Benefits of extended combined hormonal contraceptive regimens

Combined hormonal contraceptives (CHCs), which include daily combined oral contraceptive (COC) pills, weekly transdermal patches, and monthly vaginal rings, are commonly prescribed in the United States for pregnancy prevention and for their noncontraceptive benefits. In national surveys conducted between 2015 and 2019, about 79.8%, 8.2%, and 10.4% of reproductive age women who have ever had sexual intercourse have used pills, patch, and ring for contraception, respectively.¹ Overall, these methods have moderate effectiveness with an estimated 12-month probability of failure of 7.2%.²

CHCs are traditionally prescribed as a 28-day regimen, with 21 days of active hormone use followed by a hormone-free interval (HFI) typically of 7 days (21/7) for a scheduled monthly bleed. Shortening, delaying, or eliminating the HFI has several advantages, including increasing the effectiveness of CHCs for contraception, decreasing withdrawal bleeds, and management of menstrual-associated conditions, such as dysmenorrhea, endometriosis, bloating, breast tenderness, migraines, and catamenial seizures.^3-5 Although there are several benefits to extended CHC regimens, some clinicians may be less familiar with prescribing these formulations and discussing their use with patients.

What are extended CHC regimens?

Studies vary in the definition of what constitutes extended CHC use; however, these regimens typically consist of active CHC use beyond 21 days with a HFI under 7 days.^3,6,7 In the current market, there are products that maintain a 28-day cycle with a shorter HFI (eg, COCs with 24 days of active hormones followed by a 4-day HFI), those with active hormone use beyond 28 days without a monthly HFI (eg, 91-day regimen with 84 days of active hormone followed by a 7-day HFI), and those with continuous hormone use without a HFI interruption. The Table provides a list of marketed extended COC formulations in the United States. Outside the marketed products for extended use, patients can also shorten, delay, or eliminate the HFI of any CHC to increase active hormone use. These situations include flexible-extended regimens, which refers to an extended cycle of variable lengths in which the user decides when to initiate a HFI, typically prompted by an episode of unscheduled bleeding.⁶ 

Extended regimens can decrease the risk of ovulation

The primary contraceptive mechanism of CHCs is inhibition of the hypothalamic-pituitary-ovarian (HPO) axis to prevent ovulation.3 Ovulation inhibition is achieved by the progestin component of CHCs, which inhibits the luteinizing hormone (LH) surge required for ovulation, with additional effect from the estrogen component, which inhibits FSH and the development of a dominant follicle.^3,8 With modern, lower-dose COCs, the HPO axis is not always fully suppressed throughout the 7-day HFI.^8-10 In a prospective trial comparing pituitary secretions of FSH and LH gonadotropins and ovarian production of estradiol and inhibin-B with a 7-day vs a shortened HFI, all 4 hormones significantly increased from baseline during the 7-day HFI with an increase in FSH starting on day 4, inhibin-B on day 5, and LH and estradiol on day 6 of the HFI.⁸ In contrast, there was greater pituitary and ovarian suppression seen with the shortened 3- or 4-day HFI. With this rise in FSH during the 7-day HFI, development of a dominant follicle could occur and lead to ovulation with any inadvertent delay in restarting active pill use.8,10 In another study evaluating follicle number and size with daily transvaginal sonography during the 7-day HFI, dominant follicles (diameter ≥ 10 mm) were observed at the end of the pill-free interval in participants taking COCs containing 20 μ of ethinyl estradiol (EE).⁹

To reduce activation of the HPO axis and development of a dominant follicle, some products substitute the placebo or inert pills with EE 10 μ (Table). In a prospective study that randomly assigned participants to 3 different COC regimens (21 active/7 placebo, 84 active/7 placebo, and 84 active/7 EE 10 μ), FSH and estradiol concentrations and follicular development were decreased in the group that received EE 10 μ during the 7-day HFI compared with the other 2 groups.¹⁰ Altogether, these findings suggest that shortening the HFI limits reactivation of the HPO axis and decreases risk of development of a dominant follicle and subsequent ovulation.

Extended regimens may be more effective at pregnancy prevention

The greater ovarian suppression of extended CHC regimens can increase contraceptive efficacy. The largest study supporting the benefit of a shortened HFI is a prospective, observational cohort study including over 52,000 participants in the United States who were starting COCs.¹¹ Participants using a 24/4 COC (drospirenone/EE) had significantly lower pregnancy rates compared with participants using a 21/7 formulation. In contrast, a Cochrane review of 12 randomized clinical trials found no differences in pregnancy rates with extended (greater than 28 days of active hormone use) or continuous CHC regimens compared with traditional cyclic regimens, although these studies were underpowered for pregnancy as an outcome given the overall small number of reported pregnancies.³

Extended regimens reduce withdrawal bleeding

Patients who have medical indications, such as bleeding disorders, or a personal preference to eliminate monthly bleeding may benefit from extended CHC use.^3,6 In a randomized trial comparing bleeding patterns with a 24/4 vs 21/7 regimen of norethindrone acetate 1 mg/EE 20-μ pill, 24/4 use was associated with fewer withdrawal days (2.66 vs 3.88) and unscheduled bleeding days (0.95 vs 1.63) compared with 21/7 use.12 While shortening the HFI during cyclic use (eg, a 24/4 regimen) reduces the number of bleeding days each cycle, further extending the active hormone period (eg, 84/7, flexible-extended, or continuous use regimens) is recommended for those who wish to avoid or reduce the frequency of withdrawal bleeds. In a study comparing 24/4 to flexible-extended COC regimen of drospirenone/EE in which participants could initiate a HFI when breakthrough bleeding occurred, 74% of participants in the flexible-extended group experienced absence of bleeding (with or without spotting) compared with 28% in the cyclic group during the treatment period of 168 days.13 Continuous active hormone use without any scheduled HFI also reduces bleeding. In a study evaluating the safety and efficacy of continuous use of levonorgestrel 0.9 mg/EE 20 μ, 53% of participants achieved amenorrhea and 26% had only spotting at the end of 1 year.¹⁴

