T Nation

Testosterone Tolerance or Androgen Insensitivity

Androgen receptor down regulation has been generally disproven, rather upregulation, but there is a lot of research that points to the ability of the androgen receptor to become desensitive or basically almost useless when exposed to high doses of androgens over time. Here’s a reading on it, I’d like to know if anyone buys into this and what they do about it.

I’ve seen a lot of guys talking about how they’re either on 100mg a week or 200, but I’ve also seen the occasional 400 a week guy, which is crazy, but you usually don’t hear anything but positives aside from libido and ED issues maybe.

My fear stems from confusion I guess. When I first started any TRT it was 4 pumps of androgel daily along with a wee bit of HCG. It kept me feeling great, gained me 40 pounds of muscle, and just did its job. It kept my T up near 1,200 ng/dL, and my theory then was that my androgen receptors were extremely starved for test, which resulted in quick and noticeable gains. What doesn’t make sense about this theory is that I kept making gains for almost the entire year.

Fast forward to basically a year later and I was noticing changes again. They were subtle at first, but noticeable nonetheless. First I lost tone, then libido went, then a few pounds. I started to get facial bloat, something that had never happened to me while my levels were high and even when my E2 was elevated. I figured I had enough T in my blood to outweigh a 52 pg/mL E2 level.

Anyway, I have to theories on this…
1.) It tends to be the same for many on transdermals. If it works, it works but it will only work for a certain amount of time. You’re on borrowed time from the start, and its only a matter of time before your skin adapts as a result of external factors (maybe even the gel itself) and your stratum conreum thickens, thus leading to an overall decrease in absorbtion. For me I feel that as my T dropped, E2 and SHBG took over, just raising hell in my body.

2.) I was too high, too long and I payed the price? This one makes less sense to me because especially on the gels you aren’t always elevated. You have daily peaks and troughs that should keep a certain level of sensitivity…no? My troughs had to be down in the 400’s, and the peaks in the 1,000’s.

Where this all applies to me now is, after all that mess with the androgel, my doc puts me on androgel 1.62% for 3 months thinking that would do the trick…only made matters worse and made me hate transdermals more. He tried Testim as a last resort effort and finally started me on 60 mg test cyp a week…so extremely low. I was on that dose for about 2 months, then he tested and bumped it up to 100 mg a week for about 3 months. Finally about 5 weeks ago he bumped it to 200 mg a week, as I wasn’t feeling the 60 or 100. Now it comes down to,
1.) Have I given it enough time or am I expecting too much too fast.
Some dudes say it takes around 6-8 weeks to fully notice changes.
2.) Am I truly insensitive as a result of what I’ve done, and will this not work for me at all?
3.) Is it even possible? It doesn’t seem to add up with real world results as far as testosterone’s concerned.

There’s my little book :stuck_out_tongue:

I don’t know much about TRT as I’ve only been on it for a few months, but some of your problems seem related to the high E2, which can cause down-regulation of the androgen receptor if I recall correctly. Your testosterone was high so you felt great. Eventually, your high testosterone levels led to high estradiol. High testosterone did not down-regulate the AR. So pick a reasonable testosterone dosage and begin incorporating an AI to get your estradiol under control.

Its E2 related Bro.
Has your Doc ever tested it ?
Some guys don’t need it, but you display the classic signs…up up up on T, Then level off, than bloat and weight
gain & loss of libido. If he won’t test you can get it done privately and go from there.
Some guys need an AI on as little as 50mg per week, some are ok without one with way higher doses, most need an
AI period.

I don’t know if it is as simple as E2. If it were, one would have expected problems earlier, but the OP was doing well for a year.

Also, lots of guys with this problem add an AI and it doesn’t help.

There is probably something to the idea of androgen insensitivity. If there weren’t, why would chemical bodybuilders keep needing to take more and more testosterone for the same effects? The body of a young man pulses testosterone daily for a reason, with the high and low quite far apart. With gels, the pulses are not quite as dramatic (google for graphs).

In any case, if you are not “feeling” your T, the remedy is not always to increase the dose. Often the remedy is to DECREASE the dose and wait for the body to adapt.

[quote]seekonk wrote:
If there weren’t, why would chemical bodybuilders keep needing to take more and more testosterone for the same effects?
[/quote]

Umm because they are actually progressing closer and closer to their maximal potential, so the gains from cycles will be less than the previous one. This is just common sense.

Do you think they wouldn’t make quite the same gains, or would require such a high dose, if they took a year off and then started working out again? Doubtful.

Downregulation is complete bull shit, it doesn’t at all add up with the real world results seen in bodybuilders, and the same goes for developing an insensitivity to testosterone. You can achieve so much on a certain amount of testosterone, but you do not require more to achieve the same results. Testosterone doesn’t work that way in terms of tolerance. Throughout evolution, there has never been a time where exogenous testosterone was available until the last 60 years or so.

That means there was never a feedback established on what to do if too much exogenous test is in the body, and the same goes for unnatural amounts of muscle mass. This is not the case, however, for a downregulation mechanism such as obesity in regards to insulin resistance. The more body fat, the less sensitive the body becomes to insulin. This is a means to keep us healthy, and was developed because there was at times a surplus of food, but never until our most recent history was there a surplus of testosterone available. Whatever was going on with me was related to E2/SHBG issues from being on the gels too long without an AI.

