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Clinical Trial
. 2015;20(6):476-89.
doi: 10.3109/13625187.2015.1074675.

Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study

Ingrid J M Duijkers  1 , Christine Klipping  1 , Yvette Zimmerman  2 , Nicole Appels  2 , Maud Jost  3 , Catherine Maillard  3 , Marie Mawet  3 , Jean-Michel Foidart  3   4 , Herjan J T Coelingh Bennink  2
Affiliations
Clinical Trial

Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study

Ingrid J M Duijkers et al. Eur J Contracept Reprod Health Care. 2015.

Abstract

Objectives: The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women.

Methods: This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication.

Results: A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe.

Conclusions: Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.

Keywords: Estetrol; Estrogen; Oral contraception; Ovulation inhibition; Progestin.

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Figures

Figure 1
Figure 1. Ovulation inhibition according to the Hoogland score (A). Hoogland scores obtained during cycle 1 (B) and cycle 3 (C) with the different combinations tested during the trial. Results are expressed in percentage of participants.
Figure 2
Figure 2. Participant disposition by treatment group.
Figure 3
Figure 3. Mean (± SD), minimum and maximum value of the largest follicular diameter per participant in each group over the entire treatment period (A). Mean diameter of the largest follicle (mm) measured in each treatment group every 3 days during cycles 1 and 3 (B).
Figure 4
Figure 4. Maximum (mean ± SD) endometrial thickness value observed for each group during the trial (A). Mean endometrial thickness assessed in each treatment group every 3 days across the pretreatment cycle, treatment cycles 1 and 3, and post-treatment cycle (B). D, day; Pre T, pretreatment cycle; Post T, post-treatment cycle.
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