How to Raise or Lower SHBG: Complete Guide for Men on TRT

High SHBG reducing your free testosterone? This complete guide explains what SHBG is, optimal ranges for men on TRT, and proven ways to lower it.

By Nelson Vergel | ExcelMale.com | Updated December 2025
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When evaluating testosterone levels, most men focus exclusively on total testosterone—a single number that tells only part of the story. What many don't realize is that a protein called sex hormone binding globulin (SHBG) determines how much of that testosterone is actually available for your body to use. Understanding SHBG is essential for anyone on testosterone replacement therapy (TRT) or considering treatment, because it explains why two men with identical total testosterone levels can have dramatically different symptoms and responses to therapy.

This comprehensive guide explains what SHBG is, how it affects your hormone balance, what causes it to be high or low, and how to optimize your TRT protocol based on your SHBG status. Whether you're struggling with symptoms despite "normal" testosterone levels or trying to understand why your current protocol isn't working optimally, SHBG may hold the key.

What Is Sex Hormone Binding Globulin (SHBG)?​

Sex hormone binding globulin (SHBG) is a glycoprotein produced primarily by the liver that binds to and transports sex hormones through the bloodstream. Think of SHBG as a carrier protein that holds onto testosterone (and other sex hormones like estradiol and dihydrotestosterone) as they travel through your circulation.

The critical point is this: testosterone bound to SHBG is not available for your tissues to use. Only "free" testosterone—the small fraction not bound to any protein—can readily enter cells and activate androgen receptors. This is why measuring SHBG alongside total testosterone gives a much more accurate picture of your actual hormonal status.

How Testosterone Is Distributed in Your Blood​

In the general circulation, testosterone exists in three main fractions:
1. SHBG-Bound Testosterone (~44-65%): Tightly bound to SHBG with high affinity. This testosterone is essentially "locked up" and unavailable to tissues. It serves as a reservoir but cannot directly activate androgen receptors.
2. Albumin-Bound Testosterone (~33-54%): Loosely bound to albumin, the most abundant protein in blood. Because albumin binding is weak, this testosterone can dissociate and become available to tissues relatively easily. It's considered part of "bioavailable" testosterone.
3. Free Testosterone (~1-3%): Unbound testosterone that can immediately enter cells and exert biological effects. This is the most metabolically active fraction.
Bioavailable testosterone = free testosterone + albumin-bound testosterone. This represents the testosterone actually available for your body to use. When SHBG is high, more testosterone gets locked up; when SHBG is low, more testosterone remains bioavailable.

SHBG Binding Affinity for Different Hormones

Hormone​	Relative Binding Affinity​	Clinical Implication​
DHT	Highest (5x testosterone)	Most strongly bound; limited free DHT
Testosterone	High	Primary determinant of free T levels
Estradiol	Moderate (1/5 of testosterone)	More free E2 at low SHBG states
DHEA	Weak	Minimally affected by SHBG changes

Note: Because SHBG binds testosterone more tightly than estradiol, low SHBG states result in proportionally more free estradiol relative to free testosterone—a key consideration for men struggling with estrogen-related side effects on TRT.

How TRT Lowers SHBG Production (In Plain English)​

Think of it like this:

Your liver has a "master switch" called HNF4α that controls whether the SHBG factory is turned on or off. When testosterone levels are high (whether from TRT or natural production), testosterone tells this master switch to dial down SHBG production.

Here's the chain of events:

1. You inject testosterone (or your body produces more naturally)
2. Testosterone reaches your liver where it affects a protein called HNF4α - this protein acts like a factory manager that decides how much SHBG to make
3. High testosterone tells the factory manager to slow down - HNF4α activity decreases
4. Less factory manager activity = less SHBG gets made - your liver produces less SHBG protein

The indirect path:

Testosterone doesn't directly tell the SHBG gene "make less SHBG." Instead, it works through this middleman (HNF4α). It's like:

• Testosterone doesn't flip the SHBG switch directly
• Instead, it turns down the power to the factory manager
• The factory manager then makes less SHBG

Why this matters:

This explains why SHBG almost always drops when you start TRT—it's not a side effect, it's a predictable biological response. Your liver is simply responding to higher testosterone levels by making less of the protein that binds testosterone.

TRT Dose-Dependent Effect​

Higher doses → greater SHBG suppression:

• 50mg/week testosterone might lower SHBG modestly (10-20%)
• 200mg/week typically causes more significant suppression (30-50%)
• This is why men on higher TRT doses often have very low SHBG

Formulation Matters​

The degree of SHBG suppression varies by TRT formulation:

Injectable testosterone esters (especially short-acting):

• Create higher testosterone peaks
• More pronounced SHBG suppression
• Example: 200mg testosterone cypionate once weekly → significant SHBG drop

Transdermal gels/patches:

• More stable, physiological testosterone levels
• More modest SHBG reduction
• Less dramatic peak-driven suppression

Oral testosterone undecanoate:

• Also suppresses SHBG, similar to other formulations like intranasal or transdermal.

This Creates a Feedback Loop​

Starting TRT initiates a cascade:

1. Start TRT → Total T increases
2. SHBG decreases (over 4-12 weeks)
3. Free T percentage increases (less binding)
4. Net effect: Free T increases both from:
   • Higher total T (from TRT dose)
   • Lower SHBG (more unbound)

This is why some men need dose adjustments downward after SHBG has dropped—the initial dose that seemed "right" may produce excessive free testosterone once SHBG has been suppressed.

Clinical Example​

Before TRT:

• Total T: 300 ng/dL
• SHBG: 40 nmol/L
• Calculated free T: ~6 ng/dL

12 weeks after starting TRT (150mg/week):

• Total T: 800 ng/dL
• SHBG: 25 nmol/L (dropped 37.5%)
• Calculated free T: ~20 ng/dL

The free T increased more than you'd predict from the total T increase alone, because SHBG suppression created a "double boost."

Why This Matters​

Understanding TRT-induced SHBG suppression explains:

1. Why follow-up labs show lower SHBG - it's expected and normal
2. Why some men feel "too high" after 12 weeks - SHBG suppression wasn't factored into initial dosing
3. Why frequent injections may become MORE beneficial over time - as SHBG drops, buffering capacity decreases, making fluctuations larger
4. Why checking SHBG at follow-up is important - helps interpret free T changes

The Paradox for Low-SHBG Men​

Men who start TRT with already-low SHBG (say, 15 nmol/L due to metabolic syndrome) present a challenge:

• TRT will suppress their SHBG further (down to 10 or even single digits)
• This creates even less buffering capacity
• Making frequent injections essentially mandatory to avoid severe fluctuations

This is why the recommendation for daily or EOD injections in low-SHBG men becomes even more critical once they're on TRT—their SHBG will drop further, worsening the buffering problem.

Why SHBG Matters for Men on TRT​

The Hidden Cause of Symptoms Despite "Normal" Testosterone​

One of the most common frustrations in men's health is having symptoms of low testosterone while lab work shows "normal" total testosterone levels. SHBG often explains this paradox:
High SHBG Scenario: A man with total testosterone of 600 ng/dL but SHBG of 70 nmol/L may have free testosterone in the single digits—well below the reference range—and experience all the classic symptoms of hypogonadism: low libido, fatigue, difficulty building muscle, brain fog, and depressed mood. His "normal" total testosterone is misleading because most of it is bound and unavailable.
Low SHBG Scenario: Conversely, a man with total testosterone of 400 ng/dL but SHBG of 15 nmol/L may have free testosterone in the upper-normal range and feel fine—or he may struggle with estrogen-related side effects because low SHBG also means more free estradiol.

This is why the Endocrine Society and other professional organizations recommend measuring free testosterone (or calculating it from total testosterone and SHBG) when evaluating men for hypogonadism, particularly when total testosterone is borderline or when clinical presentation doesn't match lab values.

