AAS Clearance & Side Effects: A Case Study in Androgen Genotypes (UGT2B17 & CYP3A4AAS Clearance & Side Effects: A Case Study in Androgen Genotypes

[hawkmoon]

Hey guys,

As you know I recently decided to pull my raw genetic data and run it through Promethease, AI, etc out of pure curiosity.
I wanted to share some more interesting biochemical findings regarding how our bodies process, clear, and respond to androgens.
Maybe some of you will find it interesting or helpful.

For years, I noticed my body responded exceptionally well to modest, conservative doses (under 1g/week), while luckily avoiding typical issues like LVH, prostate issues (mostly), or hair loss (mostly).
I always chalked this up to generic "good luck," or just "genetics" but looking closer at the specific genetic markers, there is a very clear metabolic mechanism at play.

If you have ever wondered why different guys can experience wildly different side-effect profiles or require vastly different doses to progress, it often may come down to Phase I and Phase II detoxification pathways.

The Mechanics: UGT2B17 & CYP3A4​

My report highlighted two specific genotypes that heavily dictate how my body processes exogenous hormones:

1. UGT2B17 (rs7436962 - Genotype: AA)
   
   • The Science: This is the primary Phase II enzyme responsible for glucuronidation -attaching a glucuronic acid molecule to active, unesterified androgens (like testosterone and DHT derivatives) to make them water-soluble so the kidneys can excrete them.
   • The AA genotype indicates high expression and highly efficient clearance.
2. CYP3A4 (rs7774640 - Genotype: GG)
   
   • The Science: This is a major Phase I enzyme in the liver responsible for the oxidative breakdown of many medications and steroids.
   • The GG genotype represents normal, standard enzymatic function -meaning no sluggish metabolic bottlenecks or unpredictable pooling.

Spatial Separation: Why Muscle Still Grows​

It seems counterintuitive that clearing hormones faster would allow someone to grow efficiently on lower doses. The explanation lies in where these enzymes are actually expressed:

• Muscle tissue does not express UGT2B17. When you inject an esterified compound, the active hormone binds to the androgen receptors (AR) in your muscles and triggers protein synthesis completely unbothered.
• Clearing organs are packed with it. The liver, kidneys, and intestines handle the clearance.

Once the active hormone spills back out of the muscle tissue and into the bloodstream, a high-activity UGT2B17 system cleans it up rapidly.
This minimizes the cumulative Area Under the Curve (AUC) - the actual duration of time that delicate off-target tissues (like the heart, scalp, and prostate) are exposed to circulating hormones.

Because the systemic "soak" is kept to a minimum, there is less systemic inflammation and less off-target receptor over-saturation.
This keeps baseline health markers and insulin sensitivity highly preserved, meaning you can extract far more mileage out of a lower dose because the body isn't constantly fighting systemic friction.

The Dosing Cap: The Concept of Vmax​

This genetic profile also shows why pushing larger doses (2g–3g+) would be counterproductive for a system like mine.

Every clearing enzyme has a maximum operating limit Vmax.

• On a moderate, surgical protocol, a high-activity clearance pathway easily keeps up with the systemic workload.
• If you dump 2,000mg or 3,000mg of hormone into the system, you completely saturate those clearing enzymes. The metabolic highway gridlocks, the protective "shield" is lost, and the system is subjected to the exact same cumulative organ stress and lipid damage as anyone else.

How to Check Your Own Data​

If you want to look into your own metabolic clearance pathways, it's pretty straightforward:

1. Get Your Raw Data: Download your raw .txt file from any major ancestry testing service (like 23andMe or AncestryDNA).
2. Upload to Promethease: Run the file through Promethease (it costs about $12) to generate your health report.
3. Search These Specific Markers:
   • rs7436962 (UGT2B17): AA represents high clearance. AG is intermediate, and GG (or deletion variants) represents slower clearance. (Note: In Asian populations, particularly Japanese, a complete deletion of this gene is incredibly common, meaning they clear these hormones much more slowly).
   • rs7774640 (CYP3A4): GG indicates standard, highly predictable Phase I liver metabolism. AG or AA indicates slower clearance, which can cause compounds to linger and increase cardiovascular or lipid stress.

Understanding these pathways takes a lot of the guesswork out of designing a protocol.
If you have looked into this already in your own genetic profile I'd be interested to hear.

 

[specter]

So this is prob why i have been able to do absolutely stupid shit and not get hammered with sides.. makes sense, my body "burns" thru medication like it was paid to do it.

 

[hawkmoon]

So this is prob why i have been able to do absolutely stupid shit and not get hammered with sides.. makes sense, my body "burns" thru medication like it was paid to do it.

I'd be interested if you have the same allele.

