Estradiol Valerate Vs. Ethinylestradiol In Combined Oral Contraceptives: Effects On The Pituitary-Ovarian Axis

Context There are limited studies comparing 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 (an active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, Anti-Mullerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the Free Androgen Index (FAI). Design Spin-off study from a randomized trial. Setting Outpatient setting at Helsinki and Oulu University Hospitals, Finland. Participants 59 healthy, 18-35-year-old ovulatory women were enrolled. Three women discontinued. The groups were comparable as regards age and body mass index. Interventions EV 2mg+DNG 2-3mg (n=20), EE 0.03mg+DNG 2mg (n=20) and DNG 2mg (n=19) were used continuously for nine weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Main Outcome Measures EV+DNG suppressed FSH by -27% (-51:-3) (median [95%CI]) vs. EE+DNG, -64% (-78: -51), P=0.04, but AMH levels decreased similarly by -9% (-18: -0.1) vs. -13% (-28:0.2), P=0.38, respectively. EV+DNG increased SHBG levels by 56% (30:82) and EE+DNG by 385% (313:423), P<0.001. Total testosterone (T) decreased by 16% (-27: -5) in the EV+DNG group but it did not decrease in the EE+DNG group, whereas the FAI decreased by -39% (-54: -25) vs. -72% (-78: -67), PConclusions 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.