Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity: a mechanism for contraceptive failure?

Abstract

To determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian axis (HPO) activity. Prospective cohort. Reproductive-age women of normal (<25 kg/m2; n = 10) and obese (>30 kg/m2; n = 7) BMI received a very-low dose OC [20 mcg ethinyl estradiol/100 mcg levonorgestrel (LNG)] for two cycles (C1, C2). Evidence of ovulatory cycles (luteal progesterone ≥3 ng/mL) and percent body fat by air displacement were obtained prior to enrollment. Subjects were admitted for two 48-hour inpatient stays at the beginning (first inpatient stay: C1, Day 21–22) and end (second inpatient stay: C1, Day 28-C2, Day 1) of their OC hormone free interval (HFI). Luteinizing hormone (LH) samples were obtained every 15 minutes from 0900–1700 hours during the second inpatient stay. The deconvolution method was used to analyze each LH series. Estradiol (E2) and progesterone (P) were measured daily during each inpatient stay and bi-weekly in C2. LNG samples were collected during each inpatient stay from which pharmacokinetics were calculated. Mean BMI and percent body fat were greater in the obese BMI group [21.9 kg/m2 (SD 1.6) and 27.6% (SD 7.2) vs. 36.2 kg/m2 (SD 4.1) and 49.3% (SD 3.6); P<0.05]. A trend toward a longer LNG half-life (45.7 ± 8.9 hrs vs. 26.0 ± 7.8 hrs) and an increased volume of distribution (13.1 ± 4.9 L vs. 8.9 ± 4.3 L) was observed in obese compared to normal BMI women. Calculated time to achieve LNG steady state was twice as long in obese women (obese BMI 12 days; normal BMI 6 days). Although not statistically significant, the LNG maximum concentration on C2, Day 1 was lower in obese women [1.79 ng/mL (SD 0.35) vs. 2.53 (SD 0.67); P=0.06]. LH pulsatility was consistent with HPO reactivation at the end of the OC HFI in both BMI groups, with no significant differences in LH pulse parameters (baseline, half-life, pulse numbers, and average pulse mass). While no subject had evidence of ovulation (e.g. P>3 ng/mL), two obese and one normal woman exhibited E2 levels consistent with development of a dominant follicle (>200 pg/mL) during C2. Evidence of HPO reactivation is present in both obese and normal BMI women at the end of the OC HFI. However, the increased time to reach steady state in obese OC users may lengthen the interval for continued HPO activity placing them at risk for ovulation.