Gender-Affirming Hormone Therapy: What You Need to Know About Drug Interactions and Side Effects

When someone starts gender-affirming hormone therapy (GAHT), they’re not just changing their body-they’re starting a long-term medical journey. And like any long-term medication plan, it doesn’t happen in a vacuum. GAHT interacts with other drugs you might be taking. Some of these interactions are harmless. Others can be serious. Knowing what to watch for can mean the difference between feeling stable and safe-or facing unexpected side effects that throw your treatment off track.

How GAHT Works and Why Interactions Matter

Gender-affirming hormone therapy comes in two main forms: feminizing therapy for transgender women and nonbinary people assigned male at birth, and masculinizing therapy for transgender men and nonbinary people assigned female at birth. Feminizing therapy usually includes estradiol (a form of estrogen) and an anti-androgen like spironolactone or cyproterone acetate. Masculinizing therapy uses testosterone, delivered as gel, patches, or injections.

These hormones don’t just float around freely. Your body breaks them down using specific enzymes-mostly in the liver. The most important one is called CYP3A4. If another drug you’re taking affects this enzyme, it can change how fast or slow your body processes your hormones. That means your estradiol or testosterone levels could drop too low-or spike dangerously high.

And it’s not just about hormone levels. Some medications can make your body react differently to hormones. For example, if you’re on an antidepressant and start testosterone, your mood might change in ways you didn’t expect-even if your hormone levels look normal on paper. That’s because hormones and psychiatric drugs often share the same brain pathways.

Biggest Risks: HIV Medications and GAHT

Transgender people are at higher risk for HIV, so many are on antiretroviral therapy (ART). That’s where things get tricky.

Some HIV drugs, like efavirenz and nevirapine, are enzyme inducers. They speed up CYP3A4, which means your body clears estradiol faster. Studies show this can drop estrogen levels by 30-50%. That’s not just inconvenient-it can undo the physical changes you’ve worked hard for. You might notice breast tissue shrinking, mood swings returning, or hot flashes coming back.

On the flip side, drugs like cobicistat (used in combo pills like Stribild or Genvoya) block CYP3A4. This slows down estrogen breakdown. Estradiol levels can jump by 40-60% in just two weeks. That raises your risk of blood clots, stroke, or liver stress. One 2024 review of 1,843 transgender patients found that people on cobicistat-boosted regimens needed lower estradiol doses to avoid side effects.

The good news? Newer HIV drugs like dolutegravir (an integrase inhibitor) don’t interfere much. They might raise estradiol by 25-35%, but that’s usually not enough to require dose changes. If you’re starting or switching HIV meds, talk to your provider about checking your estradiol levels before and after the switch.

PrEP and GAHT: No Need to Worry

If you’re on PrEP (pre-exposure prophylaxis) to prevent HIV, you’ll be glad to know: it doesn’t interfere with GAHT. A major 2022 study followed 172 transgender people taking tenofovir/emtricitabine (Truvada or Descovy) while also on estrogen or testosterone. Hormone levels changed by less than 5%. Tenofovir levels stayed steady too.

This is huge. It means you don’t have to choose between protecting yourself from HIV and getting the hormones you need. You can do both safely. The study even used dried blood spot tests to confirm people were taking their meds correctly-92% stayed in the protective range.

One exception: long-acting cabotegravir injections (Apretude). There’s almost no data yet. Until more studies come out, stick with daily pills if you’re on GAHT. That’s the safest bet right now.

Psychiatric Meds: The Hidden Wild Card

Transgender people are more likely to experience depression, anxiety, and PTSD. Many take SSRIs like fluoxetine (Prozac) or sertraline (Zoloft). These can interact with GAHT-but not how you’d think.

SSRIs like fluoxetine block CYP2D6, another liver enzyme. That enzyme helps break down estradiol. So if you’re on fluoxetine, your estrogen levels might rise slightly. Not enough to cause alarm, but enough that you might notice more breast tenderness or mood changes.

The bigger issue? Testosterone can reduce the effectiveness of some antidepressants. A 2023 review found 17 cases where people on testosterone suddenly felt their depression returning. Their SSRI dose was unchanged, but their body was processing it differently. In every case, increasing the SSRI dose by 25-50% helped.

Then there are mood stabilizers. Carbamazepine (Tegretol), used for bipolar disorder or seizures, is a strong CYP3A4 inducer. It can slash estrogen levels by up to 40%. If you’re on this drug, your provider may need to raise your estradiol dose-or switch you to a non-interacting mood stabilizer like lamotrigine.

The scary part? Most antidepressant trials never included transgender people. So we’re guessing a lot of the time. That’s why monitoring your mood, energy, and sleep isn’t optional-it’s essential.

Other Common Medications to Watch For

Here’s a quick cheat sheet for drugs that might mess with GAHT:

• Antibiotics: Rifampin (used for TB) is a strong CYP3A4 inducer. Avoid it if you’re on estrogen. If you must take it, expect to need higher estradiol doses.
• Seizure meds: Phenobarbital, phenytoin, and topiramate can all lower hormone levels. Monitor closely.
• St. John’s Wort: This herbal supplement is a powerful CYP3A4 inducer. It can cut estrogen levels by half. Don’t take it while on GAHT.
• Blood thinners: Estradiol increases clotting risk. If you’re on warfarin or apixaban, your provider may need to adjust your dose more often.
• Thyroid meds: Estrogen can raise thyroid-binding proteins, making your T4 levels look high on blood tests-even if you’re not overmedicated. Your doctor should check free T4 and TSH, not total T4.

What You Should Do Right Now

Don’t wait for a crisis. Here’s what to do today:

1. Make a full list of every medication you take-including supplements, OTC painkillers, and herbal products.
2. Bring it to your endocrinologist or primary care provider and ask: "Which of these could affect my hormones?" Don’t assume they know.
3. Ask for hormone level checks before and 4-6 weeks after starting or changing any new medication.
4. Track your symptoms-mood, energy, breast tenderness, acne, headaches. Write them down. Patterns matter more than single numbers.
5. Don’t stop or change your meds on your own. Even if you think something’s causing a problem, talk to your provider first.

Many clinics still don’t have standardized screening for these interactions. A 2023 audit found only 41% of U.S. endocrinology clinics routinely check for drug-hormone conflicts. That means you might be the only one watching out for you.

What’s Changing in 2025

The field is moving fast. The NIH is running the Tangerine Study, tracking how 300 transgender adults respond to 12 common psychiatric drugs while on GAHT. Results will be out in mid-2025. That’s the first large-scale data we’ve ever had.

Drug companies are finally starting to test new meds in transgender people. Gilead, maker of PrEP, now requires GAHT interaction studies in all future trials. That’s a big step.

But gaps remain. We still don’t know how newer drugs like brexanolone (for postpartum depression) or long-acting cabotegravir interact with GAHT. There are only two case reports on these combinations-and both were published in 2023.

For now, the safest rule is this: if it’s new, be cautious. If it affects your liver, your mood, or your hormones, ask questions. And don’t let anyone tell you that your needs are too niche to matter. You’re not an afterthought. You’re the reason this research exists.

Final Thought: You’re Not Alone in This

Gender-affirming care is personal. But it’s also medical. And like any medical treatment, it works best when you’re informed. You don’t need to be a scientist. You just need to know what to ask for. Keep your list of meds handy. Track your body’s signals. Speak up when something feels off. Your hormones are powerful-but they’re not magic. They respond to the world around them. And with the right knowledge, you can make sure that world supports you, not works against you.