Pregnenolone makes high dose Testosterone tolerable

Ever wondered why some men feel terrible on high testosterone doses while others thrive? This groundbreaking thread reveals how pregnenolone supplementation at 50-100 mg combined with DHEA 25-50 mg daily enables men to comfortably tolerate testosterone levels exceeding 1,500 ng/dL without experiencing the anxiety, elevated heart rate, and general malaise that often accompany supraphysiological doses. Members share firsthand experiences of dramatic symptom relief after adding these upstream hormones to their protocols, suggesting that TRT's suppression of the body's natural pregnenolone and DHEA production may be responsible for many "high testosterone" side effects. The thread explores the theory that maintaining adequate levels of these precursor hormones allows for better overall hormonal balance even when running testosterone levels well above the normal range. Learn how experienced TRT users have fine-tuned their pregnenolone and DHEA dosing to eliminate problems like tachycardia, insomnia, and nervous system overstimulation that previously limited their testosterone optimization.

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Dave Lee explains that a Pregnenolone deficiency doesn't allow for higher testosterone dosages to be tolerated.
Supplementing Pregnenolone is an easy fix instead of lowering your testosterone levels.

 

To all those in difficulty dialing in, ensure IM is the method used first and foremost.

Exactly. And to a guy perfectly dialed in on IM - if he wants to try sub-q let him. If it all screws up he has a place to go back to and be ok again.

And what exactly is the science behind sub-q vs IM I dont think it matters too much. Really. The end results in many cases are pretty clear. If you respond poorly to certain food and you insist on making that food work for you and you continue to respond poorly - well, not the smartest thing in my opinion. You just stop eating this food and eat something else instead.

 

Do you think anybody knows the mechanism for sure? What matters to me is that many people get higher blood levels and feel better on IM compared to sub q injections - me included and a few close people whose protocols I've observed for some longer time, their issues and struggles on TRT. This paragraph is what we know for sure.

In the next paragraph are my own thougths on the matter. Maybe its possible in fact most of the testosterone on sub q is really absorbed as well, but just on sub q it is so slow that it cannot catch up to the body's metabolisation and excretion. I also assume some of the test may remain stuck for even much longer in the sub q nodules that form after injection. As a result on sub q injections in comparison to IM the whole process of absorbtion-metabolisation and excretion is badly altered because the absorbtion process is greatly distorted. Remember all these compounds are tested and developped for IM use.

Unless you're inadvertently injecting into your bladder or digestive tract, which are hardly subcutaneous, it's difficult to excrete a testosterone ester without involving the bloodstream. And once the ester is in the bloodstream it doesn't matter if it got there via IM or SC injection. @madman has posted research explaining how absorption works for the two injection methods. It's not considered to be an unsolved mystery. SC results in migration via the lymphatic system. Guess where this empties: the bloodstream.

Nelson has a page dedicated to the effectiveness of SC injections, with many references:

Forum list

The Most Respected Testosterone TRT Men's Health Forum Since 2013

www.excelmale.com

With respect to the anecdotes, a few isolated blood samples and accompanying subjective results are exceedingly weak evidence for the claim that SC injections are less effective than IM.

Your hypothesis that SC is "so slow that it cannot catch up to the body's metabolisation [sic] and excretion" has a glaring flaw: It's saying that the unused testosterone continues to accumulate in the body indefinitely, effectively giving it a half-life of months or years. But this has no relationship to reality. The half-lives are easily measured and do not reflect this effect.

There is just too much anecdotal info pointing in the direction of subq being inferior to IM in a lot of men. These are men who have tested over time, and we cannot discount the info provided. The total sample size over multiple forums is a LOT. This anomaly cannot be ignored. To all those in difficulty dialing in, ensure IM is the method used first and foremost.

There will always be those who are too stubborn and too set in their ways to realise this.

You can find anecdotes to support any hypothesis. But that's just the first step. Next you need to perform real scientific research to see if the idea has merit. In this case controlled studies have demonstrated that SC delivery of testosterone is quantitatively as effective as IM. This part is effectively closed to debate unless contradicted by quality research.

You can still make claims about the subjective results, but you're limited to one plausible mechanism: the differing absorption rates between SC and IM. Furthermore, this difference is only significant when the interval between injections is approaching the half-life of the testosterone ester or longer. For example, it's a hard sell in the case of daily injections of testosterone cypionate, where serum fluctuations are expected to be relatively small.

