What it the purpose of Sex Hormone Binding Globulin (SHBG) ?

My question might be a basic one, but what is the purpose of Sex Hormone Binding Globulin (SHBG)?

In general terms I appreciate that SHBG binds to Total Testosterone (along with Albumin) to give us Free Testosteron.

My question is not about what “normal values” of SHBG might be, it is more fundamental than that …… what does the body use the SHBG bound testosterone for?

Is SHBC the bodies method of reducing excess (perceived) free testosterone or …. ?

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Thread Summary:

The provided texts from the Excel Male TRT Forum explore the complex role of Sex Hormone Binding Globulin (SHBG) in male hormone health. Discussions center on its function in regulating testosterone bioavailability by binding to hormones like testosterone and estrogen, thereby influencing the levels of free and bioavailable testosterone. The forum addresses common misconceptions, particularly concerning how SHBG impacts total versus free testosterone in both natural physiology and during Testosterone Replacement Therapy (TRT). Additionally, the sources touch upon factors affecting SHBG levels, such as aging, liver conditions, thyroid issues, and other hormones, alongside potential interventions to manage them for optimal health.

 

@Nelson Vergel and @Cataceous
Can you find evidence for both theories/explanations (shbg on TRT etc)?

 

@Nelson Vergel and @Cataceous
Can you find evidence for both theories/explanations (shbg on TRT etc)?

The references were inbedded in the content:

NO TRT (normal physiology):

Sex hormone-binding globulin profoundly influences the distribution of testosterone between bound (inactive) and free (active) forms. Under normal physiological conditions, SHBG helps determine an individual’s total testosterone requirement by binding a consistent fraction of the hormone – if SHBG levels rise, the body elevates total T production to maintain adequate free T, and if SHBG falls, the body curtails production to prevent free T excess pure.amsterdamumc.nl In healthy men, this feedback mechanism leads to an inverse relationship between SHBG and endogenous T output, ensuring relative stability of free testosterone pure.amsterdamumc.nl clindiabetesendo.biomedcentral.com.

First PDF Attached Summary:

Summary of "Serum levels of sex hormone-binding globulin (SHBG) are not associated with lower levels of non-SHBG-bound testosterone in male newborns and healthy adult men"

Objective:
The study challenges the widely held belief that higher levels of sex hormone-binding globulin (SHBG) reduce the bioavailability of testosterone by lowering non-SHBG-bound testosterone (non-SHBG-T, i.e., free plus albumin-bound testosterone) in vivo. While in vitro models predict that increased SHBG should lower non-SHBG-T, the authors hypothesized that in living humans, especially those with an intact hypothalamo-pituitary-gonadal (HPG) axis, the relationship may be different due to feedback mechanisms affecting testosterone production and clearance.

Study Design and Participants:

Cross-sectional study of:

400 healthy adult men aged 40–80 years (divided into age decades)

106 male newborns (aged 1–6 months)

Both groups had measurements of SHBG, total testosterone, and calculated non-SHBG-T.

Key Methods:

Hormone levels measured using validated immunoassays.

Non-SHBG-T calculated using established formulas, assuming a fixed albumin concentration.

Linear regression and correlation analyses assessed relationships between SHBG, total testosterone, and non-SHBG-T, adjusting for age and BMI where appropriate.

Main Results:

In Newborns:

SHBG levels were much higher, and both total and non-SHBG-T were much lower than in adults.

SHBG was significantly positively associated with total testosterone but not associated with non-SHBG-T.

After adjusting for age, the association with non-SHBG-T remained statistically insignificant.

In Adult Men:

SHBG increased with age; both total and non-SHBG-T decreased with age.

SHBG was strongly positively associated with total testosterone across all age groups.

SHBG was not or only weakly positively associated with non-SHBG-T; any associations were minimal and sometimes statistically insignificant after adjustment for age and BMI.

The age-related increase in SHBG did not account for the age-related decline in non-SHBG-T.

