Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review

Abstract

Background: The first objective of this review was to present, based on recent literature, the most frequently applied medical options (oral contraceptive pills (OCPs) and progestogens) for the management of symptomatic endometriosis, and evaluate their effectiveness in treating premenopausal women with endometriosis-associated pelvic pain, dysmenorrhea, non-menstrual pelvic pain and dyspareunia. The second objective was to review the concept of progesterone resistance and newly available treatment options.

Methods: We reviewed the most relevant papers (n = 73) on the efficacy of OCPs and progestogens as medical therapy for endometriosis, as well as those on progesterone resistance and new medical alternatives (oral gonadotropin-releasing hormone (GnRH) antagonist). Eleven papers, essentially reviews, were selected and scrutinized from among 94 papers discussing the concept of progesterone resistance.

Results: Having reviewed the most significant papers, we can confirm that OCPs and progestogens are effective in two-thirds of women suffering from endometriosis, but that other options are required in case of failure (in one-third of women due to progesterone resistance) or intolerance to these compounds. It is clear that there is a need for effective long-term oral treatment capable of managing endometriosis symptoms, while mitigating the impact of side effects. Biochemical, histological and clinical evidence show that estrogens play a critical role in the pathogenesis of endometriosis, so lowering levels of circulating estrogens should be considered an effective medical approach. The efficacy of three oral GnRH antagonists is discussed on the basis of published studies.

Conclusion: There is a place for GnRH antagonists in the management of symptomatic endometriosis and clinical trials should be conducted, taking into account the different phenotypes in order to propose novel algorithms.

Keywords: GnRH antagonist; add-back therapy; dysmenorrhea; endometriosis; oral contraceptive pills; pelvic pain; progesterone resistance; progestogens.

Figure 1

GnRH antagonist mechanism of action.

Figure 2

Expected estradiol (E2) levels during the menstrual cycle, under GnRH agonist and under GnRH antagonist therapy without and with add-back therapy (ABT).

Figure 3

Mean percentage of bone mineral density (BMD) loss at week 24 (lumbar spine) in the different groups of women treated by different doses of GnRH antagonist (elagolix 150 mg once daily; elagolix 200 mg twice daily; linzagolix 75 mg, 100 mg and 200 mg once daily; and relugolix 40 mg combination therapy (CT): relugolix plus add-back therapy, once daily).

Figure 4

Mean percentage of BMD loss at week 52 (lumbar spine) in the different group of women treated by different doses of GnRH antagonist (elagolix and linzagolix). Patients randomized to linzagolix 200 mg were switched to linzagolix 100 mg at week 24.

Figure 5

E2 level up to week 24 in women under placebo, linzagolix (LGX) 75 mg, 100 mg and 200 mg. Patients under placebo were switched to linzagolix 100 mg at week 12.

Figure 6

Mean change from baseline in the visual analog scale (VAS) score for pelvic pain for 28 days before the end of treatment period (adapted from Osuga et al. [104]).