HSA | FSA CARDS ARE NOW ACCEPTED

Last reviewed: May 12, 2026 Last updated: May 12, 2026

Written by: Jay Hastings , CEO of PlexusDx

Jay Hastings is the CEO of PlexusDx, a precision health company focused on genetic testing, blood biomarker insights, and personalized wellness recommendations. He has more than 20 years of experience across healthcare innovation, genomics, laboratory operations, healthcare investing, and strategic finance. His work has included scaling healthcare startups, leading CLIA lab integrations, and helping expand consumer access to precision health tools.

Medically reviewed by: Jayden Lee, PharmD, EMBA

Jayden Lee, PharmD, EMBA, is the PlexusDx Medical Science Liaison with a PharmD and MBA specializing in pharmacogenomics and clinical product development, with a proven ability to bridge the gap between genomic research and practical patient outcomes. Dr. Lee has more than 10 years of professional experience in clinical pharmacy, academia, and research.

This article is part of the PlexusDx Education Hub — your resource for evidence-based guidance on Hormones & Fertility. Browse all Hormones & Fertility education

Two men walk out of the same lab with the same number on their testosterone report: 500 ng/dL, comfortably in range. One feels vital, strong, and clear-headed. The other feels perpetually flat, with low energy, reduced drive, and the inexplicable sense that his testosterone is doing nothing. The difference isn’t the number — it’s what that number conceals. SHBG — sex hormone-binding globulin — is the protein that determines how much of that total testosterone is actually available to your cells. The Precision Peptide Genetic Test analyzes SHBG variants as part of the Men’s Hormone panel spanning 14 pathways, 49 peptides, and 150+ genetic insights.

What SHBG Does

SHBG is an alpha-2 glycoprotein produced primarily by the liver and secreted into the bloodstream, where it acts as a carrier protein for sex hormones. SHBG binds testosterone, DHT (dihydrotestosterone), and estradiol with high affinity — holding them tightly enough that the hormones cannot enter cells or activate hormone receptors while bound. Albumin, another blood protein, also binds testosterone but with much lower affinity, meaning albumin-bound testosterone is partially bioavailable. SHBG-bound testosterone is not bioavailable at all.

The result is that circulating testosterone exists in three fractions: free testosterone (unbound, immediately bioavailable — roughly 1–3% of total), albumin-bound (weakly bound, partially bioavailable — roughly 30–44%), and SHBG-bound (tightly sequestered, not bioavailable — roughly 54–68%). The “bioavailable testosterone” figure adds free plus albumin-bound. SHBG genotype determines what percentage of total testosterone ends up in that inactive, sequestered fraction — and therefore how much is actually available for androgen pathway signaling.

The Genetics of SHBG Production

SHBG expression is regulated by a promoter region containing a (TAAAA)n dinucleotide repeat polymorphism — a variable-length sequence where the number of TAAAA repeats influences how actively the gene is transcribed. Longer repeats are associated with lower SHBG transcription and lower circulating SHBG levels; shorter repeats drive higher transcription and higher circulating SHBG. Because SHBG production is partially heritable — twin studies suggest genetics accounts for roughly 40–60% of SHBG level variance — this repeat polymorphism represents a meaningful source of the inter-individual variation in free testosterone seen across men with identical total testosterone levels.

Additional SNPs add precision to the genetic picture. rs1799941 (A/G in the promoter region) has been associated with higher circulating SHBG in genome-wide association studies — the G allele is linked to elevated production. rs6258 (Asp327Asn in exon 8) affects SHBG’s binding affinity for testosterone directly: the Asn327 variant produces an SHBG protein with reduced testosterone-binding efficiency, meaning even when SHBG levels are similar, the variant protein holds testosterone less tightly. Together, these variants shape both how much SHBG is produced and how effectively it sequesters testosterone once in circulation.

High SHBG, Low SHBG — Two Hormonal Profiles

The practical divergence between high and low SHBG genotypes becomes clearest when viewed alongside total testosterone numbers:

High SHBG genotype: More circulating SHBG means a larger fraction of total testosterone is sequestered. Two men with total testosterone of 500 ng/dL — one with SHBG of 80 nmol/L and one with SHBG of 20 nmol/L — can have free testosterone levels that differ by a factor of two or more. The high-SHBG individual may experience symptoms consistent with androgen insufficiency — low energy, reduced libido, poor recovery, difficulty maintaining lean mass — despite a total testosterone number that appears adequate on standard labs. Their androgen pathway signaling is running below what total testosterone suggests.

Low SHBG genotype: Less circulating SHBG means more testosterone remains free or albumin-bound, producing higher bioavailable testosterone from the same total. These individuals tend to experience stronger androgenic signaling per unit of total testosterone. Clinically, they may also aromatize more freely — since more free testosterone is available to the aromatase enzyme (CYP19A1) for conversion to estradiol.