Interpretation and Discussion:

Contrary to mathematical models, higher SHBG in vivo does not reduce non-SHBG-T in healthy males (newborns or adults); if anything, the association is slightly positive.

The HPG axis appears to compensate for changes in SHBG by adjusting testosterone production, maintaining non-SHBG-T within a narrow range.

The age-related decline in non-SHBG-T is not due to increased SHBG but likely due to other age-related changes in the HPG axis, such as altered feedback sensitivity and reduced Leydig cell responsiveness.

In neonates, the lack of association between SHBG and non-SHBG-T suggests a highly sensitive and functional HPG axis during early life.

Limitations:

Cross-sectional design limits causal inference.

Potential health selection bias in older adult participants.

Hormone assays in neonates may be less accurate at low concentrations, but findings are consistent with other studies.

Conclusion:

In both male newborns and healthy adult men, SHBG levels do not meaningfully reduce non-SHBG-bound testosterone levels.

The widespread assumption that higher SHBG lowers bioavailable testosterone in vivo is not supported in populations with an intact HPG axis.

Age-related increases in SHBG do not explain the decline of non-SHBG-T with age in healthy men.

Implications:

Clinical assessment of androgen status in men should consider that SHBG variations may not significantly impact bioavailable testosterone, especially in those with a healthy HPG axis.

Further research is needed to clarify the mechanisms behind age-related changes in testosterone bioavailability and HPG axis function.

 

On TRT:
"In all cases, bioavailable testosterone levels should also be monitored as testosterone therapy lowers SHBG".

The benefits and risks of testosterone replacement therapy: a review - PMC

Increased longevity and population aging will increase the number of men with late onset hypogonadism. It is a common condition, but often underdiagnosed and undertreated. The indication of testosterone-replacement therapy (TRT) treatment requires ...

pmc.ncbi.nlm.nih.gov

 

The references were inbedded in the content:
...

Yes, and the AI misinterpreted them, as shown in detail above.

To be honest, I do not see how Grok 3 would disagree that rules that apply to "normal physiology" not necessarily apply to men on TRT.
...

That's not what's being said. In the specific case of free testosterone and SHBG the same rules do apply, because selecting the dose rate under TRT is analogous to the body's direct regulation of free testosterone by altering its production rate of testosterone. In either case, free testosterone is virtually independent of SHBG.

@Nelson Vergel and @Cataceous
Can you find evidence for both theories/explanations (shbg on TRT etc)?

I and others have been laying out the case for this for years. It's all here in the forum, e.g. here is an earlier post.

 

@Cataceous
I meant if we had example cases it would be easier to comprehend. We both had a bit discussion about the topic and I think you are right. The details are hard to evaluate. E.g. some TRT clinics prescribe a dht derivative in order to increase free T by lowering shbg. They claim that is what happens, however, they never share the data. I believe they don't take into account that they added x amount of steroids, that is the influx of hormones increased. That's another topic though but I think that's what confuses people. A complete picture would include t, dht and e; bound and free.

 

@Cataceous
I meant if we had example cases it would be easier to comprehend. We both had a bit discussion about the topic and I think you are right. The details are hard to evaluate. E.g. some TRT clinics prescribe a dht derivative in order to increase free T by lowering shbg. They claim that is what happens, however, they never share the data. I believe they don't take into account that they added x amount of steroids, that is the influx of hormones increased. That's another topic though but I think that's what confuses people. A complete picture would include t, dht and e; bound and free.

In fact I recall at least two or three examples posted over the years, though I'd be hard pressed to find them. I believe @Gman86 was one of them. The idea is that a guy on TRT maintains that dosing while adding some other androgenic steroid. The outcome is typically a double whammy for SHBG. First, the higher androgenicity drives down production of SHBG, and second, if the steroid binds well to SHBG then that further lowers the effective level of SHBG. The key point is that after things settle down with the new protocol, free testosterone is found to be unchanged. This is because only the dose rate of testosterone is determining free testosterone.

