In a patient with persistently elevated sex hormone‑binding globulin (SHBG) and elevated testosterone, and no identifiable disease, medication effect, or imaging abnormalities, should genetic testing for SHBG‑related polymorphisms be pursued to assess a possible hereditary protein‑binding disorder?

Genetic Testing for SHBG Polymorphisms in Isolated Elevated SHBG and Testosterone

In a patient with persistently elevated SHBG and elevated total testosterone, where all secondary causes have been excluded, genetic SHBG polymorphisms are a recognized phenomenon but genetic testing is not clinically indicated because these variants do not alter free testosterone levels or cause disease.

Understanding the Clinical Picture

Your patient presents with an intriguing biochemical pattern that warrants careful interpretation. The 2025 EAU guidelines 1 and 2018 Endocrine Society guidelines 2 both emphasize that conditions elevating SHBG (including genetic variants) can raise total testosterone into the high-normal or even supranormal range while free testosterone remains normal. This is precisely what you're observing.

The Genetic Evidence

What We Know About SHBG Polymorphisms

Several common genetic variants in the SHBG gene do exist and are relatively prevalent:

• rs1799941, rs6259, rs727428, and rs6258 are the most studied polymorphisms 3, 4
• These variants affect SHBG production by 10-25% 3
• They consequently alter total testosterone levels by 4-21% 3
• Critical finding: A 2025 study of 999 healthy men found that while these SNPs significantly affected SHBG and total testosterone concentrations, they had no clear effects on measured free testosterone except for a trend in rs6259 homozygotes 3

The Key Clinical Insight

The 2018 Endocrine Society guidelines 2 describe a compelling case: a man with a complete SHBG gene missense mutation who had SHBG deficiency, very low total testosterone, but normal free testosterone, normal gonadotropins, normal male development, and normal spermatogenesis. This demonstrates that SHBG variations, even severe ones, do not impair androgen action when free testosterone is normal.

Why Genetic Testing Is Not Indicated

1. Free Testosterone Is the Determinant of Clinical Status

The European Male Aging Study data 2 definitively showed that:

• Men with low free testosterone have hypogonadal symptoms regardless of total testosterone
• Men with low total testosterone but normal free testosterone do not have hypogonadal symptoms 2
• This validates the "free hormone hypothesis" that intracellular hormone activity depends on free, not total, hormone concentrations 2

2. Genetic Variants Don't Cause Disease

A large Norwegian study of 5,309 men 5 found that rs1799941 (which raises SHBG by 24.7% and total testosterone by 14.7%) was not associated with myocardial infarction, type 2 diabetes, cancer, or mortality. This argues against any pathological significance of genetically elevated SHBG.

3. No Therapeutic Implications

Even if you identified a specific SHBG polymorphism:

• It would not change management
• It would not indicate treatment
• It would not predict disease risk
• The patient is biochemically and clinically normal if free testosterone is normal

Your Diagnostic Approach

Measure free testosterone using one of these methods 2:

1. Equilibrium dialysis followed by LC-MS/MS (gold standard)
2. Calculated free testosterone using validated formulas (acceptable alternative)
3. Avoid direct immunoassays for free testosterone (unreliable)

If Free Testosterone Is Normal:

• Reassure the patient that this represents a benign variant in SHBG regulation
• No further workup is needed
• No treatment is indicated
• Document that elevated total testosterone is secondary to elevated SHBG
• The 2025 EAU guidelines 1 list "ageing, smoking, AIDS/HIV" as causes of elevated SHBG; genetic variation is an additional recognized mechanism

If Free Testosterone Is Also Elevated:

• Reconsider your exclusion of secondary causes
• Evaluate for exogenous androgen exposure more carefully
• Consider rare androgen-secreting tumors
• Assess for conditions causing androgen overproduction

Common Pitfalls to Avoid

1. Don't treat elevated total testosterone when free testosterone is normal - this represents overdiagnosis
2. Don't pursue expensive genetic testing that won't change management 3
3. Don't assume pathology exists simply because numbers are outside reference ranges
4. Always measure free testosterone in patients with altered SHBG 2 - this is the guideline-recommended approach

The Bottom Line

Your patient likely has a genetic polymorphism affecting SHBG production (present in up to 58% of the population for some variants 3), but this is a benign biochemical variant, not a disease. The 2025 research 3 confirms these polymorphisms affect SHBG and total testosterone but not free testosterone or clinical outcomes. Genetic testing would be academically interesting but clinically useless - it won't guide treatment or predict prognosis.