T Nation

What is TRT and What is NOT TRT

@highpull just won the thread

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Ok here it comes. Those who are not interested in reading scientific literature and go through details, skip this post, it’s not for you.

First I’ll take a study where good evidence is present that SHBG binds androgens and inactivates them.


At 24 weeks of age, steroid hormone profiling of serum and urine by LC-MS/MS revealed that male SHBG-Tg mice have increased total serum concentrations of T and DHT (~200-fold)

This is because of HPA stimulation (lack of negative feedback) because the SHBG-Tg mice have SHBG.

As you can see, LH increased because in mice with artificially added SHBG the free T decreases. This decrease gets fully compensated by increasing total T and therefore again free T. So the hypothalamus supports the free hormone hypothesis.

Our findings provide for the first time clear experimental validation of the free hormone hypothesis with respect to sex steroids, i.e. that SHBG-bound T in the circulation is restricted from entering into target tissues and eliciting its physiological functions in vivo . Unexpectedly however, the most striking effect of SHBG is not to decrease free T concentrations, but to increase total androgen and estrogen concentrations. This occurs via at least two mechanisms: hypothalamic-pituitary feedback stimulation (as evidenced by increased LH and concentrations of precursor androgens which themselves do not bind to SHBG) and increased circulating ligand half-life.

Interesting: Blood E2 increased too, normal WT mice don’t have detectable E2 in the blood but rats with SHBG do.

Using a more sensitive, dedicated LC-MS/MS method E2 was undetectable in WT male mice, whereas in SHBG-Tg males (n = 9), values above the limit of quantification (1.3 pg/mL) were observed in four of them. These low to undetectable values could not be attributed to the known fluctuating T concentrations in male mice, as shown by the consistent lack of E2 in WT mice with a s.c. continuous-release T implant. The lack of E2 was also not due to limitations of the LC-MS/MS method, as shown in castrated SHBG-Tg males with s.c. silicone E2 implants, or female mice E2 concentrations measured randomly in the estrous cycle were increased in female SHBG-Tg vs. WT mice

(Also there seems to be a nonsensical statement in the discussion (more on problems here later):

We also found no phenotypic evidence for ligand-independent effects of SHBG, since no differences were seen in gonadectomized or pre-pubertal animals.

Since these animals don’t have SHBG naturally. So taking away something that’s added artificially shouldn’t impact the organism)

My problem with this study in particular is that the mice used don’t have any SHBG normally, so there is no need for mechanisms to use it and so they evolved using “only” free testosterone.
This in my opinion puts a big damper on the findings since the study can’t prove more than a binding of the T in the blood stream.
I think it is more complicated than that though, but I can’t find a critical outlook in this in the study, so I assume they didn’t test for the uptake mechanisms.
The study was published in Nature, one of the biggest and best research publishers. It also was published not long ago (IIRC 2016). I’m wondering why a paper that peer-reviews high level studies routinely didn’t critique that point enough to get the researchers to do one or two more experiments.

An SHBG homologue known as the androgen-binding protein is expressed locally in the testis of mice and rats but hepatic Shbg expression and secretion is lacking postnatally in these rodent models. Therefore a mouse model expressing a human SHBG transgene (SHBG-Tg) has been established previously

So here are some papers trying to go beyond that.
These are from 2005! So the newer paper should have tried to refute or prove the claims.

In this paper they review a study in which the megalin receptor (a receptor that’s similar in genome and function to the LDL-Receptor, both internalize after binding their substrate, in this case SHBG) is implicated in transporting SHBG and the bound hormone into the cell.

They took mice which have SHBG naturally.

This appears to be true in vivo, at least temporally, as female mice that lack megalin show abnormalities in vaginal opening in response to estrogen, and megalin-deficient male mice exhibit defects in testicular descent in response to androgens.

This could not be compensated by giving more T or E2. So there seems to be evidence for a free T independent pathway.

