I’ve covered this issue in many posts, but I thought it would be helpful to put more information in one thread and expand on the topic.
TL;DR: Under TRT, free testosterone is proportional to the dose rate and inversely proportional to the metabolic clearance rate. The liver accounts for most of the metabolism of testosterone, while conversion to DHT accounts for up to 10-20%, and conversion to other metabolites including estradiol is less than 2%. In steady-state conditions SHBG has little effect on free testosterone.
Background
There’s a basic equation in medical texts [ex] that links the concentration (C) of a hormone to the production rate (PR) and metabolic clearance rate (MCR) of the hormone. It is:
C = PR / MCR
The first question is: Does this proportionality apply to testosterone? The answer is “yes”, but only to free testosterone. It’s a little more complicated than simply acknowledging that testosterone bound to SHBG, albumin, etc. is not contributing. The issue is whether a drug or hormone is restrictively metabolized, which means that it is metabolized in proportion to its concentration, obeying the law of mass action—and is relatively independent of other factors, such as the rate of blood flow. Supporting references and discussion are provided below†, compliments of the Grok AI.
Production rate is the dose rate
In TRT there is usually no endogenous production of testosterone, but the dose rate is functionally equivalent to a production rate. That is, you’re introducing a certain number of milligrams per day of testosterone, and with this model it doesn’t matter if the testosterone is injected or if it is made by the testicles.
We can transform the general equation above to a testosterone-specific one:
free_testosterone = dose_rate / MCR
The units used can be whatever is convenient as long as they reconcile. For example, free testosterone can be in traditional U.S. units of nanograms per deciliter (ng/dL), the dose rate in nanograms of testosterone per second (ng/s) and MCR in deciliters per second (dL/s). If we prefer more convenient units for dosing then we could write the equation as:
free_testosterone(ng/dL) = 1.65(ng-week/mg-s) * dose_rate(mg T/week) / MCR(dL/s)
As an example, some years back I was injecting testosterone enanthate every other day and had pretty steady serum testosterone. Measurements taken at various doses let me estimate my MCR as about 4.1 dL/s—when using Vermeulen calculated free testosterone. With this I could predict my free testosterone at doses I had never tried. If I wanted to estimate my free testosterone when taking 120 mg of testosterone cypionate per week, then I would multiply the 120 mg by the 70% testosterone content and put the resulting 84 mg T/week in the formula:
free_testosterone(ng/dL) = 1.65(ng-week/mg-s) * 84(mg T/week) / 4.1(dL/s) = 33.8 ng/dL
Note that the normal range for Veremulen free testosterone is about 7-25 ng/dL.
The metabolic clearance rate
We’ve established that we can directly control free testosterone via the testosterone dose rate. Now let’s examine the part that is less under our control, the metabolic clearance rate. Deferring to Grok:
As an aside, ChatGPT is promoting a higher maximum for DHT conversion, up to 20%. But this doesn’t affect the basic principles.
I have frequently asserted that hepatic metabolism of testosterone should be stable in the near- to medium-term, barring illness or injury. I include some supporting statements by Grok below††. We do have evidence that in the long-term MCR declines with age. For example, in one large dose-response study older men achieved higher levels of free testosterone than younger men at the same dose.
This leaves conversion to DHT as the only other significant component of testosterone metabolism. It is known that if you knock out conversion of testosterone to DHT with a 5-alpha reductase inhibitor—e.g. finasteride—then you do see an increase in free testosterone. But this is a dubious way to reduce your MCR constant by at most 5-20%.
SHBG
Conspicuously absent from this discussion is SHBG. That’s because in spite of popular perception, it has a minimal effect on free testosterone in steady-state conditions. If we accept two principles discussed above then this is effectively proven: testosterone elimination is proportional to free testosterone, and the dose rate must be matched by the elimination rate. From this it falls out that free testosterone is proportional to the dose rate and must be independent of SHBG.
Body Weight
There does not appear to be evidence that body weight has direct effects on the liver's metabolism of testosterone. From Grok: "In the absence of liver dysfunction like NAFLD, body weight does not have a direct influence on the liver’s metabolism of testosterone. The liver’s enzymatic machinery (e.g., CYP3A4, conjugation enzymes) appears to function consistently across a range of body weights in healthy individuals."
Conclusion
Under TRT free testosterone is directly tied to the dose rate. Interfering with DHT production can reduce the effective metabolic clearance rate of testosterone and cause some increase in free testosterone. Interfering with other extrahepatic metabolism is expected to have negligible effects. Hepatic metabolism is generally going to be stable in healthy individuals.
