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. And like any long-term medication plan, what you take alongside your hormones matters. Gender-affirming hormone therapy can interact with other drugs in ways that either reduce effectiveness or raise risks. These aren’t theoretical concerns. Real people, real side effects, real changes in how their medications work.

How Hormones Work in the Body

Feminizing hormone therapy usually means taking estradiol-often as a patch, pill, or injection-and an anti-androgen like spironolactone or cyproterone acetate. Masculinizing therapy means taking testosterone, usually as a gel, injection, or pellet. These aren’t simple chemicals. They’re processed by your liver, broken down by enzymes, and can interfere with or be interfered with by other drugs.

The biggest player here is the CYP3A4 enzyme. It’s responsible for breaking down about half of all medications you take. Estradiol is mainly metabolized through this pathway. That means anything that boosts or blocks CYP3A4 can change how much estradiol stays in your system. Testosterone, on the other hand, gets converted by enzymes like 5-alpha reductase and aromatase. These are less commonly affected by other drugs, which is why testosterone interactions are fewer and less dramatic.

Antiretrovirals and HIV Medications: A High-Stakes Mix

Transgender women are 40 times more likely to be living with HIV than cisgender women. That means many people on feminizing hormones are also taking antiretroviral therapy (ART). And here’s where things get tricky.

Some HIV drugs, like efavirenz and rifampin, speed up CYP3A4. That means they can drop estradiol levels by 30-50%. If you’re on one of these, you might start feeling like your hormones aren’t working anymore-less breast development, mood swings, or fatigue. Your provider may need to bump up your estradiol dose.

On the flip side, drugs like cobicistat (used in combo pills like Stribild or Descovy) block CYP3A4. That can cause estradiol to build up-sometimes by 40-60%. That raises the risk of blood clots, high blood pressure, or liver stress. One study found estradiol levels spiked within two weeks of starting cobicistat. Monitoring hormone levels after switching ART is not optional-it’s essential.

Good news? Integrase inhibitors like dolutegravir don’t interfere with estradiol. They’re the safest choice if you’re starting both HIV treatment and GAHT at the same time.

PrEP: Safe to Use With Hormones

If you’re on PrEP to prevent HIV, you’re probably taking tenofovir disoproxil fumarate and emtricitabine (TDF/FTC). A 2022 study of 172 transgender people on PrEP and GAHT found no meaningful changes in hormone levels or PrEP effectiveness. Estradiol didn’t affect how well tenofovir worked. Testosterone didn’t change how the body processed the PrEP drugs. Levels stayed within safe, protective ranges.

This is one of the clearest, most reassuring findings in recent years. You can safely take PrEP with GAHT. No dose adjustments needed. Just keep getting tested every three months, as recommended.

Psychiatric Medications: The Hidden Risk

Transgender people experience depression, anxiety, and PTSD at rates two to three times higher than the general population. Many are on SSRIs like fluoxetine or sertraline. But here’s the gap: almost no clinical trials for antidepressants include transgender participants.

Some SSRIs, especially fluoxetine and paroxetine, can slow down CYP2D6, another liver enzyme. That can slightly raise estradiol levels. Not enough to be dangerous, but enough to cause unexpected side effects-like breast tenderness or mood shifts-if you’re already on the higher end of your hormone dose.

Bigger concern: carbamazepine, phenytoin, and rifampin (used for seizures or TB) are strong CYP3A4 inducers. They can make estradiol less effective. One case report described a transgender woman who lost breast development after starting carbamazepine. Her estradiol levels dropped by 60%. Her dose had to be doubled.

Testosterone doesn’t seem to interfere with most antidepressants. But a 2023 review found 17 cases where people on testosterone needed higher doses of their antidepressants within six weeks of starting hormones. Why? Possibly because testosterone changes brain chemistry in ways that affect serotonin. If your mood suddenly worsens after starting testosterone, don’t assume it’s just adjustment. Talk to your provider about checking your antidepressant levels.

Other Common Medications to Watch

- Birth control pills: These contain estrogen. If you’re already on feminizing hormones, adding another estrogen source can raise your risk of blood clots. Stop oral contraceptives before starting GAHT.

- Statins (like atorvastatin): These are broken down by CYP3A4. High estradiol levels may increase statin concentration, raising the risk of muscle damage. Monitor for unexplained muscle pain.

- Thyroid medication: Estradiol increases thyroid-binding proteins. That can make your free T4 levels look low on blood tests-even if you’re not hypothyroid. Your doctor may need to adjust your levothyroxine dose based on symptoms, not just lab numbers.

- Antibiotics: Most are fine. But rifampin is a strong CYP3A4 inducer. If you’re on it for TB, expect your estradiol to become less effective. Plan ahead.

What About GnRH Agonists?

GnRH agonists like leuprolide are used to pause puberty in teens or suppress natural hormones in adults. The good news? They don’t interact with any HIV meds, antidepressants, or common prescriptions. They’re metabolized differently-through the kidneys, not the liver. That makes them one of the safest options when you’re on multiple medications.

But they’re expensive. And they can cause bone density loss if used long-term without calcium or vitamin D. Always pair them with monitoring.

What Should You Do?

1. Make a full list of every medication, supplement, and over-the-counter drug you take-including CBD, St. John’s Wort, and herbal teas.

2. Bring it to every appointment. Don’t assume your provider knows what you’re on. Many clinics still don’t have standardized screening tools.

3. Ask for hormone level checks after starting or changing any new medication. Estradiol and testosterone levels should be checked 4-6 weeks after a drug change.

4. Don’t stop or change doses on your own. Even if you feel fine, a small change in metabolism can have big consequences over time.

5. Use a pharmacist. Many pharmacies now have pharmacists trained in transgender health. They can flag interactions you might miss.

What’s Changing in 2025?

The NIH is running the Tangerine Study, tracking how 300 transgender adults respond to 12 common psychiatric drugs alongside GAHT. Results are expected in mid-2025. That’s the first large-scale data we’ll have on antidepressants and hormones.

The FDA is now pushing drugmakers to include transgender people in clinical trials. Gilead, the maker of Truvada and Descovy, now requires GAHT interaction data for all new PrEP studies. That’s a big shift.

But gaps remain. We still don’t know how cabotegravir (the long-acting PrEP shot) interacts with hormones. Or how newer antidepressants like brexanolone affect testosterone levels. We’re learning fast-but we’re not done.

Bottom Line

Gender-affirming hormone therapy is safe. But safety doesn’t mean ignoring other meds. The real risk isn’t the hormones themselves-it’s the blind spots in care. Many providers still don’t know how GAHT interacts with HIV drugs, antidepressants, or even common antibiotics.

Your best defense? Be informed. Keep track. Ask questions. And never assume something is safe just because no one’s talked about it yet.