Normal SHBG Levels in Men​

Reference ranges vary by laboratory, but typical adult male SHBG ranges are:
SHBG Reference Ranges by Age

Age Group​	SHBG Range (nmol/L)​	Clinical Notes​
Young Adult Male (18-30)	10-57 nmol/L	Average ~30-35 nmol/L in healthy men
Middle-Aged Male (40-60)	18-76 nmol/L	SHBG tends to increase with age
Older Male (>60)	20-85+ nmol/L	Explains declining free T with age
Men on TRT	Often decreases	Exogenous T typically lowers SHBG

Important: A 2017 study in European Urology examining men seeking treatment at a men's health clinic found SHBG ranged from 6 to 109 nmol/L—nearly a 20-fold difference. This enormous variation underscores why SHBG testing should be routine for all men being evaluated for testosterone deficiency.

What Causes High SHBG?​

Elevated SHBG reduces bioavailable testosterone even when total testosterone appears normal. Understanding the causes can help identify correctable factors:

Medical Conditions​

• Hyperthyroidism: Excess thyroid hormone strongly increases SHBG production. Men with undiagnosed hyperthyroidism often present with low free testosterone symptoms.
• Liver Disease/Cirrhosis: Paradoxically, while the liver produces SHBG, cirrhosis often elevates SHBG levels through complex hormonal changes.
• HIV Infection: Associated with elevated SHBG, contributing to hypogonadal symptoms common in HIV-positive men.
• Anorexia/Severe Caloric Restriction: Extended caloric restriction raises SHBG significantly.

Medications and Substances​

• Anticonvulsants: Phenytoin, carbamazepine, and other anticonvulsants can increase SHBG substantially.
• Oral Estrogens: Oral estrogen therapy (including in transgender women) dramatically increases SHBG.
• Alcohol Use: Chronic alcohol consumption can elevate SHBG levels.

Age and Genetic Factors​

SHBG naturally increases with age—approximately 1-2% per year after age 40. Combined with declining testosterone production, this creates a "double hit" that explains why many older men have low free testosterone even with borderline-normal total testosterone. Genetic polymorphisms in the SHBG gene also contribute to individual variation.

What Causes Low SHBG?​

Low SHBG is increasingly common and is strongly associated with metabolic dysfunction.
Low SHBG does not mean more free testosterone is available, on average. Free testosterone is determined by the production rate, or the dose rate when under TRT. The grain of truth in the statement is that the reduced buffering capacity of low SHBG means transients in production or dosing produce larger, though short-lived excursions in free testosterone.
Low SHBG prior to TRT itself is often a marker of underlying health issues:

Metabolic Conditions​

• Obesity: Strong inverse relationship between BMI and SHBG. Visceral adiposity (belly fat) is particularly impactful. Weight loss typically raises SHBG.
• Insulin Resistance/Type 2 Diabetes: Hyperinsulinemia directly suppresses hepatic SHBG production. Low SHBG is an independent predictor of type 2 diabetes development—often appearing years before diagnosis.
• Metabolic Syndrome: The combination of central obesity, dyslipidemia, hypertension, and glucose intolerance is strongly associated with low SHBG. Research shows low SHBG independently predicts cardiovascular disease and metabolic syndrome.
• Non-Alcoholic Fatty Liver Disease (NAFLD): Hepatic steatosis impairs SHBG production.

Hormonal Factors​

• High Androgen Levels: Testosterone and other androgens suppress SHBG production. This is why SHBG typically decreases on TRT—exogenous testosterone feeds back to lower SHBG.
• Growth Hormone/IGF-1 Excess: Conditions like acromegaly lower SHBG.
• Hypothyroidism: Low thyroid hormone reduces SHBG production (opposite effect of hyperthyroidism).

Medications​

• Anabolic Steroids: Oral 17-alpha-alkylated steroids (like oxandrolone, stanozolol) dramatically lower SHBG by directly affecting liver production.
• Glucocorticoids: Chronic corticosteroid use (Cushing's syndrome or therapeutic) reduces SHBG.
• Certain Progestins: Some progestational agents lower SHBG levels.

Optimizing TRT Based on Your SHBG Status​

If You Have Low SHBG​

Men with low SHBG face unique challenges on TRT. Because SHBG acts as a "reservoir" for testosterone, low SHBG means:
• Total testosterone levels may appear lower than expected for a given dose
• Free testosterone may be high relative to total testosterone
• Testosterone clears more quickly, causing fluctuations
• Free estradiol may be disproportionately elevated, causing estrogen-related side effects
Protocol Recommendations: Most men with low SHBG do better with daily or every-other-day (EOD) injections of smaller testosterone doses. This maintains more stable blood levels and helps prevent the peaks that drive excessive aromatization to estradiol. Large, infrequent injections (e.g., 200mg once weekly) often cause significant fluctuations and side effects in low-SHBG men.
Address Underlying Causes: Because low SHBG is often a marker of metabolic dysfunction, addressing obesity, insulin resistance, and fatty liver can improve SHBG levels and overall health. Weight loss, improved diet, and better glucose control may naturally raise SHBG over time.

If You Have High SHBG​

Men with high SHBG often need higher testosterone doses to achieve adequate free testosterone levels. Their challenges include:
• Total testosterone may appear "normal" while free testosterone is low
• May require doses that push total testosterone above typical ranges to achieve symptom relief
• Less prone to estrogen-related side effects (SHBG also binds estradiol)
Protocol Recommendations: Higher weekly doses may be necessary. Some clinicians suggest that high-SHBG men can do well with once or twice weekly injections since the SHBG provides a buffer against fluctuations. However, response varies individually. The key metric is achieving adequate free testosterone levels for symptom resolution.
Evaluate Underlying Causes: Check thyroid function—hyperthyroidism is a common, treatable cause of elevated SHBG. Review medications that may be elevating SHBG. Consider liver function testing.

Strategies to Lower Elevated SHBG​

If high SHBG is limiting your response to TRT, several strategies may help:
1. Treat Underlying Conditions: Correct hyperthyroidism, address liver disease, discontinue medications that elevate SHBG if possible.
2. Increase Protein Intake: Higher protein diets are associated with lower SHBG levels. Vegetarian/vegan diets with low protein intake tend to increase SHBG.
3. Boron Supplementation: Some studies suggest boron (3-10mg daily) may modestly reduce SHBG, though evidence is mixed.
4. Stinging Nettle Root: May bind to SHBG and displace testosterone, though clinical evidence is limited.
5. Optimize Testosterone Dose: Exogenous testosterone itself lowers SHBG over time. Higher doses have greater SHBG-lowering effect, though this must be balanced against side effects.
6. DHT-Derived Compounds: In clinical settings, DHT-derived medications like proviron (mesterolone) or low-dose danazol can significantly lower SHBG. These require medical supervision.

Strategies to Raise Low SHBG​

Raising chronically low SHBG is more challenging than lowering high SHBG. The focus should be on addressing the metabolic dysfunction that typically underlies low SHBG:
1. Weight Loss: Losing excess body fat, particularly visceral fat, is the most effective way to raise SHBG. Even modest weight loss improves SHBG levels.
2. Improve Insulin Sensitivity: Exercise, dietary changes (reducing refined carbohydrates), and if needed, medications like metformin can improve insulin sensitivity and raise SHBG.
3. Reduce Alcohol Consumption: Moderating alcohol intake supports liver health and SHBG production.
4. Address Fatty Liver: NAFLD impairs SHBG production. Weight loss, dietary changes, and avoiding hepatotoxic substances can improve liver function.
5. Thyroid Optimization: Ensure thyroid function is normal—hypothyroidism lowers SHBG.
Important Note: Very low SHBG that doesn't respond to lifestyle interventions may simply be genetic. In such cases, focus on optimizing your TRT protocol (more frequent, smaller doses) rather than trying to change SHBG levels.

