Gender-Affirming Hormone Therapy: Key Drug Interactions and Side Effects to Watch For

When someone starts gender-affirming hormone therapy (GAHT), they’re not just changing their body-they’re starting a long-term medical journey. For transgender women, that often means taking estradiol and an anti-androgen like spironolactone or cyproterone acetate. For transgender men, it’s usually testosterone, given as gel, injection, or pellet. These treatments work. They help people feel more aligned with themselves. But they don’t exist in a vacuum. They interact with other medications-sometimes in ways that aren’t obvious, and sometimes in ways that can be dangerous.

How GAHT Metabolism Creates Interaction Risks

The body breaks down hormones using specific enzyme systems, mainly in the liver. The most important one for GAHT is called CYP3A4. Estradiol, whether taken as pills or patches, relies heavily on this system. If another drug speeds up or slows down CYP3A4, it changes how much estradiol stays in your bloodstream. That can mean your hormone therapy stops working-or you get too much of it, raising your risk of blood clots or other side effects.

Testosterone is different. It’s mostly broken down by enzymes called 5-alpha reductase and aromatase. That means it doesn’t interact with CYP3A4 as much. But it still plays nice-or clashes-with other drugs, especially those that affect mood, liver function, or heart health.

GnRH agonists like leuprolide are another story. They shut down your body’s natural hormone production. They don’t get metabolized the same way as estrogen or testosterone. That’s why they rarely interact with other medications. But they’re often used at the start of treatment, so knowing how they fit into the bigger picture matters.

Antiretroviral Therapy: A Critical Overlap

Transgender people, especially transgender women, are at higher risk for HIV. That means many are on antiretroviral therapy (ART) while also taking GAHT. This overlap is common-and risky if not managed.

Some HIV drugs, like efavirenz, are enzyme inducers. They make your liver break down estradiol faster. Studies show this can drop estrogen levels by 30% to 50%. That means you might feel like your hormone therapy isn’t working: mood swings, low libido, or hot flashes return. Your doctor might think you’re noncompliant, when really, your meds are fighting each other.

On the flip side, drugs like cobicistat (used in combos like darunavir/cobicistat) are strong inhibitors. They slow down estradiol breakdown. That can cause estrogen levels to spike by 40% to 60% in just two weeks. That’s a red flag for blood clots, stroke, or high blood pressure. If you’re starting a new HIV med, your estradiol dose may need to be lowered-sometimes by half.

Good news: integrase inhibitors like dolutegravir don’t interfere much. They might slightly raise estradiol levels, but not enough to worry about. And GnRH agonists? No known interactions with any ART. That makes them a safer option if you’re on complex HIV treatment.

PrEP and GAHT: Mostly Safe, But Still Monitor

Pre-exposure prophylaxis (PrEP), like Truvada or Descovy, is vital for HIV prevention. A major 2022 study tracked 172 transgender people on both PrEP and GAHT for 12 weeks. The results were reassuring: hormone levels didn’t change meaningfully. Tenofovir levels (the active part of PrEP) stayed steady too. No dose changes were needed.

But here’s the catch: most of that data comes from oral PrEP (TDF/FTC). Long-acting injectable PrEP, like cabotegravir, is newer. There are only two published case reports on its interaction with GAHT. No one knows yet if it affects hormone levels. Until more data comes in, stick with oral PrEP if you’re on estradiol, unless your provider says otherwise.

Psychiatric Medications: The Hidden Conflict

Transgender people experience higher rates of depression, anxiety, and PTSD. Many take SSRIs like fluoxetine or sertraline. Here’s the problem: some of these drugs block CYP2D6, an enzyme that also helps break down estradiol. That means your estrogen levels could rise unexpectedly. You might get breast tenderness, headaches, or nausea-not because your dose is too high, but because your body can’t clear it anymore.

Worse, some mood stabilizers do the opposite. Carbamazepine, phenytoin, and rifampin are strong CYP3A4 inducers. They can slash estradiol levels by 30% or more. If you’re on one of these for bipolar disorder or seizures, your hormone therapy might stop working. You might need a higher dose of estradiol-or switch to a different anti-androgen like spironolactone, which is less affected.

Testosterone has fewer known interactions with psychiatric meds. But a 2023 review found 17 cases where people on testosterone needed to increase their antidepressant dose by 25% to 50% within six weeks. Why? It’s not fully understood. Maybe testosterone changes brain chemistry in ways that reduce antidepressant effectiveness. Or maybe it improves mood so much that the antidepressant isn’t needed anymore. Either way, watch for changes in mood, energy, or sleep after starting testosterone.

Other Common Medications to Watch

You might be on other meds you don’t think are connected. Here’s what to check:

• Blood thinners (warfarin): Estradiol can increase clotting factors. If you’re on warfarin, your INR might drop. Your doctor will need to check it more often.
• Insulin or diabetes meds: Testosterone can improve insulin sensitivity, which might lower your blood sugar. You might need less insulin or metformin.
• Thyroid meds: Estradiol increases thyroid-binding proteins. That can make your free T4 levels look low-even if you’re fine. Your doctor should check TSH, not just T4.
• Statins: Some studies suggest testosterone may raise LDL cholesterol. If you’re on a statin, your levels might need closer monitoring.
• Seizure meds: As mentioned, carbamazepine and phenobarbital can interfere with estradiol. Lamotrigine and valproate seem safer.

What Doctors Should Do-And What You Should Ask For

Too many providers still treat GAHT like it’s separate from everything else. It’s not. You need a full medication review before starting, and again every time you add or change a drug.

Here’s what to ask:

• “Does this new medication interact with my hormones?”
• “Should I get my estradiol or testosterone level checked after starting this?”
• “Is there a safer alternative if this one interferes?”

Also, ask for therapeutic drug monitoring. That means getting a blood test to check your actual hormone levels-not just relying on dose charts. It’s not always offered, but it’s the best way to know if your treatment is working.

The Bottom Line: Safety Is Possible-But Not Automatic

Gender-affirming hormone therapy is one of the safest medical treatments out there when properly managed. Serious side effects are rare. But that doesn’t mean you can ignore other meds. The biggest risk isn’t the hormones themselves-it’s the lack of coordination between providers.

If you’re on GAHT and take any other prescription, over-the-counter, or herbal product, tell your endocrinologist. Don’t assume they know. Bring a full list. Include supplements, birth control, pain meds, even CBD oil.

And if your provider says, “It’s fine,” but you feel off-trust yourself. Ask for a hormone level test. Ask for a second opinion. Your health matters. You deserve care that sees the whole picture, not just one part of you.