Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives

Abstract

Objectives: Estetrol (E4) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E4 blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E4/DRSP and E4/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters.

Methods: This was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E4/3 mg DRSP; 5 mg, 10 mg or 20 mg E4/150 μg LNG; or 20 μg EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated.

Results: A total of 109 women were included in the study. Carrier proteins were minimally affected in the E4/DRSP and E4/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E4 groups, and the effects on triglycerides elicited by the E4 groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E4 groups.

Conclusions: E4-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters.

Keywords: Bone markers; Drospirenone; Endocrinology; Estetrol; Levonorgestrel; Lipid metabolism; Liver function.

Figure 1. Allocation of subjects by treatment group (ITT and AST populations).

Figure 2. Mean (SD) percentage change from baseline to cycle 1 day 24 in SHBG (ITT population).

Figure 3. Box whisker plots for E₄/DRSP, E₄/LNG (all treatment groups) and EE/DRSP of relative changes from baseline to cycle 3 day 24 for lipid and lipoprotein parameters (ITT population). The edges of the boxes represent the 25th and 75th sample percentiles (quartiles); the vertical line in the boxes shows the median; and whiskers are drawn up to the smallest and largest value within 1.5 times the interquartile range.