Nelson Vergel
Founder, ExcelMale.com
ExcelMale Consensus
Yes. Markedly elevated sex hormone-binding globulin, or SHBG, sometimes produces a normal, high-normal, or above-range total testosterone result while free testosterone stays low. In a symptomatic man with unusual SHBG, free testosterone plus LH and FSH often gives a clearer picture of testicular function than total testosterone alone.
A prospective 2026 study offers one of the clearest human examples so far. Among 20 men selected for markedly elevated SHBG and low free testosterone, 15 had elevated LH and/or FSH plus symptoms or signs consistent with primary hypogonadism. Twelve of those 15 had total testosterone above 450 ng/dL, and four had total testosterone above 916 ng/dL.
[/QUOTE]
A man with fatigue, lower sexual function, or other symptoms associated with androgen deficiency might receive a reassuring total testosterone result and stop the evaluation there. Markedly elevated SHBG changes the meaning of the total number.
The 2026 study gives clinicians and patients a useful example of why the relationship among total testosterone, free testosterone, SHBG, LH, and FSH matters more than one isolated result.
High SHBG binds a larger share of circulating testosterone, so total testosterone sometimes rises without a similar rise in the unbound fraction.
Most circulating testosterone is bound to SHBG or albumin. Only a small fraction circulates as free testosterone. SHBG binds testosterone with high affinity, and changes in SHBG alter the relationship between total and free testosterone.
In many men, the hypothalamic-pituitary-testicular axis compensates. The pituitary raises LH, the testes produce more testosterone, and free testosterone stays within range. Total testosterone often rises during this compensation because more hormone is held in the SHBG-bound pool.
The problem appears when testicular reserve is inadequate. LH rises, but the testes fail to produce enough additional testosterone to maintain free testosterone. Total testosterone might still look normal or high because SHBG remains elevated.
This creates the paradox. An impressive total testosterone result might sit beside biochemical evidence of inadequate androgen production.
The 2026 study found primary testicular insufficiency in men whose total testosterone ranged from low to well above the laboratory reference range.
Researchers evaluated 20 men with SHBG above 100 nmol/L and low free testosterone. Fifteen met the study criteria for primary hypogonadism based on low free testosterone, symptoms or signs, and elevated LH and/or FSH.
The laboratory reference range for total testosterone was 264 to 916 ng/dL. The adult free testosterone reference range was 66 to 309 pg/mL, with age-specific lower limits used in the analysis.
Total testosterone was measured with CDC Hormone Standardization-certified LC-MS/MS. Free testosterone was measured by standardized equilibrium dialysis followed by LC-MS/MS.
The primary hypogonadism group had mean SHBG of 105.3 nmol/L, mean total testosterone of 682 ng/dL, mean free testosterone of 33 pg/mL, mean LH of 14 IU/L, and mean FSH of 25 IU/L.
Read the study here:
Hormonal Profiles of Men with Highly Elevated SHBG and Primary Testicular Dysfunction Support Free Hormone Hypothesis
Four men had total testosterone above 916 ng/dL while free testosterone stayed below the study reference limit and gonadotropins were elevated.
Their total testosterone values were 1,189, 1,094, 1,054, and 1,057 ng/dL.
Their free testosterone values were 45.4, 41.0, 41.9, and 54.5 pg/mL.
Three of the four had gynecomastia.
Those numbers make the clinical problem easy to see. A clinician who viewed only total testosterone might interpret these men as having abundant androgen exposure. Free testosterone and pituitary feedback pointed in the opposite direction.
Elevated LH and FSH show that the pituitary is pushing the testes harder, which supports primary testicular dysfunction when free testosterone is low.
LH stimulates Leydig cells to produce testosterone. FSH reflects the Sertoli cell and spermatogenic side of testicular function. When testicular output falls, reduced negative feedback allows LH and FSH to rise.
The Endocrine Society recommends LH and FSH measurement to distinguish primary from secondary hypogonadism after biochemical androgen deficiency is identified.
A useful interpretation pattern is:
This is why the 2026 study is clinically interesting. The symptom questionnaires alone were not the strongest evidence. Elevated gonadotropins provided independent physiologic evidence that the reproductive axis was responding as if androgen output were inadequate.
