Original research articlePituitary–ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation
Introduction
The use of an estrogen/progestin combination for emergency contraception, consisting of two doses taken 12 h apart, each containing 0.1 mg ethinyl estradiol (EE) plus 0.5 mg levonorgestrel (LNG), was reported by Yuzpe almost 30 years ago [1]. Another regimen that has been studied extensively consists of two doses of 0.75 mg LNG, given with an interval of 12 h [2]. A large multicenter comparative study of these two methods demonstrated higher efficacy and lower incidence of side effects associated with LNG [3].
Knowledge and use of emergency contraception (EC) is gradually increasing, but remains limited and with pronounced differences among different countries. Millions of women could be free from unplanned or unwanted pregnancies if EC were widely accessible [4]. One of the obstacles for introducing this method is the belief, in spite of the paucity of evidence, that the primary mechanism of action of EC is interference with implantation. Because EC is ingested within a few days after intercourse and coitus does not cause fertilization of the ovum in the postovulatory period [5], the most relevant, albeit not necessarily only, mode of action of EC must be associated with its administration in the fertile segment of the preovulatory period.
We previously reported a mode-of-action study in which the time of administration of the Yuzpe regimen was standardized to the size of the leading follicle [6]. The medication was administered when the leading follicle had attained either one of three different mean diameters, 12–14 mm, 15–17 mm, and ≥18 mm. After taking the medication, women were followed-up daily for a total of 5 days to determine whether or not ovulation took place within that period. Spermatozoa may retain their fertilizing capacity in the female genital tract for up to 5 days [5]; therefore, if ovulation does not occur in this time period, one can be reasonably certain that had unprotected intercourse occurred prior to treatment, the possibility of conception would be nil. Overall, treatment suppressed follicular rupture in 43% of treated cycles and caused ovulatory dysfunction in an additional 20%. The closer to ovulation the treatment was given, the lesser the probability of interfering with this process. These findings provide reasonable explanation for the higher efficacy of the Yuzpe regimen the sooner it is given after intercourse as well as to its overall 20–40% failure rate to prevent expected pregnancies [7]. Here we report the results of a similar mode-of-action study using LNG alone.
Because there are no systematic dose-effectiveness studies reported that justify the doses used in the LNG regimen, it seemed appropriate to determine whether the mode of action to be investigated here is preserved, and the incidence of adverse events decreased, when the dose is reduced. Therefore, we also evaluated half of the standard dose, by giving a single dose of 0.75 mg, which, from the practical point of view, also simplifies compliance.
Thus, this study was designed to assess the effect of LNG, given in the follicular phase upon the leading follicle, hormonal levels and adverse events. Two doses of 0.75 mg, given 12 h apart, or a single dose of 0.75 mg, were compared.
Section snippets
Materials and methods
The study was conducted at ICMER in Santiago, Chile, and PROFAMILIA in Santo Domingo, Dominican Republic. Approval was granted by the Ethics Committee of each center and by the Eastern Virginia Medical School Institutional Review Board.
A total of 58 healthy women were enrolled, 29 at each center, after they gave informed consent. They were 18–40 years old, with regular menstrual cycles in the past 3 months, nonbreastfeeding, protected from pregnancy by tubal ligation or nonhormonal IUDs and had
Results
Fifty-five of the 58 subjects enrolled, completed all three treatment cycles. One subject had abnormal follicular development and she was discontinued and excluded from analysis. Two subjects did not complete the third cycle, one due to concurrent gastritis and the other due to inability to comply with the protocol because of new job. Therefore, data is available for 57 cycles with the standard dose, 56 cycles with the single and 56 cycles with placebo.
Women in both clinics were similar
Discussion
The results of this study show that administration of LNG in the follicular phase interferes with the ovulatory process and that its efficacy depends on the temporal proximity of treatment to the preovulatory hormonal level. Treatment given before the onset of the LH surge prevented follicular rupture or caused ovulatory dysfunction during the 5-day period in 79–86% of women. As expected, the larger the leading follicle at the time of treatment, the more likely EC is given during or after the
Acknowledgments
We thank Laboratorios Silesia S.A. for producing the placebo pills and for supplying all the pills in coded vials as needed for the study. We also wish to thank Mrs. A. Brandeis, Mrs. G. Bravo, Mrs. E. Nuñez and Ms. A.S. Tejada for their technical assistance. We gratefully acknowledge the financial support for this study provided by the Consortium for Industrial Collaboration in Contraceptive Research (CICCR), a program of the Contraceptive Research and Development Program (CONRAD), Eastern
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