Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women

Abstract

Background: Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation.

Study design: This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated.

Results: Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%).

Conclusion: In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.

Fig. 1

Mean UPA serum levels per site during 12 weeks of treatment.

Fig. 2

Immunohistochemical assessment of the proliferation marker Ki-67 pre- and post-treatment of UPA. The summary chart shows mean Ki-67 histoscore, a semiquantitative score allocated to each endometrial compartment — glands, surface epithelium and stroma — according to the percentage of nuclei showing positive staining. Ki-67 gland histoscore=% of glands stained×nuclear score (NS) (NS: 0=no staining; 1=b10% of nuclei show staining in positively stained glands; 2=10%–50%; 3=N50%). Surface epithelium histoscore=% surface epithelial cells showing staining. Stroma histoscore=% stromal cells showing staining. Note that histoscore values allow comparison of Ki-67 labeling between pre- and post-treatment states, but not comparison between compartments.