Read the Endocrine Society Clinical Practice Guideline on Testosterone Therapy in Men With Hypogonadism
No. The study strongly supports the free hormone hypothesis in a selected high-SHBG group, but its small sample and cross-sectional design do not settle every question about testosterone transport and tissue action.
The free hormone hypothesis proposes that unbound hormone crosses cell membranes and drives biologic action, while protein-bound hormone mainly serves as a circulating reservoir.
Testosterone biology is more complex because albumin and SHBG binding are dynamic. Research continues on how bound fractions contribute to delivery and signaling.
A 2025 Journal of Clinical Endocrinology & Metabolism debate illustrates the remaining disagreement over how much clinical weight free testosterone deserves.
Debate About the Free Testosterone Hypothesis: Useful Tool or Misguided Mirage?
The practical point is narrower. When SHBG is markedly elevated, total testosterone might no longer represent testosterone availability in the same way as in a man with ordinary SHBG.
The 2026 data support using free testosterone and gonadotropins to resolve this mismatch rather than dismissing symptoms because total testosterone is normal or high.
Free testosterone deserves added attention when total testosterone and the clinical picture disagree or when SHBG is substantially abnormal.
The Endocrine Society recommends morning fasting total testosterone as the initial biochemical test in most men, repeated on a separate morning before diagnosis.
When total testosterone is near the lower limit or a condition alters SHBG, the guideline recommends free testosterone by equilibrium dialysis or an accurate calculation.
Direct analog free testosterone immunoassays are discouraged because binding-protein changes distort their results.
Situations linked with higher SHBG include:
Lower SHBG also changes interpretation, especially in obesity, insulin resistance, type 2 diabetes, and hypothyroidism.
For a broader explanation of hormone testing, see:
How to Read Your TRT Blood Panel: Every Marker Explained
Testosterone Assays: Understanding Total and Free Testosterone Testing
High SHBG in men is associated with aging, liver disease, hyperthyroidism, HIV, several medications, estrogen exposure, and genetic variation.
The cause matters because SHBG is a binding protein, not a diagnosis.
A high result should prompt a review of thyroid function, liver health, medications, nutritional status, alcohol exposure, chronic illness, and relevant clinical history.
The 2026 investigators described their high-SHBG group as a natural experiment because extreme binding created a large separation between total and free testosterone.
This observation does not mean every mildly elevated SHBG result produces clinically important androgen deficiency.
A practical evaluation starts with the reason for the high SHBG and then asks whether free testosterone and the HPT axis show evidence of inadequate compensation.
Standardized equilibrium dialysis paired with a high-quality testosterone assay is the strongest direct laboratory approach when SHBG is markedly abnormal.
Free testosterone measurement has a long history of poor standardization. Assays differ in calibration, dialysis conditions, temperature, membrane characteristics, and downstream testosterone measurement.
These differences create reference-range confusion across laboratories.
A 2023 study established reference intervals using a standardized equilibrium dialysis procedure plus CDC-certified LC-MS/MS.
In healthy nonobese adult men, the reported free testosterone interval was 66 to 309 pg/mL. Men aged 19 to 39 had a higher interval of approximately 120 to 368 pg/mL.
Reference Intervals for Free Testosterone in Adult Men Measured Using a Standardized Equilibrium Dialysis Procedure
The key lesson is to interpret the result against the method-specific reference range. A free testosterone number without knowing the assay method has limited value.
For more technical detail:
Optimized Direct Equilibrium Dialysis for Free Testosterone Analysis by LC-MS/MS
Yes. A validated calculation is useful when total testosterone, SHBG, and albumin are measured accurately, especially when direct equilibrium dialysis is unavailable.
Calculated free testosterone is an estimate based on binding assumptions. Extreme SHBG levels expose differences among equations because the models do not handle testosterone binding in exactly the same way.
Recent work on SHBG and albumin binding also shows that older simplified binding models do not capture every aspect of testosterone transport.
For routine clinical care, a well-validated calculation remains more useful than a direct analog free testosterone immunoassay.
In an unusual high-SHBG case where the diagnosis remains uncertain, standardized equilibrium dialysis offers stronger evidence.
ExcelMale also has a detailed discussion of calculated hormone values:
A Novel Spreadsheet Method for Calculating Free Testosterone, Free DHT, and Free Estradiol
Low free testosterone together with elevated LH or FSH is the key biochemical pattern suggesting primary testicular dysfunction when total testosterone looks normal or high.