Another post of mine with some technical references on this subject:

C

Post in thread 'Permanent crash of estrogen?'

May 31, 2024

... When Asked to provide medical evidence supporting some of his comments he can never do it

Let's see you cite some examples. In our last outing you stormed out without asking for evidence. But if you're asking now then I'm happy to share some other references that your friend readalot/tareload provided.

The basics are encapsulated in this quote:

However, as discussed in Chapter 5, unbound drug concentrations will not be affected by decreases in the protein binding of restrictively metabolized drugs. Therefore, no dosage alterations are required for these...​

• Cataceous

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Detailed Briefing: The Purpose and Role of Sex Hormone Binding Globulin (SHBG)​

This briefing reviews the multifaceted role of Sex Hormone Binding Globulin (SHBG) in the human body, particularly concerning testosterone regulation, based on the provided forum discussion and linked research excerpts. It aims to clarify its function, how it interacts with other hormones and binding proteins, and its implications for both normal physiology and Testosterone Replacement Therapy (TRT).

1. What is SHBG and Its Primary Function?​

SHBG is a protein primarily produced by the liver that binds to sex hormones, including testosterone, dihydrotestosterone (DHT), and estradiol, in the bloodstream. Its fundamental purpose is to regulate the transport, tissue delivery, bioactivity, and metabolism of testosterone and other sex steroids.

• Binding Affinity and Capacity: SHBG binds testosterone with high affinity, while human serum albumin (HSA) binds it with lower affinity but has a higher binding capacity due to its abundance. "Most circulating testosterone is bound to its cognate binding proteins—sex hormone−binding globulin (SHBG), human serum albumin (HSA), cortisol-binding globulin, and orosomucoid; these binding proteins play an important role in regulating the transport, tissue delivery, bioactivity, and metabolism of testosterone."
• Homodimer Structure: SHBG circulates as a homodimer, requiring calcium and zinc ions for its structural integrity. Each monomer has two laminin G-like (LG) domains that form pockets for hormone binding. The binding of androgens and estrogens imparts different conformations to the SHBG molecule.
• Production: While SHBG can be produced locally in the testes, uterus, and brain, "most circulating SHBG in humans is produced in the liver." Hepatic lipids, tumor necrosis factor-α, and interleukin-1 inhibit liver production of SHBG, while thyroid hormones indirectly increase it.

2. Testosterone Fractions and Bioavailability:​

Circulating testosterone exists in different forms, impacting its biological activity:

• Total Testosterone: The sum of all testosterone, whether bound or unbound.
• Free Testosterone: The fraction unbound to any plasma protein, considered biologically active as it can readily diffuse into cells and interact with androgen receptors. "Only 1% to 4% of circulating testosterone is unbound or free."
• Bioavailable Testosterone: The sum of free testosterone plus HSA-bound testosterone. "HSA-bound testosterone, which is bound with low affinity, can dissociate from HSA in the tissue capillaries and effectively be available for biological activity."
• SHBG-Bound Testosterone: Historically considered "locked away" and biologically inactive. However, emerging research suggests that "SHBG-bound testosterone may not be entirely inactive; certain tissues can internalize the SHBG-testosterone complex, making it bioavailable under specific conditions."

Key Point: Free testosterone is often a better indicator of how an individual feels than total testosterone alone, especially in clinical settings. "Many hormone-savvy doctors consider free T in the low range as evidence of possible hypogonadism, even if total T is 'normal.'"