Testing SHBG: What You Need to Know​

SHBG should be part of any comprehensive hormone evaluation. Here's what to know about testing:
When to Test: SHBG should be measured at baseline before starting TRT and periodically during treatment (typically annually or when adjusting protocols). Test when total testosterone doesn't explain symptoms, when adjusting dosing, or when experiencing unexplained side effects.
Test Timing: Unlike testosterone, SHBG levels are relatively stable throughout the day and don't require early morning testing. However, testing alongside morning testosterone (before 10 AM) ensures all values are comparable.
Calculating Free Testosterone: With total testosterone, SHBG, and albumin values, free testosterone can be calculated using validated equations (like the Vermeulen equation). This calculated free testosterone correlates well with equilibrium dialysis, the gold-standard method.
Free Androgen Index (FAI): The ratio of total testosterone to SHBG (FAI = Total T / SHBG × 100) provides a quick estimate of androgenic activity. However, FAI becomes unreliable at extreme SHBG levels and should not substitute for calculated or measured free testosterone in clinical decision-making.

SHBG FAQ​

What is SHBG?​

SHBG (sex hormone-binding globulin) is a protein that binds testosterone in the blood. Bound testosterone is inactive; the unbound (free) fraction is what your tissues actually use. SHBG level determines how much of your total testosterone is free.

How do you increase SHBG?​

Improving insulin sensitivity and losing visceral fat raises SHBG, since low SHBG tracks with metabolic syndrome. Injection structure, thyroid status, and estrogen also influence it. Change one variable at a time and confirm with labs.

How do you lower SHBG?​

High SHBG is addressed by adjusting injection frequency and dose, managing thyroid output, and controlling estrogen. Do it gradually with lab monitoring so free testosterone does not overshoot.

What is a normal SHBG level for men?​

Most labs report a reference range of roughly 10 to 57 nmol/L. The more useful target is where your free testosterone lands, with SHBG as the context behind it.

Does injection frequency affect SHBG symptoms?​

Yes. Low-SHBG men clear testosterone faster and often feel better splitting the weekly dose into every-other-day or daily injections, which keeps levels steadier between shots.

Related reading: the testosterone dose calculator and the community thread how to increase SHBG when it is too low.

Conclusion: SHBG Is Essential to Understanding Your Testosterone Status​

Sex hormone binding globulin is far more than a technical footnote in hormone testing—it's a critical determinant of how much testosterone is actually available to your tissues. Men with identical total testosterone levels can have dramatically different symptoms and treatment responses based on their SHBG status.
For men on TRT or considering treatment, understanding your SHBG level helps explain why certain protocols work better than others and guides optimization. Low SHBG men typically benefit from frequent, smaller doses; high SHBG men often need higher overall doses to achieve adequate free testosterone.
Beyond TRT, SHBG provides valuable metabolic information. Low SHBG is an independent predictor of type 2 diabetes, metabolic syndrome, and cardiovascular disease—often appearing years before these conditions develop. Monitoring SHBG and addressing underlying causes like obesity and insulin resistance can improve both hormonal status and overall health.
The bottom line: if you're evaluating testosterone status or optimizing TRT, always measure SHBG. It transforms a one-dimensional total testosterone number into a meaningful assessment of your actual hormonal environment.

Related ExcelMale Forum Discussions​

Explore these community discussions for additional insights and real-world experiences:
• Sex Hormone Binding Globulin (SHBG): Is It Good or Bad? – Comprehensive overview of SHBG's role in men's health
• What Is the Purpose of Sex Hormone Binding Globulin (SHBG)? – Discussion of SHBG's biological functions
• How to Lower Your Sex Hormone Binding Globulin – Strategies for managing elevated SHBG
• How to Lower SHBG and Increase Free Testosterone – Practical approaches to optimizing free testosterone
• SHBG - Study Confirms Wide Variation in Serum Levels – Research supporting routine SHBG testing
• Injection Frequency Effect on SHBG – How dosing protocols impact SHBG levels
• Low SHBG Guys: Will Increasing Injection Frequency Make Any Difference? – Experiences with protocol adjustments for low SHBG
• Low SHBG = Lower Dosed, More Frequent Injections. Why? – Understanding the rationale for low-SHBG protocols
• Help Me Understand SHBG Levels and Injection Protocols – Guidance on matching protocols to SHBG status
• Minimum Dosage or Frequency for Low SHBG – Dosing strategies for men with low SHBG

Key References​

1. Goldman AL, Bhasin S, Wu FC, et al. A Reappraisal of Testosterone's Binding in Circulation. Endocrine Reviews. 2017. [PMC Full Text]
2. Kupelian V, et al. Association of Testosterone and SHBG With Metabolic Syndrome and Insulin Resistance. Diabetes Care. 2010. [PMC Full Text]
3. Ramachandran S, et al. TRT: Pre-treatment SHBG levels and age may identify clinical subgroups. Andrology. 2020. [PubMed]
4. Trost LW, Mulhall JP. SHBG and Total T Levels in Men with Adult Onset Hypogonadism. Cardiovasc Diabetol Endocrinol Rep. 2020. [Springer Full Text]
5. Daka B, et al. Inverse association between serum insulin and SHBG. Endocrine Connections. 2012.
6. Sex hormone-binding globulin changes with androgen replacement. J Clin Endocrinol Metab. [PubMed]
7. New Insights in the Diagnostic Potential of SHBG—Clinical Approach. Int J Mol Sci. 2024. [PMC Full Text]
8. MedlinePlus. SHBG Blood Test. [MedlinePlus]

Disclaimer: This article is for informational purposes only and does not constitute medical advice. SHBG interpretation should be done in the context of a comprehensive clinical evaluation. Hormone management requires individualized assessment by a qualified healthcare provider. Always consult your physician before making changes to your treatment protocol.

About ExcelMale.com: ExcelMale is a men's health forum with over 24,000 members and 20+ years of archived discussions on testosterone replacement therapy, hormone optimization, and sexual health. Founded by Nelson Vergel, author of Testosterone: A Man's Guide and Beyond Testosterone, ExcelMale provides evidence-based information and peer support for men navigating hormone health decisions.

 

SHBG (sex hormone binding globulin) controls how much testosterone is biologically active. What it is, why it matters, and how to raise or lower it naturally.

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 …. ?

_________________________________

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.

 

A Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications (2017)​

Anna L Goldman, Shalender Bhasin, Frederick C W Wu, Meenakshi Krishna, Alvin M Matsumoto, Ravi Jasuja


Essential Points

• 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

Binding proteins in the peripheral circulation are important in regulating the transport, bioavailability, and metabolism of their cognate ligands, such as steroid hormones, fatty acids, vitamins, and drugs. The major sex steroid hormones—testosterone, 5α-dihydrotestosterone, and 17β-estradiol—bind predominantly to sex hormone−binding globulin (SHBG) and to human serum albumin (HSA) and to a lesser extent to corticosteroid-binding globulin (CBG) and orosomucoid. SHBG, which is secreted by the liver, binds to testosterone with high affinity and is an important determinant of the distribution of circulating testosterone into its bound and free fractions (1). HSA is one of the most abundant and versatile proteins in circulation; although it binds testosterone with lower affinity than SHBG does, its high binding capacity and high concentration allow it to buffer fluctuations in testosterone levels (1). The characteristics of testosterone binding to CBG and orosomucoid and the biological roles of these binding proteins in regulating testosterone bioavailability remain incompletely understood.

Total testosterone refers to the sum of the concentrations of protein-bound and unbound testosterone in circulation. The fraction of circulating testosterone that is unbound to any plasma protein is referred to as the free testosterone fraction. The term bioavailable testosterone refers to the fraction of circulating testosterone that is not bound to SHBG and largely represents the sum of free testosterone plus HSA-bound testosterone (Fig. 1) (2); the term reflects the view that HSA-bound testosterone, which is bound with low affinity, can dissociate from HSA in the tissue capillaries and effectively be available for biological activity. The free testosterone fraction can be measured directly by the equilibrium dialysis or ultrafiltration method or calculated from total testosterone, SHBG, and HSA concentrations using published mass action binding algorithms (3–6). The bioavailable fraction can be measured using the ammonium sulfate precipitation method or the concanavalin A method, or it can be calculated from total testosterone, SHBG, and HSA concentrations (7). Although the pioneers who originated the concept of bioavailable testosterone envisioned it as the sum of HSA-bound and unbound fractions of circulating testosterone (2), the methods used to measure bioavailable testosterone concentrations, namely, the ammonium sulfate precipitation and concanavalin A methods, quantitate it as the non−SHBG-bound fraction of circulating testosterone, which approximates but is not equivalent to its original conceptualization as the sum of HSA-bound plus unbound testosterone levels (8).


