A 38-year-old man came to me last year with a total testosterone of 680 and symptoms that read like classic hypogonadism — low energy, low libido, brain fog, body composition shift, poor exercise recovery. His prior clinician had told him his testosterone was normal and there was nothing to do. The total looked normal on paper. His SHBG was 78. His free testosterone — the actual bioavailable fraction — was 6.2 pg/mL, which is well below optimal and consistent with everything he was describing. He was hypogonadal at the tissue level despite a normal-looking total. Nobody had run the right numbers, so nobody had seen the actual problem.
This is one of the most common diagnostic misses I encounter in hormonal medicine, and it sits squarely on a single misunderstood marker: sex hormone binding globulin. SHBG is the variable that explains why two patients with identical total testosterone or estradiol can have completely different symptom pictures and completely different responses to treatment. Once you understand it, the whole concept of "normal" hormone labs starts looking very different.
What SHBG actually does
Sex hormone binding globulin is a glycoprotein produced primarily by the liver. Its job is to bind sex hormones — testosterone and estradiol most importantly, with weaker binding to other steroids — and transport them through the bloodstream. Hormone bound to SHBG is biologically inactive. It cannot leave the vascular compartment, cannot enter target tissue, and cannot bind to its receptor. It is in storage, not in circulation in any functional sense.
What matters at the tissue level is the unbound, free fraction — the small percentage of total hormone that is not tethered to a binding protein and is therefore available to enter cells and produce a biological effect. For testosterone in men, this free fraction is typically 1 to 3% of the total. For estradiol in women, the free fraction is similar. The remaining 97 to 99% is bound — most of it to SHBG, with a smaller fraction to albumin.
This is why total hormone is a misleading number on its own. A patient with high SHBG and high total testosterone may have less free testosterone available to tissue than a patient with low SHBG and lower total testosterone. The total tells you how much hormone is in the bloodstream. The free tells you how much is doing anything. They are not the same number, and the gap between them matters clinically.
Why SHBG goes up or down
SHBG is not a fixed value. It moves in response to several inputs, and the direction of movement tells me something about what else is going on.
SHBG goes up with:
- Estrogen excess relative to androgens (oral estrogen replacement raises SHBG dramatically, transdermal much less so — this is one reason delivery method matters)
- Hyperthyroidism or excess thyroid hormone replacement
- Liver disease and chronic alcohol use
- Aging in men — SHBG climbs progressively with age, which is why total testosterone can stay flat in a man who is becoming progressively symptomatic
- Caloric restriction and very low body weight
- Some medications including certain anticonvulsants
SHBG goes down with:
- Insulin resistance and hyperinsulinemia (this is one of the most clinically important drivers — elevated insulin directly suppresses hepatic SHBG production)
- Obesity, particularly visceral adiposity
- Hypothyroidism
- Androgen excess
- Growth hormone excess
- Certain medications including glucocorticoids and exogenous androgens
The pattern matters. A 45-year-old man with low SHBG, central adiposity, and a fasting insulin of 16 is showing me a metabolic problem expressed through his hormonal labs. Treating his testosterone without addressing his insulin resistance will produce a partial response at best. A 52-year-old woman with high SHBG on oral hormone therapy is showing me that the delivery method is binding up the hormone she just took, and switching to a transdermal preparation often resolves the symptoms her oral preparation never quite addressed.
How to read the numbers correctly
The labs that actually answer the bioavailability question are not the standard total-only panels most patients have on file. The complete picture requires:
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- Total testosterone (and total estradiol in women)
- SHBG
- Albumin (already on most metabolic panels)
- Free testosterone — measured directly by equilibrium dialysis or calculated from the above using the Vermeulen equation. Calculated free testosterone using the standard equation is reasonably accurate when SHBG is in normal range; direct measurement is preferable when SHBG is at extremes.
- Bioavailable testosterone — the sum of free plus albumin-bound, since the albumin-bound fraction dissociates readily and is functionally available
For optimal ranges, the numbers I use clinically:
- Free testosterone in men: optimal is generally above 15 pg/mL, with most symptomatic men below 10
- SHBG in men: optimal is roughly 20 to 50 nmol/L. Above 60 in a symptomatic man with normal-looking total testosterone is a classic high-SHBG hypogonadism pattern. Below 20 in a man with central adiposity is usually pointing me toward insulin resistance.
