Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women

doi:10.1016/j.contraception.2010.01.016

Contraception

Volume 81, Issue 6, June 2010, Pages 474-480

https://doi.org/10.1016/j.contraception.2010.01.016 Get rights and content

Abstract

Background

This study was conducted to compare oral contraceptive (OC) pharmacokinetics (PK) in normal-weight [body mass index (BMI) 19.0–24.9] and obese (BMI 30.0–39.9) women.

Study Design

During the third week of the third cycle of OC use, we admitted 15 normal-weight and 15 obese women for collection of 12 venous specimens over 24 h. Using radioimmunoassay techniques, we measured levels of ethinyl estradiol (EE) and levonorgestrel (LNG). During the same cycle, women underwent twice-weekly sonography to assess ovarian follicular development and blood draws to measure endogenous estradiol (E2) and progesterone levels.

Results

Obese women had a lower area under the curve (AUC; 1077.2 vs. 1413.7 pg⁎h/mL) and lower maximum values (85.7 vs. 129.5 pg/mL) for EE than normal-weight women (p=.04 and <0.01, respectively); EE trough levels were similar between BMI groups. The similar, but smaller, differences in their LNG levels for AUC and maximum values (C_max) were not statistically significant. While peak values differed somewhat, the LNG trough levels were similar for obese and normal-weight women (2.6 and 2.5 ng/mL, respectively). Women with greater EE AUC had smaller follicular diameters (p=.05) and lower E2 levels (p=.04). While follicular diameters tended to be larger among obese women, these differences were not statistically significant.

Conclusion

OC hormone peak levels are lower among obese women compared to normal-weight women, but their trough levels are similar. In this small study, the observed PK differences did not translate into more ovarian follicular activity among obese OC users.

Introduction

Several studies have reported higher oral contraceptive (OC) failure rates in overweight and obese women than in normal-weight women, while other studies have not found this association [1], [2], [3]. These previous studies largely relied on self-reported patterns of OC use, pregnancy, and body weight, sometimes long after these events took place. Thus, the studies published so far are not able to distinguish method failure from user error and also may be limited by misclassification of body weight.

A plausible mechanism for increased OC failure among obese women would be more frequent ovulation during OC use due to incomplete ovarian suppression. Among obese women, incomplete ovarian suppression leading to ovulation could be a consequence if they achieve lower serum levels of the OC hormones compared to normal-weight women. The effective availability of drugs may differ by body weight for many reasons including variations in absorption, distribution, binding, metabolism or clearance [4], [5]. Steroids are lipophilic and will have a larger volume of distribution in obese compared to normal-weight individuals. This finding has been confirmed in studies of contraceptive injections and implants that find lower serum levels among obese women [6], [7], [8]. Differences in circulating levels of contraceptive hormones may not, however, predict failure rates. In studies of contraceptive implants and injections, the lower serum levels found in the obese women were not associated with contraceptive failure. To permit ovulation and OC failure, pharmacokinetic (PK) differences must be associated with less ovarian suppression.

Most PK studies of OC hormones have been small and limited to normal-weight women; thus, we found little data regarding PK differences between normal weight and obese OC users. A recent study compared 10 normal-weight and 10 obese OC users, and found that the obese women had more hypothalamic–pituitary–ovarian axis activity during OC use [9]. The purpose of the present study was to assess oral contraceptive PK among obese and normal-weight women and to explore whether PK results are associated with differential ovarian suppression. Because of the sustained popularity of the OC and the increasing prevalence of obesity in the United States, clarifying any differential effectiveness by body weight has enormous clinical relevance.

Section snippets

Materials and methods

The 30 women who participated in this PK study were a volunteer subgroup recruited from 226 women enrolled in a randomized, double-blind clinical trial that assessed ovarian function among normal-weight and obese women using one of two OC formulations. The Columbia University Institutional Review Board approved these studies, and all participants gave informed consent.

Results

Thirty women participated in the 24-h PK study. Fig. 1 shows the flow of participants through each stage of the study. We excluded two participants because compliance checks showed that they were not taking the OC except for the PK day itself (OC nonuser); we excluded these participants from all analyses because they would not have steady-state levels. Table 1 shows the baseline characteristics of the remaining 28 participants. The participants from the two BMI groups differ in body weight and

Discussion

This PK study shows that the peak circulating levels of OC hormones are lower among obese (BMI 30–39.9) than among normal-weight (BMI 19.0–24.9) women using a monophasic 28-day pill regimen containing 30 mcg EE and 150 mcg LNG. The differences shown in Fig. 2A and B are greater for EE than for LNG. While the peak values are clearly higher in normal-weight participants than in obese participants, all levels after 12 h, in particular the trough levels (i.e., those at t24), do not differ by BMI

Acknowledgments

This study was a substudy within a clinical trial supported by NIH Grant: R01 HD04578. Duramed Pharmaceuticals donated oral contraceptives and supported the pharmacokinetic assay analyses. Progesterone and estradiol analyses were supported by NIH CTSA Grant: 1 UL1 RR024156-03.

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Original research articlePharmacokinetics of a combined oral contraceptive in obese and normal-weight women

Abstract

Background

Study Design

Results

Conclusion

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgments

Contraception

Contraception

Contraception

Contraception

Contraception

Am J Obstet Gynecol

Contraception

Original research article
Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women