Original research articleEffects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive
Introduction
Oral contraceptives (OCs) are an effective method of birth control and are utilized by a large number of women in the United States at some time during their reproductive years. Despite excellent efficacy, it is recognized that OCs do not provide complete suppression of ovarian follicular development [1], [2], [3]. During the standard 7-day hormone-free interval (HFI) of a conventional 28-day OC regimen, ethinyl estradiol (EE) and the progestin component are cleared from the circulation approximately 2 to 3 days after the last active combination pill is taken, allowing several hormone-free days during which recovery of the hypothalamic–pituitary–ovarian axis occurs [1], [4], [5]. The pituitary gland begins to secrete gonadotropins and levels of follicle-stimulating hormone (FSH), inhibin B and estradiol increase. As a result, ovarian follicular growth may occur. The hormonal events that take place during the 7-day HFI resemble those observed during the early follicular phase of a normal spontaneous menstrual cycle and could lead to an increased risk of escape ovulation [4], [5].
Ovarian activity during use of OCs has been correlated with increased intermenstrual bleeding, and enhanced ovarian suppression may result in improved cycle control [6]. Also, it has been suggested that the 7-day HFI may be associated with hormone-withdrawal symptoms (due to fluctuations in endogenous hormone levels) that could potentially be minimized by modification of the placebo interval [5], [7], [8], [9]. Increased pituitary–ovarian suppression may decrease the risk of follicular development, escape ovulation and unintended pregnancy and potentially contribute to improvements in hormone-related symptoms and breakthrough bleeding.
Methods for maintaining pituitary–ovarian suppression by modification of the HFI have included shortening the duration of the HFI to less than 7 days, continuous administration of active combination tablets and using low-dose estrogen in place of placebo during the usual HFI [5], [10], [11], [12], [13], [14]. This report describes the impact on ovarian activity of supplementing the usual 7-day HFI with 10 mcg/day EE compared to placebo in women using a 28-day conventional OC containing 150 mcg of levonorgestrel (LNG)/30 mcg of EE.
Section snippets
Study design and population
This was a prospective, multicenter, randomized, open-label study conducted at three sites in the United States from July 2005 to November 2005. The study was conducted in accordance with the Declaration of Helsinki and applicable guidelines for Good Clinical Practice; the Novum Independent Institutional Review Board reviewed and approved the protocol and informed consent prior to study initiation.
Premenopausal, nonpregnant, nonlactating females 18 to 35 years old, with no history of ovarian
Study population
Twenty-six subjects were enrolled and randomized to one of two treatment arms (10 mcg of EE, n=11; or placebo, n=15). Randomization was stratified by site, and there were incomplete randomization blocks at each site, so slightly more subjects were treated with placebo than with EE. All randomized subjects completed the study. The demographic characteristics of the subjects are summarized in Table 1. There were no differences between the two treatment groups.
The intent-to-treat (ITT) cohort
Discussion
Based on the endocrine data obtained during this study (estradiol, FSH, LH and inhibin B levels), the administration of 10 mcg/day of EE during the traditional 7-day HFI was associated with substantially greater and more persistent suppression of ovarian function than provided by placebo in women who were already taking a 28-day OC with active combination tablets containing 150 mcg of LNG/30 mcg of EE for the preceding 21 days. While this study evaluated hormone levels in users of a
Acknowledgment
This study was funded by Duramed Research, Bala Cynwyd, PA. The data were presented as an oral presentation on October 23, 2006, at the 62nd Annual Meeting of the American Society of Reproductive Medicine in New Orleans, LA.
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