberty mostly normally (I just have reduced body hair and the previously mentioned slight gynecomastia). My voice changed, I look normal, etc. I just don't shave, and I have a hard time putting on muscle. These aren't really "problems" as far as most doctors are concerned.

    Also, since my LH and FSH are not elevated, my HPA does not welcome higher levels of testosterone; my LH dropped to 0 when I was on 3 patches of Androderm. Thus, if I was to go on 250 mg of T per week for 3.5 years like the guy in the Weidemann paper did, I would atrophy just like everyone else would...
  10. Structure

    Structure Member

    I forgot to mention: yes, they told me the particular point mutation, and I have a copy of the results of the genetic test. It is in exon 1 (the transactivation domain). In one set of tests, this particular mutant AR required 5 times as much plasmid as the wild type to function similarly, although binding was not affected.
  11. Excallibro

    Excallibro Member

    It's interesting how the body works around these cases, which are diversity in action, regardless of cause. You're not a lab rat, but your situation is fascinating to hear about.

    Some receptors in the body can be potentiated with other drugs or substances. Have you run across anything about this angle in the literature?
  12. Structure

    Structure Member

    No, I haven't, though I'd be interested in hearing about it. The closest thing to what you are describing that I have read about are the SARMs that are currently in development...
  13. Structure

    Structure Member

    Getting back to my original question: does anyone have any advice for what kind of cycle I should try? This is an area I know nothing about, and would really appreciate it if one of you experts could point me in the right direction.
  14. Structure

    Structure Member

  15. Structure

    Structure Member

    Here's what I would do, but I don't know what I'm talking about:

    Does anyone have a better idea?
  16. Structure

    Structure Member

    After thinking about this some more, it seems that any cycle would be a bad idea.

    I've been reading through the threads, and I see a lot about 'genetic potential'. If I'm already at my genetic potential (given that my genetic potential is lower due to the mutant AR), then even after I made some gains from a cycle, I'd mostly lose them since I'd have exceeded my genetic potential. Unless, of course, I wanted to stay on a cycle forever (which I don't).

    Again, I'm new to this, so please chime in if you can help. Thanks.
  17. Millard Baker

    Millard Baker Member

    This is a very interesting question and one that I've never encountered on this forum. It is possible that high-dose anabolic steroids could overcome insensitivity of androgen receptor to some degree but I do not know enough about PAIS/MAIS. While you may not suffer typical side effects related to AR, there are many other conversions that can have effects outside the AR. These will have to be accounted for and I'm not sure how these conversions are affected by PAIS. However, I'm not sure how the approach to cycle planning would differ from others without PAIS.

    There are a few articles on meso about the androgen receptor. If you have not read this, they may provide further insight:

    Introduction to Anabolic Steroids by Bill Roberts

    Androgen Receptor Regulation by Bill Roberts

    Androgen Action and the Androgen Receptor by John Berardi
  18. Structure

    Structure Member

    Thanks for the links. Since I have MAIS, my AR is much more functional than say someone with PAIS --- I could have gone my whole life without knowing I even had this mutation. However, even people with PAIS can overcome some of their limitations by staying on (relatively) high dose androgens for years. I'm guessing that they don't particularly mind the testicular atrophy effects (if they in fact experience LH shutdown), since they already have very small testes to begin with (as small as 5 ml is not uncommon with PAIS).

    I'm pretty happy with how I look already, but there's always that question of "how much more could I achieve if it wasn't for my genetic limitation?" I'd guess that if I want to go beyond what my genes allow, and I don't want to shrink my nuts, then I'd have to be okay with cycling on and off for as long as I want to be bigger, and then just accept the fact that when I finally stop cycling, I'm going to lose my gains. Is this pretty much how it works for other people? In other words, for those of you that want to be ridiculously huge, much larger than your genes will allow, do you just keep cycling on and off forever? It seems the only thing that is different for me is that my genes set the bar lower as far as what I can achieve without gear.
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Did you ever locate the report? It would be interesting to know the change in amino acid. Also, was it reported or published?

    On another note, I have written on the future use of assays other than static T. This might be a good thread discussion.
  20. Structure

    Structure Member

    The report was never lost. Yes, it has been published before. If you go to the androgen receptor mutations database, you'll see that there are only a handful of mutations that are known to cause MAIS; the number dwindles significantly when you look at exon 1 in particular.

    I'll stop short of explicitly stating the mutation. While only my doctors have that information, it still feels like publishing my driver's license number.