Extended-Cycle Oral Contraceptive Pills with 10 μG Ethinyl Estradiol Pills in Place of Placebo Pills

Abstract

The elimination of monthly withdrawal bleeding with use of extended-cycle (84 pills) monophasic birth-control pills has modernized oral contraceptives. The use of ethinyl estradiol 10 μg pills in place of the seven placebo pills addresses the problems posed by 21/7 formulations of low-dose birth-control pills, which allow early stimulation of ovarian follicles, and of the early 84/7 formulations, which had higher rates of unscheduled bleeding and spotting.

Keywords

extended-cycle oral contraceptives hormone-free interval

Since the introduction of the first birth-control pill (Enovid-10) in May 1960, oral contraceptives have maintained their preeminent position among the contraceptive methods in most developed countries. Over the decades, they evolved in many dimensions. Important safety improvements were made by reducing the hormonal content of pills. New progestins were developed to increase the serum half-lives of those compounds, which reduced unscheduled bleeding and spotting. Later, changes in progestins were made to reduce the androgenic side effects of those longer-acting progestins. Multiphasic formulations were developed to offer different doses of hormones throughout the cycle. New delivery systems were introduced, with transvaginal ring and transdermal patches to enhance successful utilization.

The only feature of combined hormonal contraceptives that remained unchanged for decades was packaging of seven placebo pills in each packet, or instructions to wait 7 days without hormones to induce scheduled withdrawal bleeding. This periodic bleeding, which was perceived as menstruation by women, was very important to the initial acceptance of the pill for psychological, not medical, reasons. Early pill formulations contained high doses of both estrogen and progestin. For example, Enovid consisted of mestranol 150 μg and norethynodrel 9.85 mg. Each pill of Enovid contained an amount of progestin equivalent to approximately 10 days of a standard ethinyl estradiol (EE) 35 μg pill (such as Ortho Novum 1/35®), 20 days of a lower progestin dose pill (such as Brevicon®/Modicon®) and more progestin than is found in an entire packet of low-progestin pills (such as Ovcon® 35). At these high doses, systemic side effects of the early pills (such as nausea, vomiting, breast tenderness, melasma, fluid retention and weight gain) were relatively common. Each of these symptoms was highly suggestive of pregnancy. Since oral contraceptives were new, women had no basis on which to trust their efficacy. All previous contraceptive methods had clearly functioned as barriers to sperm entry into the upper genital tract at the time of ovulation; condoms, spermicide, diaphragms and coitus interruptus all clearly worked this way. Very few people understood the workings of the hypothalamic–pituitary–ovarian axis or the concept of negative feedback well enough to trust the new approach that pills offered to fertility control. Women's hopes for pill efficacy were high, but their skepticism was still obvious.

In the face of these common side effects, there was no way to promptly reassure a woman that she was not pregnant. Rapid pregnancy tests were not available. The most common pregnancy test available in 1960 was called ‘the rabbit test’. The urine of a woman who was at least 6 weeks beyond her last menses was injected into a female animal (usually a rabbit, rat or frog). If the woman was pregnant, the high levels of hormones in her urine would stimulate growth of follicles (cysts) in the ovaries of the test animal. These cysts could be visualized when the animal was sacrificed several days later. The expression ‘the rabbit died’, which arose as a socially acceptable way to convey a positive pregnancy-test result, was somewhat misleading; the rabbit always died. Clearly this technology was not adequate to answer a pill user's question as to whether or not she should start her next pill pack. Building scheduled withdrawal bleeding into routine pill use reassured the patient that the pills were working and that the woman using the pills was not pregnant.

Another concern that troubled early potential users of pills was that using artificial hormones might somehow damage their reproductive systems and adversely affect their long-term fertility. The scheduled bleeding associated with the placebo pills was intended to demonstrate to users that ‘everything was still working’. The fact that at those high doses, the early pills could likely have induced bleeding in an octogenarian, who had not had any residual ovarian follicles for three decades, was not discussed. In those days, menstruation was seen as an unequivocal affirmation of continued fertility. The pill-induced bleeding was assumed to be menstruation, so it made the pill more acceptable to women.