This table is a framework rather than a diagnostic rule.
Testosterone testing should be repeated when appropriate. Symptoms need clinical evaluation. Abnormal thyroid, liver, pituitary, medication, sleep, nutritional, or systemic factors also deserve attention.
Primary testicular insufficiency is broader than testosterone production. Elevated FSH, testicular history, fertility status, prior chemotherapy or radiation, injury, infection, genetic conditions, and testicular examination provide additional context.
No. A normal total testosterone does not reliably rule out biochemical testosterone deficiency when SHBG is substantially abnormal.
This exception should not be stretched into a claim that total testosterone lacks value.
Total testosterone remains the recommended first-line test for most men because standardized assays are widely available and total testosterone usually tracks androgen status reasonably well.
The concern arises when binding proteins distort the relationship.
Earlier European Male Ageing Study data also found hypogonadal signs and symptoms in men with low calculated free testosterone despite normal total testosterone.
Low Free Testosterone Is Associated With Hypogonadal Signs and Symptoms in Men With Normal Total Testosterone
The 2026 study adds a more extreme example. Some men had total testosterone above 1,000 ng/dL while free testosterone stayed low and gonadotropins were elevated.
Men usually want to know whether a high total testosterone result rules out a problem, what SHBG level matters, and which free testosterone test deserves trust.
Yes. Four men in the 2026 study had total testosterone above 916 ng/dL, including values above 1,000 ng/dL, while free testosterone remained low and LH or FSH was elevated.
The 2026 study selected men with SHBG above 100 nmol/L. The study laboratory reference range was 13 to 71 nmol/L.
There is no universal SHBG cutoff where total testosterone suddenly becomes unreliable. Interpretation depends on assay methods, free testosterone, gonadotropins, age, symptoms, and the clinical setting.
No. Many men compensate by producing more testosterone, which preserves normal free testosterone despite higher SHBG.
Low free testosterone becomes more concerning when the pituitary is already increasing LH or FSH and compensation is still inadequate.
Yes. Endocrine Society guidance supports free testosterone assessment when a condition alters SHBG or when total testosterone sits near the lower reference limit.
The result should come from equilibrium dialysis or a validated calculation rather than a direct analog free testosterone immunoassay.
Yes. Standardized equilibrium dialysis is the reference direct method, while direct analog immunoassays are inaccurate when binding proteins vary and are not recommended by the Endocrine Society.
ExcelMale has several related discussions for readers who want assay details, reference ranges, and broader TRT laboratory context.
A high total testosterone result sometimes deserves more scrutiny when SHBG is markedly elevated.
The 2026 study changes the clinical conversation because the strongest signal did not come from symptom questionnaires. The strongest signal came from the men’s own gonadotropins.
LH and FSH stayed elevated despite total testosterone values well above levels usually considered reassuring.
For men with high SHBG, the useful question is not whether total testosterone looks good in isolation. The useful question is whether free testosterone, LH, FSH, symptoms, and the clinical setting tell one coherent story.
Nelson Vergel, B.S. Chemical Engineering, MBA, is founder of ExcelMale.com, a men’s health educator, patient advocate, and author. His work includes more than three decades of personal TRT experience, service on NIH and FDA advisory panels, and books including Testosterone: A Man’s Guide, Beyond Testosterone, The hCG Advantage, and The Peptide Consensus.
Updated August 26, 2026.
ExcelMale is a men’s health forum with more than 24,000 members and over 20 years of archived discussions on testosterone replacement therapy, sexual health, blood testing, fertility, peptides, metabolic health, and related topics.
The forum combines peer discussion with research summaries, clinical education, and practical experience from men who have spent years monitoring hormone therapy and health outcomes.
Yes. Markedly elevated sex hormone-binding globulin, or SHBG, sometimes produces a normal, high-normal, or above-range total testosterone result while free testosterone stays low. In a symptomatic man with unusual SHBG, free testosterone plus LH and FSH often gives a clearer picture of testicular function than total testosterone alone.
A prospective 2026 study offers one of the clearest human examples so far. Among 20 men selected for markedly elevated SHBG and low free testosterone, 15 had elevated LH and/or FSH plus symptoms or signs consistent with primary hypogonadism. Twelve of those 15 had total testosterone above 450 ng/dL, and four had total testosterone above 916 ng/dL.