 

There is just too much anecdotal info pointing in the direction of subq being inferior to IM in a lot of men. These are men who have tested over time, and we cannot discount the info provided. The total sample size over multiple forums is a LOT. This anomaly cannot be ignored. To all those in difficulty dialing in, ensure IM is the method used first and foremost.

There will always be those who are too stubborn and too set in their ways to realise this.

You still caught up on all that bullshit?

What all those bro forums were many have no clue how the use of exogenous T works.

The ones changing their protocols every 4-6 weeks because they do not feel good.

These same men using inaccurate assays when testing FT let alone using different labs/assays.

Let's even throw all of the UGL gear used in the mix!

LMFAO!

If anything the main difference between sub-q vs IM would be that absorption may be slower but this point would be moot depending on half-life/injection frequency.

Sure there are numerous men who may not feel well when injecting strictly sub-but highly doubtful it has anything to do with absorption/effectiveness of the T.

Hope you understand that regardless of whether you are injecting sub-q or IM let alone the esterified T used (short, medium, long) that the main role of the ester is to control the release rate of the prodrug (esterified T) from the oily depot.

Whether injecting IM let alone sub-q the esterified T (cyp, enanthate, prop, BLAH, BLAH) is not active until it is cleaved which happens only when it enters the bloodstream as it is rapidly hydrolyzed by esterase enzymes and all that you are left with is pure T.


"Subsequently, the prodrug permeates through the wall of blood cells and is hydrolyzed"

"These blood cells will finally hydrolyze the prodrug compound to T"




*The oil depot forms a continuous phase after injection but will be dispersed and encapsulated at the injection site after some days. This in turn largely influences the way the prodrug becomes available; after release from the oil depot, it is present in the interstitial fluid which is drained through the lymph into the systemic circulation. Subsequently, the prodrug permeates through the wall of blood cells and is hydrolyzed





My reply to you in a previous thread:

post #100

Daily Sub Q TRT injection ?

Hey guys please forgive if this has already been addressed. Current protocol is 100mg every week (every 6 days). Hearing good things about sub q injections. Doc is fine with me doing it. She says to inject 0.07ml daily with insulin Syringe. Question is how many mg’s is that? How many would I be...

www.excelmale.com

Regarding the absorption/effectiveness of T should be no difference between sub-q vs IM mind you there are some men who do not feel well injecting sub-q let alone claim they hit much lower numbers but I would be suspect in most cases unless they are :

*following the same protocol (dose T/injection frequency)

*staying consistent and waiting the full 4-6 weeks for blood levels to stabilize

*getting blood work done at 6 weeks

*using the same lab, same assays (most accurate), and testing at the true trough.




Only when the above steps have been followed and labs from the sub-q and IM protocol can be fairly compared then one can truly state such!

 

I just want to thank all of you for what you for your input! I have learned a lot here! Please keep it coming!

 

There is just too much anecdotal info pointing in the direction of subq being inferior to IM in a lot of men. These are men who have tested over time, and we cannot discount the info provided. The total sample size over multiple forums is a LOT. This anomaly cannot be ignored. To all those in difficulty dialing in, ensure IM is the method used first and foremost.

There will always be those who are too stubborn and too set in their ways to realise this.

I am being treated by one of the leading urologists in Canada.

Sub-q test injections have been used by some doctors since the early 2000s and my urologist was one of the early pioneers involved in a 2005 pilot study and has been treating his patients using subcutaneous testosterone injections for almost 15 years!

He treats hundreds of men and many are injecting sub-q.

Other studies have come out since 2005 backing the effectiveness of sub-q trt injections.

Subcutaneous Testosterone Injection Studies

Subcutaneous Testosterone: An Effective Delivery Mechanism for Masculinizing Young Transgender Men (2014)

www.excelmale.com

I have been on trt for almost 5 years and strictly inject sub-q into abdominal fat and my TT/FT levels have always been consistently in the high-end!




STABLE TESTOSTERONE LEVELS ACHIEVED WITH SUBCUTANEOUS TESTOSTERONE INJECTIONS (2005)

M.B. Greenspan, C.M. Chang
Division of Urology, Department of Surgery, McMaster University,
Hamilton, ON, Canada


Objectives

The preferred technique of androgen replacement has been intramuscular (IM) testosterone, but wide variations in testosterone levels are often seen. Subcutaneous (SC) testosterone injection is a novel approach; however, its physiological effects are unclear. We, therefore, investigated the sustainability of stable testosterone levels using SC therapy.


