The New England Journal of Medicine (NEJM): Published on July 6, 2017

Endometriosis is a chronic, estrogen-dependent, inflammatory condition that is characterized by the implantation of endometrial-like tissue outside the uterus and affects 6 to 10% of women of reproductive age.

Symptoms:

Endometriosis symptoms include dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia, as well as the less common symptoms of pain at ovulation, constipation, and painful urination. Endometriosis-associated pain can decrease the patient’s quality of life and result in substantial economic burden. Dyspareunia can have profound interpersonal and psychological consequences.

Causes:

Endometriosis has multifactorial causes, including retrograde menstruation, genetic and environmental factors, alteration of the immune system, and ectopic differentiation of mesenchymal stem cells.

Estrogen plays a necessary role in the pathophysiology of endometriosis, since it promotes the implantation of endometrial tissue in the peritoneum, has proliferative and antiapoptotic effects in endometrial cells, and stimulates local and systemic inflammation.

On the basis of the “estrogen threshold hypothesis,” complete estrogen suppression may not be needed to control endometriosis-associated pain, and estrogen may be adjusted to a level that is adequate to control pain but minimizes hypoestrogenic effects.

Medical management and its limitations:

First-line therapies for endometriosis-related pain include nonsteroidal antiinflammatory drugs (NSAIDs) and progestin-containing oral contraceptives.

Second-line therapies involve injectable depot formulations of gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate. Although the injectable agents are effective and reduce estrogen levels to postmenopausal levels, they are associated with side effects (e.g., progressive bone loss and severe vasomotor symptoms), which limit their use to 6 months without hormone-replacement therapy. Medical options remain limited.

Progestins are associated with bleeding, weight gain, and mood changes, and endometriosis is often associated with progesterone resistance.

Androgenic agents such as danazol are associated with acne, hirsutism, and changes in lipid profiles.

Pain management usually requires repeated courses of medical therapies or multiple surgical treatments until menopause.

Surgical ablation or excision of lesions can be effective; however, symptoms often recur within 12 months, and more radical surgery (hysterectomy or oophorectomy) is a last resort.

TAKE HOME MESSAGE:

Authors performed two similar multicenter, double-blind, randomized, placebo-controlled, phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) of 6-month treatment with elagolix at two doses in women with moderate or severe endometriosis-associated pain.

In the trials, authors found that women with moderate or severe endometriosis-associated pain who received two different doses of elagolix had significantly lower scores for dysmenorrhea and nonmenstrual pelvic pain than did those who received placebo after 3 months and 6 months of treatment.

Elagolix is an oral, nonpeptide GnRH antagonist. Proof-of-concept phase 2 studies of elagolix showed efficacy in controlling both dysmenorrhea and nonmenstrual pelvic pain, with an acceptable safety profile at a dose (once-daily 150 mg) that produces partial estrogen suppression. A phase 1 study showed that elagolix (at a dose of 200 mg twice daily) led to nearly full estrogen suppression.

In conclusion, the use of elagolix at two doses — 150 mg once daily and 200 mg twice daily — resulted in reductions in two of the hallmark pain symptoms of endometriosis, dysmenorrhea and nonmenstrual pelvic pain, after both 3 months and 6 months of treatment.

Consistent with the mechanism of action, elagolix treatment resulted in hypoestrogenic effects, including hot flushes and changes in bone mineral density and lipid levels.

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