Hugh Taylor, MD, discusses first- and second-line medical therapy for endometriosis

Oral contraceptives remain the first-line treatment for endometriosis, but progestin resistance and side effects limit their effectiveness in a substantial share of patients, making oral GnRH antagonists a valuable second-line option, according to Hugh Taylor, MD, Chair, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine. The discussion continues Taylor's remarks on endometriosis as a systemic disease.

Taylor described oral contraceptives as an accessible starting point with important limitations.

"Oral contraceptives are the first-line therapy. They're easy, widely accepted, relatively safe, and very inexpensive, so a great first-line therapy," he said. "The problem is that much of the endometriosis we see is resistant to progestins, which are the main component of the oral contraceptive."

He advised clinicians to anticipate treatment failure and follow up quickly.

"Expect about a third of patients to be resistant to your first-line therapy," Taylor said, adding that up to half may experience a significant side effect. Because endometriosis patients are more prone to depression and anxiety, he noted, progestin-related mood effects are more common in this population.

“Within about 6 to 8 weeks, I will have them back in the office or at least touch base with them, expecting a third to fail with continued pain and several others to have oral contraceptive side effects.”

Distinguishing side effects from resistance

Taylor drew a sharp line between managing side effects and addressing true resistance.

"If they have progestin resistance, if they don't respond, if the pain doesn't get better, switching from one pill to the other is not the answer. Our research has shown that they often have diminished or absent progesterone receptor function. So no progestin will work," he said, cautioning that switching pills in resistant patients only delays effective treatment. For side effects such as depression, however, trying a different progestin or pill is reasonable first.

Oral GnRH antagonists as second-line

For progestin-resistant patients, Taylor pointed to oral GnRH antagonists as a transformative second-line therapy.

"Although endometriosis may be resistant to progestin, it always needs some estrogen to survive. And if we lower estrogen enough with a GnRH antagonist, we can effectively treat endometriosis," he said, noting the oral formulations have replaced older injectable GnRH agonists that were "a big impediment" to use.

He detailed the 2 approved options: relugolix combination therapy, a once-daily tablet with built-in low-dose estradiol and norethindrone add-back to prevent vasomotor symptoms and bone loss; and elagolix, available at 150 mg once daily for mild disease and 200 mg twice daily for greater efficacy, the latter requiring separate add-back therapy for longer-term use. Taylor also cited danazol as an effective, inexpensive, if underused, second-line option, with acne or rare hirsutism as principal side effects.