Here’s the best experiment from the original study:
(RAP blocks the megalin receptor)

From: https://www.cell.com/cell/fulltext/S0092-8674(05)00651-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867405006513%3Fshowall%3Dtrue

To explore the effect of this endocytic pathway for SHBG/ABP on the cellular metabolism of testosterone, we determined uptake of [3H]testosterone in BN16 cells in the presence of unlabeled SHBG. After 5 hr, approximately 11% of the tracer was associated with the cells, a process that was blocked by RAP. Megalin-mediated uptake of testosterone was critically dependent on the amount of SHBG present in the culture medium as shown by varying the molar ratio of carrier and testosterone. At a ratio of carrier to steroid of 5:1 when 95% of the steroid is bound to SHBG, cell association of [3H]testosterone was absolutely dependent on megalin activity as evidenced by RAP inhibitability. At a molar ratio of 1:10 when 98% of [3H]testosterone is free, cell association was independent of megalin and insensitive to RAP. At a molar ratio of 1:1 when 20% of testosterone is complexed, uptake was partially dependent on megalin activity. In the human circulation (adult males), the ratio of SHBG to testosterone is approximately 3:1. SHBG bound testosterone was unable to enter cells when megalin was blocked by RAP and instead accumulated in the medium of the cells.

That quite clearly demonstrates that SHBG bound testosterone

  1. gets taken up into cells through a specific mechanism
  2. has defined properties in tissues that miss androgen induced changes when this pathway gets inhibited


Assuming a pivotal role of megalin in sex-steroid signaling, it is intriguing to note that megalin null mice do not share all of the anomalies seen in mice deficient for the AR (e.g., testicular feminization) or estrogen receptors (ER) (e.g., uterine hypoplasia).

So MICE that lack the receptor DONT have all the symptoms of a complete lack of androgens and estrogens ergo there must be other mechanisms for them to enter the cell. These could either be other SHBG receptors or free T diffusing through the plasma membrane of the cell. I think the latter is probable.

To me, all of this in conclusion, looks like both pathways get used by the body to produce different results. The second and third studies I linked look a lot more error prove than the first one, from the get go. Also the argument that if 95+% of T and other hormones is bound to SHBG or ABP and there is efficient uptake needed, that the diffusion might be too slow, is believable. So I’d say that there is not enough evidence to say that only one thing happens but good evidence to suggest that free T as well as SHBG-bound T have their defined roles in the human body. All of the papers here don’t have to contradict each other, they could add to each other.

I’m very open to discussion here. Could be that my analysis is not enough and I’m missing something that points clearly to the one or the other hypothesis. It’s a shame I can’t paint a clearer picture at the moment, maybe I’ll come back to this later.

I don’t know if this is true. I can’t substantiate it and I would not at first sight blame the kinetics of the uptake as that should not be that acute since there’s the mentioned lag time.

This actually is absolutely correct in my opinion.
@dbossa is right if the hypothesis alone is correct. Otherwise it would maybe be an oversimplification or just wrong. But since we don’t know I guess the way to go is the way Mr. Bossa does it, trial and error. The trends physicians see are often there before we have evidence.

So I would not count that out.

Edit: a few months later and I see I forgot one important thing.

Estradiol for example doesn’t only act in the cell but there are membrane receptors (this is very new stuff so for testosterone I don’t know if there are known membrane T receptors) which promote the fast E2 effects. SHBG bound E2 seemingly is functional and acts on these.


Another point that supports that the free hormone hypothesis is outdated.


This thread become an instant classic after these 2 posts. Gentleman, you just wrote T-Nation history.


Thank you @lordgains! I will give this some thought and get back to you. Thank you for taking a look and spending some calories (calories that could have gone to pure anabolic goodness) in the name of science-ing the anabolic masses.


While those are excellent contributions, I think you are deeply discounting this true gem:

See @dbossa, I didn’t bold the part mentioning you; despite the numerous logical skid marks you leave smeared all throughout this forum, I still deeply believe you are trying to help men. Thank you again for your service in this capacity (sincere).

