High testosterone is like … finasteride? Say what!

[Cataceous]

It’s not quite as off-the-wall as it sounds. We know that as serum testosterone increases the 5α-reductase enzyme starts to saturate, leading to a reduced efficiency in DHT creation, illustrated thusly:

Even so, with high testosterone a lack of DHT is not going to be a problem; there’s still going to be a lot of it, likely at supraphysiological levels. A T/DHT imbalance is possible, though this would seem to be a more subtle problem.

However, what’s going on with other 5α-reductase-mediated processes? It seems possible that there are deleterious effects on these processes through competitive inhibition that increases with the level of testosterone. For example, there may be a reduction in the conversion of progesterone to dihydroprogesterone. This is cited as one of the possible reasons for finasteride-induced side effects. Clearly the overall effect is going to be less dramatic, as lack of DHT is likely a significant factor when finasteride is in play. Additionally, the effects on 5α-reductase activity from competitive inhibition are likely less drastic than those from finasteride. Nonetheless, with individual variability it seems plausible that some men will experience problems from this, which serves as a further reminder that high levels of testosterone are not necessarily benign.

Some comments by ChatGPT:

In summary, it is entirely plausible that high levels of serum testosterone can competitively inhibit the conversion of other steroid substrates by 5α-reductase, including the conversion of progesterone to dihydroprogesterone. The structural similarities and abundance of testosterone in such scenarios create a scenario ripe for competitive inhibition. This is a fascinating area of research with potential implications for understanding various physiological and pathological conditions. …​

To be fair, it does mention some caveats:

• Complexity: Hormonal regulation is highly complex, and many factors can influence the activity of 5α-reductase. This isn’t a simple “one substrate wins” scenario.​

​

• Feedback Mechanisms: The body has negative feedback loops to regulate hormone production, so simply increasing testosterone wouldn’t necessarily cause a sustained reduction in other 5α-reductase products.​

​

• Tissue Specificity: The effects could be tissue-specific since the levels and forms of 5α-reductase vary throughout the body.​

 

[Nelson Vergel]

We have had data about how exogenous testosterone can decrease upstream neurosteroids. I am sure that decrease is worse at higher T doses.

Anabolic steroids and TRT decrease SHBG, DHEA, pregnenolone and progesterone in men.

Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man. Ruokonen A, et al. J Steroid Biochem. 1985. Abstract The influence of high doses of testosterone and anabolic steroids on testicular endocrine function...

www.excelmale.com

Allopregnanolone is one of the most important neurosteroids involved in mood. It is dependent on 5 alpha reductase.

Allopregnanolone in mood disorders

ABSTRACT The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAAR), and the down-regulation of its biosynthesis has been attributed to the development of mood disorders, such as depression, anxiety, and post-traumatic stress...

www.excelmale.com

I searched on perplexity:

The effect of supraphysiologic testosterone on allopregnanolone levels in men is complex and involves several interrelated mechanisms:

## Neurosteroid Biosynthesis

Supraphysiologic testosterone administration can lead to changes in neurosteroid biosynthesis, particularly affecting allopregnanolone levels:

1. **Decreased Allopregnanolone**: Long-term administration of high doses of testosterone has been associated with a decrease in brain allopregnanolone content[1][4]. This reduction is likely due to the down-regulation of neurosteroid biosynthesis pathways.

2. **5α-reductase Expression**: Testosterone administration can cause a decrease in the expression of 5α-reductase type I mRNA, which is a key enzyme in the biosynthesis of allopregnanolone[1][4]. This decrease in enzyme expression contributes to the reduced allopregnanolone levels.

## Behavioral Effects

The changes in allopregnanolone levels due to supraphysiologic testosterone can have significant behavioral implications:

1. **Aggression**: The decrease in brain allopregnanolone content has been associated with increased aggressive behavior[1][4]. This may partly explain the phenomenon of "steroid rage" observed in some individuals using anabolic-androgenic steroids.

2. **Mood Alterations**: Allopregnanolone is a potent modulator of GABA_A receptors, and its reduction can lead to changes in mood, potentially contributing to irritability and anxiety[3].

## Compensatory Mechanisms

The body may attempt to compensate for the effects of supraphysiologic testosterone:

1. **Androgen Backdoor Pathway**: Allopregnanolone is an intermediate in an androgen backdoor pathway from progesterone to dihydrotestosterone[3]. This pathway may be affected by supraphysiologic testosterone levels, potentially altering allopregnanolone production.

2. **Intratumoral Testosterone**: In the context of prostate cancer, long-term androgen deprivation therapy can lead to similar or even higher intratumoral testosterone levels compared to pre-castrate levels[2]. This suggests complex regulatory mechanisms that may also influence allopregnanolone synthesis.

## Clinical Implications

Understanding the relationship between supraphysiologic testosterone and allopregnanolone has important clinical implications:

1. **Cognitive Function**: Both testosterone and allopregnanolone play roles in cognitive function. Alterations in their levels may impact cognitive performance in older men[6].

