Original research articleUlipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens☆
Introduction
Emergency contraception (EC) provides women a means to reduce the likelihood of becoming pregnant after unprotected intercourse, and since the advent of dedicated products some 15 years ago, utilization of EC has increased significantly worldwide. Oral EC aims at interfering with an ovulation that has not yet occurred. The days just prior to ovulation are the most crucial for EC efficacy, since intercourse these days carries the highest probability of conception [1], [2], [3]. Oral EC regimens must be able to prevent ovulation for at least 5 days to be highly effective because spermatozoa can maintain fertilizing capacity in the female genital tract for that long [3], [4]. In clinical practice, when a woman presents for EC, we seldom know in which stage of the ovulatory process she is because cycle length and ovulation day may vary, so EC is given as quickly as possible in the hopes of catching the process early.
The progestin levonorgestrel (LNG) at a dose of 1.5 mg has become the most widely accessible and commonly used EC method and is licensed for use within 72 h of unprotected sexual intercourse. In recent trials in western populations, LNG prevented fewer than 70% of expected pregnancies [5], [6] while in two earlier World Health Organization-sponsored studies, the estimate was closer to 80–85% [7], [8]. However, the precision of the methodology to obtain these estimates has been questioned [9], [10], [11]. The primary mechanism of action of oral EC is to interfere with the ovulatory process by preventing or delaying ovulation. From previous studies, it has become clear that the ability of LNG to interfere with the ovulatory process decreases as ovulation nears. Once the ovulatory process has been triggered by the luteinizing hormone (LH) surge, LNG does not appear to prevent the follicle from rupturing, an event that normally takes place shortly after [12], [13], [14], [15], [16].
Ulipristal acetate (UPA), a more recent EC option, is a selective progesterone (P) receptor modulator with antagonistic and partial agonistic effects at the P receptor (a P agonist/antagonist). The primary mechanism of action of UPA for EC is inhibition or delay of ovulation. UPA is marketed worldwide as a 30-mg micronized tablet to be taken within 120 h of unprotected sex. In a pooled analysis of two randomized head-to-head efficacy trials, women who received UPA were significantly less likely to become pregnant than women who received LNG [odds ratio (OR): 0.55, 95% confidence interval (CI): 0.32–0.93]. If EC was used within 24 h of unprotected sexual intercourse, when most women tend to present for EC, the risk of pregnancy for women who received UPA was two-thirds lower than for women who received LNG (OR 0·35, 95% CI: 0.11–0.93) [6]. From previous studies, it would appear that UPA interferes with the ovulatory process even in the presence of rising LH, delaying follicular rupture by 5 days in a significant proportion of women [17], [18].
For the purpose of studying drug effects on ovulation, the moment of intake in relation to descriptive parameters of the ovulatory process can be standardized. We have previously conducted three randomized, double-blind, placebo-controlled pharmacodynamic studies using similar methodology, each assessing the effect of LNG, UPA or LNG+meloxicam on the ovulatory process during the 5 days following treatment administered in the advanced follicular phase. LNG regimens studied were the standard 1.5-mg dose (either 0.75 mg × 2, with a 12-h interval between doses or a single 1.5-mg dose) and a standard UPA 30-mg micronized dose [15], [18], [19]. In addition, a novel regimen was studied that associated the standard dose of LNG (1.5 mg) with meloxicam (15 mg), a prostaglandin-endoperoxide 2 inhibitor, previously known as cyclooxygenase-2 (COX-2) inhibitor. The addition of meloxicam was hypothesized to be synergistic in the prevention of ovulation at the level of the ovary, via inhibition of the follicular prostaglandin synthesis that triggers follicular rupture in response to the LH surge [19].
Although clinical efficacy trials suggest that UPA is more effective than LNG for EC, especially when taken rapidly after unprotected intercourse, no pharmacodynamic study has directly compared their capacity to inhibit ovulation. In order to compare the different EC regimens, we pooled the raw data from our three pharmacodynamic studies and assessed the three regimens with respect to the occurrence of ovulation in the days following treatment.
Section snippets
Study design
The primary objective of this analysis was to estimate and compare the different regimens with respect to the proportion of subjects in whom follicular rupture did not occur in the 5 days following treatment. We also evaluated the effect of treatment on LH and P levels and described the subsequent outcome of follicles.
Analysis was done using data from three studies conducted by the same group of investigators using similar randomized, double-blind, placebo-controlled crossover study designs.
Baseline characteristics
A total of 163 cycles were included in the present analysis, 48 LNG, 31 LNG+meloxicam, 34 UPA and 50 placebo cycles (Table 1). The baseline demographic characteristics were similar in the four groups. Subjects were not at risk of pregnancy at the time of treatment; they were all treated at a similar time with regard to day of cycle, mean follicular diameter and baseline estradiol and P levels (Table 2). Mean LH levels at the time of treatment were also comparable (range: 16–26 IU/L) with a
Discussion
The results of the present analysis suggest that UPA is able to delay follicular rupture for at least 5 days in a significantly higher proportion of women than LNG when given in the late follicular phase, at the time when the LH peak is imminent. At this time in the cycle, LNG cannot delay or block ovulation any better than placebo, and follicular rupture occurs shortly and similarly after treatment with LNG or placebo. Since in routine clinical setting we rarely know at what point in the cycle
Acknowledgments
The authors acknowledge the outstanding team of investigators from ICMER, Santiago, Chile, Profamilia, Santo Domingo, Dominican Republic and HRA Pharma, Paris, France, who collaborated in the original publications: M. Pavez, ML Forcelledo, F Alvarez, R Massai, A Faundes, AM Salvatierra, AS Tejada, MV Reyes, C Jesam, R Maldonado, DP Levy and E Gainer.
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Funding: We gratefully acknowledge financial support provided by CONRAD, Virginia, USA, Fondecyt, Santiago, Chile and HRA Pharma, Paris, France.