 

[specter]

I'd be interested if you have the same allele.

My guess would deff be yes, ive talked with my friend alot about gentic poymorfisms and what does what, he has worked with some of the danish state medical hospitals about it for future testing, so they could see wich patients would react best to specific medications, its in extremly early stages but sounds like the future.

 

[luki7788]

Interesting idea.

The only problem with AI is that it will always try to give you an answer, no matter what.
If you start asking follow-up questions and challenge its explanation, you'll notice that it often starts agreeing with you, changing its reasoning and explaining the same thing in different ways until it eventually contradicts itself.

So it's an interesting concept but I still take it with a grain of salt.

 

[hawkmoon]

Interesting idea.

The only problem with AI is that it will always try to give you an answer, no matter what.
If you start asking follow-up questions and challenge its explanation, you'll notice that it often starts agreeing with you, changing its reasoning and explaining the same thing in different ways until it eventually contradicts itself.

So it's an interesting concept but I still take it with a grain of salt.

This is of course true , which is why I don't seek confirmation with AI guided research and always have it cite sources so I can read the original material. You must tailor your queries properly and set the persona and guardrails.

AI is just my lab assistant doing the grunt work

 

[specter]

Interesting idea.

The only problem with AI is that it will always try to give you an answer, no matter what.
If you start asking follow-up questions and challenge its explanation, you'll notice that it often starts agreeing with you, changing its reasoning and explaining the same thing in different ways until it eventually contradicts itself.

So it's an interesting concept but I still take it with a grain of salt.

Its not a concept ? its already known it affects how you process drugs/medications, like how you can influence the uptake of some oral drugs by drinkin lemon juice wich is why there is warnings in some inserts telling you to avoid or be carefull because it affects the enzymes that further changes the drug concentration in your blood.

 

[hawkmoon]

This paper is focused on leukemia treatment but illustrates how UGT2B17 works in different tissues and with different agents, including androgens.

In this case it is deactivating anticancer treatments.

Non-canonical transcriptional regulation of the poor prognostic factor UGT2B17 in chronic lymphocytic leukemic and normal B cells - PMC

High expression of the glycosyltransferase UGT2B17 represents an independent adverse prognostic marker in chronic lymphocytic leukemia (CLL). It also constitutes a predictive marker for therapeutic response and a drug resistance mechanism. The key ...

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[hawkmoon]

Its not a concept ? its already known it affects how you process drugs/medications, like how you can influence the uptake of some oral drugs by drinkin lemon juice wich is why there is warnings in some inserts telling you to avoid or be carefull because it affects the enzymes that further changes the drug concentration in your blood.

That is CYP34A, the less interesting enzyme but still highly relevant. Glycosyltransferase UGT2B17 is the heavy hitter for us IMO.

 

[specter]

That is CYP34A, the less interesting enzyme but still highly relevant. Glycosyltransferase UGT2B17 is the heavy hitter for us IMO.

Yeah i know, just trying to make the coupling that we know gene/enzymes/expression can affect drugs and its not so much a concept as something we already know happens, know we are down to pinpointing what does what exactly.

 

[luki7788]

Its not a concept ? its already known it affects how you process drugs/medications, like how you can influence the uptake of some oral drugs by drinkin lemon juice wich is why there is warnings in some inserts telling you to avoid or be carefull because it affects the enzymes that further changes the drug concentration in your blood.

You didn’t understand me. It’s probably because of the language difference.

By “concept” I don’t mean that it is only a theory. I mean that this explanation is still not 100% reliable. Like I said, AI will always try to give an answer, no matter what, and sometimes it simply makes up some facts to make the answer fit and sound believable.

That’s all I mean.

 

[specter]

You didn’t understand me. It’s probably because of the language difference.

By “concept” I don’t mean that it is only a theory. I mean that this explanation is still not 100% reliable. Like I said, AI will always try to give an answer, no matter what, and sometimes it simply makes up some facts to make the answer fit and sound believable.

That’s all I mean.

Ah yeah i didnt get that, my bad man, usually we agree

 

[alfresco]

Interesting idea.

The only problem with AI is that it will always try to give you an answer, no matter what.
If you start asking follow-up questions and challenge its explanation, you'll notice that it often starts agreeing with you, changing its reasoning and explaining the same thing in different ways until it eventually contradicts itself.

So it's an interesting concept but I still take it with a grain of salt.

I have a friend who is a software engineer for Salesforce in San Francisco and he says pretty much the same thing. He has to, is required to, use AI as a function of his job otherwise

 

[specter]

I have a friend who is a software engineer for Salesforce in San Francisco and he says pretty much the same thing. He has to, is required to, use AI as a function of his job otherwise

My IT guy says the same, AI is fine to use as a tool, if you understand how to use it and still check that what it says is factual and not just somer reddit post.

