Estradiol Valerate vs Ethinylestradiol in Combined Oral Contraceptives: Effects on the Pituitary-Ovarian Axis

Abstract

Context: Limited studies have compared the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. Objective: To compare estradiol valerate (EV)+dienogest (DNG), EE+DNG, and DNG alone (active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, anti-Müllerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the free androgen index (FAI). Methods: This spin-off study from a randomized trial enrolled 59 healthy, 18 to 35-year-old ovulatory women, outpatients at Helsinki and Oulu University Hospitals, Finland, who were randomized to EV 2 mg+DNG 2-3 mg (n=20); EE 0.03 mg+DNG 2 mg (n=20); and DNG 2 mg (n=19) for 9 weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Age and BMI were comparable between groups; 3 women discontinued. Results: EV+DNG suppressed FSH by -27% (-51% to -3%) (median [95% CI]) vs EE+DNG, -64% (-78 to -51), P=0.04, but AMH levels decreased similarly by -9% (-18 to -0.1) vs -13% (-28 to 0.2), P=0.38, respectively. EV+DNG increased SHBG levels by 56% (30% to 82%) and EE+DNG by 385% (313% to 423%), P<0.001. Total testosterone decreased by 16% (-27% to -5%) in the EV+DNG group but it did not decrease in the EE+DNG group, whereas the FAI decreased by -39% (-54% to -25%) vs -72% (-78% to -67%), P<0.001. DNG alone did not induce changes in any of these parameters. Conclusion: Compared with EE+DNG, treatment with EV+DNG resulted in milder pituitary downregulation and reduced induction of hepatic SHBG synthesis - potentially carrying more beneficial health effects.