Normal test can feel terrible

When a man walks into his doctor's office complaining about exhaustion, brain fog, low motivation, and declining sexual performance, the first thing most physicians do is order a testosterone test. The number comes back somewhere in the middle of the normal range, and the doctor closes the chart and tells the patient he is fine. But the patient is not fine, and the reason why comes down to a protein most people have never heard of.

Testosterone in the blood does not float around freely. Most of it is attached to carrier proteins, and the most important of these is something called SHBG, which stands for sex hormone-binding globulin. SHBG is a protein produced mainly by the liver, and its job is to grab onto testosterone molecules and carry them through the bloodstream. The problem is that when testosterone is bound to SHBG, it cannot enter cells, cannot activate receptors, and cannot actually do anything useful in the body.

Think of it this way. You could have a warehouse full of a product, but if every single unit is locked inside shipping containers that nobody can open, none of it reaches the people who need it. Total testosterone is the measurement of everything in the warehouse, locked containers and all, and that is the number most doctors are looking at when they tell you your levels are normal.

What actually matters to the body is something called free testosterone, which is the small fraction of testosterone that is not bound to SHBG or any other protein and is therefore available to enter cells and do its job. In most men, free testosterone makes up only about two to three percent of total testosterone. So if SHBG is elevated, that tiny free fraction shrinks even further, and the body starts experiencing the symptoms of low testosterone even when total levels look perfectly fine on paper.

This is not a theoretical edge case. Research published in journals like the Journal of Endocrinological Investigation has shown that measuring only total testosterone can miss a meaningful number of men who actually have low bioavailable hormone levels. A study comparing different measurement methods found that relying on total testosterone alone can lead to missed diagnoses of something called hypogonadism, which is the medical term for when the body is not producing or delivering enough testosterone to function properly.

The symptoms of low free testosterone look exactly like the symptoms of low total testosterone because the body cannot tell the difference. Low energy, difficulty concentrating, reduced drive, problems with sexual function, slower recovery from exercise, changes in mood, and loss of muscle mass are all things that show up when cells are not getting enough testosterone, regardless of what the total number on a lab report says. A 2006 paper in the American Journal of Medicine noted the direct connection between testosterone availability and erectile function, reinforcing the idea that what reaches the tissue is what drives outcomes.

So why does SHBG go up in the first place? Several factors are known to raise SHBG levels. Age is one of them, because SHBG tends to increase as men get older, which is part of why testosterone-related symptoms become more common with age even in men who appear to have normal total levels. Thyroid function plays a role. Certain medications can influence it. Liver function matters because the liver is where SHBG is made. There is also research suggesting that body composition changes can affect SHBG, and a 2025 pilot study looking at a weight loss drug called tirzepatide found that it influenced metabolic hypogonadism and SHBG levels in men with obesity, which points to the connection between fat metabolism and how the body handles sex hormones.

Endurance athletes are another group where this becomes relevant. A 2023 review on male endurance athletes found that low energy availability, meaning not eating enough to support training volume, can suppress testosterone and disrupt hormonal signaling. Chronic stress and undereating create a metabolic environment where the body may shift how it regulates these hormones, and SHBG is part of that picture.

The measurement of free testosterone also comes with its own complications. There are different ways to calculate or measure it, and not all of them are equally accurate. Something called equilibrium dialysis is considered the gold standard method, which means it is the most accurate way to directly measure how much free testosterone is actually present. However, many labs use a calculated estimate based on total testosterone and SHBG levels, or they use an older direct measurement method that research has shown can produce unreliable results. A 2013 paper in the journal Aging Male compared free testosterone by direct measurement and calculated estimate against equilibrium dialysis in a real clinical population and found meaningful differences between the methods, which matters a lot when someone's diagnosis or treatment depends on the number.

This is why the recommendation is to run all three markers together. Total testosterone gives you the overall picture of how much the body is producing. SHBG tells you how much of that is being tied up and locked away. And free testosterone, ideally measured well or calculated carefully, tells you what is actually available to the tissues. Running only total testosterone is like checking whether a bank account has money in it without checking how much of it is frozen or inaccessible.

There is also newer research looking at the molecular pathways that regulate how SHBG itself behaves. A 2026 computational biology paper examined novel protein pathways that influence how much testosterone becomes bioavailable through SHBG interactions, suggesting that the story of how the body controls testosterone availability is more complex than just a single number can capture.

When a man feels terrible despite a normal testosterone result, the answer is not always that his symptoms are in his head or that nothing is wrong. The biology of how testosterone moves through the body and gets delivered to the cells that need it is more layered than a single lab value can represent, and understanding that layer is what separates a complete hormonal evaluation from an incomplete one.

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References

1. Hong Y. Uncovering novel protein pathways regulating bioavailable testosterone through sex hormone-binding globulin. Comput Biol Chem. 2026. Source
2. La Vignera S, Cannarella R, Garofalo V et al.. Short-term impact of tirzepatide on metabolic hypogonadism and body composition in patients with obesity: a controlled pilot study. Reprod Biol Endocrinol. 2025. Source
3. Abildgaard J, Aleliunaite A, Horvath C et al.. Sex hormone-binding globulin controls sex-specific lipolytic activity in human abdominal subcutaneous adipocytes. Mol Metab. 2025. Source
4. Kacker R, Hornstein A, Morgentaler A. Free testosterone by direct and calculated measurement versus equilibrium dialysis in a clinical population. Aging Male. 2013. Source
5. Agretti P, Pelosini C, Bianchi L et al.. Importance of total and measured free testosterone in diagnosis of male hypogonadism: immunoassay versus mass spectrometry in a population of healthy young/middle-aged blood donors. J Endocrinol Invest. 2021. Source
6. Lin KY, Sun HY, Liu WD et al.. Hypogonadism among HIV-positive men who have sex with men in Taiwan: Prevalence and associated factors. J Microbiol Immunol Infect. 2024. Source
7. Cupka M, Sedliak M. Hungry runners - low energy availability in male endurance athletes and its impact on performance and testosterone: mini-review. Eur J Transl Myol. 2023. Source
8. Bassas Arnau L. Exploration of testicular function. Endocrinol Nutr. 2009. Source
9. Mikhail N. Does testosterone have a role in erectile function? Am J Med. 2006. Source
10. Deutschbein T, Mann K, Petersenn S. Total Testosterone and Calculated Estimates for Free and Bioavailable Testosterone: Influence of Age and Body Mass Index and Establishment of Sex-Specific Reference Ranges. Horm Metab Res. 2015. Source

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