2. **Sexual Function**: Changes in neurosteroid levels, including allopregnanolone, can affect sexual function. The neurosteroid androsterone, which is related to allopregnanolone in the steroid biosynthesis pathway, has been correlated with sexual interest in men[7].

3. **Prostate Cancer Treatment**: Supraphysiological testosterone therapy has shown potential in treating certain cases of enzalutamide-resistant prostate cancer[8]. The effects on allopregnanolone in this context warrant further investigation.

In conclusion, supraphysiologic testosterone administration in men can lead to a decrease in allopregnanolone levels through down-regulation of neurosteroid biosynthesis pathways. This change can have significant effects on behavior, mood, and potentially cognitive function. However, the body's compensatory mechanisms and the complex interplay between different steroid hormones make this relationship nuanced and context-dependent.

Citations:
[1] Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior - PubMed
[2] https://erc.bioscientifica.com/view/journals/erc/24/11/ERC-17-0155.xml
[3] Allopregnanolone - Wikipedia
[4] Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior - PMC
[5] Effects of Progesterone and Testosterone on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys - Neuropsychopharmacology
[6] Frontiers | An Updated Review: Androgens and Cognitive Impairment in Older Men
[7] https://jamanetwork.com/journals/jamapsychiatry/fullarticle/209516
[8] https://www.europeanurology.com/article/S0302-2838(19)30449-X/fulltext

 

[Seagal]

It’s not quite as off-the-wall as it sounds. We know that as serum testosterone increases the 5α-reductase enzyme starts to saturate, leading to a reduced efficiency in DHT creation, illustrated thusly:

View attachment 49552
Even so, with high testosterone a lack of DHT is not going to be a problem; there’s still going to be a lot of it, likely at supraphysiological levels. A T/DHT imbalance is possible, though this would seem to be a more subtle problem.

However, what’s going on with other 5α-reductase-mediated processes? It seems possible that there are deleterious effects on these processes through competitive inhibition that increases with the level of testosterone. For example, there may be a reduction in the conversion of progesterone to dihydroprogesterone. This is cited as one of the possible reasons for finasteride-induced side effects. Clearly the overall effect is going to be less dramatic, as lack of DHT is likely a significant factor when finasteride is in play. Additionally, the effects on 5α-reductase activity from competitive inhibition are likely less drastic than those from finasteride. Nonetheless, with individual variability it seems plausible that some men will experience problems from this, which serves as a further reminder that high levels of testosterone are not necessarily benign.

Some comments by ChatGPT:

In summary, it is entirely plausible that high levels of serum testosterone can competitively inhibit the conversion of other steroid substrates by 5α-reductase, including the conversion of progesterone to dihydroprogesterone. The structural similarities and abundance of testosterone in such scenarios create a scenario ripe for competitive inhibition. This is a fascinating area of research with potential implications for understanding various physiological and pathological conditions. …​

To be fair, it does mention some caveats:

• Complexity: Hormonal regulation is highly complex, and many factors can influence the activity of 5α-reductase. This isn’t a simple “one substrate wins” scenario.​

​

• Feedback Mechanisms: The body has negative feedback loops to regulate hormone production, so simply increasing testosterone wouldn’t necessarily cause a sustained reduction in other 5α-reductase products.​

​

• Tissue Specificity: The effects could be tissue-specific since the levels and forms of 5α-reductase vary throughout the body.​

Tissue specificity.
I don't believe that the observed saturation is due to enzyme exhaustion. There must be more feedback loops.

However, I support the slow and low approach to TRT.
Again, we need more basic research...

 

[Cataceous]

Tissue specificity.
I don't believe that the observed saturation is due to enzyme exhaustion. There must be more feedback loops.
...

If you're interested in the details, here's the study containing the graph. They say:

Modeling the free E2 vs. free testosterone and free DHT vs. free testosterone relationships showed that our data are consistent with Michaelis-Menten enzyme kinetics in both cases.​

Michaelis–Menten kinetics - Wikipedia

en.wikipedia.org

Further addition of substrate would not increase the rate, and the enzyme is said to be saturated.​

 

[Seagal]

If you're interested in the details, here's the study containing the graph. They say:

Modeling the free E2 vs. free testosterone and free DHT vs. free testosterone relationships showed that our data are consistent with Michaelis-Menten enzyme kinetics in both cases.​

Michaelis–Menten kinetics - Wikipedia

en.wikipedia.org

Further addition of substrate would not increase the rate, and the enzyme is said to be saturated.​

Thank you Cataceous. I was positively surprised about the statistics. The biostatistics department was on board.
I will read in more detail... Figure 1 free DHT seems to double when going from 300 to 600mg T.
What I assumed with my previous post is that over time enzymatic conversion* would slowly adjust (similar to the honeymoon period).
* "Vmax represents the limiting rate approached by the system at saturating substrate concentration for a given enzyme concentration".
The authors measured T and metabolites every month for 5 months. I suppose they would have mentioned if there was a time-dependent change in metabolites and ratios, or not, since they aimed to compare young vs old men.

