Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity

Abstract

Background: This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity.

Study design: Ovulatory reproductive-age women with normal weight (BMI <25 kg/m(2); n=10) and with obesity (BMI >30 kg/m(2); n=10) received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (follicle-stimulating hormone and luteinizing hormone) was measured during the second inpatient stay. Estradiol (E(2)) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2.

Results: BMI was greater in the obese compared to the normal-BMI group [37.3 kg/m(2) (SD, 6.0) vs. 21.9 kg/m(2) (SD, 1.6); p<.05]. The LNG half-life was significantly longer in the obese group (52.1+/-29.4 vs. 25.6+/-9.3 h, p<.05), which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD, 0.5) vs. 2.5 ng/mL (SD, 0.7)] and a longer time to reach steady state (10 vs. 5 days) in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended toward greater HPO activity in the obese group. Additionally, more obese (6/10 vs. 3/10 normal BMI, p>.05) women exhibited E(2) levels consistent with development of a dominant follicle and P levels consistent with ovulation (2/10 vs. 1/10) during Cycle 2.

Conclusions: Compared to women with normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.

Figure 1

Study flow after eligibility cycle (black circles = active pills, white circles = 7-day hormone OC-free interval or placebo pills)

Fig. 2

LNG Pharmacokinetic Parameters (Dark grey = normal BMI, light grey = obese BMI) Values represent means and standard deviations. *: p value< 0.05 difference within Cycles between obese and normal BMI groups. a: p value < 0.05 difference within the normal BMI group between Cycle 1 and Cycle 2. b: p value < 0.05 difference within the obese BMI group between Cycle 1 and Cycle 2. Abbreviations: time to maximum concentration (T_max), maximum concentration (Cmax), area under the curve (AUC), volume of distribution (V_D), clearance (CL).

Fig. 3

EE Pharmacokinetic parameters (Dark grey = normal BMI, light grey = obese BMI) Values represent mseans and standard deviations *: p value< 0.05 difference within Cycles between obese and normal BMI groups. Abbreviations: time to maximum concentration (T_max), maximum concentration (C_max), area under the curve (AUC), volume of distribution (V_D), Clearance (CL).

Fig. 4. Gonadotropin pulsatility on the last day of the 7-day hormone-free interval (Top Panel) and ovarian hormone levels during the hormone-free interval in Cycle 1 and during the first week of Cycle 2 (bottom panel) in one typical obese subject who developed a dominant follicle and one typical normal BMI subject

HFI: hormone-free interval; Diamonds (◆) mark LH pulses; Solid line: LH and E2; Dashed line: FSH and P.

Fig. 5

Mean LH, FSH, and estradiol (E₂) levels

Fig. 6

Calculated time to reach LNG steady-state (steady-state = T_1/2 × 5) concentrations based on the serum sample series from Cycle 2, Day 1 (the first day of restarting active oral contraceptive pills after a 7-day hormone-free interval).