Figure 1. Partitioning of testosterone in the systemic circulation. Circulating testosterone is bound tightly to SHBG (green = high-affinity binding) and weakly to albumin, orosomucoid (ORM), and CBG (blue = low-affinity binding) (11). Only 1% to 4% of circulating testosterone is unbound or free. The combination of free and albumin-bound testosterone is also referred to as the “bioavailable testosterone” fraction.

Biology of Binding Proteins and Their Role in the Transport, Distribution, Metabolism, and Bioavailability of Testosterone

At least four structurally distinct binding proteins are known to bind testosterone in human circulation: SHBG, HSA, CBG, and orosomucoid. Among these, SHBG has received the most attention because of its high binding affinity for testosterone. These binding proteins influence the tissue bioavailability and metabolic clearance rate of testosterone by regulating the amount of free testosterone available for biological action in the tissue. The roles of HSA, CBG, and orosomucoid in regulating testosterone’s bioavailability are less well understood, and we do not know how disease states or conditions that may differentially alter the circulating concentrations of HSA, CBG, and orosomucoid impact the binding of testosterone to SHBG. Current computations of free and bioavailable testosterone account only for the potential impact of alterations in HSA and SHBG, ignoring CBG and orosomucoid and other potentially interacting proteins and steroid hormones.




SHBG

SHBG, a homodimeric glycoprotein with a molecular mass of approximately 90 kDa (13), was first identified by Mercier et al. (14), who separated a testosterone-binding β-globulin by electrophoresis. An estradiol-binding protein was independently isolated the same year (15), and competitive steroid-binding studies showed that the two proteins were identical (16). Consequently, it became known as the testosterone-estradiol binding globulin. This binding protein has since been shown to bind to and act as a transport protein for other sex steroid hormones as well and is, therefore, more commonly known as the SHBG (4, 11).

The SHBG protein is encoded by a single gene on the short arm of chromosome 17, which includes eight exons (17). Three distinct promoters—PL, PT, and PN—can initiate transcription from three separate sites in exon 1, resulting in three variants: 1L, 1T, and 1N. The typical wild-type SHBG protein is the product of translation of a transcript produced under the influence of promoter PL and the other seven exons. A variant, SHBG-T, is missing exon 7 but includes the product of exon 1T produced under the influence of promoter PT (18).

SHBG circulates as a homodimer. Calcium and zinc ions are required for holding the dimer together (19); thus, chelating agents, such as EDTA, can dissociate the SHBG dimer. Each SHBG monomer contains two laminin G−like (LG) domains at the N-terminal end of the protein, encoded by exons 2 to 5 (20). These LG domains form pockets that enable the binding of sex hormones. The serine residue within this binding pocket is important in androgen and estrogen binding and forms hydrogen bonds with functional groups at the C3 position of the A ring of testosterone (21) and with the C17 hydroxyl group in the D ring of estradiol (22). Thus, the binding of androgens and estrogens imparts different conformations to the SHBG molecule. The SHBG protein contains three oligosaccharides; two oligosaccharides are attached at two N-glycosylation sites on asparagine and one at an O-glycosylation site on threonine (23). SHBG levels, which typically range from 10 to 56 nmol/L, can be measured using immunofluorometric and chemiluminescent assays or by dihydrotestosterone binding assays (24).

Although reports indicate that SHBG has been produced locally in the testes, uterus, and brain, most circulating SHBG in humans is produced in the liver. The product of the SHBG gene in the testes is called the androgen-binding protein, which has different oligosaccharides and is not secreted into the circulation. SHBG production in the liver is inhibited by hepatic lipids and by tumor necrosis factor-α and interleukin-1, rather than by insulin directly, which was reported previously (25). Thus, the low SHBG levels seen in obesity and diabetes are most likely the result of low-grade inflammation and increased amounts of hepatic lipids rather than high insulin levels (26). Selva and Hammond have shown that thyroid hormones increase SHBG production indirectly by increasing hepatocyte nuclear 4 alpha gene expression, which is a major regulator of SHBG transcription (27).

The distribution of SHBG-bound testosterone differs in men and women: In the presence of estradiol, about 20% of binding sites are occupied by testosterone (11). The reported association constant for binding of testosterone to SHBG has varied among published studies depending on the experimental conditions, but it is consistently reported to be around 1 × 109 L/mol with two binding sites on each SHBG homodimer (4, 5, 28–31). Known variants, including the rs6258, rs143521188, rs143269613, rs146779355, and rs373769356 polymorphisms, decrease affinity for testosterone and higher equilibrium dissociation constant (Kd) values (32, 33). Notably, previous binding studies have assumed that the two binding sites on the SHBG homodimer are equivalent. A recent reappraisal of testosterone binding to SHBG using modern biophysical techniques indicated that the two binding sites on the SHBG dimer are not equivalent and that there is an allosteric interaction between the binding sites on the SHBG dimer such that the second testosterone molecule binds SHBG with a substantially different affinity than the first binding site (34). The allosteric model of the multistep binding of testosterone to SHBG is discussed later in this review.




Additional Potential Roles of SHBG and Orosomucoid

The classic genomic signaling that mediates the biological actions of testosterone involves its passive diffusion into the cellular cytoplasm [Fig. 4(a)], association with the androgen receptor, translocation into the nucleus, and binding to the DNA response element to modulate transcription of specific androgen-responsive genes. Although passive diffusion is widely observed in multiple cell types, the globulin family proteins are postulated to facilitate cellular steroid uptake [Fig. 4(b)–4(d)]. 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 (13, 77–79). These binding proteins are also postulated to serve other functions, as described later (80–88).


Figure 4. Multiple hypothetical mechanisms for the cellular uptake of testosterone and downstream signaling. (a) The model depicts the “free” hormone hypothesis. In this model, testosterone (T) that is not bound to SHBG or HSA or other binding proteins diffuses across the plasma membrane and binds to the androgen receptor (AR). The liganded AR recruits coregulators and chaperone proteins translocate to the nucleus and bind to androgen response elements (AREs) on androgen-responsive target genes, which activates the transcription of target genes. (b) The megalin-dependent mode of testosterone entry. According to this model, SHBG-bound testosterone is internalized into the cell through an endocytic process mediated by the membrane protein megalin. Once internalized, SHBG-bound testosterone is released at the low pH within the lysosome. (c) The SHBG receptor-testosterone system. The SHBG dimer has multiple binding sites—two sites (simplified as one in this model) bind testosterone, and one site binds to a membrane receptor. It may be that only unbound SHBG is able to bind to the receptor, then the SHBG-receptor-testosterone complex is coupled to the activation of a G protein (GP), the accumulation of intracellular cyclic adenosine monophosphate (cAMP), and activation of protein kinase A (PKA). PKA may modulate AR function by activating AR through phosphorylation (not depicted) (92). (d) Steroid ligand2dependent interactions between SHBG and at least two matrix-associated proteins in the fibulin family (fibulin-1D and fibulin-2) contribute to the extravascular sequestration of SHBG in some tissues, such as the breast, prostate, and endometrial stroma. According to this model, ligand-dependent interactions between SHBG and fibulins modulate their binding to various signaling molecules, such as integrins, to modify signaling pathways that regulate cell adhesion, proliferation, and migration. mRNA, messenger RNA.

