Why TRT Works for Some Men and Not Others: The Genetic Answer

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 and fertility. Browse all Hormones & Fertility education

Two men, same provider. Nearly identical baseline labs, similar age and body composition, comparable goals. They start the same androgen optimization protocol on the same day. Three months later, one is doing significantly better — energy restored, mood stable, body composition shifting favorably. The other sees marginal improvement at best, is dealing with elevated estrogen, mood swings, and is questioning whether any of it is working.

Same protocol. Completely different biology. Neither result has anything to do with effort, adherence, or chance — because androgen-pathway optimization engages a biological system that is genetically individualized across at least six distinct dimensions. Understanding those dimensions before a protocol begins is what separates a strategy calibrated to a man's actual biology from one calibrated to what worked for someone else.

The Six Genetic Dimensions of Androgen Protocol Response

The PlexusDx Precision Peptide Genetic Test analyzes 14 pathways, 49 peptides, and 150+ genetic insights — including 6 Reproductive Health insights that collectively explain the genetic architecture of androgen response. Each operates on a different part of the hormone cascade, and all six vary independently between men.

SHBG — The Availability Dimension
Before testosterone can bind the androgen receptor, it must first be free in circulation. Sex hormone binding globulin (SHBG) binds testosterone tightly, holding it inactive. SHBG variants producing elevated expression or higher binding affinity reduce the free testosterone fraction — meaning less testosterone is available to drive androgen effects regardless of total circulating levels. Two men can carry identical total testosterone with one having double the free testosterone of the other, purely because of SHBG genetics. SHBG Genetics: Why Your Free Testosterone Varies covers this bioavailability layer in full.

CYP19A1 — The Conversion Dimension
Free testosterone is not guaranteed to remain testosterone. Aromatase, encoded by CYP19A1, converts testosterone to estradiol. High-activity CYP19A1 variants route a larger fraction of any testosterone elevation toward estrogen synthesis — raising E2 while reducing the androgen substrate available for receptor binding. Men with high-activity aromatase genetics are more likely to encounter elevated estrogen on androgen protocols, not because of a protocol problem but because their genetics are actively diverting substrate. CYP19A1 and Estrogen Conversion in Men covers this conversion dynamic in detail.

AR (CAG Repeats) — The Sensitivity Dimension
Even when free testosterone successfully reaches the androgen receptor, the receptor's efficiency at translating that signal into cellular action is itself genetically variable. Longer AR CAG repeat sequences reduce transactivation efficiency — the receptor binds testosterone normally but generates a weaker downstream signal. A man with longer CAG repeats may experience symptoms consistent with androgen insufficiency even when his testosterone and free testosterone look normal on bloodwork, because the receptor is reading the signal at reduced efficiency. Androgen Receptor CAG Repeats: Sensitivity Explained covers the receptor dimension in full.

SRD5A2 — The DHT Dimension
For many androgen-dependent tissues, DHT — not testosterone — is the operative molecule. SRD5A2 variants determine how efficiently testosterone is converted to dihydrotestosterone, which binds the androgen receptor with two to three times the affinity of testosterone and dissociates more slowly. High-activity SRD5A2 amplifies the androgen signal at DHT-sensitive tissues; lower-activity variants deliver a weaker signal at those same tissues from the same testosterone substrate. SRD5A2 and 5-Alpha Reductase Genetics covers the DHT conversion step in detail.

LHCGR / FSHR — The HPTA Dimension
When exogenous androgens are introduced, the HPTA axis suppresses endogenous testosterone production through negative feedback. How deeply that suppression occurs — and how reliably the axis recovers when protocols are adjusted — is shaped by LHCGR and FSHR receptor genetics. Men with different receptor variants don't suppress or recover at the same rate, and FSHR variants affecting baseline spermatogenesis directly shape how fertility is affected by protocols. HPTA Axis Genetics: LH, FSH, and Fertility Preservation covers this axis dimension in full.

CYP17A1 / CYP11A1 — The Source Dimension
Upstream of everything sits the adrenal steroid cascade. CYP17A1 and CYP11A1 determine how efficiently the body synthesizes pregnenolone and DHEA — the precursors that feed testosterone synthesis through the adrenal pathway before testicular production enters the picture. Men with lower CYP17A1 17,20-lyase efficiency start every conversation about androgen optimization from a smaller adrenal precursor contribution to their baseline. DHEA and Pregnenolone Pathway Genetics covers the upstream source layer in full.

Why Six Variables Multiply — Not Add

The reason androgen protocol response is so variable isn't that any one of these dimensions is especially wide. It's that all six vary simultaneously and independently, and their effects compound rather than simply add together.

