Estrogen-progestin balance is more important than absolute level of estrogen. Endrikat et al12 conducted a study to compare two 20 μg EE pills containing different progestins, and to compare 2 levonorgestrel-based formulations with differing EE amounts. An OC of 20 μg EE/100 μg levonorgestrel was compared with a preparation of 20 μg EE/500 mg norethisterone. A 30 μg EE/150 mg levonorgestrel pill was used as a standard reference preparation.
Overall, the 30 μg EE preparation showed a lower cumulative incidence of breakthrough bleeding compared with the 20 μg EE/100 μg levonorgestrel and 20 μg EE/500 μg norethisterone pills over 13 cycles (1.0% vs 4.1% vs 11.7%, respectively). However, the 20 μg EE/500 μg norethisterone pills consistently had higher breakthrough bleeding rates than the 20 μg EE/100 μg levonorgestrel pill. This suggests that, although the higher EE component in the 30 μg pill was important when comparing 2 formulations with the same progestin, the difference in progestins of the two 20 μg EE pills was most likely responsible for the differing rates of breakthrough bleeding.
This study highlights the ability to achieve greater cycle control by titrating the EE component of an OC in a balanced ratio with the same progestin, but suggests that the absolute quantity of EE in a given pill may be less important than maintaining a balance between the 2 hormones or less important than the impact of different progestins on breakthrough bleeding rates.
The delicate balance between estrogen and progesterone supplementation required for contraception may also lead to progestin-induced decidualization and endometrial atrophy, which can result in asynchronous, erratic bleeding.7,13 This has been primarily studied in long-acting progestin-only contraceptives such as implants. Alterations in angiogenic factors14 may play a role. Hysteroscopic studies have shown abnormalities in superficial endometrial blood vessels in terms of size, proliferation, and fragility in women using Norplant.13,15,16 Abnormalities in endothelial cells and extracellular matrix proteins,17 tissue factor,18 and endometrial lymphoid cells19 may contribute to breakthrough bleeding in progestin-dominant environments.
Available OC formulations, doses, and regimens
More than 30 formulations of combination OCs are available in the US, with different doses and types of estrogen and progestin ( TABLE 1 ).20 Approved OCs have been studied in clinical trials to assess contraceptive efficacy and cycle control; however, comparisons between studies regarding bleeding phenomena are impaired by inconsistent terminology.3
While some studies describe breakthrough bleeding and spotting according to their recognized definitions, others simply refer to intermenstrual bleeding or use spotting to refer to any unexpected bleeding. In addition, cycle control studies of OC users frequently do not account for the effects of missed pills, use of concomitant medications, or smoking. The percentage of women who experience breakthrough bleeding in a given cycle varies widely even in different trials of the same formulation.
Pay attention to progestin level. Conventional wisdom holds that OCs with the lowest doses of EE (≤20 μg) are associated with more breakthrough bleeding.11 However, even moderately low doses of either EE or progestin can increase the incidence of breakthrough bleeding. For example, when 3 pills with the same estrogen and progestin (50 μg EE/100 μg norethin-drone; 35 μg EE/100 μg norethindrone; and 35 μg EE/50 μg norethindrone) were compared in 192 women over 8 cycles, the pill containing the lowest amount of norethindrone (35 μg EE/50 μg norethisterone) caused the highest rates of breakthrough bleeding (decreasing to approximately 50% by cycle 8 as compared with 35% in the 35 μg EE/100 μg norethindrone pill and 25% in the 50 μg EE/100 μg norethindrone pill).21
In addition, the number of intermenstrual bleeding days plateaued more slowly as the amount of both hormones in the OC formulations decreased. This underscores the importance of the relative proportions of estrogen and progestin contained in combination OCs and its impact on breakthrough bleeding.
Similarly, a large comprehensive study in 1991 women compared 7 different formulations of combination OCs containing different dose combinations of EE and norgestimate—20/250, 50/250, 35/125, 20/60, 50/60, 30/90, 25/125.25 Total inter-menstrual bleeding was more frequent at lower doses of either estrogen or progestin. However, as long as a similar estrogenprogestin ratio was maintained, bleeding rates were considered acceptable (approximately 10% of days per cycle with bleeding). The authors also noted that in the low-dose range of OCs, small changes in the absolute amount of either EE or norgestimate might result in noticeable changes in bleeding.