Patients and methods

Between May and September 2005, we conducted a small pilot study involving 10 male patients with symptomatic late-onset hypogonadism. Every patient had been stable on TE 200 mg IM for 1 year.

*Patients were instructed to self-inject with testosterone enanthate (TE) 100 mg SC (DELATESTRYL 200 mg/cc, Theramed Corp, Canada) into the anterior abdomen once weekly. Some patients were down-titrated to 50 mg based on their total testosterone (T) at 4 weeks.

Informed consent was obtained as SC testosterone administration is not officially approved by Health Canada. T levels were measured before and 24 hours after injection during weeks 1, 2, 3, and 4, and 96 hours after injection in weeks 6 and 8.

At week 12, PSA, CBC, and T levels were measured, however; the week 12 data are still being collected.


Results

Prior to initiation of SC therapy, T was 19.14+3.48 nmol/l, hemoglobin 15.8+1.3 g/dl, hematocrit 0.47+0.02, and PSA 1.05+0.65 ng/ml. During the first 4 weeks, there was a steady increase in pre-injection T from 19.14+3.48 to 23.89+9.15 nmol/l (p¼0.1). However, after 8 weeks the post-injection T (25.77+7.67 nmol/l) remained similar to that of week 1 (27.46+12.91 nmol/l). Patients tolerated this therapy with no adverse effects.


Conclusions

A once-week SC injection of 50–100 mg of TE appears to achieve sustainable and stable levels of physiological T. This technique offers fewer physician visits and the use of a smaller quantity of medication, thus lower costs. However, the long-term clinical and physiological effects of this therapy need further evaluation.




I also attached a 2006 pilot study.....other recent studies have been done between 2006-2019!

 

. @madman has posted research explaining how absorption works for the two injection methods. It's not considered to be an unsolved mystery.

I will state this really simpliefied the way I have simplified it in my head after too many hours spent thinking about that. Dont put too much attention on my hyptothesis why - I dont really know why, I just know what is the end result with many people.

Do I get higher t levels on IM compared to sub-q and do I feel better? - YES

Did I see the same in my friends - YES

Have I read that experience from enough other users on the TRT forums that confirm my experience - YES

The above facts are far more important for me than any scientific research out there. We discussed above in detail why me and another forum user often value anecdotal experience far more than the scientific evidence in the realm of HRT. The scientific data is a good thing, but Im more interested in consistently working solutions.

The anectodal experience of a bodybuilder pulled me out of the sub q misery. So as far as I'm concerned and get asked I would any day recommend doing IM over sub q until someone is optimized, and I would tell him after that you can experiment with sub q if you like. This is my stance on the matter, you can have your own of course based on your interpretation of the available data and your personal experience.

Àns one question from me to you - even if all the scientific data shows sub q really works as well as IM, but for a good portion of people IM makes brings their levels higher and makes them feel better what they should do - ignore all that becauae the studies say so?

 

...
Do I get higher t levels on IM compared to sub-q and do I feel better? - YES

Did I see the same in my friends - YES

Have I read that experience from enough other users on the TRT forums that confirm my experience - YES
...

This is getting nowhere. These accounts do not address the many possible confounding variables.

...
Àns one question from me to you - even if all the scientific data shows sub q really works as well as IM, but for a good portion of people IM makes brings their levels higher and makes them feel better what they should do - ignore all that becauae the studies say so?

You have no evidence that your "good portion of people" is actually more than one out of every thousand or even every million men on TRT. The controlled studies do not suffer from such selection bias.

 

You have no evidence that your "good portion of people" is actually more than one out of every thousand or even every million men on TRT.

Yes I dont, but you've read enough of these experiences on the forums yourself as well Im sure.

 

I inject subq daily, but have also been told by many doing the same that they did better on IM. I don’t think it’s an issue of TT/FT. If someone was a little lower on both doing subq they could just raise the does. I’m a weird metabolizer but I’ve had 250-350 free T doing subq exclusively in 20-26mg daily amounts.

I perfectly accept that some people do better on IM, and it likely has little to do with TT and FT numbers, but other metabolites and related effects. Similar to how pregnenolone cream vs oral pregnenolone has wildly different effects on people, which I’ve experienced too.

