Hormonal contraception, past, present, and future part 2: optimizing combined oral contraceptives to decrease risks...

Pincus and his group's initial research on hormonal contraception focused on progesterone. However, the natural compound could not be utilized in clinical practice because of the high incidence of breakthrough bleeding and its low oral availability. This led to the introduction of orally active progestins. The estrogen was added to ensure proper cycle control.

Concern about side effects of combined oral contraceptive pills (COC) and specifically the increased occurrence of thromboembolism was raised at the very early stages of clinical use. These were attributed to the estrogenic component, ethinyl estradiol (EE). The first pill scare followed the publication in 1977 of evidence of thromboembolism-related mortality in COC users. This and subsequent alarming publications acted as the engine for a successful attempt to substantially decrease the daily content of EE in a COC. Over time, adverse events were also reported for the newer progestins compared to levonorgestrel.

Attempts have been made to utilize natural estrogens in COC based on the assumption that this will reduce adverse effects. The wide range of progestins available for use in COC renders comparisons between preparations more challenging. Each progestin has its own androgenic, antiandrogenic, antiestrogenic, and mineralocorticoid activity and, consequently, a unique risk and benefit profile.