Elsevier

Contraception

Volume 85, Issue 5, May 2012, Pages 480-488
Contraception

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

https://doi.org/10.1016/j.contraception.2011.10.003Get rights and content

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.

Introduction

Contraceptive prevalence surveys throughout the world reveal high levels of unmet needs for family planning and of unintended pregnancy [1]. Development of a wider range of safe and effective contraceptive options with user-friendly, acceptable characteristics has the potential to reduce unmet need for contraception and may bring additional health benefits to women. The study presented below indicates one promising route to such a development.

Progesterone antagonists and progesterone receptor modulators (PRMs) represent a class of progesterone ligands that may exert contraceptive action by different mechanisms. PRMs have been shown to inhibit ovulation, oppose the proliferation of the endometrium and induce amenorrhea [2], [3], [4], [5], [6], [7], [8], [9]. In a study where the progesterone antagonist mifepristone was used orally at a low daily dose, ovulation was suppressed in over 90% of the cycles, and amenorrhea was observed in 65% to 90% of the cycles as well [10].

Several studies have evaluated the contraceptive potential of the PRM ulipristal acetate (UPA), previously known as VA-2914 or CDB-2914 [11]. UPA is a derivative of 19-norprogesterone that binds specifically to the human progesterone receptors (PRs) [12]. It is a potent, orally active modulator of the PR, known to block progesterone action in target tissues [13]. UPA is devoid of glucocorticoid activity but exhibits a modest antiglucocorticoid activity, lower than that of mifepristone [14], [15], [16]. A single dose of 10–100 mg of UPA administered with a follicle of 14–16 mm caused a dose-dependent delay in the time interval from treatment to follicular rupture [17]. When given as emergency contraception in a single dose of 30 mg in the preovulatory phase, the luteinizing hormone (LH) peak was postponed, and follicle rupture was delayed [8]. In a study in mice subjected to gonadotrophin-induced superovulation, the administration of UPA 1 h before human chorionic gonadotrophin administration resulted in a greater than 90% inhibition of oocyte release, strongly suggesting a direct effect of the compound upon dominant follicles [7].

Two recent studies confirmed the effectiveness of UPA (30 mg) as an emergency contraceptive pill [18], [19]. Another study evaluating a daily oral administration of UPA has demonstrated suppression of ovulation and amenorrhea in a majority of women [20]. This new lead appears to have the potential of being an “estrogen-free” contraceptive with possibly fewer side effects than contraceptives delivering ethinyl estradiol. It would also induce amenorrhea, which appears to be both acceptable and beneficial to many women [21].

The Population Council in collaboration with National Institute of Child Health and Human Development (NICHD) is developing a 3-month contraceptive vaginal ring (CVR) containing UPA as a method of estrogen-free hormonal contraception. Contraceptive vaginal rings offer advantages for drug delivery over those associated with oral administration. After insertion of a ring into the vagina, steroids are rapidly absorbed by vaginal tissues and pass into the systemic circulation. Vaginal drug delivery maintains relatively constant blood levels throughout ring use [22], [23] and shows an increased bioavailability of steroids as compared with other routes of administration [24]. Additional benefits may result because CVRs do not require daily attention, and may thus improve compliance. Moreover, rings do not require a trained provider for insertion and removal, and they are controlled by the users [25], [26].

A Phase 1 study of a CVR releasing 400–500 mcg per day of UPA (CDB-2914) was previously completed in 12 women [27]. CVR delivery of UPA permitted rapid absorption into the blood stream. UPA serum levels reached a plateau of 2–3 ng/mL within 72 h of ring insertion and remained at that level for the 1-month duration of the study. However, ovulation was suppressed in only 3 out of 12 subjects, indicating an insufficient dose of the PRM.

Based on those results, a new ring delivering a higher dose of UPA was designed and tested in a 3-month proof-of concept study. The main objective was to determine whether the continuous delivery of 600–800 mcg of UPA could achieve 80% to 90% inhibition of ovulation and induce amenorrhea in a similarly high proportion of women. The effect of this form of administration of UPA upon the endometrium was also evaluated as a key objective.

Section snippets

Method and materials

This prospective, open-labeled, three-center trial was conducted at Instituto Chileno de Medicina Reproductiva in Santiago, Chile; at USC Los Angeles, CA; and PROFAMILIA in Santo Domingo, Dominican Republic, in accordance with the guidelines of the Declaration of Helsinki. Approval was granted by the Ethics Committee of each center and by the Institutional Review Board of the Population Council (NY).

After providing informed consent, 39 healthy women, 13 at each center, were tested for normal

Results

Thirty-seven women completed the study. Two volunteers discontinued early, citing personal reasons. The mean age and gravidity of participants who completed the study were 35.3±4.4 years (±SD) and 3.1±1.2, respectively. The mean body weight and BMI were 62.4±10.2 kg and 25.4±3.1 kg/m2, respectively. Participants from Chile were significantly older, while body weight and BMI were lowest in the Dominican Republic and highest in Los Angeles (Table 1).

Discussion

The current study tested the effects on ovarian activity and menstrual bleeding of 600–800 mcg/day of UPA released from a newly formulated vaginal ring. Ovulation, as judged by ultrasound and hormonal data, was observed in one third of the treatment periods. Thus, the present ring formulation seems more effective for preventing ovulation than previously tested rings releasing lower dosages of UPA, but is not yet the fully effective dose. This is in agreement with UPA serum levels attained with

Acknowledgments

This study was supported by a grant from the National Institute of Child Health and Human Development of the National Institutes of Health (grant number U54 HD 29990). The authors would like to thank HRA Pharma, Paris, France, for supplying ulipristal acetate for the study.

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