GnRH Antagonists with or without Add-Back Therapy: A New Alternative in the Management of Endometriosis?

Abstract

To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women with endometriosis-associated pelvic pain. We reviewed the most relevant papers (n = 27) on the efficacy of new medical alternatives (oral GnRH antagonists) as therapy for endometriosis. We first briefly summarized the concept of progesterone resistance and established that oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis. Since clinical evidence shows that estrogens play a critical role in the pathogenesis of the disease, lowering their levels with oral GnRH antagonists may well prove effective, especially in women who fail to respond to progestogens. There is a need for reliable long-term oral treatment capable of managing endometriosis symptoms, taking into consideration both the main symptoms and phenotype of the disease. Published studies reviewed and discussed here confirm the efficacy of GnRH antagonists. There is a place for GnRH antagonists in the management of symptomatic endometriosis. Novel algorithms that take into account the different phenotypes are proposed.

Keywords: GnRH antagonist; add-back therapy; dysmenorrhea; elagolix; endometriosis; linzagolix; pelvic pain; progesterone resistance; relugolix.

Figure 1

Expected E2 levels during the menstrual cycle and under gonadotropin-releasing hormone (GnRH) antagonist therapy with and without add-back therapy (ABT).

Figure 2

Percentage of subjects who showed clinically meaningful responses with respect to dysmenorrhea at 24 weeks.

Figure 3

Mean percentage BMD loss at week 24 (lumbar spine) in women treated with different doses of gonadotropin-releasing hormone (GnRH) antagonist (150 mg elagolix once daily, 200 mg elagolix twice daily; 75 mg, 100 mg and 200 mg linzagolix once daily; and 40 mg relugolix plus ABT once daily).

Figure 4

Dysmenorrhea rapidly decreased from severe at baseline to mild by week 8 and was sustained through to week 24. Error bars show the upper and lower limit of 95% confidence intervals; * p values compare relugolix combination therapy vs a placebo with respect to change in NRS dysmenorrhea defined previous page scores by week 24. CT = combination therapy; LS = least squares.

Figure 5

Combined symptom-oriented and phenotype-adapted approach. When the main symptom is endometriosis-associated pain and pregnancy is not desired, different algorithms are proposed according to the phenotype.

Figure 6

Combined symptom-oriented and phenotype-adapted approach to endometriosis-associated infertility.