Clinical Review

Sizing up a new generation of OCs

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Ultra-low-dose formulations are thought to offer a number of advantages over earlier oral contraceptives, including a reduced risk of thromboembolism and stroke, and fewer concerns about breast cancer. But what does the evidence show?



  • Oral contraceptives formulated with estrogen doses as low as 15 to 25 μg have been proven clinically effective and generally are associated with a lower incidence of estrogenrelated side effects.
  • In general, ultra-low-dose pills have resulted in bleeding patterns consistent with those of higher-dose preparations.
  • One study of women taking 20 μg ethinyl estradiol (EE2) and 100 μg levonorgestrel over 2 years found no significant changes from baseline levels of triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein A-1 and B.
  • The enhanced hepatic enzyme activity associated with some anticonvulsants can limit the efficacy of OC therapy.

The first combination oral contraceptive (OC), approved by the FDA in 1960, contained 150 μg mestranol and 10,000 μg norethynodrel. In the years since its introduction, equally effective but lower-dose OCs have been developed that are associated with fewer unpleasant side effects. Since 1988, no OC has contained more than 50 μg ethinyl estradiol (EE2) or its biologic equivalent. EE2 now is the only estrogen used in OC formulations.

Ultra-low-dose OCs, formulated with estrogen doses as low as 15 to 25 μg, have been proven clinically effective. In addition, newer progestins with less androgenic activity continue to become available. The latest are “third-generation” progestins that have minimal progestational side effects. One of them is drospirenone, which exhibits both antiandrogenic and antimineralocorticoid activity. Today the primary differences between OC preparations center on their androgenic, mineralocorticoid, and sex-hormonebinding globulin effects. TABLE 1 lists the androgenic qualities of each progestin.


Androgenicity of progestins in OC formulations

GestodeneNorethindrone acetateNorgestrel
DesogestrelEthynodiol diacetateLevonorgestrel

Mechanism of action

OCs inhibit ovulation by suppressing the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), thereby halting ovarian follicular development. While this decreases endogenous production of estrogen and progesterone, the serum levels of these hormones remain high, as they are the main ingredients of the pills.

Ultra-low-dose OCs became clinically available in the 1990s. Several formulations now are offered in the United States and internationally, all of them containing EE2. The dosing is 15, 20, or 25 μg in monophasic pills. One biphasic formulation containing 20 μg EE2 has reduced the pillfree interval to 2 days, followed by 5 days of 10 μg EE2. (Two other ultralow-dose OCs have reduced the pill-free interval to 5 days.) Triphasics include formulations that have 25 μg of EE2 and increasing amounts of desogestrel (100, 125, and 150 μg), as well as those that contain 30 to 40 μg EE2 and increasing amounts of levonorgestrel (50, 75, and 125 μg). Another triphasic contains 20, 30, and 35 μg of EE2 and 1,000 μg norethindrone. See FIGURE 1 for a more complete listing.

The progestin content of monophasic formulations typically is 150 μg desogestrel or 75 μg gestodene, although one brand contains 100 μg norethindrone and another contains 100 μg levonorgestrel. A recently approved monophasic OC contains 30 μg EE2 and 3,000 μg drospirenone. (As mentioned earlier, the progestin has antiandrogenic and antimineralocorticoid activity.) When desogestrel is the progestin in low-dose triphasics, it is administered in the amount of 100 μg on cycle days 1 through 7, increasing to 125 μg on days 8 through 14, and 150 μg on days 15 through 21.

Interestingly, a number of the 20-μg-EE2 formulations have been noted to have follicular-phase levels of circulating estradiol. When low-dose pills were evaluated with respect to the pulsatile character of gonadotropin secretion, the LH pulse frequency during the treatment cycle was significantly inhibited, compared with the control cycle. Overall, gonadotropin secretion is at a low level during treatment with these contraceptives.1

The 20-μg preparations also have been associated with reduced ovarian activity. With the 15-μg formulations, there is greater variation in the interval between cessation of OCs and the resumption of ovulation. Researchers have hypothesized that the gradually decreasing estradiol levels (with the 15-μg formulations) are responsible for this problem, as well as for occasional breakthrough ovulation.2

Overall failure rates are interpreted in terms of women-years of use, known as the Pearl index. When compliance is adequate, OC therapy has a failure rate of less than 1 in 100 women-years, i.e. a Pearl index of less than 1.


Davis and colleagues reported an overall improvement in dysfunctional uterine bleeding—i.e., a lower incidence of spotting and breakthrough bleeding—with OCs containing more than 35 μg EE2 plus norgestimate.3 Unfortunately, data are limited on bleeding patterns associated with formulations containing less than 35 μg of EE2. In general, ultra-low-dose pills have resulted in bleeding patterns consistent with those of higher-dose preparations. Breakthrough bleeding occurs more often in the first 3 to 4 cycles and decreases with longer duration of use in patients given OCs for dysfunctional uterine bleeding.3 OCs containing norethindrone acetate appear to have the least favorable bleeding profile (i.e., the highest incidence of breakthrough bleeding) even when taken correctly.4


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