[/QUOTE]
A man with fatigue, lower sexual function, or other symptoms associated with androgen deficiency might receive a reassuring total testosterone result and stop the evaluation there. Markedly elevated SHBG changes the meaning of the total number.
The 2026 study gives clinicians and patients a useful example of why the relationship among total testosterone, free testosterone, SHBG, LH, and FSH matters more than one isolated result.
How Does High SHBG Produce Low Free Testosterone?
High SHBG binds a larger share of circulating testosterone, so total testosterone sometimes rises without a similar rise in the unbound fraction.
Most circulating testosterone is bound to SHBG or albumin. Only a small fraction circulates as free testosterone. SHBG binds testosterone with high affinity, and changes in SHBG alter the relationship between total and free testosterone.
In many men, the hypothalamic-pituitary-testicular axis compensates. The pituitary raises LH, the testes produce more testosterone, and free testosterone stays within range. Total testosterone often rises during this compensation because more hormone is held in the SHBG-bound pool.
The problem appears when testicular reserve is inadequate. LH rises, but the testes fail to produce enough additional testosterone to maintain free testosterone. Total testosterone might still look normal or high because SHBG remains elevated.
This creates the paradox. An impressive total testosterone result might sit beside biochemical evidence of inadequate androgen production.
What Did the 2026 High-SHBG Study Find?
The 2026 study found primary testicular insufficiency in men whose total testosterone ranged from low to well above the laboratory reference range.
Researchers evaluated 20 men with SHBG above 100 nmol/L and low free testosterone. Fifteen met the study criteria for primary hypogonadism based on low free testosterone, symptoms or signs, and elevated LH and/or FSH.
The laboratory reference range for total testosterone was 264 to 916 ng/dL. The adult free testosterone reference range was 66 to 309 pg/mL, with age-specific lower limits used in the analysis.
Total testosterone was measured with CDC Hormone Standardization-certified LC-MS/MS. Free testosterone was measured by standardized equilibrium dialysis followed by LC-MS/MS.
| Group | Number of Men | Total Testosterone | Mean Free Testosterone | Mean LH | Mean FSH |
|---|---|---|---|---|---|
| 1A | 4 | Above 916 ng/dL | 45.7 pg/mL | 9.7 IU/L | 15.3 IU/L |
| 1B | 8 | 450-916 ng/dL | 32.2 pg/mL | 14.1 IU/L | 21.6 IU/L |
| 1C | 3 | Below 450 ng/dL | 17.7 pg/mL | 20.4 IU/L | 49.0 IU/L |
The primary hypogonadism group had mean SHBG of 105.3 nmol/L, mean total testosterone of 682 ng/dL, mean free testosterone of 33 pg/mL, mean LH of 14 IU/L, and mean FSH of 25 IU/L.
Read the study here:
Hormonal Profiles of Men with Highly Elevated SHBG and Primary Testicular Dysfunction Support Free Hormone Hypothesis
How Extreme Was the Mismatch in Men With Total Testosterone Above 916 ng/dL?
Four men had total testosterone above 916 ng/dL while free testosterone stayed below the study reference limit and gonadotropins were elevated.
Their total testosterone values were 1,189, 1,094, 1,054, and 1,057 ng/dL.
Their free testosterone values were 45.4, 41.0, 41.9, and 54.5 pg/mL.
Three of the four had gynecomastia.
Those numbers make the clinical problem easy to see. A clinician who viewed only total testosterone might interpret these men as having abundant androgen exposure. Free testosterone and pituitary feedback pointed in the opposite direction.
Why Do LH and FSH Matter When SHBG Is High?
Elevated LH and FSH show that the pituitary is pushing the testes harder, which supports primary testicular dysfunction when free testosterone is low.
LH stimulates Leydig cells to produce testosterone. FSH reflects the Sertoli cell and spermatogenic side of testicular function. When testicular output falls, reduced negative feedback allows LH and FSH to rise.
The Endocrine Society recommends LH and FSH measurement to distinguish primary from secondary hypogonadism after biochemical androgen deficiency is identified.
A useful interpretation pattern is:
- Low free testosterone plus elevated LH or FSH points toward primary testicular dysfunction.