Maybe you’ve seen this (Sept 2020). Interesting discussion:

The findings of this study provide further support for the idea that the mechanism for the strong positive correlation between the circulating levels of SHBG and total testosterone in men is more complex than the stoichiometry of a high affinity circulating transport protein which controls metabolic clearance, and its ligand. Instead, the positive correlation in untreated, but not in testosterone-treated men, implies that SHBG regulates testicular negative feedback either directly or by modulating the entry of testosterone or estradiol into cells in the hypothalamus and/or pituitary to control gonadotropin synthesis and secretion, and thereby testosterone levels.

Look at those free T levels of the T-treated men:

Someone tell the Doc they should be up at least 25 ng/dL free T (range of guys here was 4.6-9.5 ng/dL). Puny, girly men @yeti308 !!

And you continue to misquote me, which is why I got out of this discussion. I have never, not ONCE, said men NEED 25-30 to resolve symptoms. Please send me the quote where I said that they NEED that much specifically. What I actually said, as you continue to take my every word out of context, is that when we ask the physicians about their patients who report no symptoms, they noticed that the vast majority had a minimum of 25-30 or higher. This is what they OBSERVED. Some have symptom resolution with less. I have also seen the exact same thing happen on my end. I do NOT target a number, EVER. I’ll repeat what I do again, for the thirteenth time. Here goes:


What I observe is that the vast majority of men who DO resolve symptoms tend to have 25-30 as a minimum.

You can continue to state skid marks and logical fallacies and me avoiding debate until you’re blue in the face. The simple fact is that you take virtually everything everyone says out of context, over complicate it, and then drown it in math.

I ask you to re-read this comment over 100 times (not that I think it will make the slightest bit of difference). For a smart person, you’re not too bright.

You can also post your evidence of the risks demonstrated by a free T of 30 or 40 because there are NONE. Again, you’re drowning this thread with assumptions and accusing others of doing the same. There is NO EVIDENCE that a free T of 30-40 causes harm. None, nada, zip, zero. If you believe there is, provide it. I want to see evidence that a man on TRT with a free T of 30-40 demonstrated harm.

Re-read this comment another 100 times.

“For the readers out there who got this far”:

This is what NOT TO DO IF YOU WANT TO GET BETTER. Period. End of story. The guys that are a mess are the guys that obsess with the tiniest of details like this guy.

Hi Danny, thanks for the clarification, I appreciate it. I understand your point.

The onus is not on me (in this debate) to show evidence that free T of 30-40 ng/dL carries risks or causes harm. As an experimental treatment that takes a guy outside the physiologic range of free T levels in humans, the onus is on the provider who is practicing this to demonstrate it does not cause harm. Big difference.

I’ve already listed out the risks of this. And there’s anecdotal evidence (some I’ve already shared - ME). For those predisposed, elevated Hct, BP, elevated shear stress on the lumen, premature cardiovascular failure, CNS damage, beta-agonist receptor upregulation, electrical disturbances of the heart. Blah, blah, blah. Not in the least sexy or fun/popular to pay attention to untl it happens to you.

I observe you keep wanting to straddle the fence with this “supra-level” stuff. I’ll give you the benefit of the doubt that given human variability, some guys really do need to run 40 ng/dL free T.

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All this was going on, but you blame the testosterone and tell people to fear it. You’re a dumbass. Sorry, you are. You cannot demonstrate it was the testosterone. For crissakes you had preexisting arrhythmia and got on a cycle plus thyroid with high hct etc. etc. But it’s the testosterone, right??

It’s guys like you that I make videos about. You are the Lord King of assumptions and then accuse people of doing the same. None, and I can insist NONE of anything you stated here is of value. It’s absolute, pure, 100% BS. You might as well go in a thyroid forum and tell everyone about the dangers of thyroid. Or an HCT forum. Or an arrhythmia forum… and on and on an on. Go tell them about the dangers. Meanwhile, the rest of us are doing JUST FINE. There’s just NO WAY that you took shit to the extreme while you had preexisting conditions and it messed you up, right? NO WAY, right??

