Combined Oral Contraceptive Type May Positively Influence Health Outcomes

Woman hands opening birth control pills in hand. eating Contraceptive pill. Contraception reduces childbirth and pregnancy concept.
Investigators compare the effects of contraceptive agents containing estradiol valerate plus dienogest, ethinylestradiol plus dienogest, or dienogest alone on the suppression of pituitary and ovarian activity.

The degree to which combined oral contraceptives downregulate the pituitary-ovarian axis may translate into beneficial health outcomes, including decreased risk for venous thromboembolism (VTE) and decreased impact on hepatic metabolism, according to the results of a study published in the Journal of Clinical Endocrinology & Metabolism.

Researchers studied the effects of combined oral contraceptives taken continuously for 9 weeks by 56 ovulatory women aged 18 to 35 years between April 2014 and December 2016 at Helsinki and Oulu University Hospitals in Finland. The study participants were categorized into 3 groups based on the oral contraceptive agent used: natural estradiol valerate (EV) 2 mg plus dienogest (DNG) 2 to 3 mg (EV+DNG); synthetic ethinylestradiol (EE) .03 mg plus DNG 2 mg (EE+DNG); and DNG 2 mg

The investigators analyzed serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone, anti-Müllerian hormone, progesterone, testosterone, estradiol, estrone, androstenedione, and estrone-3-sulfate using liquid chromatography-tandem mass spectrometry. Sex hormone-binding globulin levels were also obtained, as they may reflect VTE risk in women using hormonal contraception. Twelve-hour fasting blood samples were collected at baseline between menstrual cycle days 1 to 5, and blood samples were obtained at weeks 5 and 9.

The combinations of EV+DNG and EE+DNG were found to decrease FSH by 27% and 64% (P =.04), to decrease anti-Müllerian hormone levels by 9% and 13% (P =.38), and to increase sex hormone-binding globulin levels by 56% and 385% (P <.001), respectively. Total testosterone levels decreased only in the EV+DNG group (by 16%); however, the free androgen index (FAI) decreased in both the EV+DNG and EE+DNG groups by 39% and 72%, respectively (P <.001). No changes in hormonal outcomes were reported in the group receiving only DNG.

“EV+DNG seems to exert less pronounced pituitary downregulation and lower hepatic impact than EE+DNG,” the authors said. “Moreover, even though the FAI values clearly decreased after treatment with EV+DNG, the FAI remained higher than after treatment with EE+DNG, which may be of clinical significance.”

Limitations of this study include its small sample size and the short follow-up period. The authors suggested future research is needed to focus on long-term clinical consequences, including VTE risk, efficacy in managing hyperandrogenic conditions, and effects on libido and metabolism to determine the benefits of women taking combined oral contraceptives containing natural vs synthetic estrogens.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Haverinen A, Luiro K, Kangasniemi MH, et al. Estradiol valerate vs. ethinylestradiol in combined oral contraceptives: effects on the pituitary-ovarian axis. J Clin Endocrinol Metab. Published online March 13, 2022. doi:10.1210/clinem/dgac150