Doctor's Review: Medicine on the Move

January 20, 2022


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Low-dose combined oral contraceptives

Maintaining efficacy while minimising side effects and risks

Canadian women enjoy more choice than ever with regard to hormone-based contraception. Among the latest developments is a low-dose combined oral contraceptive pill. These new agents have been produced with the goal of maintaining excellent pregnancy prevention while minimizing the adverse events, whether life-threatening or simply inconvenient, that have traditionally been associated with hormone-based contraception.

Combined oral contraceptives are available in a variety of formulations, but all contain a form of estrogen, usually ethinyl estradiol, and a progestin, such as norethindrone acetate, levonorgestrel, or drospirenone. They all work by preventing ovulation through suppression of release of follicle-stimulating hormone (FSH) by the pituitary gland. This in turn prevents development of a dominant follicle in the early days of the menstrual cycle and the resulting surge in luteinizing hormone (LH) that triggers ovulation.1

Lowering the dose

In the decades since combined oral contraceptives were first introduced in the 1960s, doses and types of estrogens and progestins have been modulated in an effort to achieve the highest level of efficacy with the lowest risk of serious adverse events and troublesome side effects. Important changes include the development of third- and fourth-generation progestins, such as norgestimate and norelgestromin,2 as well as reductions in estrogen dose, since estrogen has been shown to drive the risk of serious thrombotic events3,4,5 in a dose-dependent manner.6

Shortening the hormone-free interval

Traditionally, combined oral contraceptives have been prescribed in a 28-day cycle consisting of 21 days of active hormone therapy followed by a 7-day hormone-free interval, during which time patients may discontinue therapy altogether or take a placebo pill. During the hormone-free interval, bleeding triggered by hormone withdrawal mimics a natural menstrual period, and one of the primary benefits of the 21/7 cycle was perceived to be that it closely resembles women’s natural menstrual cycle. But another consequence of this interval is the emergence of hormone-withdrawal-associated symptoms. In fact, many of the adverse events associated with combined oral contraceptives are not direct effects of the hormone treatment itself but of hormone withdrawal.7

Thus, an additional strategy for improving the risk/benefit balance of combined oral contraceptives is to reduce the hormone-free interval, either by shortening the monthly duration of the interval or by having fewer intervals overall. Not only can this limit the troublesome side effects that lead women to discontinue therapy, such as bloating, breast tenderness, headaches, and nausea, but it has the added benefit of reducing or even eliminating cyclic bleeding.8

In a key trial of a COC of 10 mg EE with NETA in a 24/2/2 schedule (24 days active hormonal treatment, 2 days EE only, 2 days placebo) women reported only light periods of withdrawal bleeding of less than two days in a cycle.10

Fully 32% of women in the study reported a complete absence of all bleeding in the first cycle, rising to 49% by cycle 13. That rate is higher than those reported by users of other COCs but the data is sparse and no direct comparisons exist. It does suggest, however, that this dosing schedule does provide a reasonable alternative to the common off label practice in which some women attempt to achieve amenorrhea by skipping the placebo pills of a standard monthly-cycle COC and proceed directly to the next active cycle without an HFI.11

Importantly, this reduction in withdrawal bleeding does not occur at the expense of efficacy. On the contrary, there is evidence that a shorter hormone-free interval contributes to follicular suppression,8,9 potentially allowing for even lower doses of estrogen to be used without sacrificing efficacy. There is also evidence that the increased follicular suppression reduces the risk of contraceptive failure (i.e., an escape ovulation) when pills are missed.12

This article was accurate when it was published. Please confirm rates and details directly with the companies in question.


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