Your credibility, in my eyes, has gone down to zero. A lot of fancy words, chastising others for improper sentence structure, plays on words by taking things out of context, overcomplicating the simple because it was just ‘too simple’ for you, etc. etc. Never ONCE providing any actual benefit or feedback for someone looking help. You just post studies and math and charts and graphs to make yourself look all important. I see right through it. I have no need to overcomplicate my language. I have no need to confuse people or make them feel like idiots. People have issues and want a clear, concise, and SIMPLE explanation as to what they need to do to get better and you are demonstrably incapable of doing this.

There is no evidence. Please do explain to the class how one demonstrates a LACK of evidence, Mr Critical Thinker.

I’m not straddling a damn thing. You’re obsessed with numbers. I don’t care about a range. I care about ensuring the guy feels ‘normal’. Not super-human. NORMAL. If they want to get jacked or bang their wives three times a day, as @lordgains stated in his analogy, that is NOT TRT and is not what we are trying to achieve to be NORMAL.

As long as you keep stating ‘supra-level stuff’ it’s because you’re obsessing with the numbers. If someone has preexisting conditions they need to consult with their physicians before doing ANY TREATMENT OF ANY KIND, or ANY FORM OF PHYSICAL ACTIVITY, whether it be TRT or anything else.

Didn’t say a “LACK of evidence”, I stated

That’s the way science works. That’s the way clinical trials are designed to screen the efficacy and safety of a drug or medical treatment.

Appreciate your comments on my experience. All of these treatments I was taking were Dr. prescribed and presumably therapeutic (thyroid and nandrolone). You are correct I can’t prove it was the testosterone and didn’t mislead anyone by implying that. Just urging caution.

Either your reading comprehension is bad or you are a deceptive POS. Or maybe you made a mistake. Maybe all three (I really don’t know). I think we are good at this point.

You’re stating the onus is on the provider who is practicing this to demonstrate it does not cause harm.

There is no evidence of harm. Do you see how this works? Perhaps you are the one who needs a lesson in critical thinking?

Patient: “Is there any evidence of harm at this dose? The onus is on you to demonstrate a lack of harm.”

Doctor: “There is no evidence of harm at this dose. There is over 80 years of study on testosterone and we still have no evidence of harm after all this time”

To add to your nonsense, you were also taking nandrolone. But it was the testosterone, right? Everyone on T-Nation, listen up! Preexisting conditions, too much thyroid, too low body fat, too high hct, cycle levels of testosterone, and nandrolone are SAFE! However, beware of TRT because that can send you to the hospital!

Great job. I applaud you. The hole you’re digging keeps getting deeper an deeper with each comment. Keep going!! Let’s see how much more credibility you can lose past the zero mark.

For the record here’s what I wrote:

The only deviation (from Rx) I made was increasing the T dose. Hct was 50%. Zero nandrolone or oxandrolone at the time. Thyroid dose was medically prescribed for hypothyroidism. Does this prove it was the T? No. But it does paint a picture for when things go wrong with outside the mainstream protocols, you are on your own.

I really wanted to give you the benefit of the doubt @dbossa, but this last exchange in my mind demonstrates why guys should run from people like you, @yeti308, TOT, T-Mills, and “anti-aging” clinics. Everything’s good until something does go wrong then full court press to blame the patient, disavow the “steroid” user, and come up with any and all methods to excuse and exonerate the reckless practices. In my case I stated above I took full responsibility for bumping up the Testosterone to 325 mg/week (what happened to titrating the dose up to symptom resolution?), but instead of understanding my point about caution, you misrepresent my position.

For the reader, here was my TT profile leading up to my AFIB incident:


I was in the second week up upping my dose from 120 mg/week of TC to 325 mg/week (injection 2x per week).

Peak at week 2 was about 2600 and trough about 1770 ng/dL. SHBG is 55 nmol/L.

Here’s the calculated range of free T:

In reality, equilibrium dialysis free T typically 20% lower than Vermeulen calculation above. So I estimate I was somewhere between 30 and 50 ng/dL on my free T in week 2.

I wasn’t aware of electrical issue with my heart until after the incident. Previous EKGs and Echos were fine. But cardiologist mentioned it could have been missed, and that the particular issue (that got picked up after the AFIB incident) is usually there from birth. Take care of yourselves.

