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.

Conclusions: 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.