Hormone Replacement Therapy: What Medications It Interacts With and Why

Oct, 30 2025

When you start hormone replacement therapy (HRT) for menopause, you’re not just adding one drug to your routine-you’re changing how your whole body processes other medicines. Many women don’t realize that the estrogen and progestin in HRT can make some of their other medications work less effectively-or even cause dangerous side effects. This isn’t theoretical. Real cases have been documented: women on lamotrigine for depression saw their symptoms return after starting HRT, not because their depression got worse, but because their blood levels of lamotrigine dropped by nearly half.

How HRT Changes How Your Body Processes Medicines

HRT doesn’t just replace hormones-it tricks your liver into changing how it breaks down other drugs. Estrogen, especially in oral pills, tells your liver to make more of certain enzymes, like UGT1A4. This enzyme is responsible for cleaning up medicines like lamotrigine, an anticonvulsant used for epilepsy and mood disorders. When estrogen ramps up UGT1A4, lamotrigine gets cleared from your blood faster. That means you’re not getting the full dose anymore, even if you’re taking the same pill.

This isn’t just about lamotrigine. The same mechanism affects other drugs metabolized by liver enzymes, including some antibiotics, tuberculosis meds, and HIV treatments. The NHS warns that HRT can make epilepsy harder to control because of these interactions. The problem is worse with oral HRT because the hormones go straight to the liver after swallowing. Skin patches, on the other hand, deliver hormones slowly through the skin, bypassing the liver’s first pass. That’s why patches are less likely to interfere with other meds.

Medications That Don’t Play Well With HRT

Here are the most common and dangerous interactions you need to watch for:

• Lamotrigine: Estrogen-based HRT can cut lamotrigine levels by up to 50%. Women have reported worsening depression or seizures after starting HRT. Stopping HRT often brings lamotrigine levels back up.
• St. John’s wort: This herbal supplement for mild depression speeds up the breakdown of estrogen. It can make HRT less effective, leading to hot flashes, mood swings, or breakthrough bleeding. The NHS explicitly says to avoid it with HRT tablets.
• Corticosteroids (like hydrocortisone): HRT increases a protein called CBG in the blood, which binds to cortisol. This makes standard cortisol blood tests useless for checking if your hydrocortisone dose is right. You might be underdosed and not even know it.
• Anticoagulants (warfarin, apixaban): Estrogen can slightly increase clotting risk, which may counteract blood thinners. Your doctor may need to monitor your INR more closely if you’re on both.
• Thyroid hormone (levothyroxine): HRT can increase thyroid-binding proteins, making your thyroid hormone less available. You might need a higher dose of levothyroxine after starting HRT.
• Resveratrol: Found in red wine and supplements, this compound mimics estrogen and may interfere with HRT’s action, though evidence is still weak.

Even something as simple as a multivitamin with high-dose B6 or magnesium can affect how HRT is absorbed. Always tell your pharmacist or doctor what you’re taking-even if you think it’s "just natural."

Why Transdermal HRT Might Be Safer

If you’re on multiple medications, especially those with narrow therapeutic windows, switching from oral HRT to a patch or gel might be the smartest move. Transdermal delivery avoids the liver’s first-pass metabolism. That means fewer enzyme changes, fewer drug interactions, and more stable hormone levels.

The NHS confirms that patches are "less affected" by substances like St. John’s wort or antibiotics. A woman on lamotrigine who switched from Femoston (oral) to an estradiol patch saw her lamotrigine levels stabilize within weeks. No dose changes. No worsening symptoms. Just a different delivery method.

It’s not a magic fix-patches still contain estrogen-but they reduce the risk dramatically. If you’re on epilepsy meds, antidepressants, or thyroid drugs, ask your doctor if a patch is an option. You might not need to stop HRT-you just need to change how it’s delivered.

The Cortisol Trap: When HRT Skews Lab Results

One of the sneakiest HRT interactions isn’t about how well a drug works-it’s about how doctors think it’s working. If you’re taking hydrocortisone for adrenal insufficiency and then start HRT, your total cortisol blood levels will jump. Not because you’re making more cortisol, but because HRT increases a protein that binds cortisol in the blood.

Here’s the problem: standard cortisol tests measure total cortisol, not the active free form. So your doctor might see high numbers and think you’re overdosed, when you’re actually normal-or even underdosed. The Pituitary Foundation says this makes cortisol tests useless for monitoring hydrocortisone replacement in women on HRT. The solution? Use ACTH stimulation tests or measure free cortisol directly. Don’t rely on routine cortisol panels.

What to Do Before Starting HRT

Don’t wait for problems to show up. Before you start HRT, make a full list of everything you take:

1. All prescription drugs (including painkillers and sleep aids)
2. All supplements (vitamins, herbs, fish oil, resveratrol)
3. All over-the-counter meds (ibuprofen, antacids, cold pills)
4. Any herbal teas or wellness tonics

Take this list to your doctor or pharmacist. Don’t assume they’ll ask. Most won’t unless you bring it up. If you’re on lamotrigine, warfarin, or hydrocortisone, be extra clear. Say: "I’m on HRT and I need to know if this will affect my other meds."

Also, ask: "Is there a patch or gel version of HRT that would be safer for me?" Many doctors still default to pills because they’re cheaper and more familiar. But if you’re on other meds, that’s not always the best choice.

Red Flags: When to Call Your Doctor Immediately

Some interactions don’t cause slow decline-they cause sudden danger. If you start HRT and notice any of these, contact your doctor right away:

• Sudden, severe headache or dizziness
• Swelling in hands, feet, or ankles (could mean fluid retention from steroid interactions)
• Worsening depression, anxiety, or seizures
• Unexplained bruising or bleeding (possible blood thinner interference)
• Loss of vision, slurred speech, or weakness on one side of the body

These could signal a blood clot, stroke, or dangerously low drug levels. Don’t wait. Don’t assume it’s "just menopause."

What About Bioidentical HRT?

Some women turn to "bioidentical" hormones, marketed as more natural and safer. But here’s the truth: they still contain estrogen and progesterone. Whether they’re made in a lab or compounded in a pharmacy, they interact with your liver the same way. There’s no evidence that bioidentical HRT avoids interactions with lamotrigine, corticosteroids, or anticoagulants. In fact, because they’re not standardized, you might not even know how much estrogen you’re getting-making interactions harder to predict.

Regulators like the FDA and European Medicines Agency warn that compounded bioidentical HRT lacks safety data. Stick to FDA-approved formulations. They have documented interaction profiles. Compounded ones don’t.

The Bottom Line

HRT can be life-changing for menopause symptoms-but it’s not a simple hormone swap. It’s a system-wide shift that affects how your body handles every other medicine you take. The interaction with lamotrigine is just the tip of the iceberg. Cortisol tests, blood thinners, epilepsy drugs, even herbal supplements-all can be thrown off by estrogen.

The safest approach? Be proactive. Know your meds. Ask about patches. Don’t assume "natural" means safe. And never start or stop HRT without talking to your doctor about everything else you’re taking. Because when hormones and medications collide, the consequences aren’t theoretical-they’re real, measurable, and sometimes life-threatening.

If you’re on HRT and another medication, don’t guess. Ask. Check. Monitor. Your safety depends on it.