Gilbert’s Syndrome, Glucuronidation and Your Hormones:

What Your GP Probably Never Told You — And Why It Matters Before Menopause

By Dr Hazel Batten, Integrative GP at Remede Wellness Medicine

For years, as a conventional GP, I gave the same reassurance to patients whose blood tests came back with a slightly elevated bilirubin: “You have Gilbert’s syndrome. It’s completely benign. Nothing to worry about.”

I said it confidently, because that is what we were taught. Gilbert’s syndrome — a common genetic variant affecting around 1 in 10 people — was presented to us in medical training as a harmless quirk of bilirubin metabolism. Interesting on a blood test, irrelevant in practice.

But as I moved into integrative and functional medicine, and began looking far more deeply at the liver’s role in hormone metabolism, I started to question that reassurance — particularly for women in their reproductive and perimenopausal years.

Because the same enzyme that is reduced in Gilbert’s syndrome — UGT1A1 — is also responsible for clearing oestrogen from the body. And when oestrogen clearance is impaired, the downstream effects can be wide-ranging, subtle, and entirely missed if nobody is looking for them.

This article is not intended to alarm anyone about Gilbert’s, or to put anyone off using hormones — quite the opposite. Menopausal hormone therapy (MHT) can be genuinely life-changing, and I prescribe it regularly. But understanding your individual biology means we can support it properly, choose the right type and route of hormones, and address the root causes rather than just the symptoms.

First: What Is Gilbert’s Syndrome?

Gilbert’s syndrome is caused by a genetic variant in the UGT1A1 gene — most commonly a TA-repeat insertion in the gene’s promoter region (known as UGT1A1*28). This variant reduces the activity of the UGT1A1 enzyme by up to 70–80%, meaning the liver processes bilirubin more slowly than usual.

The result is mildly elevated unconjugated bilirubin — typically noticed on a routine blood test, often fluctuating with stress, fasting, illness or exercise. Symptoms, if present at all, are usually mild: occasional fatigue, a faint yellowing of the whites of the eyes, or nausea.

In standard medical practice, patients are told it is benign and requires no treatment. For many purposes, this is true. But the story does not end with bilirubin.

The key point

UGT1A1 does not only clear bilirubin. It also conjugates and clears oestrogen — specifically 17β-estradiol and its metabolites, including 4-OH oestrogens. In vitro studies demonstrate that bilirubin and oestrogen compete for the same binding site on UGT1A1. When bilirubin is high, oestrogen clearance slows. When the enzyme is genetically reduced, both processes are affected simultaneously.

The Liver’s Role in Hormone Clearance

Most people think of oestrogen as something that is produced by the ovaries and then simply ‘runs out’ at menopause. In reality, oestrogen metabolism is an ongoing, active process — and the liver is central to it.

Once oestrogen has done its job in the body, it needs to be inactivated and excreted. This happens in a two-phase liver detoxification process:

Phase 1: Hydroxylation

Oestrogen is converted into various metabolites — primarily 2-OH, 4-OH and 16-OH oestrogens. The ratio of these metabolites matters. The 2-OH pathway is generally considered protective. The 4-OH pathway produces more reactive, potentially carcinogenic metabolites, particularly if not cleared efficiently.

Phase 2: Glucuronidation (UGT1A1)

This is where UGT1A1 comes in. Glucuronidation attaches a glucuronic acid molecule to the oestrogen metabolite, making it water-soluble and ready for excretion via bile and urine. If this step is impaired — either genetically (Gilbert’s) or due to nutritional deficiencies, gut dysbiosis, or other factors — oestrogen and its metabolites can recirculate rather than being excreted.

The Gut Connection: Beta-Glucuronidase

There is an additional layer of complexity. Certain gut bacteria produce an enzyme called beta-glucuronidase, which can cleave the glucuronic acid molecule that the liver has carefully attached to oestrogen — effectively reactivating it and allowing it to be reabsorbed from the gut back into circulation. This is sometimes called the ‘oestrobolome’ — the portion of the gut microbiome that regulates circulating oestrogen levels.

An imbalanced gut microbiome, with high beta-glucuronidase activity, can therefore worsen the picture significantly — independent of any genetic UGT1A1 issues.

How This Shows Up in the Premenopausal Years

This is where I see the most missed opportunities in clinical practice. Women in their 30s and 40s presenting with a range of hormonal symptoms are rarely investigated through the lens of oestrogen clearance. Their Gilbert’s — if it has been identified at all — has been dismissed. Their gut health has not been considered. Their oestrogen metabolite pathways have never been tested.

And yet the clinical picture can be remarkably consistent. Women with impaired oestrogen clearance — whether due to UGT1A1 variants, gut dysbiosis, nutritional insufficiencies or a combination — may present with:

None of these symptoms are diagnostic of impaired oestrogen clearance in isolation — but taken together, in a woman with known or suspected Gilbert’s syndrome, they form a clinical picture that warrants investigation rather than reassurance.

A Word on SHBG

Sex hormone binding globulin (SHBG) is produced by the liver, and its production is stimulated by oestrogen. In women with impaired oestrogen clearance and persistently elevated oestrogen exposure, SHBG may rise — binding more of the circulating testosterone and other hormones, and reducing their bioavailability.

This can create a paradoxical picture: total hormone levels appear normal or even high on standard blood tests, but free hormone levels are low. Women may experience symptoms of low testosterone (fatigue, low libido, poor concentration) even when their total levels look adequate. Standard testing misses this entirely.

