Abstract
Combined hormonal contraceptives have been increasingly marketed and prescribed in extended regimens to manage menstrual-cycle-related complaints and accommodate patients’ preferences. Extended regimens provide less frequent menstruation and may confer better ovarian follicular suppression and, thus, more effective pregnancy prevention. Most healthcare providers prescribe extended regimens and believe that menstrual suppression is safe; many women, when given the choice, would prefer to menstruate less frequently. However, most women will experience breakthrough bleeding, which may limit patient acceptance of an extended regimen. Recent studies have addressed strategies for minimizing unscheduled bleeding, but further research is needed to identify how best to tailor regimens to the medical needs and preferences of individual women.
Combined oral contraceptive pills (COCs) have been available to women for over 50 years, and while the combinations of estrogen and progestin have varied significantly, there has been little deviation in how the regimen is prescribed. COCs were first packaged as 21 days of hormone pills followed by 7 days of placebo pills (21/7) in order to mimic the physiologic menstrual cycle. Until the last decade, there had been few studies on altering this regimen, despite early data showing that women, when given the opportunity to extend their cycle to 63 days of hormones followed by 7 days hormone free (63/7), preferred to menstruate less often and had comparable side effects to the 21/7 regimen [1]. Many healthcare providers modify the 21/7 regimen for select patients, but not until recently has there been an increased interest in the medical and lay literature in altering a woman's menstrual cycle, both for health benefits and for the patients’ preferences.
An extended regimen of combined hormonal contraception omits or decreases the hormone-free interval. Regimens may include continuous daily hormones without a hormone-free interval, continuous hormones with initiation of a hormone-free interval only when persistent breakthrough bleeding occurs, or continuous hormones for more than 21 days followed by a scheduled interval of 7 or fewer days of either placebo or low-dose estrogen. While there has been increased research on the use of extended cycles, there is no consensus on which regimens optimize menstrual-symptom management while minimizing breakthrough bleeding. This review aims to present the current findings regarding the use of extended cycles of combined hormonal contraception.
Clinical indications
Studies have documented that during the hormone-free interval of combined hormonal regimens, many women experience menstrual-related symptoms such as dysmenorrhea or migraine headaches [2,3], which may be alleviated by using extended cycles [4,5]. Investigators are continuing to identify other conditions that could potentially be treated with extended cycles. A recent study of a 24-week extended regimen of 3 mg drosperinone and 30 μg ethinyl estradiol (EE) found that premenstrual-type symptoms improved significantly during the extended cycle compared with a 21/7 regimen [6]. In addition, these women showed the greatest symptom relief during their sixth month of continuous use, suggesting that longer cycles may have greater benefit.
Extended regimens provide better follicular suppression and thus theoretically confer better pregnancy prevention. A recent randomized, open-labeled trial followed 36 women aged 18–35 years who were stratified into either 3 months of continuous or 3 months of 21/7 COC, containing either 30 μg EE and 150 μg levonorgestrel or 35 μg EE and 250 μg norgestimate [7]. Follicular suppression was analyzed with transvaginal ultrasound during the initial 3 months and during the fourth month when no hormonal contraception was used. Compared with women using the 21/7 regimen (n = 16), women using continuous hormones (n = 20) developed equivalent numbers of small follicles (less than 4 mm in size) but developed no dominant follicles (greater than 10 mm in size), compared with eight dominant follicles in the women on 21/7. This is consistent with previous work, which found that decreasing the duration of the hormone-free interval provides better follicular inhibition [8]. While these data suggest that extended regimens may provide more effective contraception than standard 21/7 regimens, future research will need to explicitly study this comparison.
Patient preferences
Many women are requesting and receiving prescriptions for extended regimens to menstruate less frequently. When asked how often they would prefer to menstruate, 59% of 1460 women in the USA aged 18–40 years would rather menstruate less than once a month; 33% would rather not menstruate at all [9]. Among 1195 German women aged 15–49 years, 65–74% desired less frequent menses, with the main reasons being the desire for fewer intense menstrual complaints, better hygiene and improved quality of life [10]. Conversely, the main reason that German women reported wanting a monthly withdrawal bleed was fear of pregnancy, illustrating the need for patient education regarding the effectiveness of hormonal contraception, the symptoms of early pregnancy, and the fact that hormone withdrawal bleeding does not rule out the possibility of pregnancy.
