Orilissa works by blocking the hormone signal that tells your body to produce estrogen — and less estrogen means less fuel for endometriosis pain.

The Simple Version

Think of your body's hormone system like a chain of messages. Your brain sends a signal (GnRH) to the pituitary gland, which tells your ovaries to make estrogen. Estrogen then feeds the endometrial tissue — including the tissue that's growing where it shouldn't be, causing your endometriosis pain.

Orilissa (Elagolix) works by blocking the receiver for that brain signal. It sits on the GnRH receptors in your pituitary gland like a key stuck in a lock — preventing the real key (GnRH) from turning on estrogen production. The result: your estrogen levels drop, and the endometrial tissue shrinks and becomes less active, which reduces pain.

This is why Orilissa is called a GnRH antagonist — it antagonizes (blocks) the GnRH receptor.

What Happens in Your Body

Step by Step

1. You take Orilissa — The pill is absorbed through your digestive system. It reaches peak levels in your blood within about 1 hour.
2. Orilissa reaches the pituitary gland — It binds to GnRH receptors, blocking the natural GnRH hormone from activating them.
3. Estrogen production drops — With the signal blocked, your ovaries produce less estrogen. The amount of suppression depends on the dose.
4. Endometrial tissue becomes less active — Less estrogen means the endometrial tissue — both inside and outside the uterus — gets less stimulation. It thins, bleeds less, and causes less pain.

Dose-Dependent Suppression

One of Orilissa's unique features is that its estrogen-lowering effect is dose-dependent:

• 150 mg once daily produces partial estrogen suppression — enough to reduce pain while keeping some estrogen circulating (which is better for bone health)
• 200 mg twice daily produces more complete estrogen suppression — more effective for severe pain but with greater risk of bone density loss and menopausal-type side effects

This dose flexibility is something older GnRH treatments didn't offer. Your doctor can tailor the dose to balance pain relief against side effects.

How Long Does It Take to Work?

Most women begin to notice improvement in endometriosis pain within the first month of treatment. In clinical trials, statistically significant pain reduction was seen as early as Month 1 for both the 150 mg and 200 mg doses.

However, the full effect builds over time. Many patients experience continued improvement through the first two to three months. If you're not noticing any benefit after two to three months, talk to your doctor about whether the dose needs to be adjusted or whether a different treatment might work better.

How Long Does It Stay in Your System?

Orilissa has a relatively short half-life of about 4 to 6 hours. This means the drug is mostly cleared from your system within a day of your last dose. This is actually an advantage — if you experience side effects, they tend to improve quickly once you stop taking it.

After stopping Orilissa:

• Menstrual periods typically return within 1 to 2 months
• Estrogen levels begin recovering within days
• Bone density changes may take longer to reverse and may not fully recover (this is the one effect that can linger)

What Makes Orilissa Different from Similar Medications?

Orilissa vs. Lupron Depot (Leuprolide)

Lupron is a GnRH agonist, while Orilissa is a GnRH antagonist. Here's the key difference:

• Lupron initially overstimulates the GnRH receptors, causing a temporary hormone surge ("flare") before eventually shutting them down. This flare can temporarily worsen symptoms in the first few weeks.
• Orilissa directly blocks the receptors from the start — no flare, no initial worsening. Estrogen levels begin dropping right away.

Other differences:

• Orilissa is a daily pill; Lupron is an injection given monthly or every 3 to 6 months
• Orilissa offers dose flexibility (partial vs. near-complete suppression); Lupron is essentially all-or-nothing
• Orilissa clears your system in hours; Lupron's effects last weeks to months after the last injection

Orilissa vs. Myfembree (Relugolix Combination)

Myfembree is a newer oral GnRH antagonist that combines Relugolix with estradiol and norethindrone (hormonal "add-back" therapy). The add-back hormones are included to reduce bone loss and hot flashes.

• Myfembree may have fewer bone density side effects because of the add-back therapy
• Orilissa does not include add-back therapy, giving doctors more control over hormone levels but with greater bone loss risk
• Both are daily oral medications

For a full comparison of treatment options, see Alternatives to Orilissa.

Orilissa vs. Hormonal Birth Control

Hormonal birth control (pills, patches, IUDs) is often the first-line treatment for endometriosis. These work by stabilizing or suppressing hormone fluctuations, but they don't specifically target the GnRH pathway like Orilissa does.

Orilissa is typically tried when hormonal birth control hasn't provided enough pain relief, or when a patient can't take hormonal contraceptives.

Why Understanding the Mechanism Matters

Knowing how Orilissa works helps you understand:

• Why side effects happen — Hot flashes, bone loss, and mood changes are all related to lower estrogen. See our full guide on Orilissa side effects.
• Why timing matters — The 200 mg dose needs to be taken every 12 hours because of the short half-life.
• Why treatment duration is limited — Prolonged estrogen suppression leads to bone density loss, which is why the higher dose is limited to 6 months.
• Why certain drug interactions exist — Medications that increase Orilissa levels (like Cyclosporine) can amplify its estrogen-suppressing effects. Learn more in our drug interactions guide.

Final Thoughts

Orilissa works by intercepting the hormonal signal that drives endometriosis pain. It blocks GnRH receptors in the pituitary gland, reducing estrogen production and calming the endometrial tissue causing your symptoms. Its dose-dependent approach gives doctors flexibility to balance pain relief with side effects — something that wasn't possible with older GnRH treatments like Lupron.

If you think Orilissa might be right for you, talk to your doctor. For help finding a prescriber, check out our guide on how to find a doctor who can prescribe Orilissa. Already have a prescription? Search Medfinder to find it in stock near you.