This is one reason why a full hormone panel — including SHBG, free hormone calculations, and ideally oestrogen metabolite testing — gives a far more complete picture than a single hormone level.

Supporting MHT Use Safely in Women with Impaired Glucuronidation

I want to be very clear here: Menopausal hormone therapy is not contraindicated in women with Gilbert’s syndrome or impaired glucuronidation. For most women, the benefits of appropriate MHT — for bone, heart, brain, mood, sleep and quality of life — are substantial, and withholding it on the basis of a UGT1A1 variant alone would not be clinically justified.

But it does mean that how we prescribe, and what we support alongside the prescription, matters more in these women. Here is how I approach it in practice:

1. Choose Transdermal Over Oral Oestrogen

Oral oestrogen undergoes significant first-pass metabolism in the liver, creating a larger burden on hepatic clearance pathways, including UGT1A1. Transdermal oestrogen (patches, gels, sprays) bypasses first-pass metabolism entirely, delivering oestrogen directly into the bloodstream at lower effective doses. For women with any liver clearance considerations, this is almost always my preferred route.

2. Use Body-Identical Hormones

Body-identical (micronised) progesterone (Utrogestan) is preferred over synthetic progestogens (progestins). Synthetic progestins can further burden liver metabolism and have different receptor profiles. Micronised progesterone is metabolised more cleanly and has a better safety and tolerability profile, particularly for mood and sleep.

3. Consider Oestrogen Metabolite Testing (DUTCH Test)

The DUTCH (Dried Urine Test for Comprehensive Hormones) measures not just oestrogen levels but the full spectrum of oestrogen metabolites — including the 2-OH, 4-OH and 16-OH pathways, and the extent to which they are being methylated and cleared. For women with suspected impaired clearance, this provides information that a standard blood panel cannot.

4. Support Glucuronidation Nutritionally

Several nutrients and foods actively support UGT enzyme activity and broader liver detox pathways. These include cruciferous vegetables (broccoli, Brussels sprouts, kale — which contain glucosinolates and DIM), calcium D-glucarate (which inhibits beta-glucuronidase activity in the gut), magnesium (a cofactor for phase 2 detox), and B vitamins, particularly B6, B9 and B12, which support methylation alongside glucuronidation.

5. Address the Gut Microbiome

Reducing beta-glucuronidase activity — the enzyme that reactivates cleared oestrogen in the gut — is a clinically meaningful intervention. This involves supporting a diverse, healthy microbiome through dietary fibre, fermented foods, and targeted probiotic support where indicated. Stool testing can identify whether beta-glucuronidase activity is elevated.

6. Monitor, Adjust, and Test Appropriately

Women with impaired clearance may need different monitoring than standard MHT prescribing. This includes tracking symptoms carefully (not just relying on blood levels), repeating SHBG and free hormone calculations as the dose is titrated, and being alert to signs of oestrogen accumulation — breast tenderness, bloating, mood changes — that might indicate the clearance support needs to be increased alongside or before adjusting the MHT dose.

What to Ask Your Doctor

If any of this resonates — whether you have been told you have Gilbert’s syndrome, you have persistently elevated bilirubin, or you recognise the hormonal pattern described above — these are worth exploring with a practitioner who looks at the whole picture:

• Has my UGT1A1 genetic variant ever been considered in the context of my hormonal health?
• Has anyone looked at my oestrogen metabolite pathways, not just my oestrogen levels?
• Has my SHBG been measured, and has free oestrogen and free testosterone been calculated?
• Has the route of my hormones been considered in relation to my liver’s clearance capacity?
• Has my gut microbiome ever been evaluated as part of my hormonal picture?

You may not get these questions answered in a ten-minute GP appointment. But you deserve a practitioner who is willing to ask them.

A Final Thought

When I look back at the number of times I told a patient that Gilbert’s syndrome was ‘completely benign and nothing to worry about’, I do not feel embarrassed — I was working within the framework I had been given, and I said what was true within that framework.

But I do feel a sense of responsibility now. Because some of those women — the ones who also had terrible PMS, or couldn’t tolerate the pill, or whose periods became steadily heavier through their 30s — may have had something more useful to investigate than just a bilirubin number to explain away.

The science connecting UGT1A1 function, oestrogen clearance, and hormonal symptoms in women is not fringe or alternative. It is published in peer-reviewed journals and increasingly recognised in functional and integrative medicine. It simply hasn’t made it into the standard GP training yet.

My hope is that posts and articles like this one help bridge that gap — not to alarm, but to inform. Because knowing your biology is not a reason to be afraid of hormones. It is a reason to use them wisely.

Clinical Note

This article is written for educational purposes and reflects the clinical perspective of an integrative GP. It is not a substitute for individualised medical advice. The evidence base connecting UGT1A1 variants and oestrogen clearance is emerging and not yet fully established in prospective clinical trials; the clinical observations described here are consistent with current mechanistic understanding and functional medicine practice, but should be interpreted in the context of an ongoing and evolving evidence base. If you have concerns about your hormonal health, please seek assessment from a qualified clinician.

Key References

• Lv X et al. Novel insights into UDP-glucuronosyltransferase 1A1 dysfunction and Gilbert’s syndrome on estrogen metabolism and breast cancer. ScienceDirect, 2026.
• Guillemette C et al. UGT genomic diversity: Beyond one enzyme, one gene. Drug Metabolism Reviews, 2014.
• Vanhorebeek I et al. Is Gilbert syndrome a new risk factor for breast cancer? Medical Hypotheses, 2011.
• Baker JM et al. Estrogen metabolism and the gut microbiome. Maturitas, 20