Potential role of SHBG in the prostate

In the 1990s, several investigators reported that SHBG might bind to cell surface binding sites on prostate cells and activate intracellular signaling on its own [Fig. 4(c)] (89–91). However, the cell surface receptors for SHBG have not been isolated or fully characterized. Therefore, we do not know whether SHBG has an independent role in regulating prostate growth or function. The postulated SHBG receptor−testosterone system, as well as the megalin-dependent transport of testosterone into the cell, are discussed in later sections [Fig. 4(b)].




Potential role of SHBG and fibulins in the endometrium

Fibulins are secreted glycoproteins in the blood and extracellular matrix that act as bridging peptides between elastin fibers and cell surface integrins and become incorporated into the fibrillar extracellular matrix. There are seven members of the fibulin family, each with a different biological role. Steroid hormone−dependent interactions between SHBG and at least two fibulin family members (fibulin-1D and fibulin-2) may contribute to the extravascular accumulation and distribution of SHBG within the endometrial stroma, where it has been reported to control sex steroid access to target cells (93). This interaction may provide a molecular scaffold for signaling molecules such as integrins and represents a new mechanism of steroid hormone action [Fig. 4(d)] (93–96). These protein−protein interactions suggest additional regulation of the bioavailability of testosterone at the tissue level through tissue-binding proteins such as fibulins.




Circulating SHBG level as a biomarker of metabolic risk

In epidemiologic studies, low total testosterone levels have been associated with increased risks of diabetes and metabolic syndrome, a cluster of conditions including hypertension, insulin resistance, central obesity, and dyslipidemia, which predispose individuals to an increased risk of cardiovascular disease. 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 (97, 98). Among children and adolescents, SHBG may also be a biomarker for metabolic syndrome risk (99), and lower levels were more robustly associated with the risk of metabolic syndrome in boys than in girls (100). We do not know whether SHBG is merely a marker of metabolic risk or whether SHBG plays a causal role in the pathophysiology of metabolic disorders such as diabetes and metabolic syndrome.




Role of orosomucoid in acute and chronic infections

Orosomucoid, an acute phase reactant, evolved from the immunoglobulin protein superfamily (101). Inflammatory modulators, such as cytokines and chemokines, influence the expression of the AGP gene and orosomucoid synthesis (102). Circulating orosomucoid concentrations are increased in the setting of infection (103, 104), and orosomucoid was recently established as an effective prognostic marker of the severity of sepsis (105). Orosomucoid plays an important role in the inflammatory response by inhibiting neutrophil migration in sepsis through a nitric oxide−dependent mechanism (103). It may also have a protective function by binding to lipopolysaccharide and enhancing its clearance from the body (106) and by inhibiting platelet aggregation to prevent hypercoagulability in sepsis (107, 108). Orosomucoid has also been reported to regulate the bioavailability of protease inhibitors in persons with chronic HIV infection (109), which may have important implications for therapeutic drug monitoring (110). Orosomucoid may play a similar role in the distribution and bioavailability of testosterone in persons infected with HIV or hepatitis C virus (HCV), who often display marked alterations in binding protein (Table 2) concentrations.

Synthesis​

Sex steroid bioactivity and the respective roles of SHBG and HSA are more complex than originally believed. 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 historical linear models and the resulting equations for calculating free testosterone based on these legacy models are widely used and may potentially increase the risk of misclassifying men seeking testosterone therapy. A novel multistep EAM of the binding of testosterone to SHBG provides a close approximation of free testosterone levels using equilibrium dialysis, but clinical experience with this new model is currently limited. 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. These steps would reduce the risk of disease misclassification and optimize clinical decision-making in the management of androgen disorders in men and women.

 

Classic and Novel SHBG effects on the Cardiovascular System in Men

In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone-binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid...

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SHBG: biomarker and hepatokine?

Over the past decade, there have been important breakthroughs in our understanding of the regulation and function of sex hormone-binding globulin (SHBG). A recent genome-wide association and Mendelian randomization study have provided new insights at the population level. A thorough study of...

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Estradiol induces Allosteric Coupling and Partitioning of Sex Hormone Binding Globulin Monomers Among Conformational States Ravi Jasuja, Daniel Spencer, Abhilash Jayaraj, Liming Peng, Meenakshi Krishna, Brian Lawney, Priyank Patel, B. Jayaram, Kelly M. Thayer, David L. Beveridge, Shalender...

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Allosterically coupled multi-site binding of testosterone to human serum albumin Abhilash Jayaraj, Heidi A. Schwanz, Daniel J. Spencer, Shalender Bhasin, James A. Hamilton, B. Jayaram, Anna L. Goldman, Meenakshi Krishna, Maya Krishnan, Aashay Shah, Zhendong Jin, Eileen Krenzel, Sashi N. Nair...

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C. Marc Luetjens and Gerhard F. Weinbauer


2.1 Introduction

Androgens are essential for the development and function of male reproductive organs, for example, maturation of secondary sexual characteristics, libido, and stimulation of spermatogenesis. Beyond that, androgens influence many somatic organ functions, which are covered in various chapters in this volume. In fact, a large number of organs express androgen receptors (Dankbar et al. 1995). Physiological effects of androgens depend on different factors such as the number of androgen molecules, distribution of androgens and their metabolites inside the cell, interaction with the receptors, polyglutamine number of the amino-acid sequence in the androgen receptor, and receptor activation (Palazzolo et al. 2008). In order to achieve sufficient exposure to androgens in target tissues, their peripheral and local levels must be well balanced and the transport mechanisms must be in place. Obviously, production and clearance/excretion rates must be in balance as well. The action of androgens in target cells depends on the number of steroids that can penetrate into the cells, the extent of metabolic conversions within the cells, the interactions with the receptor proteins, and, finally, upon the action of the androgen receptors at the genomic level. Unless mentioned specifically, this chapter refers to human data. It provides a timely overview of this topic and focuses on Leydig cells, regulation of Leydig cell function, steroidogenesis, transport and metabolism of testosterone, and genomic/non-genomic androgen actions. For more detailed and extensive descriptions on the various topics, the reader may also find the book The Leydig Cell in Health and Disease edited by Payne and Hardy (2007) useful.




2.4 Testosterone transport

During transport in plasma, testosterone is mainly bound to albumin or to SHBG which is produced by hepatocytes. Androgen-binding protein, with similar steroid-binding characteristics when compared to SHBG, is produced by Sertoli cells in the testis, and is a b-globulin consisting of different protein subunits. In rats, SHBG is expressed in Sertoli cells, secreted preferentially into the seminiferous tubules, and migrates into the caput epididymidis where it is internalized by epithelial cells and modulates androgen-dependent sperm maturation. Testicular SHBG isoforms are found in sperm and released from sperm during the capacitation reaction. Plasma SHBG has about 95 kDa molecular weight, 30% of which is represented by carbohydrates, and possesses one androgen binding site per molecule. Human testicular SHBG transcripts are expressed in germ cells and contain an alternative exon 1 sequence, appearing to encode an SHBG isoform that is 4–5 kDa smaller than plasma SHBG. The testosterone binding capacity is also much lower compared to the plasma SHBG (Selva et al. 2005). In normal men, only 2% of total testosterone circulates freely in the blood, while 44% is bound to SHBG and 54% to albumin. The binding affinity of testosterone to albumin is about 100 times lower compared to SHBG. However, since albumin concentration is far higher than that of SHBG, the binding capacity of both proteins for testosterone is approximately the same. The ratio of testosterone bound to SHBG over free SHBG is proportional to SHBG concentration. Direct measurement of free testosterone is impractical in routine practice so several equations are used to estimate the free testosterone concentration in serum (see Chapter 4).

Apparently, the dissociation of testosterone from binding proteins takes place predominantly in capillaries. The interaction of binding proteins with the endothelial glycocalyx leads to a structural modification of the hormonal binding site and thereby to a change in affinity. As a result, testosterone is set free and can diffuse freely into the target cell, or binds together with SHBG to megalin (Fig. 2.5), a cell importer protein (Hammes et al. 2005). Megalin is expressed in sex-steroid target tissues and is a member of the LDL receptor superfamily of endocytotic proteins. In the serum, 98–99.5% of the sex steroids are protein-bound, and endocytosis is quantitatively more relevant for tissue delivery of biologically active steroid hormones than free diffusion. To date several different ways have been described by which steroids can enter the target cells, and which of these are the most relevant pathways to take up the various steroid hormones is still being debated.

