Why do some men need supraphysiological doses of testosterone to achieve normal levels

[Gianluca]

Considering the daily natural production of a healthy young male, you would think that if someone inject 100mg tot weekly either using a daily or EOD protocol with an ester like Cypionate, we would see both TT and FT above range, theoretically.

However, people like me: for example I inject 20mg daily, and my levels are TT 5/600 with a FT of 19/20, it doesn't make sense then right?

What I think is happening:

Low SHBG can play a role potentially converting fast Test into metabolites. Testosterone itself can also be metabolized fast. Since we inject the testosterone I do not think we can talk about absorption loss, especially with IM injection. Yet, the "loss" seem to be super fast. I inject at 7am and a couple of hours after when I pull my blood the testosterone already disappeared before it peaks?

@Cataceous @madman what else do you guys think is happening?

 

[Vince]

Considering the daily natural production of a healthy young male, you would think that if someone inject 100mg tot weekly either using a daily or EOD protocol with an ester like Cypionate, we would see both TT and FT above range, theoretically.

However, people like me: for example I inject 20mg daily, and my levels are TT 5/600 with a FT of 19/20, it doesn't make sense then right?

What I think is happening:

Low SHBG can play a role potentially converting fast Test into metabolites. Testosterone itself can also be metabolized fast. Since we inject the testosterone I do not think we can talk about absorption loss, especially with IM injection. Yet, the "loss" seem to be super fast. I inject at 7am and a couple of hours after when I pull my blood the testosterone already disappeared before it peaks?

@Cataceous @madman what else do you guys think is happening?

Are you a fast metabolizer of medicines? - Excel Male TRT Forum

Differences in your DNA that make up the CYP2D6 gene can change how well you are able to break down certain medicines. If you break down a medicine too fast or too slowly, this may cause a bad reaction to the medicine. By testing your DNA (with a pharmacogenetic test), we may find DNA...

www.excelmale.com

 

[Vince]

CYP17A1: This gene plays a role in the synthesis of testosterone.

 

[Cataceous]

Considering the daily natural production of a healthy young male, you would think that if someone inject 100mg tot weekly either using a daily or EOD protocol with an ester like Cypionate, we would see both TT and FT above range, theoretically.
...

In fact this is usually the case. 100 mg per week in divided doses puts my total testosterone over 1,200 ng/dL, and this is common. @Readalot shared data supporting this proposition.

...
However, people like me: for example I inject 20mg daily, and my levels are TT 5/600 with a FT of 19/20, it doesn't make sense then right?
...

Your low SHBG suppresses total testosterone. Free testosterone is proportional to the dose rate. By what method are you determining free testosterone? I hope it's not via the useless direct method. What is calculated free testosterone?

...
Low SHBG can play a role potentially converting fast Test into metabolites. Testosterone itself can also be metabolized fast. Since we inject the testosterone I do not think we can talk about absorption loss, especially with IM injection. Yet, the "loss" seem to be super fast. I inject at 7am and a couple of hours after when I pull my blood the testosterone already disappeared before it peaks?
...

The metabolic clearance rate of testosterone is determined by liver function and by the level of free testosterone. SHBG has very little to do with it. Furthermore, more effective liver function proportionally reduces free testosterone; it does not affect the apparent half-life of testosterone esters. The half-life is tied to the drop in serum testosterone over time. While most men injecting testosterone cypionate daily will see pretty steady serum testosterone, I have seen exceptions, men who appear to be fast absorbers. In these cases the apparent half-life of cypionate is considerably reduced; they do see unusually large drops over the course of a day.

 

[Vince]

AI Overview
Based on the provided search results, the

UGT2B17 gene plays a significant role in testosterone metabolism and clearance, specifically through glucuronidation, a process that makes testosterone easier to excrete.
Individuals with a deletion in the UGT2B17 gene show reduced glucuronidation of testosterone and therefore lower levels of testosterone glucuronide in their urine. This suggests that reduced activity of the UGT2B17 enzyme can lead to potentially higher testosterone levels due to slower clearance from the body.
Other genes are also involved in testosterone metabolism and synthesis, including:

• CYP17A1: Crucial for the production of testosterone and other steroid hormones.
• SHBG: Influences how testosterone is transported and made available in the bloodstream.
• CYP19A1 (aromatase): Converts testosterone to estrogen.
• SRD5A2: Converts testosterone to the more potent androgen, DHT.

However, the UGT2B17 gene deletion is directly linked to the rate at which testosterone is cleared from the body.



Genetic and phenotypic variation in UGT2B17, a testosterone-metabolizing ...
Abstract * Objective. A number of candidate gene and genome-wide association studies have identified significant associations between single nucleotide polymorp...

National Institutes of Health (NIH) (.gov)

UGT2B17

 

[Nelson Vergel]

Thread 'Heavier Men May Require Higher TRT Doses'

Jun 6, 2020

We finally have a study that looked at this common question.

Effect of Weight on Serum Testosterone Levels with Subcutaneous Testosterone Enanthate in Men with Testosterone Deficiency

Introduction

Obesity is a common issue among men and is often associated with low testosterone (T) levels. This association complicates the management of testosterone deficiency (hypogonadism) in overweight and obese individuals. It is known that men with a higher body mass index (BMI) need higher doses of transdermal testosterone therapy (TTh), like T 2% gel, to get their T levels back to normal...