†The proposition that testosterone is restrictively metabolized in humans in proportion to its free concentration, following the law of mass action, is supported by several studies and reviews that discuss testosterone metabolism, its binding to proteins like sex hormone-binding globulin (SHBG) and albumin, and the kinetics of its clearance. The law of mass action implies that the rate of testosterone metabolism is dependent on the concentration of free (unbound) testosterone, as only the free fraction is biologically active and available for metabolic processes. Below are some key references that provide evidence for this proposition, focusing on the role of free testosterone and its metabolism in humans:
Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. Journal of Clinical Endocrinology & Metabolism, 84(10), 3666-3672.
††Stability in the Absence of Liver Insults
Yes, the hepatic metabolism of testosterone is expected to be stable in the absence of insults to the liver, such as injury or disease. The liver is a robust organ that efficiently processes testosterone under normal, healthy conditions. This metabolism occurs through two main phases:
Effect of Aging on Hepatic Metabolism
Aging itself does reduce the efficiency of hepatic metabolism of testosterone, but it’s important to clarify that aging is not typically considered a disease—it’s a natural physiological process. With advancing age, several changes in liver function can impact how testosterone is metabolized:
TL;DR: Under TRT, free testosterone is proportional to the dose rate and inversely proportional to the metabolic clearance rate. The liver accounts for most of the metabolism of testosterone, while conversion to DHT accounts for up to 10-20%, and conversion to other metabolites including estradiol is less than 2%. In steady-state conditions SHBG has little effect on free testosterone.
Background
There’s a basic equation in medical texts [ex] that links the concentration (C) of a hormone to the production rate (PR) and metabolic clearance rate (MCR) of the hormone. It is:
C = PR / MCR
The first question is: Does this proportionality apply to testosterone? The answer is “yes”, but only to free testosterone. It’s a little more complicated than simply acknowledging that testosterone bound to SHBG, albumin, etc. is not contributing. The issue is whether a drug or hormone is restrictively metabolized, which means that it is metabolized in proportion to its concentration, obeying the law of mass action—and is relatively independent of other factors, such as the rate of blood flow. Supporting references and discussion are provided below†, compliments of the Grok AI.
Production rate is the dose rate
In TRT there is usually no endogenous production of testosterone, but the dose rate is functionally equivalent to a production rate. That is, you’re introducing a certain number of milligrams per day of testosterone, and with this model it doesn’t matter if the testosterone is injected or if it is made by the testicles.
We can transform the general equation above to a testosterone-specific one:
free_testosterone = dose_rate / MCR
The units used can be whatever is convenient as long as they reconcile. For example, free testosterone can be in traditional U.S. units of nanograms per deciliter (ng/dL), the dose rate in nanograms of testosterone per second (ng/s) and MCR in deciliters per second (dL/s). If we prefer more convenient units for dosing then we could write the equation as:
free_testosterone(ng/dL) = 1.65(ng-week/mg-s) * dose_rate(mg T/week) / MCR(dL/s)
As an example, some years back I was injecting testosterone enanthate every other day and had pretty steady serum testosterone. Measurements taken at various doses let me estimate my MCR as about 4.1 dL/s—when using Vermeulen calculated free testosterone. With this I could predict my free testosterone at doses I had never tried. If I wanted to estimate my free testosterone when taking 120 mg of testosterone cypionate per week, then I would multiply the 120 mg by the 70% testosterone content and put the resulting 84 mg T/week in the formula:
free_testosterone(ng/dL) = 1.65(ng-week/mg-s) * 84(mg T/week) / 4.1(dL/s) = 33.8 ng/dL
Note that the normal range for Veremulen free testosterone is about 7-25 ng/dL.
The metabolic clearance rate
We’ve established that we can directly control free testosterone via the testosterone dose rate. Now let’s examine the part that is less under our control, the metabolic clearance rate. Deferring to Grok:
Testosterone Metabolism Overview
Testosterone is metabolized through two main routes:
Hepatic metabolism: This occurs in the liver, where the majority of testosterone (roughly 88-95%) is broken down into inactive compounds like androsterone and etiocholanolone, which are then conjugated and excreted.
- Extrahepatic metabolism: This happens in peripheral tissues (outside the liver) and includes conversions to active metabolites like DHT and estradiol, as well as some minor pathways.
Extrahepatic Conversions
Here’s what we know about the key extrahepatic transformations:
- Conversion to DHT: In peripheral tissues such as the prostate, skin, and hair follicles, testosterone is converted to DHT by the enzyme 5α-reductase. This accounts for approximately 5-10% of total testosterone metabolism in men.
- Conversion to Estradiol: In tissues like adipose tissue, the brain, and skin, testosterone is aromatized to estradiol by the enzyme aromatase. This accounts for about 0.2-0.6%, as you noted, which is a minor fraction.
