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The best prophet of the future is the past: oral contraception and novel components.

Contraception remains a major point of contention in almost all aspects of our society, from political to religious to medical, despite extensive and consistent evidence that reaffirms the profound health benefits of effective contraception. Why contraception evokes such strong emotions is not entirely clear, though its inherent linkage to sex and sexuality, and most importantly, to female sexuality, is likely a key factor. However, as opposed to those who rail against the availability and use of contraception because of political or religious convictions, I have never understood the basis for attacks on the use of hormonal contraception from a medical or patient safety point of view. Granted, the use of hormonal contraceptives that contain estrogens is associated with a small but well-defined increased risk for thromboembolic events. However, it has been demonstrated over and over again that the prevention of unintended pregnancy, whether by effective hormonal or nonhormonal methods, is associated with a profound and significant reduction in morbidity and mortality. To be sure, those who are most strident in their ‘‘concerns’’ about the safety of hormonal contraception invariably fail to mention the considerable morbidity and mortality associated with pregnancy. From the prevention of unintended pregnancy to the reductions in ovarian epithelial cancer, endometrial cancer, and ectopic pregnancy, among many other conditions, hormonal contraception improves health, saves lives, and strengthens communities and society at large. Combination hormonal regimens are typically associated with a very high rate of contraceptive effectiveness (approximately 99%) when used properly; this has been a characteristic of oral and nonoral hormonal methods for more than five decades. Accordingly, the development of new contraceptives has focused on improving tolerability and safety, so as to increase the consistent and correct use of oral contraceptives for sexually active women who choose not to become pregnant. The paper by Anita Nelson et al. in this edition of the Journal of Women’s Health reports on the development of a new regimen that may have a better impact on women’s lives than more conventional methods. Combination hormonal contraceptives have historically contained mestranol or ethinyl estradiol (EE) as its estrogenic component, with both sex steroids being associated with an increased risk for thromboembolic events as well as certain tolerability issues such as nausea and breast tenderness. While the lowering of EE doses in the development of oral contraceptives reduced the risk for thromboembolic events, an increased risk for such adverse outcomes remained, even with considerably lower daily doses of EE. Accordingly, there has long been a desire and need to develop a combination oral contraceptive that would provide effectiveness and tolerability similar to an EE-containing regimen but without using EE. One of the first approaches to the development of such a regimen was the substitution of 17-beta estradiol for EE; 17-beta estradiol (E2) is the endogenous hormone that has been considered to be a potential estrogenic component for a combination oral contraceptive regimen that could be associated with better tolerability and safety when compared with EE-containing oral regimens. The basis for this belief is a weaker hepatic impact for E2 than EE because the 17-alpha ethinyl group on the EE molecule prevents its inactivation and results in a slower metabolism, longer tissue retention, and a more pronounced hepatic effect than that found with E2. Initial attempts at incorporating E2 into oral contraceptive regimens started in the 1990s with a variety of E2 doses (1–4 mg) and combinations with a variety of progestins (e.g., norethisterone, desogestrel). While such regimens showed sufficient ovulation inhibition and a generally acceptable level of contraceptive efficacy, none of these regimens were ever developed into commercially available contraceptive regimens because of their universally unacceptable bleeding profiles. However, the potential of E2 to provide a tolerability and safety profile different from and potentially more acceptable than EE-containing pills continued to maintain interest in the development of an E2-based oral contraceptive despite the shortcomings of the initial E2-containing regimens. The approach to developing an E2-based regimen with an acceptable bleeding profile actually shifted from investigations into the estrogenic component of the regimen to the progestin. For if E2, or an E2-based estrogen such as estradiol valerate (E2V), could be combined with a progestin that could provide a more stable endometrial environment and thus reduce the unacceptable bleeding profile, then an effective E2-based contraceptive regimen could be developed and potentially characterized by a salutary contraceptive, hepatic, and hemostatic impact but without the poor bleeding profile. Indeed, progestins such as nomegestrel acetate