I’m not misrepresenting a thing. Now you even took anavar and peaks of total t exceeding 3000!. Pre-existing conditions with a ton of anabolic steroids and thyroid but you’re telling the rest of us to beware free T that surpasses the clinical range. It’s ridiculous.

I don’t tell guys to do ANYTHING you were doing. They are doing this strictly to improve their health and resolve symptoms of brain fog, erectile dysfunction, loss of libido, etc. All they are after is for these issues to be resolved so that they can lead a NORMAL life. What you were doing above is not trying to lead a NORMAL life. Having done so, along with your preexisting conditions, it bit you in the ass. You only have yourself to blame and your experience has zero to do with men on TRT looking for some semblance of normalcy.

You can keep playing this game all you want. Nobody has been ‘running from me’ so far. All I have is an inbox full of thank yous and people that decided not to kill themselves because they finally felt normal. You want to scare people and I want to help people. I’ll choose the latter ten times out of ten.

Incorrect. I did my best to show my T profile above. You should stay away from trying to math. Did my best above to characterize the issue with my heart as pre-existing even though I didn’t know about it before hand. There’s dispute (as I mention above) whether it was pre-existing as previous echo/EKG had come back ok.

A “ton” of AAS? These were prescribed as therapeutic dosages to assist with horrible joint issues. Thyroid was Rx (years with this dosage) along with nandrolone and oxandrolone intermittently for two years prior. Sure, I did understand the risk before hand (most who use these medications will not).

Who else did I blame? Your full court press smear really does not follow from everything I’ve shared up to this point. Very poor character on your part.

My only advice on here repeatedly was be cautious and be careful with who you work with. As I have repeated often, the easiest person to fool is yourself.

In conclusion, even with the knowledge and care I took to mitigate and minimize risk, bad stuff did and does happen.

Therefore, YOU should be the one to concede here as your topic is ‘What is TRT and What is NOT TRT’ where you provided your argument of how ‘supra levels’ can cause harm.

A) You were doing a cycle
B) You had a pre-existing condition (known or unknown)
C) You had total T levels surpassing 3000 (nobody I work with or the physicians I work with are doing this by any stretch of the imagination)
D) You were taking nandrolone
E) You were taking anavar
F) You were taking thyroid
G) You had very low body fat
H) You had high-ish HCT
I) You were doing very intense HITT + weight training

No, this is NOT TRT. Your argument is moot. You spent virtually the entire thread addressing the potential dangers of ‘supra levels’ and there is no evidence for any of it.

Concede that this entire thread had NOTHING to do with TRT whatsoever as the ‘dangers’ you brought up were due to your own experiences doing anything but and then warning about testosterone.


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Complete and utter BS. Go back to the first post I did. That was an informational post to explain to guys what TRT is and identify physiologically relevant range of TT. Along the way in this thread I did share my experience (my experience) as anecdotal data. I don’t know if “supra-levels” will cause harm for any given individual, but I did urge caution. Way to go now claiming I provided an argument of how “supra levels” can cause harm. I sure did make a claim that “supra levels” may cause harm.

It is unclear in my case what did cause the harm. For your grand finale, your best yet:

ad hoc poisoning the well!

Danny’s logic:

Dear Reader: All of the information that @readalot has presented in this thread should discarded because of his personal, anecdotal story that he shared to help guys further appreciate potential risks.

Take care of yourself and I wish you the best. I CONCEDE. I concede I’ve been debating with someone I should not have been debating. Lesson learned. I believe these were attributed to Mark Twain:


You’ve truly honed your reasoning skills to razor sharp levels on Facebook.


None of the physicians you work with have guys between 30-50 ng/dL, which depending on their SHBG status could easily push them above 2000-2500 ng/dL Total T (as I just showed above)?

This is a TOT protocol.

Your statement is inaccurate and you are trying to distract from the FACT that this “cycle” is what many are doing for TOT. Of course it isn’t TRT. I went from TRT to TOT (no asking on your part why I made the change).

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