The explanation for need for the seven placebo pills per cycle is more scientific [1]. Although the progestin in the original pill had a relatively short half-life, circulating serum levels from these pills were so high that it required several days (generally 4–5) for them to drop low enough to permit endometrial sloughing. Therefore, 7 days of placebo pills were included to guarantee virtually every woman enough time to start withdrawal bleeding before she was scheduled to start her next pack of pills.

The pill-induced withdrawal-bleeding episodes were a distinct improvement for most women compared with their spontaneous cycling. The pill-induced scheduled bleedings were predictable, lighter, less painful and shorter than the women's untreated menses. The appeal of less suffering is apparent, but the significance of predictability is often overlooked. The pill gave women the ability to predict the timing of their menses. For the first time in history, women could arrange their lives around their periods rather than having their periods unpredictably interrupt their lives.

As early as the mid 1960s, physicians started to use extended-cycle, high-dose, monophasic pills to eliminate menses in specific circumstances. One of the earliest indications was to help reduce the severe dysmenorrhea from endometriosis [2 –4]. Women who suffer dysmenorrhea from other causes also comprise a very reasonable group for extended-cycle pill use. Women with polycystic ovarian syndrome (PCOS) and other anovulatory bleeding often suffer heavy flows when they do menstruate. Extended-cycle oral contraceptive (OCs) preserve the infrequent bleeding episodes that those women may appreciate, but protects them from the menorrhagia that they often are subject to with anovulatory cycling. Later, sporadic use of extended-cycle OCs to move menses to less inconvenient times became routine practice, especially to help women enjoy bleeding-free days for honeymoons, vacations, religious ceremonies and a wide variety of other events. Cote et al. estimated that increased menstrual blood loss is responsible for US$1962 per woman in work loss each year [5]. Extended-cycle OCs reduce that bleeding. More recent studies have also found that extended-cycle use of OCs decreased premenstrual-type symptoms compared with a 21/7 regimen [6].

Women who are not using hormonal contraception should have monthly menses. A lack of routine bleeding in them should raise concerns for pregnancy, for medical problems (thyroid, prolactinoma, renal failure and medication interaction), for social, psychological or lifestyle problems (eating disorders and excessive exercise), and for future health risks (infertility and endometrial cancer). Viewed from a reproductive perspective, a monthly menstruation represents failure. Pregnancy did not take place during the cycle. The bleeding episode rids the uterus of the failed endometrium and sets the stage for a possible pregnancy in the next cycle. While some women who use OCs may wish to continue monthly bleeding because they celebrate menstruation as a spiritual or natural process [101], it is important to recognize that bleeding induced by placebo pills of OCs is not menstruation and serves no biological purpose. There is no medical indication for this monthly bleeding. The OC user did not want to conceive in the prior cycle and, if she continues to use her pills, it will be because she is trying to avoid pregnancy in the next cycle. There is no ‘build up’ of materials within the uterine cavity with OCs if she does not bleed. The progestin in hormonal contraceptives significantly thins the endometrial lining and reduces blood loss, even when it is delayed for months at a time [7]. Despite ‘old wives tales’ to the contrary, there are no toxins that need to periodically be flushed from a woman's body and there is no need for her to periodically lose blood to maintain the cardiovascular protection [8]. However, the idea of routinely using extended cycles to help reduce the numbers of pill-induced bleeding episodes for all pill users was not entertained until there was a serious reassessment of the impact that the 7 days of placebos had on women's quality of life, on their acceptance of the pill and on the efficacy of low-dose formulations. The article will review new evidence regarding each of these issues and how a new extended-cycle monophasic formulation, which replaces the placebo pills with 10 μg EE pills, is a very appealing solution to these problems.

Evidence of need for extended-cycle oral contraceptives

Impact of placebo pills on patient symptoms

The first modern evidence that the traditional 21/7 packaging of OCs (21 active pills with seven placebo pills) created problems for women emerged from work done by Sulak et al. in 2000 [9]. In that landmark study, the women who complained of ‘problems with the pill’ were asked to keep diaries of their symptoms and their pill taking. The authors found that the frequency and intensity of every problem that women complained of with pill use (e.g., pain, headache, bloating, need for medication and so on) occurred more often during those 7 days than during the 21 active pill days (Table 1). In a follow-up study of women with placebo-pill problems who progressively increased the numbers of days they used active pills to reduce the numbers of hormone-free intervals, Sulak found that 64% of women desired to continue extended-cycle use. Only 14% returned to a 21/7 regimen; the others had a variety of unrelated reasons for stopping their pills, such as desire for pregnancy, hysterectomy and menopause [10].