- Other Minor Metabolites: There are additional pathways in peripheral tissues where testosterone can be converted to compounds like androstenedione (via 17β-hydroxysteroid dehydrogenase) or downstream metabolites of DHT, such as 3α-androstanediol. However, these are less significant and likely contribute less than 1-2% combined.
Total Extrahepatic Metabolism
Adding these together:
- DHT: 5-10%
- Estradiol: 0.2-0.6%
- Other minor metabolites: ~1-2%
This gives a total extrahepatic metabolism range of approximately 5-12%.
As an aside, ChatGPT is promoting a higher maximum for DHT conversion, up to 20%. But this doesn’t affect the basic principles.
I have frequently asserted that hepatic metabolism of testosterone should be stable in the near- to medium-term, barring illness or injury. I include some supporting statements by Grok below††. We do have evidence that in the long-term MCR declines with age. For example, in one large dose-response study older men achieved higher levels of free testosterone than younger men at the same dose.
This leaves conversion to DHT as the only other significant component of testosterone metabolism. It is known that if you knock out conversion of testosterone to DHT with a 5-alpha reductase inhibitor—e.g. finasteride—then you do see an increase in free testosterone. But this is a dubious way to reduce your MCR constant by at most 5-20%.
SHBG
Conspicuously absent from this discussion is SHBG. That’s because in spite of popular perception, it has a minimal effect on free testosterone in steady-state conditions. If we accept two principles discussed above then this is effectively proven: testosterone elimination is proportional to free testosterone, and the dose rate must be matched by the elimination rate. From this it falls out that free testosterone is proportional to the dose rate and must be independent of SHBG.
Body Weight
There does not appear to be evidence that body weight has direct effects on the liver's metabolism of testosterone. From Grok: "In the absence of liver dysfunction like NAFLD, body weight does not have a direct influence on the liver’s metabolism of testosterone. The liver’s enzymatic machinery (e.g., CYP3A4, conjugation enzymes) appears to function consistently across a range of body weights in healthy individuals."
Conclusion
Under TRT free testosterone is directly tied to the dose rate. Interfering with DHT production can reduce the effective metabolic clearance rate of testosterone and cause some increase in free testosterone. Interfering with other extrahepatic metabolism is expected to have negligible effects. Hepatic metabolism is generally going to be stable in healthy individuals.
†The proposition that testosterone is restrictively metabolized in humans in proportion to its free concentration, following the law of mass action, is supported by several studies and reviews that discuss testosterone metabolism, its binding to proteins like sex hormone-binding globulin (SHBG) and albumin, and the kinetics of its clearance. The law of mass action implies that the rate of testosterone metabolism is dependent on the concentration of free (unbound) testosterone, as only the free fraction is biologically active and available for metabolic processes. Below are some key references that provide evidence for this proposition, focusing on the role of free testosterone and its metabolism in humans:
Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. Journal of Clinical Endocrinology & Metabolism, 84(10), 3666-3672.
- Relevance: This study critically evaluates methods for calculating free testosterone concentrations, emphasizing that only free testosterone is biologically active and available for metabolism. The authors discuss how testosterone binds to SHBG and albumin, with only 1-2% of testosterone existing in the free form, which is subject to metabolic clearance. They highlight that the free testosterone concentration, calculated using equations based on the law of mass action, correlates closely with metabolic activity, supporting the idea that metabolism is proportional to free testosterone levels.
- Key Insight: The study uses the law of mass action to derive equations for free testosterone, noting that binding affinities (association constants) for SHBG and albumin govern the equilibrium between bound and free testosterone, which in turn influences metabolic processes.
- Access: Available on PubMed (PMID: 10523012).
- Sodergard, R., Backstrom, T., Shanbhag, V., & Carstensen, H. (1982). Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. Journal of Steroid Biochemistry, 16(6), 801-810.
- Relevance: This foundational paper describes the application of the law of mass action to calculate free testosterone concentrations in human plasma. It provides a mathematical model for the binding of testosterone to SHBG and albumin, demonstrating that the free fraction is determined by the equilibrium constants and is the primary form available for metabolism. The study emphasizes that metabolic clearance rates are directly related to the free testosterone concentration, as bound testosterone is not readily accessible to metabolizing enzymes.
- Key Insight: The authors establish that the free testosterone fraction, governed by mass action principles, is critical for understanding its metabolic fate in the liver and other tissues.
- Access: Available on PubMed (PMID: 7202087).
- Dunn, J. F., Nisula, B. C., & Rodbard, D. (1981). Transport of steroid hormones: Binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. Journal of Clinical Endocrinology & Metabolism, 53(1), 58-68.
