Gender-Affirming Hormone Therapy: Interactions and Side Effects with Other Medications

When someone starts gender-affirming hormone therapy (GAHT), they’re not just changing their body-they’re changing how their body processes every other medication they take. It’s not just about estrogen or testosterone anymore. It’s about how those hormones talk to the pills you’re already taking for HIV, depression, high blood pressure, or even acne. And if you’re not paying attention to those conversations, things can go sideways-fast.

Why This Matters More Than You Think

Transgender people are more likely to be on multiple medications than cisgender people. According to the 2021 National Transgender Survey, nearly 40% report having at least one chronic health condition, and 3.4 times more are living with HIV. That means many folks on GAHT are also taking antiretrovirals, antidepressants, or blood pressure meds. The problem? Most of these drugs were never tested with hormone therapy in mind.

You might think, “My doctor knows what I’m on.” But a 2023 audit of U.S. endocrinology clinics found only 41% had a standard checklist for checking drug interactions. That’s not a system-it’s luck.

How Feminizing Hormones Interact with Common Drugs

Feminizing therapy usually means estradiol (either pills, patches, or gels) plus an anti-androgen like spironolactone or cyproterone acetate. Estradiol is mostly broken down by an enzyme in your liver called CYP3A4. If something else you’re taking changes how this enzyme works, your estrogen levels can swing wildly.

Antiretrovirals are the biggest red flag. Some HIV meds boost CYP3A4, which means your body clears estrogen faster. Efavirenz, for example, can drop estradiol levels by 30-50%. That’s not just inconvenient-it can mean your hormones stop working. On the flip side, drugs like darunavir/cobicistat (a common combo) can make estrogen levels jump 40-60%. That raises your risk of blood clots, stroke, or high blood pressure. No one wants to start GAHT and end up in the ER because their estrogen spiked.

Integrase inhibitors like dolutegravir are safer. They raise estrogen levels a bit-around 25-35%-but not enough to need a dose change. Still, your provider should check your estradiol levels 4-6 weeks after starting or switching HIV meds.

Psychiatric meds are trickier. Fluoxetine (Prozac) and paroxetine (Paxil) block CYP2D6, another enzyme that helps break down estrogen. That can lead to higher estrogen levels, even if you’re on a low dose. Meanwhile, carbamazepine (used for seizures or bipolar disorder) turns on CYP3A4 and can make estrogen less effective. There’s no clear rulebook here. One study found 17 cases where testosterone therapy made antidepressants stop working-patients needed dose increases of 25-50% within six weeks.

Testosterone and What It Does to Other Drugs

Testosterone is simpler in some ways. It doesn’t rely heavily on CYP3A4. Instead, it’s processed by enzymes like 5-alpha reductase and aromatase. That means fewer drug interactions overall. But that doesn’t mean zero.

Antiretrovirals don’t interfere with testosterone. Studies show no meaningful changes in testosterone levels when taken with any HIV drug, including boosted protease inhibitors. That’s good news.

Psychiatric drugs are where things get murky. There’s almost no data on how SSRIs, SNRIs, or mood stabilizers behave with testosterone. But we know this: testosterone changes brain chemistry. It can affect serotonin, dopamine, and cortisol. If you’re on fluoxetine or sertraline, you might notice your mood shifts faster or differently than before. Some people feel more irritable. Others feel clearer-headed. Neither is wrong-but you need to track it.

Blood thinners like warfarin can be affected. Testosterone can increase red blood cell production, which may alter how your body responds to anticoagulants. Your INR (a measure of blood clotting time) should be checked more often in the first 3 months of starting testosterone.

What About PrEP? Is It Safe?

PrEP-pre-exposure prophylaxis-is life-saving for HIV-negative people at risk. And yes, it’s safe with GAHT. A major 2022 study at the Conference on Retroviruses and Opportunistic Infections followed 172 transgender people on tenofovir/emtricitabine (Truvada or Descovy) while on hormone therapy. The results? No meaningful changes in hormone levels. No changes in PrEP drug levels either. Tenofovir diphosphate (the active form) stayed within protective ranges in 92% of participants.

That’s huge. It means you don’t need to pick between HIV prevention and gender-affirming care. You can do both. But here’s the catch: you still need to get your PrEP levels checked. Some people metabolize tenofovir differently. A simple dried blood spot test every 12 weeks can confirm you’re protected.

GnRH Agonists: The Silent Players

GnRH agonists like leuprolide (Lupron) are often used as puberty blockers or to suppress natural hormones before starting estrogen or testosterone. The good news? They don’t interact with almost anything. No known interactions with HIV meds, antidepressants, or blood pressure drugs. They’re metabolized differently-mostly through the kidneys, not the liver. That makes them one of the safest options.

But here’s what no one tells you: GnRH agonists can make you more sensitive to other drugs. Because they shut down your natural hormone production, your body’s baseline changes. A dose of antidepressant that worked fine before might now feel too strong-or too weak. That’s not the drug’s fault. It’s your new hormonal environment.

What You Should Do Right Now

You don’t need to wait for a perfect system. You can protect yourself today.

1. Make a full list of every medication, supplement, and OTC drug you take-even the ones you forgot about. Include birth control, herbal teas, and acne creams.
2. Bring it to your provider-not just your endocrinologist, but your primary care doctor, psychiatrist, and pharmacist. Ask: “Could any of these affect my hormones-or my hormones affect them?”
3. Ask for hormone level checks at 4-6 weeks after starting or changing any new medication. Estradiol and testosterone levels should be tracked, not assumed.
4. Track your symptoms. If your mood changes, your skin breaks out, your period returns (if you’re on testosterone), or you feel dizzy or swollen-write it down. These aren’t just side effects. They’re data.
5. Use a medication app. Apps like Medisafe or MyTherapy let you share your list with providers and flag potential interactions. Don’t rely on memory.

What’s Still Unknown

We’re learning fast, but there are big gaps. No one knows how cabotegravir (the long-acting PrEP shot) interacts with GAHT. We don’t know how newer antidepressants like brexanolone behave with testosterone. And while Gilead and other companies are now required to include transgender people in trials, most past studies didn’t.

The NIH’s Tangerine Study, running through 2025, is one of the first to look at 12 psychiatric drugs and GAHT together. Preliminary data is expected in early 2025. Until then, proceed with caution-and curiosity.

The Bottom Line

Gender-affirming hormone therapy is safe. But safety doesn’t mean “no risks.” It means you’re aware of them. The interactions aren’t scary if you’re informed. They’re manageable if you’re proactive.

You don’t need to choose between being yourself and being healthy. You need a team that listens. A provider who checks your labs. A pharmacist who asks about your hormones. A system that doesn’t treat you as an afterthought.

Start today. Write down your meds. Ask the questions. Demand better. Your body deserves nothing less.