- Low free testosterone plus low or inappropriately normal LH and FSH points toward secondary or functional hypogonadism and deserves a different evaluation.
- High SHBG plus normal free testosterone and normal gonadotropins suggests compensation is preserving androgen availability.
This is why the 2026 study is clinically interesting. The symptom questionnaires alone were not the strongest evidence. Elevated gonadotropins provided independent physiologic evidence that the reproductive axis was responding as if androgen output were inadequate.
Read the Endocrine Society Clinical Practice Guideline on Testosterone Therapy in Men With Hypogonadism
Does the 2026 Study Prove the Free Hormone Hypothesis?
No. The study strongly supports the free hormone hypothesis in a selected high-SHBG group, but its small sample and cross-sectional design do not settle every question about testosterone transport and tissue action.
The free hormone hypothesis proposes that unbound hormone crosses cell membranes and drives biologic action, while protein-bound hormone mainly serves as a circulating reservoir.
Testosterone biology is more complex because albumin and SHBG binding are dynamic. Research continues on how bound fractions contribute to delivery and signaling.
A 2025 Journal of Clinical Endocrinology & Metabolism debate illustrates the remaining disagreement over how much clinical weight free testosterone deserves.
Debate About the Free Testosterone Hypothesis: Useful Tool or Misguided Mirage?
The practical point is narrower. When SHBG is markedly elevated, total testosterone might no longer represent testosterone availability in the same way as in a man with ordinary SHBG.
The 2026 data support using free testosterone and gonadotropins to resolve this mismatch rather than dismissing symptoms because total testosterone is normal or high.
When Should Free Testosterone Receive More Attention Than Total Testosterone?
Free testosterone deserves added attention when total testosterone and the clinical picture disagree or when SHBG is substantially abnormal.
The Endocrine Society recommends morning fasting total testosterone as the initial biochemical test in most men, repeated on a separate morning before diagnosis.
When total testosterone is near the lower limit or a condition alters SHBG, the guideline recommends free testosterone by equilibrium dialysis or an accurate calculation.
Direct analog free testosterone immunoassays are discouraged because binding-protein changes distort their results.
Situations linked with higher SHBG include:
- Aging
- HIV
- Cirrhosis or hepatitis
- Hyperthyroidism
- Some anticonvulsants
- Estrogen exposure
- SHBG gene variants
Lower SHBG also changes interpretation, especially in obesity, insulin resistance, type 2 diabetes, and hypothyroidism.
For a broader explanation of hormone testing, see:
How to Read Your TRT Blood Panel: Every Marker Explained
Testosterone Assays: Understanding Total and Free Testosterone Testing
What Causes High SHBG in Men?
High SHBG in men is associated with aging, liver disease, hyperthyroidism, HIV, several medications, estrogen exposure, and genetic variation.
The cause matters because SHBG is a binding protein, not a diagnosis.
A high result should prompt a review of thyroid function, liver health, medications, nutritional status, alcohol exposure, chronic illness, and relevant clinical history.
The 2026 investigators described their high-SHBG group as a natural experiment because extreme binding created a large separation between total and free testosterone.
This observation does not mean every mildly elevated SHBG result produces clinically important androgen deficiency.
A practical evaluation starts with the reason for the high SHBG and then asks whether free testosterone and the HPT axis show evidence of inadequate compensation.
What Is the Best Way to Measure Free Testosterone When SHBG Is High?
Standardized equilibrium dialysis paired with a high-quality testosterone assay is the strongest direct laboratory approach when SHBG is markedly abnormal.
Free testosterone measurement has a long history of poor standardization. Assays differ in calibration, dialysis conditions, temperature, membrane characteristics, and downstream testosterone measurement.
These differences create reference-range confusion across laboratories.
A 2023 study established reference intervals using a standardized equilibrium dialysis procedure plus CDC-certified LC-MS/MS.
In healthy nonobese adult men, the reported free testosterone interval was 66 to 309 pg/mL. Men aged 19 to 39 had a higher interval of approximately 120 to 368 pg/mL.
Reference Intervals for Free Testosterone in Adult Men Measured Using a Standardized Equilibrium Dialysis Procedure
The key lesson is to interpret the result against the method-specific reference range. A free testosterone number without knowing the assay method has limited value.