- Relevance: This study quantifies the binding of testosterone to plasma proteins and establishes that the free testosterone concentration is a small but critical fraction that drives its biological activity and metabolism. It discusses how the law of mass action governs the equilibrium between free and bound testosterone, with only free testosterone being available for uptake by tissues and subsequent metabolism, primarily in the liver via reduction and conjugation pathways.
- Key Insight: The paper provides evidence that the metabolic clearance rate of testosterone is proportional to its free concentration, as enzymes such as 5α-reductase and those involved in glucuronidation act primarily on the unbound fraction.
- Access: Available on PubMed (PMID: 7195404).
- Testosterone Metabolism - an overview | ScienceDirect Topics.
- Relevance: This overview details the metabolic pathways of testosterone, emphasizing that its metabolism begins with the reduction of the 4-5 double bond in the A-ring, a rate-limiting step catalyzed by 5α- and 5β-reductase enzymes. It notes that testosterone is subject to rapid turnover and homeostatic regulation, with the free fraction being the primary substrate for these metabolic processes. The text supports the idea that the rate of metabolism is proportional to the free testosterone concentration, consistent with the law of mass action.
- Key Insight: The rapid metabolism of testosterone in the liver (phase I and phase II metabolism) is driven by the availability of free testosterone, with the majority of testosterone being converted to androsterone and etiocholanolone glucuronides for urinary excretion.
- Access: Available on ScienceDirect.
- Ekins, R. (1990). Measurement of free hormones in blood. Endocrine Reviews, 11(1), 5-46.
- Relevance: This review discusses the principles of free hormone measurement and the role of free hormone concentrations in metabolic processes. It specifically addresses testosterone, noting that its metabolism follows the law of mass action, where the free fraction is the biologically active component available for enzymatic transformation. The review highlights how the equilibrium between free and bound testosterone, governed by binding affinities to SHBG and albumin, determines the rate of metabolism.
- Key Insight: The paper underscores that the metabolic clearance of testosterone is directly related to its free concentration, as only free testosterone can interact with metabolizing enzymes in tissues like the liver.
- Access: Available on PubMed (PMID: 2180688).
- Law of Mass Action: The law of mass action states that the rate of a chemical reaction (such as testosterone metabolism) is proportional to the concentration of the reactants (free testosterone). The cited studies consistently show that only free testosterone is available for metabolism, and its concentration is determined by the equilibrium with SHBG and albumin, which is modeled using mass action principles.
- Metabolic Pathways: Testosterone is primarily metabolized in the liver through reduction (via 5α- and 5β-reductase) and conjugation (glucuronidation and sulfation), with the free fraction being the substrate for these enzymes. The rapid turnover of testosterone, with a plasma half-life of approximately 10 minutes when unbound, supports the restrictive metabolism proportional to free concentration.
- Free Testosterone Measurement: Accurate measurement of free testosterone, often using equilibrium dialysis or calculations based on mass action equations (e.g., Vermeulen or Sodergard methods), is critical for assessing its metabolic availability. Discrepancies in calculated versus measured free testosterone can arise due to variations in SHBG and albumin levels, but these methods confirm that metabolism is driven by the free fraction.
††Stability in the Absence of Liver Insults
Yes, the hepatic metabolism of testosterone is expected to be stable in the absence of insults to the liver, such as injury or disease. The liver is a robust organ that efficiently processes testosterone under normal, healthy conditions. This metabolism occurs through two main phases:
- Phase I (Oxidation): Enzymes, primarily cytochrome P450 (CYP450), oxidize testosterone into metabolites like androsterone and etiocholanolone.
- Phase II (Conjugation): These metabolites are then conjugated (e.g., via glucuronidation or sulfation) to make them water-soluble for excretion.
Effect of Aging on Hepatic Metabolism
Aging itself does reduce the efficiency of hepatic metabolism of testosterone, but it’s important to clarify that aging is not typically considered a disease—it’s a natural physiological process. With advancing age, several changes in liver function can impact how testosterone is metabolized:
- Decreased Liver Volume and Blood Flow: As we age, the liver’s size and the blood flow it receives tend to decline, reducing its overall capacity to process substances, including testosterone.
- Reduced Enzyme Activity: There’s often a decrease in the activity of cytochrome P450 enzymes, which are critical for the phase I metabolism of testosterone.
- Slower Hepatic Clearance: Research suggests that aging leads to a reduced ability of the liver to clear testosterone from the bloodstream, meaning it’s metabolized less efficiently compared to younger individuals.
- In a Healthy Liver: Without insults like injury or disease, the hepatic metabolism of testosterone remains stable and effective.
- With Aging: Although aging isn’t a disease, it does impair the liver’s efficiency in metabolizing testosterone due to natural declines in liver volume, blood flow, and enzyme activity.