3. SHBG's Regulatory Mechanisms and Beyond Passive Transport:​

SHBG is not merely a passive carrier; it actively participates in hormone regulation and may have other physiological roles:

• Stable Hormone Supply: SHBG helps ensure a steady supply of hormones, preventing rapid fluctuations.
• Protection and Transportation: It protects testosterone from immediate breakdown or excretion.
• Allosteric Binding: The binding of testosterone to SHBG is more complex than previously thought, involving an allosteric interaction where the two binding sites on the SHBG dimer are not equivalent and bind testosterone with different affinities. "The allosteric model of the multistep binding of testosterone to SHBG is discussed later in this review."
• Cellular Uptake: Beyond passive diffusion, SHBG may facilitate cellular steroid uptake through mechanisms like megalin-dependent endocytosis or via an SHBG receptor-testosterone system linked to G proteins and cAMP. "Binding proteins, such as SHBG, have been described as multifunctional proteins, capable of regulating the response to steroid hormones as well as their entry into cells."
• Tissue-Specific Rolesrostate: SHBG might bind to cell surface sites on prostate cells and activate intracellular signaling, though these receptors are not fully characterized.
• Endometrium: Interactions between SHBG and fibulin family members (fibulin-1D and fibulin-2) may contribute to SHBG's extravascular accumulation in the endometrial stroma, influencing sex steroid access to target cells. "These protein−protein interactions suggest additional regulation of the bioavailability of testosterone at the tissue level through tissue-binding proteins such as fibulins."
• Interactions with Other Factors: Magnesium has been shown to influence testosterone-SHBG affinity. "The change in magnesium levels inside the biological serum concentration range (0.75–0.95 mM) could lead to an enhancement of the Bio-T. In fact, the affinity of T to SHBG seems to change slightly with the magnesium concentration."

4. SHBG Levels and Clinical Implications:​

SHBG levels are influenced by various factors and have significant clinical implications:

• Hormonal Regulation: Estrogen stimulates SHBG production in hepatocytes, while androgens inhibit it. Thyroid hormones are also potent stimulators. "Sex hormone-binding globulin concentration in serum is under hormonal regulation and primarily regulated through opposing actions of sex steroids on hepatocytes: estrogen stimulates and androgen inhibits SHBG production."
• Normal Physiology vs. TRT:Normal Physiology: In healthy individuals, the hypothalamic-pituitary-gonadal (HPG) axis primarily regulates free testosterone levels. If SHBG increases, the HPG axis compensates by increasing total testosterone production to restore free testosterone to its setpoint. Therefore, in normal physiology, changes in SHBG primarily affect total testosterone, not steady-state free testosterone. "in normal physiology, free testosterone is what the body regulates, not total testosterone, and changes in SHBG levels primarily influence total testosterone rather than free testosterone."
• Testosterone Replacement Therapy (TRT): The situation changes with exogenous testosterone. TRT suppresses the HPG feedback loop, meaning the body's natural compensatory mechanisms are overridden. In this context, "SHBG shifts (often a decrease) directly translate to changes in free T without the usual compensatory production changes." A drop in SHBG during TRT can increase free testosterone and bioavailability.
• High SHBG:Causes: Aging, liver conditions (fatty liver, cirrhosis, cancer), hyperthyroidism, high estrogen levels, certain medications (HIV drugs, anticonvulsants), heavy alcohol use, chronic inflammation.
• Consequences: Lower free testosterone, leading to symptoms of low T (fatigue, decreased muscle gains, increased body fat, low libido, depressed mood, cognitive fog). High SHBG can also mask a low-T diagnosis, as total T might appear normal while free T is low.
• Management: Increasing testosterone output (exercise, weight loss), TRT (androgens tend to lower SHBG), treating underlying conditions (thyroid disorders, liver health), and certain supplements/medications (DHEA, boron). The goal is not to eliminate SHBG but to keep it in a healthy range.
• Low SHBG:Causes: Obesity and metabolic syndrome (often an early warning sign for type 2 diabetes), external androgens (anabolic steroids, TRT), genetic variations, high growth hormone, hypothyroidism, insulin treatment.
• Consequences: Can lead to a higher percentage of free T. While seemingly beneficial, extremely low SHBG can complicate testosterone management, causing rapid hormone fluctuations and side effects like acne, hair loss, or estrogenic effects due to high free androgen levels.
• Management: Addressing underlying health issues (diabetes, hypothyroidism), tailoring hormone therapy (smaller, more frequent dosing), and monitoring for side effects.
• Biomarker of Metabolic Risk: "In longitudinal analyses, SHBG levels rather than total or free testosterone levels have been independently and prospectively associated with incident diabetes and metabolic syndrome after adjustments for age, adiposity, and comorbid conditions." However, it's unclear if SHBG is merely a marker or plays a causal role in these disorders.

