Original research articleEffects of the Yuzpe regimen, given during the follicular phase, on ovarian function☆
Introduction
Emergency contraception (EC) is being strongly promoted as a means to prevent unwanted pregnancies in special situations such as condom accidents, sexual abuse, and unprotected intercourse occurring around mid cycle, when there is a high probability of pregnancy. It is estimated that wider use of EC would greatly reduce the number of unwanted pregnancies and the number of abortions resulting from them.
The use of an estrogen/progestin combination for EC, consisting of two doses, 12 h apart of 100 μg ethinyl estradiol (EE) plus 500 μg levonorgestrel (LNG), was reported by Yuzpe over 20 years ago [1]. Subsequent studies have confirmed the contraceptive efficacy of this method [2], [3], [4].
Because this treatment is given shortly after intercourse, and coitus taking place in the postovulatory period is unlikely to be fertile, the most relevant, albeit not only, mode of action must be associated with administration in the preovulatory period, when coitus is more likely to be fertile. When EC is given in the preovulatory phase, it may delay or suppresses ovulation, thus preventing fertilization.
In some settings, such as Latin American countries, the introduction of EC requires documented evidence on its mode of action. Therefore, it is important to determine how meaningful is the contribution of ovulation delay or inhibition on its mode of action when the Yuzpe regimen is given in the preovulatory phase.
Two studies have shown that, when the Yuzpe regimen is administered before the luteinizing hormone (LH) surge, it may blunt or delay the LH peak [5], [6]. Administration at the time of the LH peak had no effect on LH, whereas variable ovarian steroidogenic response was seen ranging from no effect to diminished progesterone (P) or estradiol (E2) plasma levels in the luteal phase [7]. These studies were conducted in a small number of participants, and in none of them was follicular development evaluated. Here we report a study in which the time of administration of the drug was standardized to the size of the leading follicle, instead of the chronological date of the cycle. The medication was administered in either one of three different periods of the follicular phase: the mid-follicular phase, advanced-follicular phase, and pre-ovulatory phase. 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 [8]; therefore, if ovulation does not occur in this period, one can conclude that had unprotected intercourse occurred prior to treatment, the possibility of conception would be minimal or nil.
On the other hand, one of the main drawbacks of this method is its high incidence of unpleasant side effects, particularly nausea and/or vomiting, probably caused by the very high dose of steroids and their repeated administration [3]. For this reason, we also assessed the anti-ovulatory effectiveness and side effects associated with half the dose of the Yuzpe regimen, that is, 50 μg EE and 250 μg LNG, given twice, 12 h apart.
Section snippets
Materials and methods
The study was conducted at Instituto Chileno de Medicina Reproductiva 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.
Thirty healthy women were enrolled at each center after giving their informed consent. They were protected from pregnancy by tubal ligation, abstinence, or barrier methods and had no contraindications to the use of oral
Results
No significant differences were found in weight and height of women, between clinics, stratified by groups; therefore, results from the two clinics were pooled. Two women discontinued the study during the resting cycle, one after the full-dose treated cycle and the other before the half-dose treated cycle. A third woman completed the half-dose treated cycle, but during the ensuing placebo cycle she did not reach the pre-assigned follicular diameter so that the pills were not administered.
Discussion
The results presented show that administration of the Yuzpe regimen in the follicular phase prevents the occurrence of ovulation in the ensuing 5 days in a significant proportion of cases. This effect is seen when the mean diameter of the leading follicle is 12–17 mm at the time of treatment, but is absent when treatment is given at more advanced stages of the follicular phase. The effectiveness of this regimen for delaying or inhibiting ovulation is minimal when half the dose is used and null
Acknowledgements
The authors would like to thank Laboratorios Silesia S.A. for their generous supply of EE/LNg and placebo pills. They also thank Mrs. A. Brandeis, Mrs. G. Bravo, Mrs. E. Nuñez, and Ms. Ana Sofia Tejada for their technical assistance. The views expressed do not necessarily reflect the views of USAID or CONRAD.
References (25)
- et al.
Ethinylestradiol and dl-norgestrel as a poscoital contraceptive
Fertil Steril
(1977) - et al.
A multicenter clinical investigation employing ethinyl estradiol combined with dl-norgestrel as a postcoital contraceptive agent
Fertil Steril
(1982) - et al.
Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception
Fertil Steril
(1979) - et al.
Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. III. Effects of preovulatory administration following the luteinizing hormone surge on ovarian steroidogenesis
Fertil Steril
(1983) Anovulatory luteal cycles in primates
Contraception
(1983)- et al.
Pharmacologic production of luteinized unruptured follicles by prostaglandin synthetase inhibitors
Fertil Steril
(1987) - et al.
Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome
Fertil Steril
(1985) - et al.
The pattern of the luteinizing hormone surge in spontaneous cycles is related to the probability of conception
Fertil Steril
(1993) - et al.
Relationship between midcycle luteinizing hormone surge quality and oocyte fertilization
Fertil Steril
(2000) - et al.
Updated estimates of the effectiveness of the Yuzpe regimen of emergency contraception
Contraception
(1999)
Post coital contraceptionpilot study
J Reprod Med
The effectiveness of the Yuzpe regimen of emergency contraception
Fam Plann Perspect
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Support for this study (CSA-98-205 and CSA-98-211) was provided by the Contraceptive Research and Development Program, Eastern Virginia Medical School, under a cooperative agreement with the United States Agency for International Development (USAID).