• Nelson Vergel
• trt dose weight
• Replies: 38
• Forum: Testosterone Basics & Questions

• 

 

[Cataceous]

Thread 'Heavier Men May Require Higher TRT Doses'

Jun 6, 2020

We finally have a study that looked at this common question.

Effect of Weight on Serum Testosterone Levels with Subcutaneous Testosterone Enanthate in Men with Testosterone Deficiency

Introduction

Obesity is a common issue among men and is often associated with low testosterone (T) levels. This association complicates the management of testosterone deficiency (hypogonadism) in overweight and obese individuals. It is known that men with a higher body mass index (BMI) need higher doses of transdermal testosterone therapy (TTh), like T 2% gel, to get their T levels back to normal...

• Nelson Vergel
• trt dose weight
• Replies: 38
• Forum: Testosterone Basics & Questions

• 

Weight is probably related only indirectly to the observations. Obesity would be strongly correlated with metabolic syndrome and low SHBG. The low SHBG is what drives down total testosterone, but not free testosterone. Therefore it's unlikely that heavier men on TRT actually need higher doses.

It's a different scenario for obese men not on TRT, where both free and total testosterone are expected to be lower due to a dampening of the HPTA by increases in estradiol; the greater quantity of adipose tissue enhances aromatization.

 

[Nelson Vergel]

More BMI= More blood volume to dilute the dose. Dilution creates lower T blood concentrations, requiring a dose increase.

 

[Gianluca]

By what method are you determining free testosterone? I hope it's not via the useless direct method. What is calculated free testosterone?

throughout the years I used mostly the direct method. However, since the discussions in here, a couple years ago I started to use the Equilibrium ultrafiltration from LabCorp, and FT levels came back about the same as direct method. I also calculated FT with the Tru calculator, and FT matched the Equilibrium Ultrafiltration results, I believe I tried this 2 or 3 times.

Since the cost of the test, I recently switched back to Direct method, I think I may want to try the Ultrafiltration from Quest next since it is less expensive. Personally, in 10 years I got back unusual results with the direct a few times.

The metabolic clearance rate of testosterone is determined by liver function and by the level of free testosterone.

what do you think about the possibility of excessive (supraphysiological) testosterone being injected for a prolonged time (TRT), and the body sensing the excess and the liver start to clear testosterone at a much faster degree as a protective mechanism resulting in lower levels?

 

[Gianluca]

I just calculated again my FT with Tru calculator, and my FT is 18.64ng/dl, direct method is 19.4 pg/ml

 

[Cataceous]

More BMI= More blood volume to dilute the dose. Dilution creates lower T blood concentrations, requiring a dose increase.

It only works that way if you're measuring total testosterone on an absolute basis, e.g. the total milligrams in plasma. But we're measuring the total concentration in blood, which is mostly bound to the effective reservoir of SHBG and albumin. This means the concentration of total testosterone in blood is primarily governed by the concentrations of SHBG and albumin, as well as by free testosterone—think of the Vermeulen equation. As far as I know the concentrations of SHBG and albumin are regulated independently of total plasma volume. This means that an increase of blood volume does not change the steady-state binding protein concentrations, which are driving the total testosterone concentration. Meanwhile, the dose of testosterone directly and proportionately drives the free testosterone concentration. Free testosterone is then proportionally metabolized in the liver. I am not aware of research showing that larger body mass in general results in more effective liver metabolism, rather than less.

Looking at it from a simplistic intuitive standpoint, we can't model the blood as a fixed volume of fluid that each day is replaced and mixed with a fixed dose of testosterone. In this case increasing the volume and not the testosterone would lower the testosterone concentration. But the system is better modeled by a volume with fresh fluid and testosterone flowing in separately, mixing, and then flowing out at the same rate. Now what happens if the volume is doubled but the flow rates are unchanged? The testosterone concentration then is also unchanged.

 

[Cataceous]

...
what do you think about the possibility of excessive (supraphysiological) testosterone being injected for a prolonged time (TRT), and the body sensing the excess and the liver start to clear testosterone at a much faster degree as a protective mechanism resulting in lower levels?

It's an interesting hypothesis, but I'm not aware of any supporting data, and there is some pointing against it. For example, in one of the testosterone dose-response trials free testosterone remained proportional to dose even at very high doses of testosterone. Now I guess you could argue that the trial of some months wasn't long enough to cause this adaptation. But I remain skeptical that the liver clearance efficiency is going to slowly increase over time.

I just calculated again my FT with Tru calculator, and my FT is 18.64ng/dl, direct method is 19.4 pg/ml

I concede that these are pretty low numbers relative to the dose, and that ostensibly you are an outlier in your response. Assuming accurate lab numbers and dose delivery then that points to an unusually high metabolic clearance rate.

 

[Willyt]

What fascinates me is how some guys are able to tolerate large daily doses and still function normally at supraphysiologic levels.

For example, a mere 10mg of daily prop felt like speed to me. Difficult to concentrate; too wired to sleep; heart palpitations, etc. And yet some guys can take 20mg daily like candy.

I've wondered if these guys had higher natural production to begin with - i.e., a higher internal "set point" to use the thermostat analogy