For more technical detail:
Optimized Direct Equilibrium Dialysis for Free Testosterone Analysis by LC-MS/MS
Is Calculated Free Testosterone Useful When Equilibrium Dialysis Is Unavailable?
Yes. A validated calculation is useful when total testosterone, SHBG, and albumin are measured accurately, especially when direct equilibrium dialysis is unavailable.
Calculated free testosterone is an estimate based on binding assumptions. Extreme SHBG levels expose differences among equations because the models do not handle testosterone binding in exactly the same way.
Recent work on SHBG and albumin binding also shows that older simplified binding models do not capture every aspect of testosterone transport.
For routine clinical care, a well-validated calculation remains more useful than a direct analog free testosterone immunoassay.
In an unusual high-SHBG case where the diagnosis remains uncertain, standardized equilibrium dialysis offers stronger evidence.
ExcelMale also has a detailed discussion of calculated hormone values:
A Novel Spreadsheet Method for Calculating Free Testosterone, Free DHT, and Free Estradiol
What Lab Pattern Suggests Primary Hypogonadism When Total Testosterone Looks Normal?
Low free testosterone together with elevated LH or FSH is the key biochemical pattern suggesting primary testicular dysfunction when total testosterone looks normal or high.
| Total Testosterone | Free Testosterone | LH/FSH | Interpretation to Consider |
|---|---|---|---|
| High or high-normal | Normal | Normal | High SHBG with preserved compensation |
| High or normal | Low | Elevated | Primary testicular dysfunction masked by SHBG |
| Normal or low | Low | Low or normal | Secondary or functional hypogonadism needs evaluation |
| Low | Normal | Normal | Low SHBG or altered binding might explain low total testosterone |
This table is a framework rather than a diagnostic rule.
Testosterone testing should be repeated when appropriate. Symptoms need clinical evaluation. Abnormal thyroid, liver, pituitary, medication, sleep, nutritional, or systemic factors also deserve attention.
Primary testicular insufficiency is broader than testosterone production. Elevated FSH, testicular history, fertility status, prior chemotherapy or radiation, injury, infection, genetic conditions, and testicular examination provide additional context.
Does a Normal Total Testosterone Rule Out Testosterone Deficiency?
No. A normal total testosterone does not reliably rule out biochemical testosterone deficiency when SHBG is substantially abnormal.
This exception should not be stretched into a claim that total testosterone lacks value.
Total testosterone remains the recommended first-line test for most men because standardized assays are widely available and total testosterone usually tracks androgen status reasonably well.
The concern arises when binding proteins distort the relationship.
Earlier European Male Ageing Study data also found hypogonadal signs and symptoms in men with low calculated free testosterone despite normal total testosterone.
Low Free Testosterone Is Associated With Hypogonadal Signs and Symptoms in Men With Normal Total Testosterone
The 2026 study adds a more extreme example. Some men had total testosterone above 1,000 ng/dL while free testosterone stayed low and gonadotropins were elevated.
What Do Men Ask Most About High SHBG and Low Free Testosterone?
Men usually want to know whether a high total testosterone result rules out a problem, what SHBG level matters, and which free testosterone test deserves trust.
Is Low Free Testosterone Possible With Total Testosterone Over 900 ng/dL?
Yes. Four men in the 2026 study had total testosterone above 916 ng/dL, including values above 1,000 ng/dL, while free testosterone remained low and LH or FSH was elevated.
What SHBG Level Counts as Markedly Elevated?
The 2026 study selected men with SHBG above 100 nmol/L. The study laboratory reference range was 13 to 71 nmol/L.
There is no universal SHBG cutoff where total testosterone suddenly becomes unreliable. Interpretation depends on assay methods, free testosterone, gonadotropins, age, symptoms, and the clinical setting.
Does High SHBG Always Produce Low Free Testosterone?
No. Many men compensate by producing more testosterone, which preserves normal free testosterone despite higher SHBG.
Low free testosterone becomes more concerning when the pituitary is already increasing LH or FSH and compensation is still inadequate.
Should Free Testosterone Be Checked When SHBG Is High?
Yes. Endocrine Society guidance supports free testosterone assessment when a condition alters SHBG or when total testosterone sits near the lower reference limit.
The result should come from equilibrium dialysis or a validated calculation rather than a direct analog free testosterone immunoassay.
Is Equilibrium Dialysis Better Than a Direct Free Testosterone Immunoassay?