IF THE BODY BECAME TOLERANT TO TESTOSTERONE, EVEN GUYS WHO RUN NATURAL WOULD BUILD UP A TOLERANCE TO THEIR OWN T AND REQUIRE MORE.

It’s not that simple.

Just one example - some of the benefits of testosterone w.r.t. libido and mood are from its effect increasing dopamine. However, it is very well known that the body becomes tolerant to constant stimulation of dopamine production by, among other things, downregulating dopamine receptors, etc., which explains why, in many cases, the dramatic initial libido and mood improvements on testosterone do not last, especially in cases where people are on constant high doses. In many cases, doses need to be lowered and/or pulsed to recover the beneficial effects.

You could say that this is not testosterone tolerance directly, but that is just semantics - it comes down to the same thing - you become tolerant to some downstream effect of testosterone.

This is but one example. There are many other physiological systems that are affected by testosterone, and can be thrown out of whack by constant high doses. For example, SHBG could be lowered too much by high doses T, and low SHBG is associated with insulin resistance. Thyroid hormones are well-known to be affected by high doses T, and these alterations can cause problems over the long term. Other neurotransmitters and endorphins also come to mind. Etc., etc.

[quote]seekonk wrote:

It’s not that simple.

Just one example - some of the benefits of testosterone w.r.t. libido and mood are from its effect increasing dopamine. However, it is very well known that the body becomes tolerant to constant stimulation of dopamine production by, among other things, downregulating dopamine receptors, etc., which explains why, in many cases, the dramatic initial libido and mood improvements on testosterone do not last, especially in cases where people are on constant high doses. In many cases, doses need to be lowered and/or pulsed to recover the beneficial effects.

You could say that this is not testosterone tolerance directly, but that is just semantics - it comes down to the same thing - you become tolerant to some downstream effect of testosterone.

This is but one example. There are many other physiological systems that are affected by testosterone, and can be thrown out of whack by constant high doses. For example, SHBG could be lowered too much by high doses T, and low SHBG is associated with insulin resistance. Thyroid hormones are well-known to be affected by high doses T, and these alterations can cause problems over the long term. Other neurotransmitters and endorphins also come to mind. Etc., etc.

[/quote]

Okay, I will agree with you on high T and the libido taking a hit, but that’s dealing with neurotransmitters and different mechanisms. I’m talking strictly muscle and gains. The bloat I experienced clearly was a result of my E2 getting out of control, but why I lost tone and mass had to do with the thickening of my skin and the decreased absorbtion of the transdermals. I’m strictly talking body composition though, and all signs point to no when it comes to a tolerance in regards to gains. You can plateau, but that’s just genetic limitations for how much testosterone you’re using.

You mention the thyroid though, can high test bring about hyperthyroidism? That would explain some of what’s going on, and I do believe hyperthyroidism can lead to an increased SHBG, leaving my T almost useless and my E2 running wild. I also had an abnormally low cholesterol, something that can be associated with hyperthyroid.

Thanks.

bump please :slight_smile:

I would start with a complete blood workup, including cortisol, thyroid, E2, free/total T, etc.

I am also having similar symptoms. My testosterone serum levels are high, but I am experiencing low t symptoms. If I increase the dose slightly, I get better results for a couple of weeks, then back to low t symptoms. In fact, I even break out on my back when the low t really seems to hit, even though I am taking the same dose of T as the previous 3 or 4 weeks. (acne for me indicates a spike of a drop in Testosterone). Again, labs show normal range…symptoms say other wise. All I can conclude is some sort of tolerance.

I have been on T enathate for 8 years, and the tolerance began VERY slowly about two years ago and increased as I upped the dose. I am now taking 85mg every 7 days. Began at 40mg every 5th day, then 42mg, then 44mg then 46mg over a year and a half. The second year it accelerated even more, esp after doing 6 months of just HCG alone (for fertility treatments). I don’ t know what to do. My endo said he suspects there is a problem with my receptors. I may go off for 2 weeks and then start back at a low dose of 35mg every 3rd day sub q.

Thoughts?

I noticed the same problem. TRT not really working like it should for
me either. Have you checked your Ferritin? Mine is low 23 on the 20-300 range. Optimal in men is closer to 100+. Low iron means poor thyroid
hormone utilization. Regardless of how much T3/T4 you have. They won’t
function properly, and thus your overall metabolism and function is
downregulated and set at a lower point.

At least this is what I believe is happening for me at least.

dutchez7, please start your own thread and post labs with ranges.
Read the advice for new guys sticky.

There are 7 stickies in this forum, unfortunately, they are not visually marked.

We typically see and encourage 100mg T cyp/eth per week from the beginning.

Elevated E2 can create hypo symptoms while on TRT and so can low thyroid function. Do you have thyroid lab data to post.

What was your hCG dose for 6 months?

There is probably things going on that your endo does not understand. They are rarely good at TRT.