- SHBG in women: more variable based on reproductive status, but values above 100 on oral estrogen therapy often correlate with persistent symptoms despite "normal" estradiol
A standard panel that reports only total testosterone misses the high-SHBG patient entirely. This is why the comprehensive lab work we run at the first visit looks different from what most patients have had done before.
What I look for in the workup
When I evaluate someone for hormone therapy, I am looking at the whole signaling system, not just one number. The questions I am answering with the labs are: how much hormone is actually being produced, how much of what is produced is bioavailable to tissue, what is regulating SHBG up or down, and what adjacent factors — thyroid, metabolic, inflammatory — are influencing the picture.
The panel I run on a first hormone visit includes total and free testosterone, SHBG, estradiol (sensitive assay in men), DHEA-S, full thyroid (TSH, free T3, free T4, reverse T3, thyroid antibodies), fasting insulin and HbA1c, lipid panel, hs-CRP, and a complete metabolic panel including liver enzymes. In women I add progesterone timed appropriately to cycle status. In men with low SHBG I look hard at the insulin and HbA1c. In men with high SHBG I look hard at the thyroid and liver markers. The pattern across the whole panel tells me what mechanism is in play, which then tells me what treatment will actually help.
How treatment changes based on SHBG
The SHBG result changes the treatment plan in concrete ways.
For the high-SHBG hypogonadal man, simply giving more testosterone often produces a disappointing free testosterone response because the additional hormone gets bound up. Strategies that work better include addressing any thyroid excess driving the SHBG up, considering smaller more frequent dosing rather than weekly injections to avoid driving SHBG higher, and in some cases using adjuncts that lower SHBG modestly. The 38-year-old I described in the opening responded beautifully to twice-weekly subcutaneous testosterone with attention to his liver function — his free testosterone moved from 6.2 to 19, and his symptoms followed.
For the low-SHBG insulin-resistant patient, treating the insulin resistance is often as impactful as treating the testosterone. Weight loss, reduction of visceral adiposity, and improved insulin sensitivity raise SHBG back toward normal and often produce a meaningful improvement in the free hormone picture before we even get to hormone replacement. This is one of the places where hormone optimization and a medical weight loss program interact directly.
For women on oral hormone therapy with persistent symptoms, switching to transdermal estradiol often resolves what the oral preparation could not. Oral estrogen passes through the liver first and dramatically upregulates SHBG, which binds the very testosterone the patient needs for libido, energy, and tissue health. Transdermal delivery bypasses the first-pass effect and produces a much smaller SHBG response.
For men's testosterone replacement and for Biote pellet therapy, the SHBG trajectory is part of how I dose-adjust over time. A patient whose SHBG climbs on therapy is telling me something. A patient whose SHBG drops is telling me something different.
Where to go from here
If you have had hormone labs run before and were told everything looked normal but you still feel the way you feel, the most likely explanation is that the panel was incomplete. Bring whatever prior labs you have. If they did not include SHBG, free testosterone, and a full thyroid panel including reverse T3, the picture you were given was incomplete by definition. Take the hormone health assessment or book a consultation at the Columbus location or Warner Robins location. I will run the full panel, walk you through what each marker means in your specific context, and build the treatment plan from data instead of from a partial picture.
Medical disclaimer: This article is for educational purposes only and does not constitute medical advice. Individual clinical decisions should be made in consultation with a qualified healthcare provider following appropriate evaluation. References to specific treatments, dosing, or protocols are informational.
Travis spent 17+ years in high-acuity clinical medicine — emergency, cardiac ICU, and cath lab — before founding Revitalize. He is a Certified Platinum Biote hormone therapy provider, the published author of You're Not Broken — You're Unbalanced, and the founder of the Rebuild Metabolic Health Institute. His clinical writing reflects the same precision he brought to critical care: specific, honest, and built around what actually works.
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