Wikipedia
"Only a small proportion of enzyme-catalysed reactions have just one substrate, but the equation still often applies if only one substrate concentration is varied."

 

[Vince]

If you're interested in the details, here's the study containing the graph. They say:

Modeling the free E2 vs. free testosterone and free DHT vs. free testosterone relationships showed that our data are consistent with Michaelis-Menten enzyme kinetics in both cases.​

Michaelis–Menten kinetics - Wikipedia

en.wikipedia.org

Further addition of substrate would not increase the rate, and the enzyme is said to be saturated.​

Here's a copy of 2010 control trial.
Background: During testosterone (T) therapy, T is partly converted to 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT). Effects of age, testosterone dose, and body composition on total and free E2 and DHT levels are unknown.
Objective: We evaluated age and dose-related differences in E2 and DHT levels in response to graded doses of testosterone enanthate in young and older men.
Methods: Fifty-one young (aged 19-35 yr) and 52 older (aged 59-75 yr) men completed treatment with monthly injections of a GnRH agonist plus randomly assigned weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg) for 5 months.
Results: During testosterone administration, total and free E2 levels increased dose-dependently (dose effect, P<0.001) in both young and older men. Total and free E2 levels and E2:T ratios during T administration were higher in older than young men, but age-related differences in free E2 and free E2:T ratios were not significant after adjusting for testosterone levels, percentage fat mass, and SHBG. DHT levels and DHT:T ratios were dose-related but did not differ between young and older men. Mechanistic modeling of free hormone data revealed that the conversions of T to E2 and DHT were both consistent with saturable Michaelis-Menten kinetics. The in vivo Km values were estimated to be 1.83 nm for aromatase and 3.35 nm for 5alpha-reductase, independent of age. The Vmax parameter for E2 was 40% higher in older men than younger men, but Vmax for DHT was not significantly different between age groups.
Conclusions: During im testosterone administration, E2 and DHT levels exhibit saturable increases with dose. The rate of whole body aromatization is higher in older men, partly related to their higher percentage fat mass, SHBG, and testosterone levels.

 

[Vince]

If you're interested in the details, here's the study containing the graph. They say:

Modeling the free E2 vs. free testosterone and free DHT vs. free testosterone relationships showed that our data are consistent with Michaelis-Menten enzyme kinetics in both cases.​

Michaelis–Menten kinetics - Wikipedia

en.wikipedia.org

Further addition of substrate would not increase the rate, and the enzyme is said to be saturated.​

Here's the full text link to 2010 trial.

The Effects of Injected Testosterone Dose and Age on the Conversion of Testosterone to Estradiol and Dihydrotestosterone in Young and Older Men - PMC

Background: During testosterone (T) therapy, T is partly converted to 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT). Effects of age, testosterone dose, and body composition on total and free E2 and DHT levels are unknown. Objective: We ...

pmc.ncbi.nlm.nih.gov

 

[Gianluca]

It’s not quite as off-the-wall as it sounds. We know that as serum testosterone increases the 5α-reductase enzyme starts to saturate, leading to a reduced efficiency in DHT creation, illustrated thusly:

View attachment 49552
Even so, with high testosterone a lack of DHT is not going to be a problem; there’s still going to be a lot of it, likely at supraphysiological levels. A T/DHT imbalance is possible, though this would seem to be a more subtle problem.

However, what’s going on with other 5α-reductase-mediated processes? It seems possible that there are deleterious effects on these processes through competitive inhibition that increases with the level of testosterone. For example, there may be a reduction in the conversion of progesterone to dihydroprogesterone. This is cited as one of the possible reasons for finasteride-induced side effects. Clearly the overall effect is going to be less dramatic, as lack of DHT is likely a significant factor when finasteride is in play. Additionally, the effects on 5α-reductase activity from competitive inhibition are likely less drastic than those from finasteride. Nonetheless, with individual variability it seems plausible that some men will experience problems from this, which serves as a further reminder that high levels of testosterone are not necessarily benign.

Some comments by ChatGPT:

In summary, it is entirely plausible that high levels of serum testosterone can competitively inhibit the conversion of other steroid substrates by 5α-reductase, including the conversion of progesterone to dihydroprogesterone. The structural similarities and abundance of testosterone in such scenarios create a scenario ripe for competitive inhibition. This is a fascinating area of research with potential implications for understanding various physiological and pathological conditions. …​

To be fair, it does mention some caveats:

• Complexity: Hormonal regulation is highly complex, and many factors can influence the activity of 5α-reductase. This isn’t a simple “one substrate wins” scenario.​

​

• Feedback Mechanisms: The body has negative feedback loops to regulate hormone production, so simply increasing testosterone wouldn’t necessarily cause a sustained reduction in other 5α-reductase products.​

​

• Tissue Specificity: The effects could be tissue-specific since the levels and forms of 5α-reductase vary throughout the body.​

I remember commenting on this particular study here in the forum, this to be a concern for Progesterone not converting as much into allopregnenolone. Also, this study shows where the max physiological level of T are at about.