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 changing how their body processes every other medication they take. It’s not a simple swap. Estradiol and testosterone don’t float around in isolation. They interact with enzymes, receptors, and metabolic pathways that also handle antidepressants, HIV meds, blood thinners, and even over-the-counter supplements. Ignoring these interactions can mean your hormones stop working-or worse, cause unexpected side effects.

How Hormones Are Processed in the Body

Understanding interactions starts with knowing how these hormones are broken down. Feminizing therapy usually uses estradiol, often taken as pills, patches, or gels. The liver uses a group of enzymes called CYP3A4 to break it down. That’s the same enzyme that processes many HIV drugs, antidepressants, and even grapefruit juice. If something boosts CYP3A4, estradiol gets cleared too fast. If something blocks it, estradiol builds up-potentially raising the risk of blood clots or high blood pressure.

For masculinizing therapy, testosterone is the main player. It’s metabolized by 5-alpha reductase and aromatase enzymes, which convert it into stronger or weaker forms. Unlike estradiol, testosterone doesn’t rely heavily on CYP3A4, which is why it has fewer major drug interactions. But that doesn’t mean it’s risk-free. Some psychiatric meds can still affect how your body responds to it.

Anti-androgens like spironolactone and cyproterone acetate also matter. Spironolactone can raise potassium levels, especially when combined with ACE inhibitors or NSAIDs. Cyproterone acetate is a strong CYP3A4 inhibitor, so it can make estradiol levels spike dangerously if taken with other drugs that do the same.

Interactions with HIV Medications

Transgender people are at higher risk for HIV, and many are on antiretroviral therapy (ART). This is where things get tricky. Some HIV drugs can cut hormone levels in half. Efavirenz, a common NNRTI, speeds up CYP3A4, which means estradiol gets broken down faster. Studies show transgender women on efavirenz can have 30-50% lower estradiol levels-enough to lose the benefits of hormone therapy.

On the flip side, cobicistat, used to boost certain HIV drugs like darunavir, blocks CYP3A4. That causes estradiol to pile up. In some cases, levels rise by 40-60% within just two weeks. That’s not just a lab number-it can mean headaches, nausea, or even blood clots. Doctors now recommend checking estradiol levels 2-4 weeks after starting a cobicistat-based regimen.

The good news? Integrase inhibitors like dolutegravir don’t interfere much. They may raise estradiol slightly-by 25-35%-but not enough to cause harm. No dose changes are needed. For testosterone, almost all HIV meds are safe. No major drops or spikes have been found.

PrEP and Hormones: No Problem

Many transgender people use PrEP to prevent HIV. The most common form is tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). A 2022 study tracked 172 transgender participants on both PrEP and GAHT for 12 weeks. The results? Hormone levels changed by less than 5%. Tenofovir levels changed by just 3.2%. No adjustments were needed.

This study was a game-changer. Before this, many providers avoided prescribing PrEP with GAHT out of fear. Now, it’s clear: you can safely take both. Even the newer long-acting injectable PrEP (cabotegravir) shows no known interactions, though data is still limited. If you’re on PrEP, don’t stop it. Talk to your provider about monitoring, but don’t assume you need to change anything.

Psychiatric Medications: The Hidden Risk

Transgender individuals have higher rates of depression, anxiety, and PTSD. Many take SSRIs like fluoxetine or sertraline. Here’s the catch: some of these drugs can interfere with hormone metabolism. Fluoxetine and paroxetine inhibit CYP2D6, which can slow down how fast estradiol is broken down. That means higher levels-possibly leading to mood swings, breast tenderness, or increased clot risk.

Worse, some mood stabilizers do the opposite. Carbamazepine and phenytoin (used for seizures or bipolar disorder) boost CYP3A4. That can slash estradiol levels, making hormone therapy ineffective. One study found 17 transgender patients on testosterone needed to increase their antidepressant doses by 25-50% within six weeks because their depression returned. Why? Testosterone might be changing how their brain responds to the medication.

The bottom line? Don’t assume your psychiatric meds are safe just because they’re common. Your hormone levels can change how your brain reacts to them-and vice versa. Regular check-ins with your provider are critical, especially in the first three months after starting GAHT.

What About Other Common Medications?

Many everyday drugs can interfere. Blood thinners like warfarin can become more potent when combined with estradiol, raising bleeding risk. NSAIDs like ibuprofen or naproxen can raise potassium levels when taken with spironolactone, which could lead to heart rhythm problems. Even common supplements like St. John’s Wort can reduce estradiol levels by activating CYP3A4.

Birth control pills? Avoid them. They contain ethinyl estradiol, which is much stronger than natural estradiol and increases clot risk. If you’re on feminizing therapy, you don’t need additional estrogen. If you’re on testosterone, birth control pills can cause unwanted side effects and interfere with hormone balance.

Monitoring and Safety

GAHT is safe when monitored. But “safe” doesn’t mean “set it and forget it.” The best practice is to check hormone levels before starting, at 3 months, then every 6-12 months. For those on HIV meds, check estradiol levels 2-4 weeks after starting a new drug. If you’re on testosterone, monitor hematocrit and liver enzymes every 6 months.

Also, keep a full list of everything you take: prescriptions, supplements, herbs, even CBD. Many providers don’t ask. But a 2023 audit found only 41% of U.S. endocrinology clinics have standardized drug interaction screening. Don’t wait for them to ask-bring your list.

What’s Changing in 2026?

Research is moving fast. The NIH-funded Tangerine Study is tracking 300 transgender adults on 12 psychiatric meds alongside GAHT. Results are expected in mid-2025. Gilead Sciences now requires all new PrEP trials to include transgender participants. The FDA is pushing for more inclusive clinical trials. This means better data, better guidelines, and safer care.

Still, gaps remain. We don’t know much about interactions with newer psychiatric drugs like brexanolone or long-acting injectable HIV treatments. If you’re on one of these, work closely with a provider who understands GAHT. Don’t assume it’s safe just because it’s new.

Bottom line: GAHT works. It saves lives. But it’s not simple. Your body is now processing hormones differently-and that affects everything else you take. Talk to your doctor. Bring your meds. Get tested. Stay informed. You deserve care that’s as precise as your identity.