No matter what you read, you won’t know what works for you until you try it. I’ll be sticking to subq because daily injections IM seem like a recipe for scarring. I inject in the same area daily and you can’t even tell I inject there at all. I also inject other things in the same syringe though, like BPC-157 and HGH and B12 and HCG, which may make IM complicated for me.

 

I inject subq daily, but have also been told by many doing the same that they did better on IM. I don’t think it’s an issue of TT/FT. If someone was a little lower on both doing subq they could just raise the does. I’m a weird metabolizer but I’ve had 250-350 free T doing subq exclusively in 20-26mg daily amounts.

I perfectly accept that some people do better on IM, and it likely has little to do with TT and FT numbers, but other metabolites and related effects. Similar to how pregnenolone cream vs oral pregnenolone has wildly different effects on people, which I’ve experienced too.

No matter what you read, you won’t know what works for you until you try it. I’ll be sticking to subq because daily injections IM seem like a recipe for scarring. I inject in the same area daily and you can’t even tell I inject there at all. I also inject other things in the same syringe though, like BPC-157 and HGH and B12 and HCG, which may make IM complicated for me.

I actually kind of agree with this. If people truly feel better on IM versus SC, I wonder if there is some mechanism for this other than T levels? We sort of have a partial answer in that estrogen and DHT levels are comparable, but I wonder if there is something else at play.

It is also possible that when those that prefer IM made the switch, some other variable switched at the same time and the administration method may not be the issue. We could test that theory by having some guys make themselves guinea pigs and alternate them both for a few weeks at a time.

In any case, ultimately everyone should do what is best for them. But, I very strongly feel it is not wise to have a skeptical view of science and all the information that the last several hundred thousand years of scientific inquiry has brought us.

 

Yes I dont, but you've read enough of these experiences on the forums yourself as well Im sure.

I've seen two or three very credible accounts in which multiple trough measurements were taken for both IM and SC injections at the same doses and injection intervals, and using the same vials of testosterone. In these instances the SC trough measurements were unexpectedly lower. These accounts effectively remove two of the many confounding variables, the possibility of lab error and variable testosterone dose size. But other variables remain: The single measurements don't tell us what serum testosterone looks like in the rest of the injection cycle, so there's no evidence to say that the total testosterone absorbed is any different. The implication could be that these guys absorb faster via SC than IM, countering the general rule. This is at least more plausible than testosterone mysteriously disappearing, unless it was via unnoticed injection site leakage after SC injections.

...
I perfectly accept that some people do better on IM, and it likely has little to do with TT and FT numbers, but other metabolites and related effects. Similar to how pregnenolone cream vs oral pregnenolone has wildly different effects on people, which I’ve experienced too.
...

When looking for differences between IM and SC injections of testosterone esters we're pretty much limited to effects caused by the rate of absorption. Unlike pregnenolone, testosterone esters such as cypionate are effectively inert until they enter blood. Therefore any effects would have everything to do with total and free testosterone and the rates at which they change. That said, it's true that the rate of change of testosterone can have some influence on peak and trough levels of metabolites such as estradiol and DHT.

 

I've seen two or three very credible accounts in which multiple trough measurements were taken for both IM and SC injections at the same doses and injection intervals, and using the same vials of testosterone. In these instances the SC trough measurements were unexpectedly lower.

Ive also taken more than one measurement, all on trough. My friends as well. We use the same brand of testosterone which by the way is not compounded, but a pharmaceutical brand. Also since Ive transferred to IM ive taken dozens of total t tests on different doses and protocols and also ok stable protocols. Never on IM my total t was less than 1000 even when I had expected it to be and on IM Ive injected always 120-130mg because on 140mg no matter the ester I go over 1400 total t.

The last time I had a stable sub q protocol confirmed with 3 total t tests on 160mg I coudnt go above 900ng/dl t. And most important than all scientific data and measures - on sub q I didnt feel Im doing any testosterone. I dont know why so little focus is put on how people actually feel in this discussions when thats above all else...

 

inject subq daily, but have also been told by many doing the same that they did better on IM

I woundnt advice anyone do IM daily injections. Ive done and it sucks big time. EOD - no problem, but daily I wouldnt. However Ive seen a lot of guys do daily injections when they havent actually tried a proper 2-3 times per week protocol first. Also some doctors start all the people on daily sub q which for me is a flawed approach. I mean daily injections is something that should be done when really needed. Even EOD on cyp/enanthate as well. We often tend to forget the vast majority of TRT patients are not on the forums and do 150-200mg of whatever the F ester once a week and feel great.

