Thirty women participated in the 24-h PK study. 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 non-user); we excluded these participants from all analyses because they would not have steady-state levels. shows the baseline characteristics of the remaining 28 participants. The participants from the two BMI groups differ in body weight and BMI by design. The obese participants were more likely to be parous. None of the participants who smoked cigarettes reported smoking more than three cigarettes per day.
Flowchart of participants in pharmocokinetic (PK) study
Baseline characteristics of study participants
show the geometric mean serum concentrations of EE and LNG of the obese and the normal weight participants. For both hormones, the curves are lower for the obese participants. presents the AUC, Cmax, Tmax, elimination half-life, and Cmin estimates for each hormone, stratified by BMI group. For AUC, Cmax, and Cmin, the maximum values are about four times greater than the minimum values. The individual variability in the elimination half-life varies even more. To summarize the marked individual variability, shows the interquartile ranges. For EE, the obese participants have a significantly lower AUC and Cmax and an earlier Tmax than the normal weight participants. For LNG, the AUC and Cmax differences between the groups are in the same direction, but smaller. The elimination half-life for LNG was markedly longer among the obese participants. While peak values of LNG, and especially EE, were higher among normal weight participants, the trough values (Cmin) were similar. Substituting body weight, percent body fat, or fat mass for BMI did not change the results for AUC and Cmax. We found no relationship between any of the PK estimates and ethnicity, parity, or smoking status. The normal weight and obese participants had similar values for SHBG (geometric mean 70.1 nmol/L and 66.6 nmol/L, respectively, p = 0.75).
Serum concentrations of EE and LNG in 13 normal weight and 15 obese study participants
OC pharmacokinetic parameter estimates in normal weight versus obese women
As shown in , there was some evidence of more follicular activity in the obese participants but the differences were not statistically significant. indicates the proportion of participants in each BMI group with ovarian follicle diameters (FD) that were at least 8, 10, 13, or 18 mm in size. These proportions were calculated using the largest mean FD from any of the eight sonograms that each participant underwent. Because FD seen during the first week of the OC cycle may indicate ovarian activity that occurred during the preceding placebo week, we repeated this analysis excluding the sonograms obtained during the first week and the results were similar (data not shown). Finally, we repeated this analysis also excluding sonograms done during the final placebo week, and again the results were similar.
Maximum follicular diameter during one cycle of OC use in normal weight and obese women
Concentration of E2 was measured in serum from blood draws taken at all eight follow-up visits. Overall, maximum E2 levels were low in these participants (median = 16.0 pg/mL, Q1= 5.4 pg/mL, Q3 = 40.5 pg/mL), consistent with the expected ovarian suppression in OC users. Maximum serum concentration of E2 was higher in obese participants than in normal weight participants, on average (median = 18.5 pg/mL vs. median = 6.5 pg/mL, p = 0.08). We repeated this analysis excluding blood specimens obtained during the first week, and again excluding blood specimens obtained during the first week and the final placebo week, and the results were similar.
We hypothesized that ovarian activity as indicated by the maximum FD and E2 levels should be inversely associated with serum levels of EE on an individual level because EE suppresses follicle stimulating hormone (FSH). We used rank correlation to assess the strength of the association between AUC, Cmax, and Cmin and maximum FD as well as the maximum E2 during the study cycle (). All PK estimates of EE were associated with a smaller FD and a lower E2, although some of these associations did not achieve statistical significance. The relationships were similar when assessing the maximum FD from all study days or when limited to Days 7-28 or Days 7-21 only (data not shown). Because individual levels of LNG and EE are correlated (r = 0.48; p < 0.01), the LNG PK values were also related to FD and to E2; however, these associations were weaker than those described for EE and were not statistically significant (data not shown).
EE PK estimates and measures of ovarian activity during one cycle of OC use
In this study, any serum P levels of 3 ng/mL or greater were presumed a priori to indicate ovulation. Only one normal weight participant, who took the assigned pills consistently, according to the LNG compliance checks, ovulated based on a serum P = 10.1 ng/mL at cycle Day 10 and 12.4 ng/mL at Day 13. In the PK analyses, this participant had EE AUC and Cmax levels in the middle and had EE elimination half-life and Cmin values in the lowest quartile; her LNG levels were all in the lowest quartile, including the second-lowest LNG Cmin value of all participants. We also identified two obese participants who missed multiple (but not all) OCs based on the LNG compliance checks; one of them ovulated. Mean endometrial thickness during the study cycle was similar for obese and normal weight participants (6.9 mm vs. 6.3 mm, respectively, p =0.68).