Table 1.

Hormone withdrawal symptoms in oral contraceptive users.

Symptom	Percentage of women reporting symptoms		p-value
Symptom	21 active pills	7 hormone-free pills	p-value
Pelvic pain	21	70	<0.001
Headaches	53	70	<0.001
Breast tenderness	19	58	<0.001
Bloating/swelling	16	38	<0.001
Use of pain medications	43	69	<0.001

Data from [10].

Generalizing the use of extended use to women with menorrhagia, Miller et al. reported that extended-cycle use of pills (49 days) significantly reduced the costs of sanitary protection and medication associated with heavy menses [11]. Even among a sample of 270 women who did not experience ‘menstrual-related symptoms’, Ferrero et al. found that 75.6% reported that their menstrual periods interfered with their sex life, 48.7% said that menstrual periods interfere with their ability to play sports and 28.8% preferred not having their menstrual period when at work. Another quarter (26.7%) said that their menstrual periods even influenced their choices of clothes [12]. In a Cochrane review of all randomized, controlled trials published between 1966 and 2005, Edelman et al. concluded that extended-cycle regimens improve bleeding patterns compared with traditional 21/7 regimens [13].

Women's preferences for bleeding frequency with hormonal contraception

In the last decade, progestin-only contraceptive methods such as injections depot medroxyprogesterone acetate (DMPA), levonorgestrel-releasing intrauterine contraceptive system (LNG-IUS), and implants (LNG-releasing implants, etonogestrel [ENG] subdermal implants; which generally reduce or eliminate menses), have been widely used. Surveys have been conducted to determine women's attitudes towards monthly bleeding and their preferences for bleeding frequencies. The answers have been revealing; there is much diversity not only among women in different countries, but also among different age groups. In a Harris Poll conducted in the USA in 2002, approximately 40% of women aged 18–29 years wanted monthly bleeding, but over 25% never wanted to bleed. Overall, bleeding every 3 months was very popular [102]. In an earlier Dutch study, approximately a third of women of all ages preferred monthly bleeding; but a third of the 15–19-year-olds wanted bleeding every 3 months; however, a third of 25–34-year-olds and over half of women aged 45–49 years wanted to never bleed [14].

Impact of 7 days of placebo pills on pill success

In addition to diminishing a patient's quality of life, routine provision of 7 days of placebo pills each cycle also permits re-emergence of ovarian activity. With modern lower-dose OC formulations, sex-steroid levels fall rapidly during the placebo period. This rapid fall results not only in earlier bleeding, but also loss of negative feedback on the hypothamic–pituitary unit. Follicle stimulating hormone (FSH) levels rise, which induces ovarian follicular maturation, and estradiol production (Figure 1) [15 –17]. It has been hypothesized that this ovarian activation may have two potentially adverse impacts on pill success. First, with early ovarian activation, it may be more difficult to suppress ovulation, especially if the patient delays initiating her next pack of pills. The second impact is more subtle. The ovarian follicles stimulated during the hormone-free interval will undergo atresia later, during the active pill sequence. With involution of these follicles, ovarian production of estradiol falls. The patient may experience unscheduled spotting and/or bleeding. She may also suffer other estrogen-withdrawal symptoms, such as premenstrual syndrome (PMS). These symptoms may lead to discontinuation of the method.

Figure 1.

Hormone levels during 7-day hormone-free interval.