 

Ive also taken more than one measurement, all on trough. My friends as well. We use the same brand of testosterone which by the way is not compounded, but a pharmaceutical brand. Also since Ive transferred to IM ive taken dozens of total t tests on different doses and protocols and also ok stable protocols. Never on IM my total t was less than 1000 even when I had expected it to be and on IM Ive injected always 120-130mg because on 140mg no matter the ester I go over 1400 total t.
...

You controlled two variables out of at least half a dozen. Would you fly in a plane in which two thirds of the systems are never inspected? Ok, maybe there's a bit more at stake when you're 30,000 feet in the air.

I agree with you on EOD versus daily dosing of testosterone cypionate or enanthate. Most guys are not going to notice a difference when total weekly testosterone is the same. Some complain about the scheduling with EOD, but they'd probably also do ok with MWF.

 

When looking for differences between IM and SC injections of testosterone esters we're pretty much limited to effects caused by the rate of absorption.

And those effects can completely change the game. Even injecting more less frequently vs less more frequently is profoundly different. It could have something to do with dopamine signaling and things associated with that. All manner of things up and down the chain that even just rate of uptake could effect.

Can you do shallow IM with a 28-29g 1/2” pin? I’d be willing to give it a go after I’m more dialed in with my current changes. I’d be injecting twice I guess, the test IM and all else subq still since injecting as much as I do of all else IM likely wouldn’t be fun and could be a confounding variable. I don’t mind pinning at all, though I’ve never pinned IM to really know what that’s like.

I’ve never done IM, so I’d be a good candidate.

 

Can you do shallow IM with a 28-29g 1/2” pin?

Id be also very careful with that. For me this is not a ream IM, on that thing I've done 7 weeks of enanthate last year and levels were as low as sub q.
I would say if your are below 12 percent body fat maybe it will work well in the delts only. Now somebody will say it works for me - ok, maybe sub q works well for you but for some it doesnt. With shallow IM its the same thing.

I wonder if some people dont notice a difference between IM and sub q because they've done only shallow IM that doesnt put the liquid deep enough into the muscle but most probably in the fascia where vascularity is different and also it can leak outside of the muscle tissue at least partially..

Im doing my IM shots with 27g 3/4 inch, currently around 18-20 percent body fat. Not a harpoon, but it puts the oil deep enough into the muscle tissue... When I was fatter in leg and ass areas I used 26g 1 inch and 3/4 inch for delts.

 

I don’t mind pinning at all, though I’ve never pinned IM to really know what that’s like.

For me it sucked initially and my hands trembled. Sometimes you may hit a nerve and feel a bit of a pain. Sometimes after you draw the needle out of you may see blood - its totally fine. Remember to relax the msucle when you are in it and DONT aspirate, this will only increase the scar tissue and damage to the muscle.

 

@Nelson Vergel, have you climbed out of your funk? Looking back, any thoughts on how much TRT has contributed to it? I am particularly curious what role you think hCG has played, if any. Do you think being off it was problematic for you? Or, a non-factor?

I restarted after a few weeks off and I am experiencing terrible acne. As documented in some of my previous posts, I struggle to nail down what my subjective experience on hCG is. If I could answer that, it might be easier to justify the hassles…

 

I think the regimen included a bunch of supplements in changing doses, I dont think there was preg and dhea, but some other stuff I dont remember, I can recall only melatonin.

But my friend had very specific issues, when he stopped his SSRIs he got pain all over the muscles on the body and one night he got to go to the ER to get pain killers. So please dont take this as "Dave Lee stops SSRIs with melatonin"

Melatonin Acts as an Antidepressant by Inhibition of the Acid Sphingomyelinase/Ceramide System

Abstract. Background: Melatonin has been shown to have antidepressive effects. We tested whether melatonin inhibits the acid sphingomyelinase/ceramide system and mediates its antidepressive effects via inhibition of the acid sphingomyelinase and a reduction of ceramide in the hippocampus...

www.karger.com

 

Melatonin Acts as an Antidepressant by Inhibition of the Acid Sphingomyelinase/Ceramide System

Abstract. Background: Melatonin has been shown to have antidepressive effects. We tested whether melatonin inhibits the acid sphingomyelinase/ceramide system and mediates its antidepressive effects via inhibition of the acid sphingomyelinase and a reduction of ceramide in the hippocampus...

www.karger.com

I guess it is a good thing, however I cannot tolerate melatonin