5. Challenges in Measurement and Interpretation:​

The understanding of sex steroid bioactivity and the roles of SHBG and HSA is more complex than previously believed.

• Inaccurate Models: "The oversimplified assumptions of stoichiometry, binding dynamics, and binding affinity have contributed to the development of inaccurate linear binding models, which have been propagated without much critical reappraisal until now." These traditional models and equations for calculating free testosterone may lead to misclassification of individuals.
• Need for Harmonization: "Harmonized reference ranges for free testosterone are needed to demarcate individuals who are eugonadal from those who are hypogonadal, acknowledging that different symptoms may have different thresholds."
• Beyond SHBG and HSA: Current computations of free and bioavailable testosterone often only account for HSA and SHBG, "ignoring CBG and orosomucoid and other potentially interacting proteins and steroid hormones."

In conclusion, SHBG is a critical and complex protein in men's hormonal health, far beyond a simple "binder." It plays a vital role in regulating testosterone's bioavailability, and its levels can serve as a biomarker for metabolic health. Clinicians and individuals seeking hormone optimization must consider SHBG levels alongside total and free testosterone to achieve optimal health outcomes, especially in the context of TRT, where the body's natural regulatory mechanisms are altered.

 

. SHBG Levels and Clinical Implications:​

SHBG levels are influenced by various factors and have significant clinical implications:
...

• Testosterone Replacement Therapy (TRT): The situation changes with exogenous testosterone. TRT suppresses the HPG feedback loop, meaning the body's natural compensatory mechanisms are overridden. In this context, "SHBG shifts (often a decrease) directly translate to changes in free T without the usual compensatory production changes." A drop in SHBG during TRT can increase free testosterone and bioavailability.
• High SHBG:Causes: Aging, liver conditions (fatty liver, cirrhosis, cancer), hyperthyroidism, high estrogen levels, certain medications (HIV drugs, anticonvulsants), heavy alcohol use, chronic inflammation.
• Consequences: Lower free testosterone, leading to symptoms of low T (fatigue, decreased muscle gains, increased body fat, low libido, depressed mood, cognitive fog). High SHBG can also mask a low-T diagnosis, as total T might appear normal while free T is low.
• ....

We've been discussing this for years now. SHBG has little influence on free testosterone. The shift to lower SHBG under TRT does not change free testosterone at steady state. Free testosterone is determined by the dose rate and the metabolic clearance rate constant. The same applies when SHBG goes higher; it does not reduce free testosterone, whether on TRT or not.

 

The same applies when SHBG goes higher; it does not reduce free testosterone, whether on TRT or not.

We have discussed that your statement only applies for men not on TRT.

 

We have discussed that your statement only applies for men not on TRT.

We went through it again just last month, in this thread a few posts back. Being on TRT is not relevant. Free testosterone is driven by the rate of testosterone entering the system:

C

Post in thread 'What it the purpose of Sex Hormone Binding Globulin (SHBG) ?'

May 3, 2025

The above statement is only true under "normal physiology." TRT does not represent "normal physiology".
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It also applies to TRT. Grok 3 again:

Conclusion​

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Given that testosterone metabolism follows first-order kinetics with respect to free testosterone, and at steady state the dose rate equals the elimination rate, the free testosterone level is indeed directly proportional to the dose rate. The law of mass action supports this, as metabolism depends on free testosterone concentration, and restrictive metabolism reinforces that only the free...​

• Cataceous