Sex hormone-binding globulin binds not only testosterone but also estradiol. The type of binding is influenced by the different SHBG isoforms, but generally, testosterone binds threefold higher than estradiol to SHBG. For example, it could be demonstrated that post-translational changes in the carbohydrate structure of SHBG can lead to different binding affinities of the protein to testosterone or estradiol. 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. Other hormones such as thyroid hormones are also potent stimulators of SHBG production. Sex hormone-binding globulin concentration in men is about one-third to one-half of the concentration found in women. In normal, healthy men with an intact hypothalamic-pituitary-testicular axis, an increase in plasma concentrations of SHBG leads to an acute decrease of free testosterone and simultaneous stimulation of testosterone synthesis, persisting until the achievement of normal concentrations.

Testosterone concentrations in the testicular lymphatic circulation and in the venous blood are very similar, but there are essential differences in the flow rate and velocity of both systems. Therefore, the transport of testosterone in the general blood circulation occurs mainly through the spermatic vein. Androgens diffuse into interstitial fluid and then enter testicular capillaries or enter capillaries directly from Leydig cells that are in direct contact with the testicular microvasculature. The mechanism for testosterone transport from the Leydig cell into the blood or lymph is not completely known. Probably lipophilic steroids distributed within cells or small cell groups are released through passive diffusion. On the other hand, mouse studies have raised the possibility of an active testosterone transport being important for spermatogenesis (Takamiya et al. 1998), showing that gangliosides-associated testosterone transport appeared necessary for complete spermatogenesis

Steroids such as pregnenolone, progesterone, and testosterone not only rapidly pass the Leydig cell membranes, but they can also equilibrate rapidly between different testicular compartments, and the testicular secretion pattern is most likely determined by amounts that are produced inside the tissue, the permeability characteristics of the membranes and the binding proteins in various testicular fluids (Rommerts 2004). As the blood flow is much higher than the flow of interstitial fluid, most of the unconjugated steroids diffuse from the interstitial space to the blood and leave the testis via venous blood. Estradiol is produced by Leydig cells, but the amount is small, with about 20% of peripheral aromatization (Rommerts 2004).




Manuela Simoni, Flaminia Fanelli, Laura Roli, and Uberto Pagotto

4.2 Testosterone, dihydrotestosterone, and sex hormone-binding globulin in blood

Testosterone and DHT circulate in serum largely bound to transport proteins: that is albumin, which displays low affinity but very high binding capacity, and SHBG, with high affinity and low capacity. A systematic analysis of serum transport of steroid hormones and their interaction with binding proteins revealed an association constant of SHBG of 1.6 X 10.9 M-1 for testosterone and of 5.5 X 10.9 M-1 for DHT at 37 °C (Dunn et al. 1981). By comparison, the association constant of albumin for testosterone is five orders of magnitude lower (6 X 10.4 M-1 ) (Anderson 1974). The relative amounts of protein binding of circulating testosterone in men and women are shown in Table 4.1.


Table 4.1 Transport of endogenous testosterone and DHT in male and female serum

*About 1.5–2% of serum testosterone is free and is believed to represent bioactive testosterone. Free and protein-bound testosterone and DHT are in equilibrium so that when the free hormone is subtracted from circulation because of entry into the tissue, new testosterone dissociates from albumin and SHBG, a new equilibrium is promptly reached, and the free-hormone concentration in serum remains constant

*Conversely, pathophysiological conditions causing changes in binding protein concentration (e.g. pregnancy, hypo or hyperthyroidism, growth hormone (GH) excess, treatment with antiepileptic drugs) or displacement of testosterone from SHBG by drugs (e.g. danazol) results in changes in total testosterone concentration in order to maintain constant free testosterone levels

 

Thanks Madman, as always a comprehensive answer.

I think we can sum up, the answer to my question is not a simple one.

Take away points:

1) 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

2) The characteristics of testosterone binding to CBG and orosomucoid and the biological roles of these binding proteins in regulating testosterone bioavailability remain incompletely understood.

 

*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 (13, 77–79)

*These binding proteins are also postulated to serve other functions, as described later (80–88)

*Sex steroid bioactivity and the respective roles of SHBG and HSA are more complex than originally believed

 

Thanks Madman

Now bear with me while I try explain my dilemma and form a question for you.

As we know more and more people are now aiming for a particular Free Testosterone value, rather than simply increasing their previously favoured Total Testosterone values. The reasons for this are taken as understold For the purpose of this discussion. Obviously there is still the very valid “how do you feel”, “don’t aim for a number” discussion going on …. But at an early point in suggesting a TRT protocol the FT value is being considered increasingly.

If SHBG regulates the amount of Free Testosterone according to the bodies perceived needs, surely the only way that an individual can increase his Free Testosterone is by supplementing his Total Testosterone to the point that the bodies production of SHBG is overwhelmed?

But, why does the body need to regulate testosterone after it has been produced … It would seem to be more efficient it it simply produced less in the first place? Perhaps production is a slow process and SHBG is a faster control method of control?

 

Thanks for this discussion and I agree with jacb that I wonder why high SHBG occurs and whether it is beneficial. By "high" I mean outside the reference range. Similarly, why does SHBG tend to rise as a man ages, what purpose is that serving? I am 67 and my high SHBG seems to impact my free testosterone so much that while my total T is right in the middle of the reference range, the free T is either below reference range or barely above it. This has been consistent over the several months I've had regular lab work with the recommended versions of tests from Discount Labs. A course of Clomid improved the numbers of my total T by a big margin, but also my SHBG by a notable margin, with the result being a minuscule impact on my free T. I realize that low SHBG is a serious problem, but I am very far away from that being an issue.

 

Thanks for this discussion and I agree with jacb that I wonder why high SHBG occurs and whether it is beneficial. By "high" I mean outside the reference range. Similarly, why does SHBG tend to rise as a man ages, what purpose is that serving? I am 67 and my high SHBG seems to impact my free testosterone so much that while my total T is right in the middle of the reference range, the free T is either below reference range or barely above it. This has been consistent over the several months I've had regular lab work with the recommended versions of tests from Discount Labs. A course of Clomid improved the numbers of my total T by a big margin, but also my SHBG by a notable margin, with the result being a minuscule impact on my free T. I realize that low SHBG is a serious problem, but I am very far away from that being an issue.

Hi Dudley

Have you seen

is "Enclomiphene Citrate” going to replace hCG in the USA?"

The discussion has touched on the effect of Clomid (Clomiphene, 60% enclomiphene & 40% zuclomiphene) and it would not seem to be a good way to go for a high SHBG because whilst Total Testosterone will increase, so will SHBG levels, resulting (at best) in only a small change inFree Testosterone values.

Regular IM/SubQ Testosterone would still see the way to go if hCG issues are not a factor?

If hCG factors are a concern then the thread above may be of interest and I draw your attention to a VIDEO which started this debate.

 

Thanks, jacb, I just watched the video and will ask my doc about enclomiphene citrate. But I am doubtful it would work as monotherapy for me. Clomid monotherapy worked only on paper, raising my total T quite a bit without reducing my symptoms. I didn't have the side effects others find difficult, but it didn't work. I still essentially had low T because my free T remained low. I am currently trying Natesto monotherapy but am not long enough into it yet to judge whether it's working. My doc's basic approach is for me to try the things that will least shut down my body's own production of T. So he started with Clomid; now Natesto; and if Natesto doesn't work for me, then we would try a compounded cream.