Healthcare provider practice & attitudes
Recent surveys of 222 physicians in the USA and 1152 German gynecologists revealed that 90 and 97% of respondents, respectively, have prescribed extended regimens for a least a limited period of time [10,11]. In the USA, studies have found that the most frequently prescribed regimen is 84/7 [11,12], most likely reflecting the only US FDA regimen available at that time. Patients’ requests for less frequent menstruation constitute the most common reason for prescribing an extended cycle to adolescents (82% of respondents) [11] and to adults (72% of respondents) [9]. Extended cycles are also commonly prescribed for menstrual-related disorders such as dysmenorrhea, menorrhagia, anemia and cyclic headaches [10,11]. Most healthcare providers agree suppressing menses with combined hormonal contraception is safe, and monthly withdrawal bleeding is unnecessary. A study evaluating female gynecologists’ opinions toward menstrual suppression found 99% felt suppression was safe; 69% agreed with long-term and 30% agreed with occasional short-term suppression [13]. When asked to identify the role of the withdrawal bleed while on 21/7 cycles, 52% of 551 healthcare professionals, including primary-care physicians, obstetricians/gynecologists, nurse practioners and physician assistants, stated that the bleeding was unnecessary, with no health benefits, 12% felt it had health benefits and 49% thought it only served to reassure absence of pregnancy [12].
Clinical advances
Bleeding patterns
With increased use, growing attention has been given to the drawbacks of extended regimens. Breakthrough bleeding is the most common side effect of and the most common reason for discontinuing an extended regimen. A study analyzing bleeding profiles in women taking COC continuously for 1 year found that 84% of the women reported bleeding or spotting in the first 3 months [14]. However, in the final 3 months, that percentage decreased to 28%, emphasizing a trend found in other studies that the occurrence of breakthrough bleeding decreases with duration of use [15,16].
Until recently, there had been few head-to-head trials comparing the effects of different hormone regimens on breakthrough bleeding. Edelman and colleagues conducted a randomized, double-blind study that compared bleeding outcomes when varying the type of progestin and the dose of estrogen [17]. A total of 139 women aged 18–49 years took hormones continuously for 180 days, with one of four arms created by using two doses EE (20 μg or 30 μg) with either a gonane progestin (levonorgestrel 100 μg) or an estrane progestin (norethindrone 1000 μg). Women using norethindrone, regardless of estrogen dose, had less bleeding than those using levonorgestrel. Despite estrogen's theoretical benefit of stabilizing the endometrium in a progestin-dominant environment, increasing the estrogen dose did not decrease the amount of bleeding. This study, while limited by its homogeneous sample and short duration, is an important step toward improving our understanding of the impact of varying types and doses of hormones on bleeding patterns with extended cycles.
Although breakthrough bleeding can be very troublesome to women [14,16], there has been limited systematic study of how to address this common problem. In a recent study of extended cycles, women who had 7 consecutive days of breakthrough bleeding were randomized to either continue taking hormonally active pills or to institute a 3-day hormone-free interval [18]. Those who took the 3-day hormone-free interval had an expected initial increase followed by an abrupt decrease in bleeding, while those women who continued to take active pills showed prolonged bleeding. While this study instituted a hormone-free interval after 7 days, clinicians may choose to start the hormone-free interval after a shorter number of bleeding days to improve women's acceptance of an extended regimen.
Breakthrough bleeding with extended cycles may be more problematic for women with a history of heavier bleeding on a 21/7 cycle. Of the 111 women using an 18-week regimen of continuous 30 μg EE and 3 mg drosperinone, those who complained of the heaviest bleeding during the 21/7 study run-in period had the earliest average occurrence of bleeding (day 85 vs day 126) and reported heavier bleeding during the extended cycle compared with women with lighter flow in the study run-in [18]. Thus, women with heavy bleeding need to be adequately counseled regarding their higher risk of unscheduled bleeding.
Vaginal ring & transdermal patch
Other combined hormonal contraceptives have been studied, with similar results to those found with the COC. A recent observational study of 75 Brazilian women using the vaginal ring (which delivers 120 μg etonogestrel and 15 μg EE daily) in an 84/7 regimen showed that the average number of bleeding days per 84-day cycle is highest in the first extended cycle and then decreases (7, 4, 3.5 and 5.5 days per cycle) [19]. Previous study of the vaginal ring used in various extended regimens found that, while the number of bleeding days decreases with longer regimens, the number of spotting days increases [20]. In both of these studies, the vaginal ring was replaced every 21 days in accordance with recommended use; however, a small study analyzing the effectiveness of the vaginal ring found that ovarian suppression, determined by follicular diameter and serum hormone levels, was still adequate with up to 35 days of use [21]. Nevertheless, given the small sample size (n = 16), larger studies are needed before recommending the use of the vaginal ring for longer than 21 days continuously.
