A Randomized, Controlled Trial of Asoprisnil, a Novel Selective Progesterone Receptor Modulator, in Women With Uterine Leiomyomata

Abstract

The only effective medical treatment of symptomatic uterine leiomyomas has been the gonadotropin-releasing hormone agonist leuprolide acetate depot, which carries a risk of producing hypoestrogenic symptoms. High-dose progestin therapy has been used to control heavy uterine bleeding (HUB) but may cause breakthrough bleeding. Another option is asoprisnil, a selective progesterone (P) receptor modulator that has mixed P agonist and antagonist actions and is highly uterine-selective. In both primate and human studies, it has induced amenorrhea and suppressed endometrial growth. This randomized prospective, double-blind, placebo-control study, carried out at 28 sites in the United States and 1 in Canada, enrolled 129 women 18 to 49 years of age who had at least one leiomyoma measuring 3 cm or more in diameter or multiple small lesions producing a uterine volume exceeding 200 cm 3 . All participants had normal menses and no other significant pelvic pathology. They received either asoprisnil in a daily oral dose of 5, 10, or 25 mg or a placebo for 12 weeks. Uterine bleeding was monitored by daily diaries, and uterine volume was measured sonographically. The 5-, 10-, and 25-mg doses of asoprisnil suppressed uterine bleeding in 28%, 64%, and 83% of patients, respectively. These patients did not have even light bleeding while being treated. No placebo recipient responded. Dose-related rates of amenorrhea, defined as no bleeding or only spotting, were 16%, 36%, and 70%, respectively. Compared with placebo, treatment with 25 mg daily for 4 and 8 weeks was associated with a statistically significant decrease in leiomyoma volume, and by week 12 it was reduced by 36%. The higher doses of asoprisnil significantly reduced bloating and, in patients given 25 mg daily, pelvic pressure also declined significantly by week 12. Hemoglobin concentrations increased significantly more in all treatment groups than in placebo recipients. Treatment had no apparent effect on pelvic pain or dyspareunia. Hypoestrogenic symptoms were minimal. Endometrial thickness was similar in the treatment and placebo groups at the end of the study, and no hyperplasia or other adverse changes were observed. Asoprisnil therapy appeared to inhibit basal gonadotropin concentrations. There were no clinically significant changes in blood chemistry or blood pressure, and no clinically relevant cervical abnormalities were observed. Adverse effects of all types were similarly frequent in the treatment and placebo groups. These findings support the use of asoprisnil to treat complaints related to uterine leiomyomas, notably HUB and bulk-related symptoms, without significantly altering blood estrogen levels at the same time. Treatment with doses as high as 25 mg daily for 12 weeks was well tolerated.