 

In the recent years biomolecular interactions between T, SHBG, and magnesium have been studied by high performance liquid chromatography (HPLC) [92]. Excoffon and colleagues [92] provided evidence of a magnesium-mediated variation in the T-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. Magnesium binds SHBG in a nonspecific mode, leading to an uncompetitive inhibition with T in binding SHBG and to a subsequent enhancement of Bio-T availability. The binding is accompanied by a magnesium release (or uptake) with a corresponding heat effect around in magnitude 17 kJ/mol [92].

The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men

The role of nutritional status as key factor of successful aging is very well recognized. Among the different mechanisms by which nutrients may exert their beneficial effects is the modulation of the hormonal anabolic milieu, which is significantly reduced with aging. Undernutrition and anabolic...

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Thanks for this insight, Vince. What would you recommend I try?

 

Thanks, jacb, I just watched the video and will ask my doc about enclomiphene citrate. But I am doubtful it would work as monotherapy for me. Clomid monotherapy worked only on paper, raising my total T quite a bit without reducing my symptoms. I didn't have the side effects others find difficult, but it didn't work. I still essentially had low T because my free T remained low. I am currently trying Natesto monotherapy but am not long enough into it yet to judge whether it's working. My doc's basic approach is for me to try the things that will least shut down my body's own production of T. So he started with Clomid; now Natesto; and if Natesto doesn't work for me, then we would try a compounded cream.

Thanks Dudley

If I understand correctly … I believe that Low T Nation thinks that there is a fundamental difference between the effects of Clomid compared with the effects of taking only Enclomiphene. In reality the difference will be due to the missing effect of zuclomiphene found in Clomid.

You talk about mono therapy and natural T production. Some people used to try hCG mono therapy. But HCG is now hard to find and even when fully stimulated your body may not have produced enough T’?

Clomid would have proved your potential to produce T’ ….. but it was not a good long term option because of the possible side effects and the fact that free testosterone was not increased because SHBG values were also elevated by the zuclomiphene.

Low T Nation are currently offering Enclomiphene to their clients saying that like Clomid it will elevate you natural T’ production to its maximum (which may or may not be sufficient) without significantly raising SHBG and because of that, you free T’ would also increase.

The jury is still out on what happens if you don’t produce enough T’ naturally while on Enclomiphene and wish to supplement with injected T’?

 

Thanks for this insight, Vince. What would you recommend I try?

ExcelMale - #1 TRT & Testosterone Forum | Expert-Moderated Men's Health Community

Magnesium is a common element that has many functions in the human body, from energy production to providing bone density. It is also necessary for cardiovascular health. In fact, this simple mineral has been shown in a German study to dramatically reduce both cardiovascular disease mortality...

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A new video about SHBG was recently posted on YouTube by Optimale in the UK.

I found it quite informative LINK

 

Sex Hormone Binding Globulin (SHBG): Appreciating Its Function in Men's Hormone Health

Overview


Sex hormone binding globulin (SHBG) is a protein frequently discussed in conversations about testosterone, libido, and muscle gain. If you’re on a testosterone treatment journey or active in fitness, you’ve likely encountered SHBG in the context of “free” versus “total” testosterone. Some see SHBG as a hindrance to muscle gains, while others recognize its essential biological role. This guide breaks down what SHBG is and why it matters for your health.

What Is SHBG?


SHBG is a protein produced primarily by the liver. It binds to sex hormones in your bloodstream-mainly testosterone, but also dihydrotestosterone and estrogen. Think of SHBG as a “taxi” for these hormones. Most testosterone in your blood is not free-floating; about two-thirds is tightly bound to SHBG, another one-third is loosely bound to albumin, and only about 2% or less is unbound (“free”).

Types of Testosterone in the Blood

• Total Testosterone: The sum of testosterone bound to SHBG, albumin, and the small free fraction.
• Free Testosterone: Not bound to any protein or only very loosely bound; this is the biologically active component.
• Albumin-Bound Testosterone: Loosely bound and considered “bioavailable” because it can dissociate and become available to tissues.
• SHBG-Bound Testosterone: Tightly bound and historically considered “locked away,” unable to directly produce effects while linked to SHBG.

Analogy:
If you have 100 units of testosterone:

• About 2 units are free and immediately active.
• About 30 units are carried by albumin, ready to be used.
• About 68 units are tightly bound to SHBG, held in reserve.

Why Free vs. Bound Testosterone Matters


Free testosterone enters cells, activates receptors, and supports muscle growth, energy, libido, mood, and metabolism. High SHBG can bind up much of your testosterone, leaving free T low even if total T is high, leading to symptoms of low testosterone (fatigue, poor gym performance, low libido, brain fog). Conversely, low SHBG can result in a higher percentage of free T, which can seem beneficial but may also bring its own challenges.


Key Point:
Free T is often a better indicator of how you feel than total T alone. SHBG levels greatly influence your free testosterone. Many hormone-savvy doctors consider free T in the low range as evidence of possible hypogonadism, even if total T is “normal.”

SHBG’s Role in the Body


SHBG isn’t just a “bad guy” that binds up testosterone. It serves several important functions:

• Stable Supply of Hormones: SHBG ensures a steady supply of hormones, preventing wild fluctuations.
• Protection and Transportation: SHBG and albumin transport testosterone through the bloodstream and protect it from immediate breakdown or excretion.
• Regulation of Hormone Availability: By controlling the ratio of free to bound hormone, SHBG regulates which tissues absorb testosterone.

Feedback and Bioavailability:
The endocrine system senses not just total hormone but also free hormone effects. Changes in SHBG can impact feedback mechanisms in the hypothalamus-pituitary-gonadal axis, maintaining hormonal equilibrium. Some studies suggest that SHBG-bound testosterone may not be entirely inactive; certain tissues can internalize the SHBG-testosterone complex, making it bioavailable under specific conditions.

High SHBG: Causes and Consequences


Causes of High SHBG:

• Aging: SHBG often rises with age, lowering free testosterone.
• Liver Conditions: Fatty liver, cirrhosis, or cancer can increase SHBG production.
• Thyroid Levels: Hyperthyroidism increases SHBG; hypothyroidism reduces it.
• Estrogen Levels: High estradiol (from obesity, certain drugs, or aromatization of testosterone) raises SHBG.
• Medications and Diet: Some medications (HIV drugs, anticonvulsants) and heavy alcohol use can increase SHBG.
• Body Composition & Metabolic Health: Obesity usually lowers SHBG, but some metabolic issues can paradoxically raise it.
• Chronic Inflammation: Linked to higher SHBG production.

Effects of High SHBG:

• Lower free testosterone
• Low energy
• Decreased muscle gains
• Increased body fat or difficulty losing fat
• Low libido or sexual dysfunction
• Depressed mood or cognitive fog

High SHBG can mask low-T diagnosis, as total T may appear normal while free T is low.

How to Lower SHBG

• Increase Testosterone Output: Exercise (especially resistance training) and weight loss can help.
• Testosterone Replacement Therapy (TRT): Androgens like testosterone tend to lower SHBG. Adjusting TRT protocols may help.
• Treat Underlying Conditions: Address thyroid disorders, liver health, and metabolic issues.
• Supplements and Medications: DHEA, boron, and certain drugs may lower SHBG, but use caution and consult a doctor.
• TRT Modalities: Different forms of testosterone (injections, creams, or orals) may affect SHBG differently.

Note:
The goal is not to eliminate SHBG but to keep it within a healthy range.

Low SHBG: Less Is Not Always More


What Defines Low SHBG?
The reference range for SHBG in adult men is usually 10–60 nmol/L. Low SHBG is considered below the low teens or single digits.


Causes of Low SHBG:

• Obesity and Metabolic Syndrome: Often linked to low SHBG and an early warning sign for type 2 diabetes.
• External Androgens: Use of anabolic steroids or TRT can reduce SHBG.
• Genetic Variations: Some men naturally have low SHBG.
• High Growth Hormone: Conditions like acromegaly can reduce SHBG.
• Low Thyroid Function: Hypothyroidism lowers SHBG.
• Medications: Insulin treatment and other hormonal medications can lower SHBG.

