Testosterone | SHBG (rs6258)

How SHBG and the rs6258 Variant Affect Testosterone and Your Health

Testosterone circulates in the blood in two forms: bound to proteins and free. Free testosterone is the biologically active fraction that can enter cells and trigger effects on metabolism, muscle, mood, and reproductive function. The SHBG gene makes sex hormone binding globulin, a protein that binds testosterone and controls how much free testosterone is available. Genetic differences in SHBG can change how tightly the protein binds testosterone and therefore alter free testosterone levels.

Why this matters

Free testosterone is what matters for biological effects. Total testosterone can look normal while free testosterone is higher or lower than expected.
Variants in SHBG can reduce binding strength, increasing free testosterone. That change can be small or substantial depending on the genotype.
Higher free testosterone in men often supports muscle, energy, libido, and metabolic health. In women, even modest increases can raise the chance of androgen-related symptoms such as acne, oily skin, or mild hirsutism and may be associated with conditions like polycystic ovary syndrome in some contexts.
Lifestyle, body weight, and exposures to chemicals that disrupt hormones also influence SHBG and testosterone balance.

When lab tests might not tell the full story

Standard lab panels usually report total testosterone and calculate free testosterone using total testosterone and SHBG levels. Certain SHBG variants can change protein function in ways that make those calculations inaccurate. If your genotype reduces SHBG binding, calculated free testosterone may underestimate the actual biologically active fraction. If you have symptoms that do not match lab results, a direct measurement of free testosterone or equilibrium dialysis testing may provide clearer information.

Two effect alleles (TT at rs6258)

You carry two copies of the T allele for rs6258. This rare genotype, found in about 0.6% of people, substantially reduces SHBG protein ability to bind testosterone. As a result, your free or bioavailable testosterone can be significantly higher than predicted by standard calculated lab values, even when total testosterone appears normal.

Implications

Men: Higher free testosterone often supports muscle mass, energy, libido, and reproductive function. It can be metabolically favorable but still should be tracked clinically if symptoms appear.
Women: Increased free testosterone can modestly raise the likelihood of androgen-related traits such as oily skin, acne, or mild hirsutism. In some cases it may contribute to hormone patterns seen in PCOS, though genotype alone does not diagnose a condition.
Testing: Calculated free testosterone may be inaccurate. Consider discussing direct free testosterone measurement or equilibrium dialysis with your healthcare provider if symptoms do not match lab numbers.

One effect allele (CT at rs6258)

You have one copy of the T allele. This genotype reduces SHBG binding affinity to a lesser degree than TT, but still leads to higher free testosterone compared with the CC genotype. The change can be enough that calculated free testosterone underestimates your true biologically active testosterone.

Implications

Men: Slightly higher free testosterone can support muscle, libido, and metabolic health. Monitor symptoms and discuss testing if anything changes unexpectedly.
Women: You may be a bit more prone to androgen-related features such as oily skin, acne, or mild hirsutism. This is a risk factor not a diagnosis.
Testing: If clinical signs differ from calculated labs, ask your clinician about direct free testosterone testing for a clearer picture.

Zero effect alleles (CC at rs6258)

You have two copies of the common C allele. Your SHBG protein has normal binding affinity for testosterone, so typical proportions of free and bound testosterone circulate in your blood. Standard laboratory measurements and calculations should reflect your hormone status reliably.

Implications

This is the most common genotype and indicates typical SHBG function.
Routine total and free testosterone labs are usually sufficient unless there are clinical concerns.

Practical steps to support healthy testosterone balance

Genotype can influence hormone dynamics, but lifestyle choices strongly shape how genes affect health. The following strategies support balanced sex hormones and overall well being.

Diet and weight

Keep a balanced diet rich in whole foods: vegetables, fruits, lean proteins, healthy fats, and whole grains.
Maintain a healthy body weight. Excess fat, especially around the abdomen, often lowers SHBG and can raise circulating androgens.
Include adequate protein to support muscle mass and satiety.
Limit refined carbohydrates, excess sugar, and highly processed foods that promote insulin spikes. High insulin can lower SHBG and shift hormone balance.

Supplements to consider with guidance from your provider

Vitamin D: Low vitamin D is linked to several hormonal imbalances. Check levels before supplementing and follow clinical guidance.
Omega 3 fatty acids: Support metabolic and cardiovascular health.
Magnesium: Supports overall metabolic function and may support sleep and blood sugar regulation.
Herbal or hormonal supplements: Use caution and discuss with a clinician because some can alter androgen levels or interact with medications.

Lifestyle habits

Exercise regularly. Resistance training and adequate aerobic activity support healthy testosterone and body composition.
Prioritize sleep. Poor sleep reduces testosterone and disrupts metabolic health.
Manage stress. Chronic stress and elevated cortisol can negatively affect sex hormones.
Limit exposure to endocrine disrupting chemicals commonly found in some plastics, canned foods, and certain personal care products. Choose BPA-free containers, avoid heating food in plastic, and pick gentler personal care products when possible.

When to talk to a healthcare provider

If you experience symptoms such as unexpected changes in libido, energy, muscle mass, acne, irregular menstrual cycles, or increased facial or body hair.
If lab results feel inconsistent with how you feel. Discuss direct free testosterone testing or equilibrium dialysis as more accurate options.
Before starting any hormone related therapy or supplements that may affect sex hormones.

Limitations and important disclaimer

Genetics is only one piece of the puzzle. Your SHBG genotype can influence free testosterone, but environment, body composition, medications, and other genes also matter. PlexusDx provides educational information about genetic predispositions and does not provide medical advice. Always consult your healthcare provider to interpret genetic results in the context of your symptoms, medical history, and lab testing before making any medical or treatment decisions.