Side effects of progestins include nausea, weight gain, ﬂuid retention, and breakthrough bleeding caused by hypoestrogenemia. Breakthrough bleeding, although common, is usually corrected by short-term (7-day) administration of estrogen. Depression and other mood disorders are a significant problem in about 1% of women taking these medications.
The levonorgestrel intrauterine system releasing 20 μg per day of levonorgestrel reduces endometriosis-associated pain caused by peritoneal and rectovaginal endometriosis and reduces the risk of recurrence of dysmenorrhea after conservative surgery (375). Levonorgestrel induces endometrial glandular atrophy and decidual transformation of the stroma, reduces endometrial cell proliferation, and increases apoptotic activity (375). A systematic review identified two randomized trials and three prospective observational studies, all involving small numbers and a heterogeneous group of patients (376). The evidence suggests that the levonorgestrel intrauterine system reduces endometriosis associated pain with symptom control maintained over 3 years (377–380). Twelve months of treatment results in a significant reduction in dysmenorrhea, pelvic pain, and dyspareunia; a high degree of patient satisfaction; and a significant reduction in the volume of rectovaginal endometriotic nodules (377,378). After the first year of use, a 70% to 90% reduction in menstrual blood loss is observed.
Progesterone antagonists and progesterone receptor modulators may suppress endometriosis based on their antiproliferative effects on the endometrium, without the risk for hypoestrogenism or bone loss that occurs with GnRH treatment. These products are not available in the United States, and their clinical effectiveness is unproven.
Mifepristone Mifepristone (RU-486) is a potent antiprogestagen with a direct inhibitory effect on human endometrial cells and, in high doses, an antiglucocorticoid action (381). The recommended dose for endometriosis is 25 to 100 mg per day. In uncontrolled studies, mifepristone, 50 to 100 mg per day, reduced pelvic pain and induced 55% regression of the lesions without significant side effects (382,383). In an uncontrolled pilot study, low-dose mifepristone, 5mg per day, resulted in pain improvement, without change in endometriosis lesions, suggesting that this dosage was probably too low (384).
Onapristone The progesterone antagonists onapristone (ZK98299) and ZK136799, used in the treatment of rats with surgically induced endometriosis, resulted in a remission in 40% to 60% of treated animals. In animals with persistent endometriosis, growth inhibition was obtained in 48% and 85% of endometriotic lesions after therapy with onapristone and ZK136799, respectively (385).
Other Progesterone Antagonists The chemical synthesis and pharmacologic characterization of a highly potent progesterone antagonist, ZK230211, were reported, with little or no other endocrinologic effects. ZK230211 is active on progesterone receptors A and B (386). In primates, this drug blocks ovulation and menstruation at all effective doses, whereas another progesterone antagonist, ZK137316, allowed ovulation but blocked menstruation in a dose-dependent fashion (387). All progesterone antagonist–treated animals maintained normal follicular phase concentration of estradiol and returned to menstrual cyclicity within 15 to 41 days after treatment (387). Both progesterone antagonists block unopposed estrogen action on the endometriosis through their antiproliferative effect.