Original research articleWeight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials☆
Introduction
Historically, oral contraceptives (OCs) have been associated with estrogen-related side effects, including nausea, headache, and breast tenderness [1]. One goal of lowering the hormonal content of OCs, besides minimizing the rare occurrence of cardiovascular events, is to reduce the incidence of these side effects. The only trial so far comparing the incidence of side effects with OCs containing 20 versus 35 μg ethinyl estradiol (EE) showed a lower incidence of nausea, breast tenderness, and bloating with the 20 μg pills [2].
According to a recent survey, more than half of US women believe OCs cause weight gain [3]. However, evidence in favor of this common misconception has not been demonstrated in placebo-controlled trials. An early placebo-controlled trial that reported measured weight changes with OCs containing high doses of hormones found similar measured weight changes in the OC and placebo groups [4]. Additionally, two placebo-controlled trials with a triphasic OC containing 35 μg EE and norgestimate found a similar incidence of weight gain recorded as an adverse event, although measured weight gain was not reported [5]. Placebo-controlled trials evaluating the effect of low-dose OCs containing 20 μg EE on measured weight gain have not been reported.
In studies reporting the contraceptive efficacy of 20 μg OCs, minimal weight gain [6], [7] and a low incidence of discontinuation because of weight gain [8] were demonstrated. Other trials, lacking placebo controls, that examined the effects of OCs on weight found little or no effect [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. In the absence of a placebo control, any effect of an OC on weight change observed in efficacy or observational trials cannot be attributed to the OC. A placebo can be used to control for normal weight change over time, among other variables.
To generate more conclusive results on the effects of a 20 μg OC on weight and the rates of common OC-related side effects, data were pooled and analyzed from two 6-cycle, randomized, placebo-controlled, double-blind trials of a low-dose OC containing 20 μg EE and 100 μg levonorgestrel (LNG) that demonstrated efficacy for the treatment of moderate acne. Changes in measured weight and the incidence of adverse events (AEs) were compared between the OC and placebo groups.
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Patients
Healthy women at least 14 years of age with regular menstrual cycles and moderate facial acne were eligible to participate. Participants were required to have normal cervical cytology in the last 6 months or, if an abnormal Papanicolaou smear, not worse than low-grade squamous intraepithelial lesion and be under the evaluation or treatment of a physician. Participants must have had a negative pregnancy test before entering the study and have agreed to use a nonhormonal method of contraception
Disposition
Of the 721 women enrolled in the study, a similar number from each group withdrew (EE/LNG 124, placebo 125) and completed (EE/LNG 235, placebo 237) the study. Six hundred eighty-four patients (EE/LNG 337, placebo 347) took at least one dose of study medication. Body weight, blood pressure, and AEs were analyzed in a total of 704 (EE/LNG 349, placebo 355) women, which included 20 women (EE/LNG 12, placebo 8) for whom information on taking study medication was not available.
Subject demographic and baseline characteristics
The demographic and
Discussion
In the current pooled analysis of two placebo-controlled, randomized, double-blind, multicenter clinical trials, a low-dose OC containing 20 μg EE and 100 μg LNG did not cause weight gain and was safe and well tolerated. The EE/LNG and placebo groups displayed comparable changes in weight from baseline over six cycles of treatment. Estrogen-related side effects [1], such as headache, nausea, breast pain, and weight gain, occurred with a similar incidence between groups, and low, comparable
Acknowledgements
We thank the additional investigators who participated in the study: David F. Archer, MD; Alan Cooper, MD; Frank Dunlap, MD; Douglass Forsha, MD; Maria Hordinsky, MD; Michael Jarratt, MD; Joseph Jorizzo, MD; Sewon Kang, MD; Steven Kempers, MD; Nellie Konnikov, MD; André Lemay, MD, PhD; James Leyden, MD; Mark Ling, MD, PhD; Anne Lucky, MD; Alan Menter, MD; Daniel Piacquadio, MD; Walter Powell, MD; Janet Roberts, MD; David Rodriguez, MD; Hans Sander, MD; Ronald Savin, MD; Alan Shalita, MD; Daniel
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The research was supported by Wyeth-Ayerst Laboratories.
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Current Address: Dalhousie University, Halifax, Nova Scotia.