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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

Genetics affects estrogen in men through at least four distinct mechanisms — and understanding which variants you carry is the difference between a hormone strategy built on your actual biology and one built on assumptions. Estrogen in men is not a problem to eliminate. Estradiol is essential for bone density, cardiovascular function, libido, cognitive performance, and mood regulation. The question is always balance: how much is produced, how efficiently it is cleared, how sensitively tissues respond to it, and how much circulates in bioavailable form. All four of these are genetically influenced. The PlexusDx Precision Peptide Genetic Test analyzes the key variants across all four mechanisms as part of 14 pathways, 49 peptides, and 150+ genetic insights.

Pathway 1 — Production: CYP19A1 and Aromatase Genetics

The most direct genetic influence on estrogen in men is CYP19A1, the gene encoding aromatase — the enzyme that irreversibly converts testosterone to estradiol and androstenedione to estrone. Aromatase activity in men occurs primarily in adipose tissue, skin, liver, bone, and brain. CYP19A1 variants that increase enzymatic activity produce more estradiol per unit of testosterone substrate; lower-activity variants produce less.

This is the primary genetic driver of the testosterone-to-estrogen ratio in men. A man with high-activity CYP19A1 will produce more estradiol from his circulating testosterone at baseline — and substantially more when testosterone levels are elevated through any androgen-pathway protocol. The aromatase genetics don't change; the substrate they act on does. CYP19A1 and Estrogen Conversion in Men covers the production dimension in full.

Pathway 2 — Clearance: COMT, MTHFR, and Estrogen Metabolism

Producing estradiol is only half the equation. Phase 1 metabolism (CYP1A1, CYP1B1) hydroxylates estradiol into catechol estrogens — reactive intermediates that must then be rapidly inactivated through Phase 2 methylation. COMT (catechol-O-methyltransferase) performs this methylation step, using SAMe as the methyl donor. Slow COMT variants (Val158Met, Met/Met genotype) reduce clearance speed, allowing catechol estrogens to accumulate and recycle to active estrogens.

MTHFR enters here as an upstream amplifier. MTHFR variants (C677T, A1298C) impair the folate cycle that produces 5-MTHF → methionine → SAMe. Less SAMe means COMT has insufficient methyl donor to function at full capacity — slowing estrogen clearance even when the COMT enzyme itself is normal. A man with high-activity CYP19A1 (producing more estradiol) plus impaired MTHFR (limiting COMT's clearing capacity) faces estrogen accumulation from both ends simultaneously. MTHFR and Methylation: How They Shape Male Hormone Optimization covers this clearance chain in full.

Pathway 3 — Receptor Sensitivity: ESR1 and ESR2

The effects of estradiol at target tissues are mediated through estrogen receptors — ESR1 (estrogen receptor alpha) and ESR2 (estrogen receptor beta), each expressed in different tissue distributions with partially distinct downstream signaling. Variants in both receptor genes affect binding affinity, receptor expression levels, and the downstream transcriptional response to estradiol.

This means two men can carry identical estradiol levels and experience them very differently at the tissue level. Higher ESR1 sensitivity amplifies the biological response to circulating estradiol — in some tissues this is beneficial (bone density, cognitive function), in others the effects depend on overall hormonal balance. ESR2 variants affect the balance between ERα and ERβ signaling, which modulates how estrogen-dependent pathways in prostate, immune tissue, and the cardiovascular system respond. Receptor genetics add the downstream sensitivity dimension that serum estradiol measurements alone cannot capture.

Pathway 4 — Binding and Substrate: SHBG and SRD5A2

SHBG binds both testosterone and estradiol. High-SHBG variants reduce free estradiol as well as free testosterone — affecting how much estradiol circulates in bioavailable form and reaches estrogen receptors. Whether elevated SHBG is helpful or unhelpful for estrogen management depends on the full genetic context: a man with both high CYP19A1 activity (producing more estradiol) and high SHBG (binding more of it) may have very different net free estradiol dynamics than either variant suggests in isolation. SHBG Genetics: Why Your Free Testosterone Varies covers the binding dimension in full.

SRD5A2 — 5-alpha reductase — contributes to the estrogen equation indirectly through substrate competition. Testosterone can be converted to either DHT (via SRD5A2) or estradiol (via CYP19A1). Higher SRD5A2 activity routes more testosterone toward DHT, reducing the substrate available for aromatization. Men with high-activity SRD5A2 genetics have a built-in partial brake on aromatization — competing for the same testosterone pool that CYP19A1 draws from. SRD5A2 and 5-Alpha Reductase Genetics covers the DHT conversion side of this competition.

What This Means for Men on Androgen Protocols

On any androgen-pathway protocol that elevates testosterone, all four genetic mechanisms become more consequential simultaneously. More testosterone substrate means more material for CYP19A1 to aromatize — so high-activity aromatase genetics amplify their effect. More estradiol produced means more demand on COMT and the methylation cycle for clearance. More free estradiol in circulation interacts with whatever ESR1/ESR2 receptor sensitivity the man carries. And SHBG determines how much of that estradiol stays bound vs. free at every step.

A provider managing estrogen on an androgen protocol without knowing these four genetic variables is working from an incomplete map. The same protocol can produce very different estrogen pictures depending on the combination of CYP19A1, COMT, MTHFR, ESR1, SHBG, and SRD5A2 variants a man carries. The full picture of how these variables explain protocol variability is in Why TRT Works for Some Men and Not Others: The Genetic Answer and the Complete Guide to Genetic Men's Hormone Testing.

How the Precision Peptide Genetic Test Maps Estrogen Genetics in Men

The Precision Peptide Genetic Test delivers all four estrogen-relevant genetic dimensions — CYP19A1 (production), COMT and MTHFR (clearance), ESR1/ESR2 (receptor sensitivity), and SHBG plus SRD5A2 (binding and substrate competition) — as part of 6 Reproductive Health insights within a 14-pathway panel. Analysis runs on the Illumina Global Screening Array at CLIA-certified labs, covering 57 unique SNPs across 48 unique genes.

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 how your genetics shape your estrogen picture? Take the Precision Peptide Genetic Test

Frequently Asked Questions About Genetics and Estrogen in Men

What is the main gene that controls estrogen levels in men?

CYP19A1 (aromatase) is the primary genetic driver of estrogen production in men — it encodes the enzyme that converts testosterone to estradiol. High-activity CYP19A1 variants produce more estradiol per unit of testosterone substrate. The Precision Peptide Genetic Test analyzes CYP19A1 alongside COMT, SHBG, ESR1, and SRD5A2 as part of 6 Reproductive Health insights.

Can genetics cause high estrogen in men?

Yes. High-activity CYP19A1 variants increase testosterone-to-estradiol conversion. Combined with slow COMT variants or impaired MTHFR methylation — which reduces estrogen clearance — genetics can establish a baseline that favors elevated estradiol before any protocol begins. The Precision Peptide Genetic Test identifies all three variables together as part of 14 pathways and 150+ genetic insights.

Does SHBG affect estrogen levels as well as testosterone?

Yes — SHBG binds both testosterone and estradiol. High-SHBG variants reduce free estradiol as well as free testosterone. Whether this is beneficial depends on CYP19A1 production rate and ESR1/ESR2 receptor sensitivity. The Precision Peptide Genetic Test analyzes all these interactions as part of 14 pathways and 150+ genetic insights.

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.