Non-genetic factors also modulate SHBG levels — insulin resistance suppresses SHBG, hypothyroidism reduces it, and SHBG tends to rise 1–2% per year with aging (one reason free testosterone declines faster than total testosterone as men age). These are real modulators, but they operate on top of the genetic baseline your SHBG genotype establishes. Genetics sets the floor; lifestyle and physiology move the level from there.

SHBG and Androgen Pathway Protocols

In the context of androgen pathway optimization, SHBG genotype is one of the most consequential pre-protocol variables a healthcare provider can know. An individual with a high-SHBG genotype entering an androgen pathway protocol may see a smaller increase in free testosterone bioavailability per unit of total testosterone change compared to a low-SHBG genotype individual. The same total testosterone level produces fundamentally different androgenic environments downstream depending on SHBG.

Understanding SHBG genotype before beginning any androgen pathway discussion allows for more precise target-setting: free testosterone and bioavailable testosterone become the relevant numbers to track, not total testosterone alone. It also helps explain why two individuals on equivalent androgen pathway protocols can have very different symptom responses despite similar lab values. Genetics as a guide, not a guarantee — but a guide that makes the clinical conversation substantially more specific.

SHBG in the Full Men’s Hormone Genetic Panel

SHBG is the bioavailability gatekeeper in the Precision Peptide Genetic Test’s Men’s Hormone panel. It determines how much testosterone is available to the downstream signaling cascade. The other genes determine what happens to that testosterone once it’s free:

CYP19A1 (aromatase) — governs the rate at which free testosterone converts to estradiol. High SHBG individuals who achieve higher free testosterone may also need to understand their aromatase genotype, since more free testosterone available to aromatase means potentially more estrogen conversion.

AR (androgen receptor CAG repeats) — determines how sensitively androgen receptors respond to free testosterone once it enters cells. Short CAG repeats signal more aggressively per unit of free testosterone; long CAG repeats require more free testosterone to generate equivalent receptor activation.

SRD5A2 (5-alpha reductase) — governs the conversion of free testosterone to DHT, the more potent androgen that drives many androgenic effects including prostate and hair follicle sensitivity. SRD5A2 variants determine how efficiently that conversion occurs.

ESR1/ESR2 (estrogen receptors) — govern how sensitively tissues respond to the estradiol produced from testosterone via aromatase, which matters for bone density, mood, and metabolic function in men.

SHBG tells you how much testosterone reaches the system. The other genes in the panel tell you what the system does with it. Reading them together produces a complete Men’s Hormone genetic profile that no single-gene test can replicate.

The Precision Peptide Genetic Test analyzes how your genes influence hormone-related biological pathways. It does not recommend, prescribe, or determine which peptides you should use. Consult a qualified healthcare provider before beginning any peptide protocol.

Ready to discover your SHBG genotype and complete Men’s Hormone genetic profile? Take the Precision Peptide Genetic Test

Frequently Asked Questions About SHBG and Free Testosterone

What does SHBG genotype reveal about testosterone levels?

SHBG genotype influences your baseline sex hormone-binding globulin level — the protein determining how much testosterone is bound versus freely available to cells. Higher SHBG genotypes reduce bioavailability; lower SHBG genotypes release more free testosterone. The Precision Peptide Genetic Test analyzes SHBG variants across 14 pathways and 150+ genetic insights.

How does SHBG affect androgen pathway response?

SHBG determines the bioavailability of testosterone entering androgen pathway signaling. High SHBG genotypes bind more testosterone, leaving less free — meaning androgen pathway signaling runs below what total testosterone levels suggest. Knowing your SHBG genotype helps you and your healthcare provider interpret total testosterone and contextualize androgen pathway protocol conversations.

What other genes affect free testosterone alongside SHBG?

The Precision Peptide Genetic Test analyzes Men’s Hormone insights including CYP19A1 (aromatase, testosterone-to-estrogen conversion), AR (androgen receptor CAG repeats and sensitivity), SRD5A2 (5-alpha reductase and DHT conversion), and MTHFR (methylation and hormone clearance). SHBG governs how much testosterone is available; the other genes determine how sensitively and efficiently the body uses it.

This article is part of the PlexusDx Education Hub. Browse all Hormones & Fertility education

Medical and Editorial Standards

Medical review process: This article was reviewed for medical accuracy, scientific clarity, evidence alignment, and appropriate discussion of genetics, medications, supplements, biomarkers, and health-related claims.

Sources and evidence: PlexusDx educational content is developed using peer-reviewed research, clinical literature, reputable medical references, and, where applicable, public health or regulatory guidance. References are included at the end of the article when scientific, medical, or health-related claims are discussed.

Commercial transparency: PlexusDx offers genetic testing, blood biomarker testing, personalized supplement recommendations, and related precision wellness services. Product mentions are intended to help readers understand available options and should not be interpreted as medical advice.

Important disclaimer: PlexusDx educational content is for informational purposes only and should not be used as a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider before making decisions about medications, supplements, genetic testing, lab testing, or health-related care.