The transdermal patch (which contains a total of 6.0 mg norelgestromin and 0.75 mg EE) in an 84/7 regimen resulted in fewer bleeding days and a delayed time to first bleeding episode compared with a 21/7 regimen [22]. However, given the lack of long-term safety data and the increased risk of estrogenic side effects, such as venous thromboembolism, while using 28-day cycles, extended regimens with the patch should be used with extreme caution pending the results of ongoing safety studies of a 49/7 regimen.
Safety
There is a lack of long-term data on the safety of extended regimens with COC, but compared with 21/7 regimens, studies have found no significant differences in blood pressure, mean body weight, serum levels of glucose or insulin, or lipid profiles [15,23,24]. Likewise, there have been no studies specifically evaluating the risks of extended regimens and cardiovascular disease, venous thromboembolic disease, bone density or future malignancy. While it has been shown that the risk of ovarian and endometrial cancers decreases in women taking COC in a 21/7 regimen compared with women not taking COC [25], similar information is not available for extended regimens. However, no endometrial hyperplasia has been documented in a number of studies with up to 1 year of an extended regimen [14,16,26,27].
Anecdotal data have shown a rapid return to fertility in women who desired a pregnancy after using an extended regimen [15,16,25,28]. However, there has been limited investigation of the potential effects of extended cycles on future fertility. In the study described above, Birtch and colleagues also used transvaginal ultrasound to monitor follicle development during the first cycle after the three 28-day cycles of using either continuous hormones (n = 20) or a 21/7 regimen (n = 15) [7]. They found no significant differences between the groups on any measures of follicular development or in serum estradiol or progesterone levels, suggesting there would be no delay in fertility in continuous pill users compared with those on 21/7 regimens.
Conclusion
Extended cycles of combined hormonal contraception are increasingly requested by patients and prescribed by healthcare providers. In response, there has been an increase in the number of studies assessing the benefits, as well as identifying and proposing solutions to some of the drawbacks, of extended regimens. In the future, women using combined hormonal contraception will be given the tools needed to individualize their menstrual cycle, as there will no longer be one ‘standard’ cycle uniformly applied to all.
Future perspective
Both patients and healthcare providers have become more aware of options to alter a woman's menstrual cycle through increased media and scientific journal attention. In the USA, the number of prepackaged extended regimens approved or currently under review by the US FDA is steadily increasing; the first continuous regimen of combined hormone pills containing 90 μg levonorgestrel and 20 μg EE was approved in May of this year. As more drugs become FDA-approved, health are providers are likely to become more comfortable with and more willing to prescribe an extended regimen. Similarly, women may feel more at ease altering their menstrual cycle. Tolerability of extended regimens will increase as future studies expand strategies for the prevention and management of breakthrough bleeding. Increased research into the utility and effectiveness of various extended regimens will allow clinicians to better individualize regimens for patients’ medical needs and preferences. For example, the best-tolerated estrogen dose and the preferred schedule for withdrawal bleeding is likely to be different for women who use extended cycles to prevent menstrual migraine compared with women with menorrhagia. Ultimately, women using combined hormonal contraceptives will be given greater freedom and control in choosing a menstrual-cycle pattern best suited to their lifestyle.
Executive summary
Extended regimens of combined hormonal contraception accommodate patient preferences, more effectively manage many menstrual-cycle-related complaints, and may confer better pregnancy prevention.
Many women, given the choice, would prefer to menstruate less frequently.
Most healthcare providers prescribe extended regimens and believe that menstrual suppression is safe.
Current evidence suggests that improved cycle control during extended regimens may be achieved with low-dose ethinyl estradiol (20 μg versus 30 μg) in combination with norethindrone (1000 μg). However, much further research is needed to corroborate and extend these findings.
The number of extended regimens approved or under review by the US FDA is steadily increasing. The availability of these products will likely provide women with increased control over their menstrual cycles.
Footnotes
KL Gerschultz has no relevant financial interests, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties related to this manuscript.
GS Sucato received a one-time honorarium from a health media company (Dowden). The work she did for them (April 2007) was supported by a grant from Duramed, a manufacturer of extended-cycle birth-control pills. She is also a site primary investigator on two multicenter pharmaceutical studies funded by Duramed.