Consider two illustrative profiles built from the genetic landscape the Precision Peptide Genetic Test maps:

Profile A — High SHBG, High CYP19A1, Long AR CAG Repeats: Less free testosterone is available (SHBG), more of what is free converts to estradiol (CYP19A1), and what reaches the receptor generates a weaker downstream signal (AR). This man faces a compounded disadvantage at every stage of androgen signaling. The elevated estradiol from high aromatase activity also feeds back strongly to suppress GnRH and LH/FSH at the hypothalamus — creating additional HPTA suppression through the estrogen pathway. A provider who sees only the serum testosterone number and adjusts the protocol upward risks driving estradiol higher before the underlying genetics are factored in.

Profile B — Normal SHBG, Lower CYP19A1, Short AR CAG Repeats, High SRD5A2: Good free testosterone availability, minimal aromatization, a sensitive receptor, and high DHT output from available testosterone. This man may respond strongly at relatively modest androgen support levels — and his monitoring priorities differ substantially from Profile A. DHT-sensitive tissues warrant closer attention given SRD5A2 activity, and his robust receptor sensitivity means aggressive titration carries different risks than it does for Profile A.

Neither profile is better or worse. Both benefit from knowing their genetic architecture before a protocol begins rather than spending months discovering it through trial, adjustment, and error.

What Genetics Changes — and What It Doesn't

Knowing these six variables doesn't determine what protocol someone pursues, or whether to pursue one at all. Those are clinical decisions made in partnership with a qualified healthcare provider who can weigh genetics alongside symptoms, bloodwork, health history, and individual goals.

What genetics changes is the starting map. A provider who knows a patient's SHBG genetics, CYP19A1 activity, AR CAG repeat length, SRD5A2 expression, HPTA receptor sensitivity, and upstream steroid precursor capacity is working from a fundamentally more complete clinical picture than serum testosterone alone can deliver. That picture changes what gets tested, how results get interpreted, what the early monitoring strategy looks like, and how the provider explains variability to the patient when it occurs.

Genetics as a guide, not a guarantee. The six Reproductive Health insights don't predict a specific outcome on any specific protocol, and the Precision Peptide Genetic Test does not recommend, prescribe, or determine which hormone therapy is right for any individual. What it does is replace the genetic unknown with a defined, evidence-based map — which is the exact difference between a protocol built on assumptions and one built on your actual biology.

The Complete Men's Hormone Panel — All Six Insights Together

The 6 Reproductive Health insights in the Precision Peptide Genetic Test are designed to be read as a system — not as six separate data points. Together they trace the male steroid hormone cascade from upstream precursor synthesis (CYP17A1, CYP11A1) through bioavailability (SHBG), enzymatic conversion (CYP19A1, SRD5A2), receptor-level response (AR), and axis dynamics (LHCGR, FSHR). The full framework — why these six insights form a connected system and what the panel reveals for each — is covered in the Complete Guide to Genetic Men's Hormone Testing.

Each satellite post covers its gene in depth for men who want to understand a specific dimension before or after testing:

SHBG Genetics: Why Your Free Testosterone Varies — the bioavailability dimension.

CYP19A1 and Estrogen Conversion in Men — the aromatization dimension.

Androgen Receptor CAG Repeats: Sensitivity Explained — the receptor sensitivity dimension.

SRD5A2 and 5-Alpha Reductase Genetics — the DHT conversion dimension.

HPTA Axis Genetics: LH, FSH, and Fertility Preservation — the axis recovery dimension.

DHEA and Pregnenolone Pathway Genetics — the upstream source dimension.

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 map all six dimensions of your androgen genetics before your next protocol conversation? Take the Precision Peptide Genetic Test

Frequently Asked Questions About Androgen Protocol Genetics

Why do some men respond better to androgen-pathway protocols than others?

At least six genetic variables shape individual response: SHBG (bioavailability), CYP19A1 (aromatization), AR CAG repeats (receptor sensitivity), SRD5A2 (DHT conversion), LHCGR/FSHR (HPTA dynamics), and CYP17A1 (upstream precursor production). The Precision Peptide Genetic Test analyzes all 6 Reproductive Health insights together — explaining variability that serum testosterone testing alone cannot predict.

Can genetic testing tell me how I will respond to testosterone optimization?

Not in the sense of predicting specific outcomes — but the Precision Peptide Genetic Test maps six variables that shape response: SHBG (bioavailability), CYP19A1 (aromatization), SRD5A2 (DHT conversion), AR (receptor sensitivity), LHCGR/FSHR (HPTA recovery), and CYP17A1 (precursor production). That genetic baseline is meaningfully different clinical context than serum testosterone alone provides.

What is the most important genetic variable for androgen protocol response?

No single variable dominates — which is exactly the problem with single-gene analyses. SHBG determines availability, CYP19A1 shapes estradiol balance, AR governs receptor-level response, SRD5A2 controls DHT output, and LHCGR/FSHR affects axis dynamics. The Precision Peptide Genetic Test analyzes all 6 Reproductive Health insights together because no one gene tells the complete story.

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.