Development of the ratio of levonorgestrel, 0.15 mg, to ethinyl estradiol, 0.03 mg.

Screening for the most appropriate combination of hormonal components began after the synthesis of norgestrel in 1961 and the end of dependence on yam cultivation for the sex steroids used in fertility control. The concept of using a fixed combination of progestin and estrogen for 21 days followed by withdrawal for 7 days was established in the 1960s and the efficacy of oral contraceptives (OCs) was generally accepted. The goal of Wyeth became the reduction of annoying side effects. When norgestrel combinations were initially studied the usefulness of combining progestins with an estrogen content as low as 50 mcg had been demonstrated and ethinyl estradiol (EE) had been recognized as the estrogen of choice. The combination of dl-norgestrel 500 mcg and EE 50 mcg became a major success. In the early 1970s Wyeth became able to synthesize levonorgestrel and the combination of levonorgestrel 250 mcg and EE 50 mcg became Wyeths leading OC in foreign countries. Efforts to reduce the estrogen content of combined OCs were prompted by the UK retrospective studies which linked rare cardiovascular adverse effects with the estrogen content of OCs and the resulting combination of 250 mcg levonorgestrel and 30 mcg EE became the market leader in the UK. In subsequent studies favorable results were obtained with combinations that lowered both the progestin and estrogen content while maintaining the original 5:1 progestin-estrogen ratio. The 150/30 combination in particular caused fewed lipid and carbohydrate metabolic changes. Review of the data from various studies indicated that less than 30 mcg of EE resulted in an unacceptable increase in number of pregnancies and unfavorable patterns of bleeding. Results of extensive clinical studies showed that the Pearl index for the 150/30 combination did not differ significantly from that of the original 500/50 combination did not differ significantly from that of the original 500/50 combination and that both modes of action were primarily inhibition of ovulation. At the end of 12 months the 150/30 combination had the highest continuation rate of 6 OCs evaluated by the World Health Organization in 13 countries. Some evidence has been adduced to verify its clinical advantages. The author concludes that the combination of 150 mcg levonorgestrel and 30 mcg EE achieves remarkable efficacy highly acceptable cycle control and the smallest effect on metabolic parameters of any combination available today in the US.