Is Low SHBG Always a Concern?
Not always. If a man feels well and has no health problems, low SHBG may not require intervention. However, if an underlying condition such as diabetes or obesity is causing low SHBG, it is important to address it. Extremely low SHBG can complicate testosterone management, causing rapid hormone fluctuations and side effects.


Managing Low SHBG:

• Address Underlying Health Issues: Treat diabetes, hypothyroidism, and other metabolic conditions.
• Tailor Hormone Therapy: Use smaller, more frequent dosing or different TRT modalities to avoid hormone spikes.
• Monitor for Side Effects: High free androgen levels can cause acne, hair loss, or estrogenic side effects.

Striking the Balance: Ideal SHBG for Performance and Health


Key Takeaways:

• Monitor SHBG alongside testosterone; it greatly influences how you feel and perform.
• Prioritize lifestyle: Exercise, diet, weight control, and moderate alcohol intake help optimize SHBG and testosterone.
• Individualize hormone therapy: Adjust TRT based on SHBG and free testosterone, not just total T.
• Listen to your body: symptoms matter more than numbers; work with a qualified medical practitioner for personalized advice.

Though less well-known than testosterone, SHBG is essential for men’s hormonal health. Rather than being a simple villain, SHBG is a regulator and transporter that maintains hormonal balance. Problems arise when SHBG is too high or too low relative to testosterone levels. By understanding and monitoring SHBG, you can make better decisions about diet, exercise, and hormone treatments to optimize your health and performance. The goal is not to have zero SHBG or sky-high SHBG, but to maintain a healthy balance that supports your best possible well-being.

 

...
Effects of High SHBG:

• Lower free testosterone

Battle of the AIs. This is Grok 3:

I agree with your assessment that in normal physiology, it’s a misconception to think that the level of Sex Hormone-Binding Globulin (SHBG) directly affects the amount of free testosterone. Here’s why:

Understanding SHBG and Testosterone

SHBG is a protein that binds to sex hormones, including testosterone, in the bloodstream. Testosterone exists in two main forms: bound testosterone (attached to SHBG or albumin) and free testosterone (unbound and biologically active). The total testosterone level is the sum of bound and free testosterone. Because free testosterone is the form that interacts with tissues and exerts physiological effects, it’s logical that the body prioritizes regulating this fraction rather than total testosterone.

Regulation of Free Testosterone

In normal physiology, the hypothalamic-pituitary-gonadal (HPG) axis regulates testosterone production based on feedback from free testosterone levels (and to some extent, free estradiol). The hypothalamus and pituitary gland sense free hormone levels—since these can cross the blood-brain barrier and interact with receptors—and adjust gonadotropin secretion to maintain free testosterone within a target range. Total testosterone, however, is not directly regulated and can vary depending on factors like SHBG levels.

How SHBG Fits In

SHBG influences the proportion of testosterone that is bound versus free. For example:

• If SHBG levels increase, more testosterone becomes bound, which could initially reduce free testosterone. However, the HPG axis compensates by increasing total testosterone production to restore free testosterone to its regulated level.
• If SHBG levels decrease, less testosterone is bound, potentially raising free testosterone temporarily. The body then reduces total testosterone production to maintain the free testosterone setpoint.

In both cases, the end result is that free testosterone remains stable in the steady state, while total testosterone adjusts based on SHBG levels. Thus, SHBG primarily affects total testosterone, not free testosterone, under normal conditions.
Addressing the Misconception
The misconception arises from assuming that SHBG directly dictates free testosterone levels or that total testosterone is a fixed, regulated entity. In reality:

• Total testosterone is not fixed: It fluctuates depending on SHBG and the body’s need to maintain free testosterone.
• SHBG’s effect is indirect: While SHBG binds testosterone, the body’s regulatory mechanisms counteract this to stabilize free testosterone, meaning SHBG doesn’t ultimately alter free testosterone levels in normal physiology.

Role of Estradiol Metabolites

You mentioned that estradiol metabolites can be involved in this regulation, which is accurate. Estradiol, derived from testosterone via aromatization, can influence SHBG production in the liver—higher estradiol levels tend to increase SHBG. This creates an interplay: elevated SHBG could bind more testosterone, but the HPG axis adjusts total testosterone production accordingly, keeping free testosterone steady. Thus, estradiol metabolites indirectly affect the system, reinforcing the focus on free testosterone regulation.

Caveats and Context

In normal physiology, this regulatory system works effectively, so SHBG levels don’t disrupt free testosterone. However, in pathological states (e.g., hyperthyroidism or liver disease), altered SHBG levels might challenge the body’s ability to compensate fully, potentially affecting free testosterone. But your query specifies normal physiology, where these compensatory mechanisms are intact.

Conclusion

Your assessment is correct: 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. The misconception lies in thinking SHBG directly alters free testosterone in a way that isn’t corrected by the body’s feedback systems. I fully agree with your reasoning.

 

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.

The above statement is only true under "normal physiology." TRT does not represent "normal physiology".

Also, TRT does not lead to "normal physiology" when talking about "high estradiol". Example: The use of "normal" estradiol ranges that were derived from normal physiology (TRT-free) are commonly used to wrongly justify using AIs to control "high estradiol" caused by higher T. Both are misconceptions.

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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.

During testosterone replacement therapy, the picture changes: exogenous testosterone suppresses the HPG feedback loop, and SHBG shifts (often a decrease) directly translate to changes in free T without the usual compensatory production changes clindiabetesendo.biomedcentral.com pmc.ncbi.nlm.nih.gov. A drop in SHBG will generally increase free testosterone levels and bioavailability, which can enhance the therapeutic effect but also necessitates careful monitoring pmc.ncbi.nlm.nih.gov medlineplus.gov. Clinicians differentiate between total and free testosterone to get a true sense of androgen status, especially in cases of atypical SHBG levels. Ultimately, SHBG serves as a crucial regulator of hormone action: it binds testosterone, modulates its half-life and tissue availability, and thereby interplays with the endocrine feedback systems that govern hormone balance. Understanding SHBG’s role allows for more nuanced interpretation of hormone levels and optimized management of conditions like hypogonadism and TRT, as evidenced by current endocrinology and urology literature clindiabetesendo.biomedcentral.com medlineplus.gov.

 

The above statement is only true under "normal physiology." TRT does not represent "normal physiology".
...

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 fraction is cleared. Factors like SHBG affect total testosterone but not the steady-state free testosterone, which is governed by the fixed dose rate and intrinsic clearance.​

Thus, I agree with the argument: in testosterone replacement therapy with a fixed dose rate, the free testosterone level at steady state is directly and proportionally driven by the dose rate.​

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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 ...
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This is awkwardly phrased and somewhat misleading. It's describing transient behavior, as if you injected some SHBG. But SHBG does not normally change rapidly. And as described in my previous post, in the new equilibrium free testosterone returns to what it was before the change in SHBG.

In healthy men, this feedback mechanism leads to an inverse relationship between SHBG and endogenous T output, ensuring relative stability of free testosterone ...

This is incorrect because it is reversing cause and effect. The inverse relationship exists because testosterone and other androgens suppress the production of SHBG. It's not that changes in SHBG drive changes in testosterone production; they don't at steady state. The body continues to regulate for its desired level of free testosterone/free estradiol.

During testosterone replacement therapy, ... SHBG shifts (often a decrease) directly translate to changes in free T without the usual compensatory production changes clindiabetesendo.biomedcentral.com pmc.ncbi.nlm.nih.gov. A drop in SHBG will generally increase free testosterone levels and bioavailability, which can enhance the therapeutic effect but also necessitates careful monitoring pmc.ncbi.nlm.nih.gov medlineplus.gov. ...

This is incorrect. As noted at the beginning of this post, in TRT the dose of testosterone directly determines free testosterone. Higher testosterone may gradually drive SHBG lower, but this is independent of free testosterone, which is instead controlled by the dose rate and underlying metabolism.

If this is ChatGPT then it should not be relied on for information on this subject. Grok 3 seems to do much better.