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

Abstract

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.