 

[hawkmoon]

My IT guy says the same, AI is fine to use as a tool, if you understand how to use it and still check that what it says is factual and not just somer reddit post.

As a former IT guy, mostly in finance, this is what I told staff.
I had run several presentations and workshops on creating proper use cases and teaching techniques before I finally left.

It's a tool, as I told them, it is bright, but unreliable and inexperienced. Treat it like a new intern. Note it is just as eager to please as an intern as well. Most AI are sycophantic.
It can do the basic grunt work, busy work, maybe run the numbers, but never take it all for granted and release anything to a client.

 

[specter]

As a former IT guy, mostly in finance, this is what I told staff.
I had run several presentations and workshops on creating proper use cases and teaching techniques before I finally left.

It's a tool, as I told them, it is bright, but unreliable and inexperienced. Treat it like a new intern. Note it is just as eager to please as an intern as well. Most AI are sycophantic.
It can do the basic grunt work, busy work, maybe run the numbers, but never take it all for granted and release anything to a client.

Ive watched lawyers use AI in cases in from america where they even left in their prompts so the judge spottet it, jesus fuck man just think you hired a lawyer and they or their staff used AI on your case and left it in their papers..

 

[hawkmoon]

Ive watched lawyers use AI in cases in from america where they even left in their prompts so the judge spottet it, jesus fuck man just think you hired a lawyer and they or their staff used AI on your case and left it in their papers..

Yes, seen a good number of prompts pasted....that should be grounds for dismissal. Would be in my old firm.

 

[Stewie]

I'm becoming more and more fascinated with your autodidactic mindset — thanks for sharing once again your raw data breakdown. One thing worth mentioning, that's the second piece of pharmacological molecular genomics worth separating out. What you have laid out here is entirely PK (pharmacokinetics). UGT2B17 and CYP3A4 tell you about clearance rate and systemic exposure duration, which is a noteworthy snippet of info. But it's a different spectrum from PD (pharmacodynamics). What actually happens once the hormone engages the receptor.

If we only had open access to western blotting or binding assays, along with AR-specific genomic and nongenomic signaling. This would encapsulate the second piece of the hypertrophic stimuli – response.

I'm loving the nerdy stuffage.

 

[hawkmoon]

I'm becoming more and more fascinated with your autodidactic mindset — thanks for sharing once again your raw data breakdown. One thing worth mentioning, that's the second piece of pharmacological molecular genomics worth separating out. What you have laid out here is entirely PK (pharmacokinetics). UGT2B17 and CYP3A4 tell you about clearance rate and systemic exposure duration, which is a noteworthy snippet of info. But it's a different spectrum from PD (pharmacodynamics). What actually happens once the hormone engages the receptor.

If we only had open access to western blotting or binding assays, along with AR-specific genomic and nongenomic signaling. This would encapsulate the second piece of the hypertrophic stimuli – response.

I'm loving the nerdy stuffage.

Thanks for chiming in, always appreciated how you help steer me in interesting directions
I'm full of curioristy, but not enough formal training to pursue to the extent I want.

 

[Stewie]

Thanks for chiming in, always appreciated how you help steer me in interesting directions
I'm full of curioristy, but not enough formal training to pursue to the extent I want.

I appreciate that, always enjoy the back and forth.

Unfortunately there's limited direct to consumer testing for the PD. Assessing PD at the receptor pool — how efficiently promoters, coactivators, and repressors are actually being signaled. This only becomes accurate through muscle biopsies. That's the only way to see actual AR protein density and coactivator recruitment directly, rather than inferring it from your genotype, such as a portion of your PK SNPs.

There is some segmented AR-DNA genotype profiling that gives you a better snapshot than a standard Promethease pull, though. To the best of my understanding, assessing your CAG repeat length is the most accessible one. I've mentioned in the past, if curiosity piques one's interest, they could utilize Marek's AR-CAG testing, which is offered direct to consumer.

Even then, none of it touches nongenomic signaling — Akt/mTOR, MAPK/ERK, membrane-initiated Ca2+ flux. That level isn't really genotypeable with currently open access either.

If curiosity piques a deeper understanding of where your UGT2B17 and CYP3A4 enzymatic dynamics are actually taking place — take a peek at the smooth endoplasmic reticulum. There are some thought-provoking, plausible ways to limit ER stress.

https://marekdiagnostics.com/products/androgen-receptor-cag-repeat-genetic-test?srsltid=AfmBOoqnNrcOLSNi9Kk0FjN3qfb4x_ipW-8jO8l0pwMqOM4gy9UPXM1A