There is no single “best” medication for endometriosis. The right choice depends on your pain severity, whether you want to get pregnant, and how you respond to initial treatments. Clinical guidelines recommend a stepwise approach: start with hormonal contraceptives or progestins, move to more targeted hormonal therapies if those fail, and reserve the strongest options for pain that resists everything else.
First-Line Options: Hormonal Contraceptives and Progestins
For most people newly diagnosed or starting treatment, doctors begin with either a combined hormonal contraceptive (the pill, patch, or vaginal ring) or a progestin-only medication. Both are strongly recommended by European and American guidelines as initial therapy, and they work by suppressing estrogen, which fuels endometrial tissue growth outside the uterus.
Combined hormonal contraceptives reduce period pain, pain during sex, and non-menstrual pelvic pain. They’re familiar, widely available, and relatively affordable. The downside: they don’t work for roughly one-third of women with endometriosis, and their effectiveness can fade over time.
Progestins, taken on their own, are the other first-line path. One progestin that has been studied extensively for endometriosis is dienogest at 2 mg per day. In clinical trials, women taking this dose saw their pain scores drop by about 54 points on a 100-point scale, a meaningful reduction that translated to noticeably less daily pain. A lower 1 mg dose also helped, reducing scores by roughly 45 points, though the higher dose was more effective. Progestins can cause irregular bleeding, mood changes, and bloating, but most side effects are mild enough that many women stay on them long-term.
Second-Line Options: GnRH Modulators
When contraceptives or progestins don’t provide enough relief, the next step is a class of drugs that more aggressively suppresses estrogen by acting on hormone signals in the brain. These come in two forms: GnRH agonists (older, injectable) and GnRH antagonists (newer, oral).
GnRH Antagonists
The newer oral options have changed the treatment landscape. Elagolix was the first FDA-approved oral treatment specifically for endometriosis pain. In its pivotal trials, 46% of women on the lower dose and 76% on the higher dose had a meaningful reduction in period pain at three months, compared to just 20% on placebo. For non-menstrual pelvic pain, response rates were 50% and 55%, respectively. Most women notice improvement within four weeks of starting treatment.
Relugolix, taken as a combination tablet that includes low-dose estrogen and a progestin (called “add-back therapy”), is another oral antagonist option. In long-term studies, nearly 89% of women experienced at least a 20-point reduction in pain scores after two years of use. The built-in add-back therapy is a key advantage: it keeps bone density loss under 1%, which is significantly better than older treatments that strip estrogen without replacing any of it.
A systematic review comparing both drugs found that relugolix combination therapy had the most consistent long-term evidence, with sustained pain relief and a safety profile similar to placebo in terms of side effects. Elagolix also performed well but carried slightly more risk of bone thinning and other low-estrogen effects, particularly at the higher dose. Both drugs substantially reduced the need for opioid painkillers.
GnRH Agonists
GnRH agonists, given as monthly or three-monthly injections, have been used for decades. They’re highly effective at reducing endometriosis pain, but they essentially create a temporary menopause-like state, which means hot flashes, vaginal dryness, mood swings, and bone density loss. To counteract these effects, doctors prescribe “add-back therapy,” typically a small daily dose of a progestin plus calcium. Clinical studies confirm this approach significantly reduces bone loss without undermining the drug’s ability to control pain. Even with add-back, most guidelines limit use to about six to twelve months because of cumulative effects on bone health.
Third-Line Options: Aromatase Inhibitors
For women whose pain persists despite multiple medications or surgery, aromatase inhibitors represent a last-resort option. These drugs block estrogen production at the tissue level, targeting endometriosis implants directly. They are typically prescribed alongside a progestin and calcium supplementation. In a study of women with pain that had resisted all prior treatments, a six-month course of an aromatase inhibitor combined with a progestin reduced pain intensity. Guidelines reserve this option strictly for refractory cases because of side effects including joint pain and further bone density concerns.
What About Over-the-Counter Pain Relievers?
Anti-inflammatory painkillers like ibuprofen and naproxen are often the first thing women reach for, and they do help with cramping by reducing prostaglandins. But the evidence supporting their use specifically for endometriosis is surprisingly thin. A Cochrane review found only a single small trial of 24 women testing naproxen against placebo, and the review was closed in 2017 because researchers concluded more studies were unlikely. This doesn’t mean these drugs are useless for endometriosis pain. It means they haven’t been rigorously studied for it, and they don’t address the underlying disease. Most doctors consider them a temporary bridge, not a standalone treatment.
How Quickly Medications Work
Timeline matters when you’re in pain. GnRH antagonists tend to work fastest, with noticeable pain reduction within about four weeks. A follow-up visit is typically scheduled within three months to assess whether the medication is working well enough to continue. Hormonal contraceptives and progestins generally take one to three menstrual cycles before you can judge their effectiveness, since they need time to suppress hormonal fluctuations and thin the uterine lining. If your first medication isn’t helping after a reasonable trial period, switching to a different class rather than waiting indefinitely is the standard approach.
Fertility and Medication Timing
Every hormonal medication for endometriosis suppresses ovulation, which means none of them help you get pregnant while you’re taking them. A large Cochrane review of 25 trials found that ovulation-suppressing treatments offered no benefit for endometriosis-related infertility. Worse, they delayed the time to a live birth simply because conception isn’t possible during treatment. If you’re trying to conceive, these medications are typically paused. Fertility generally returns after stopping treatment, though the timeline varies by drug. GnRH antagonists clear the body relatively quickly because they’re taken orally and have short half-lives, while injectable GnRH agonists may take several months to fully wear off.
For women who need pain management now but want to preserve the option of pregnancy later, the treatment plan becomes a balancing act. Progestins and oral antagonists that can be stopped quickly tend to be preferred in these situations over long-acting injections.
Choosing Between Medications
The “best” medication is ultimately the one that controls your pain with side effects you can tolerate, fits your reproductive plans, and works within your budget and access to care. Combined contraceptives are the simplest starting point, and they work well for many women with mild to moderate symptoms. For more severe pain, progestins like dienogest offer stronger suppression with a manageable side effect profile. GnRH antagonists with add-back therapy represent the current best option for women who need aggressive pain control without major bone density consequences. And for the small percentage of women whose pain defies all standard treatments, aromatase inhibitors remain available as a last line of defense.