Yes. Standardized equilibrium dialysis is the reference direct method, while direct analog immunoassays are inaccurate when binding proteins vary and are not recommended by the Endocrine Society.
Which ExcelMale Discussions Provide More Detail?
ExcelMale has several related discussions for readers who want assay details, reference ranges, and broader TRT laboratory context.
- How to Read Your TRT Blood Panel: Every Marker Explained
- Testosterone Assays
- Optimized Direct Equilibrium Dialysis for Free Testosterone Analysis by LC-MS/MS
- A Novel Spreadsheet Method for Calculating Free Testosterone, Free DHT, and Free Estradiol
What Is the Main Clinical Lesson From High SHBG and Low Free Testosterone?
A high total testosterone result sometimes deserves more scrutiny when SHBG is markedly elevated.
The 2026 study changes the clinical conversation because the strongest signal did not come from symptom questionnaires. The strongest signal came from the men’s own gonadotropins.
LH and FSH stayed elevated despite total testosterone values well above levels usually considered reassuring.
For men with high SHBG, the useful question is not whether total testosterone looks good in isolation. The useful question is whether free testosterone, LH, FSH, symptoms, and the clinical setting tell one coherent story.
Which Studies Support This Article?
- Gagliano-Jucá T, Puri I, Ramirez-Rivera G, et al. Hormonal Profiles of Men with Highly Elevated SHBG and Primary Testicular Dysfunction Support Free Hormone Hypothesis. Journal of the Endocrine Society. 2026;10(9):bvag185. DOI: 10.1210/jendso/bvag185
- Anawalt BD, Handelsman DJ. Debate About the Free Testosterone Hypothesis: Useful Tool or Misguided Mirage? Journal of Clinical Endocrinology & Metabolism. 2025;110(10):e3536-e3540. DOI: 10.1210/clinem/dgaf370
- De Silva NL, Papanikolaou N, Grossmann M, et al. Male hypogonadism: pathogenesis, diagnosis, and management. Lancet Diabetes & Endocrinology. 2024;12(10):761-774. DOI: 10.1016/S2213-8587(24)00199-2
- Jasuja R, Pencina KM, Spencer DJ, et al. Reference intervals for free testosterone in adult men measured using a standardized equilibrium dialysis procedure. Andrology. 2023;11(1):125-133. DOI: 10.1111/andr.13310
- Jasuja R, Spencer D, Jayaraj A, et al. Estradiol induces allosteric coupling and partitioning of sex-hormone-binding globulin monomers among conformational states. iScience. 2021;24(6):102414. DOI: 10.1016/j.isci.2021.102414
- Jayaraj A, Schwanz HA, Spencer DJ, et al. Allosterically Coupled Multisite Binding of Testosterone to Human Serum Albumin. Endocrinology. 2021;162(2):bqaa199. DOI: 10.1210/endocr/bqaa199
- Winters SJ. SHBG and total testosterone levels in men with adult onset hypogonadism: what are we overlooking? Clinical Diabetes and Endocrinology. 2020;6:17. DOI: 10.1186/s40842-020-00106-3
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology & Metabolism. 2018;103(5):1715-1744. DOI: 10.1210/jc.2018-00229
- Antonio L, Wu FCW, O'Neill TW, et al. Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone. Journal of Clinical Endocrinology & Metabolism. 2016;101(7):2647-2657. DOI: 10.1210/jc.2015-4106
- Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications. Endocrine Reviews. 2017;38(4):302-324. DOI: 10.1210/er.2017-00025
About Nelson Vergel
Nelson Vergel, B.S. Chemical Engineering, MBA, is founder of ExcelMale.com, a men’s health educator, patient advocate, and author. His work includes more than three decades of personal TRT experience, service on NIH and FDA advisory panels, and books including Testosterone: A Man’s Guide, Beyond Testosterone, The hCG Advantage, and The Peptide Consensus.
Updated August 26, 2026.
What Is ExcelMale?
ExcelMale is a men’s health forum with more than 24,000 members and over 20 years of archived discussions on testosterone replacement therapy, sexual health, blood testing, fertility, peptides, metabolic health, and related topics.
The forum combines peer discussion with research summaries, clinical education, and practical experience from men who have spent years monitoring hormone therapy and health outcomes.