Extended regimens can improve other menstrual-related symptoms

Hormone levels can fluctuate during the HFI, which can exacerbate symptoms such as pelvic pain, headaches, mood symptoms, bloating, and breast tenderness.^3,5 In addition to decreasing bleeding days, CHC regimens that eliminate or decrease the HFI can treat these menstrual-related conditions. In the Cochrane review previously mentioned, participants assigned to the extended or continuous use groups had fewer headaches and less genital irritation, tiredness, bloating, and menstrual pain than participants in the cyclic group.³ A subsequent systematic review specifically investigating CHC use for the management of dysmenorrhea found that continuous and extended regimens also reduced the duration of dysmenorrhea more than cyclic use but was inconclusive regarding other pain outcomes.⁴

Extended use of the contraceptive patch and vaginal ring

Patch

There are 2 contraceptive patches currently available in the United States, 1 containing norelgestromin/EE and the other with levonorgestrel/EE. The typical use of the contraceptive patch follows a 28-day cycle in which patients apply a new patch weekly for 3 weeks followed by a 7-day HFI to allow for a withdrawal bleed. In the only study investigating clinical outcomes with extended patch use (eg, 12 weeks of consecutive patch use followed by a 7-day HFI), extended use resulted in fewer bleeding days and episodes of bleeding or spotting compared with cyclic use.¹⁵ While bleeding outcomes are favorable with extended patch use, there are concerns about increased thrombotic risk with prolonged patch use based on pharmacokinetic data. After 21 days of active hormone treatment, EE exposure was highest with the norelgestromin/EE patch compared with the etonogestrel/EE vaginal ring and levonorgestrel/30-μ EE pill.¹⁶ Another pharmacokinetic study investigated changes in serum norelgestromin and EE concentrations over 12 weeks of consecutive patch use and found that norelgestromin concentrations remained stable while EE concentrations increased about 11% per week over the study period.¹⁷ While the absolute EE concentrations were overall low and within the expected EE range defined by prior contraceptive patch pharmacokinetic data, the increasing accumulation of EE over time may have implications for the safety of extended patch use. There are no clinical trials investigating extended use of the levonorgestrel/EE patch; however, in a pharmacokinetic model, the simulated hormonal exposure to EE at week 12 was predicted to be similar to week 3 of use, indicating no accumulation of EE over time.¹⁸ Given the lack of data demonstrating the long-term safety of prolonged patch use, especially with respect to venous thromboembolism risk, extended use beyond 12 weeks is not recommended at this time. 

Vaginal ring

The 2 vaginal rings available in the United States are the etonogestrel/EE ring, which is replaced each cycle, and the segesterone acetate/EE vaginal ring which is used cyclically over 1 year. The contraceptive vaginal rings are labeled to be placed vaginally for 21 days and removed for a 7-day HFI to allow for withdrawal bleeding. Continuous use of vaginal rings is considered off-label use but is an option for patients who wish to reduce withdrawal bleeds as continuous etonogestrel/EE vaginal ring use results in fewer episodes of bleeding.¹⁹ No data currently exist on clinical outcomes of eliminating or reducing the HFI with the segesterone acetate/EE vaginal ring.

Managing irregular bleeding with extended CHC use

When prescribing extended regimens, patients should be advised they may experience bleeding irregularities, especially during the first 3 to 6 months of use.⁷ In addition to ruling out other causes of irregular bleeding, such as pregnancy, infection, and polyps, clinicians should discuss management options if the patient is bothered by the bleeding.⁷ Flexible-extended use, also described as a menstrual or bleeding signaled regimen, is 1 studied approach to managing breakthrough bleeding with continuous COC or vaginal ring administration.^20-22 With this strategy, patients use active hormone continuously until they experience 4 or more days of consecutive bleeding. At that point, patients are instructed to discontinue treatment for 4 days to allow for a withdrawal bleed before resuming active hormone use again. In 1 study investigating a bleeding-signaled regimen for continuous COC and vaginal ring use, in those who followed the regimen, two-thirds of bleeding/spotting episodes stopped within the next 5 days.²¹ While there was inconsistent adherence to this regimen, bleeding episodes persisting for more than 4 days were likely to spontaneously resolve within 4 to 8 days. Although unscheduled bleeding episodes are typically short and decrease with continued use, providers should prepare patients for unpredictable bleeding when prescribing continuous CHC use.

Final takeaway for prescribing extended CHC regimens

• For patients who desire a monthly withdrawal bleed, 24/4 COC formulations are recommended due to evidence of improved efficacy with a shorter HFI while extended or continuous regimens are preferable for those who want to reduce scheduled bleeding episodes.
• Commercial extended COC products are available in the United States (Table 1); however, clinicians can prescribe any monophasic (same dose of estrogen and progestin in each active pill) COC and instruct patients to adjust the HFI to meet their patients’ needs.
• For those using an extended-flexible regimen, it is important not to initiate an HFI during the first 21 days of active hormone use or incorporate more than 1 HFI per month because multiple HFIs can reduce contraceptive effectiveness.⁷
• While most evidence supporting extended CHC use comes from studies evaluating COCs, clinicians can also discuss off-label extended use of the patch (up to 12 weeks) and vaginal ring to improve bleeding and menstrual-related conditions.
• Counseling on extended CHC use should include anticipated guidance regarding breakthrough bleeding and strategies for management.

References

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