The Genes You Need to Know Before You Start HRT

Hormone Replacement Therapy (HRT) can be genuinely life-changing — helping with sleep, mood, hot flushes, energy, libido, and that sense of “I finally feel like myself again.”

But here’s what most women are never told:

Your genes can directly influence how well you tolerate HRT, how effectively you metabolise hormones, and whether you’re more likely to experience side effects.

This is why two women can be on the exact same HRT dose, yet have completely different experiences.

As a naturopath specialising in genetics and hormonal health, I regularly see women who feel worse on HRT — not because HRT is wrong for them, but because the type, form, or dose doesn’t match their genetic profile.

Below are the key genes that matter most before you start HRT.

BLOG CATEGORY

GENES AND GUT

MICROPLASTICS

TOP 3 GENES

DNA TEST

COMT — Your Oestrogen “Traffic Controller

COMT determines how efficiently you clear catechol oestrogens — the more stimulating forms of oestrogen.

Women with a slow COMT often experience:

  • PMS, anxiety or irritability

  • Overwhelm under stress

  • Sensitivity to hormonal changes

  • Worsening symptoms on oestrogen-based HRT

Why it matters for HRT:

  • Lower starting doses

  • These liver enzymes determine which pathway oestrogen goes down.

  • Fatigue, brain fog, slow recovery, skin sensitivity

CYP1A1 + CYP1B1 — How You Process and Convert Oestrogen

These liver enzymes determine which pathway oestrogen goes down.

  • CYP1A1 → the “safer”, detox-preferred pathway

  • CYP1B1 → the “4-OH” pathway that can create more reactive oestrogen intermediates

If CYP1B1 is upregulated genetically, women may experience:

  • Tender breasts

  • Heavy periods (before menopause)

  • Headaches on HRT

  • Feeling “wired” or inflamed

You may need:

  • More antioxidant support

  • Specific foods/nutrients to shift oestrogen down safer pathways (e.g., broccoli sprouts, DIM — only if appropriate)

  • Careful monitoring when increasing oestrogen doses

CYP3A4 — How You Clear Hormones (and Most Medications)

CYP3A4 influences how quickly you clear hormones, including oral oestrogen and progesterone.

If CYP3A4 is fast, you may burn through HRT quickly and feel like nothing is happening. If it’s slow, you may experience stronger effects on a very standard dose.

Why it matters for HRT

Women with slow CYP3A4 often experience:

  • Nausea or headaches on oral HRT

  • Irritability or mood swings

  • Feeling “drugged” or sedated

SULT1A1 — Your Sulphation Pathway

This gene helps your body deactivate and excrete oestrogen.

If SULT1A1 is slow, you may have difficulty clearing hormones, leading to:

  • Fluid retention

  • Breast tenderness

  • Bloating

  • Heightened PMS-like feelings on HRT

GST + GPX — Detox & Cellular Protection

These genes don’t metabolise hormones directly, but they protect your tissues from oxidative stress triggered by certain oestrogen metabolites.

If GST or GPX variants are present, you may be more sensitive to:

  • Oral oestrogens

  • Synthetic progestins

  • Higher doses of transdermal oestrogen

Why this matters

You’ll usually tolerate body-identical HRT better, with extra support for:

  • Glutathione

  • Selenium

  • Antioxidants

MTHFR + Methylation Genes

These influence how well you recycle and deactivate certain oestrogen metabolites.

Slow methylation may mean:

  • Slow methylation may mean:

  • Anxiety or sleep disturbances with HRT

  • Difficulty clearing stimulating hormones

What This Means for Your HRT Plan

Knowing these genes helps you determine:

What we uncover with testing:

  • Which form of HRT will suit you best

  • What dose you should start on

  • How quickly you can increase

  • Why you might be reacting or not reacting at all

It’s not about “good” or “bad” genes — it’s about matching your biology to your hormones.

When I Work With Women Starting HRT

I look at:

  • Their genetic report

  • Gut health (because gut affects oestrogen clearance)

  • Detox pathways

  • Stress tolerance

  • Sleep + mood patterns

  • Their current hormonal symptoms

And then we tailor HRT around their genetics — not the other way around.

Thinking About Starting HRT? Get Your Genes Checked First.

If you’re considering HRT — or you’re already on it but not feeling the benefits — understanding your genes can make the entire process smoother, safer and more effective.

If you’d like personalised guidance, you can book a consultation here