Extended-cycle hormonal contraceptive options

Extended-cycle use of monophasic pills with strong progestin content has been a very common off-label way of reducing menstrual frequency. Usually in this scenario, a pill with a long-acting progestin (e.g., LNG or drospirenone) is recommended [13,18]. Patients complete the first package of 21 active pills, skip the placebos and open a second packet, which they start to use the following day. Active pills are taken daily until the patient starts to experience unscheduled spotting or bleeding that she cannot tolerate. At that time, she suspends OC use for 2–4 days to develop coordinated endometrial sloughing. Then she restarts her active pills and repeats the process. Generally, a woman will be able to progressively and significantly increase the time between her scheduled bleedings. Using conventional brands of pills for this is quite feasible, but this practice generally costs the patient four extra packs of pills per year. Extended-cycle use of other hormonal contraceptive delivery systems is also appealing. Transdermal contraceptive patches have been used continuously in one trial for up to 84 days followed by a one patch-free week [19]. Contraceptive vaginal rings have been tested more extensively for extended-cycle use, being changed/replaced every 3 weeks for up to 12 months [20].

The first US FDA-approved product for extended-cycle OC use was composed of a three-tiered packet of 84 active pills (EE 30 μg/LNG 150 μg) and seven placebo pills; with the trade name Seasonale® (Duramed Pharmaceuticals, Barr Laboratories, NY, USA). Approval was based on a large multicenter study comparing the 84/7 regimen with a 21/7 regimen of the same formulation. Unique contemporaneous recordings, not only of pill use but also of bleeding and spotting, were obtained electronically [7]. More of the days of bleeding/spotting events with extended-cycle regimens were unscheduled. At this time, there are no recognized treatments for this unscheduled bleeding. Although treatments with NSAIDs and supplemental estrogen have been recommended, there are no clinical trials directly testing their efficacy in this setting. Fortunately, the number of days of unscheduled bleeding and spotting rapidly declines over time. By the fourth cycle (months 9–12 of pill use), women in each group had the same numbers of days of unscheduled bleeding and spotting, but the extended-cycle pill users had only a third the number of days of scheduled bleeding.

Recognizing that the 7 days of placebo pills might be causing problems after the first cycle, similar to those problems seen on a monthly basis with the 21/7 regimens, a new formulation (Seasonique®, Duramed Pharmaceuticals) was developed, which replaced the seven placebo pills in Seasonique with seven pills that contained EE 10 μg each. Scheduled bleeding still occurs because progestin support of the endometrium is withdrawn, but women still have some residual hypothalamic–pituitary suppression from the EE to control ovarian activity. Sulak et al. have demonstrated that with the use of the EE 10 μg pills, women had both substantial reductions in mean FSH and estradiol levels and fewer ovarian follicles [21].

Clinical efficacy

The efficacy and safety of this new formulation with 84 days of active pills containing EE 30 μg/LNG 150 μg followed by 7 days of pills with only EE 10 μg were tested in a 1-year multicenter, open-label trial [22]. The safety cohort included 1006 women aged 18–40 years who received at least one dose of Seasonique. The intent-to-treat cohort included 799 women who completed at least one cycle (91 days) of Seasonique. The efficacy data were derived from the 708 women in the intent-to-treat cohort who were aged 18–35 years at the time of enrolment. Women who became pregnant during the first 91 days of treatment were counted.

The 708 women were treated for 2177 extended cycles (91-day cycles), which is equivalent to 7075 conventional 28-day cycles. During the study, seven women became pregnant. Four of those women did not take their pills as directed (user failures). Two of the three pregnancies that occurred to women who did use their pills as directed did not occur until the women stopped taking their pills at the end of their study participation. The FDA now requires that pregnancies that are conceived within 2 weeks following cessation of contraception be counted as study failures, instead of serving as evidence of rapid return to fertility [22,23]. Using these estimates, the pregnancy rate in the prescribing information is 1.77%, but for women who used correctly and consistently, the failure rate is only 0.78%. No patient weighing more than 90 kg became pregnant [22].

Safety & tolerability

Over the 12-month study period, 16.3% of the 1006 patients in the safety population discontinued use owing to adverse events. One woman with Factor V Leiden mutation had a post traumatic venous thrombosis in her upper extremity. Only four serious adverse events (SAEs) were deemed ‘possibly related to study drug’. The SAEs included migraine headache, chololithiasis, chololithiasis with pancreatitis and cholecystitis.

The most common side effect that caused discontinuation was unscheduled bleeding and spotting; 8.2% of patients discontinued, at least in part, for this reason. Patients in the Seasonique trial also recorded their pill taking and their bleeding episodes electronically every 24 h. ‘Spotting’ was defined as vaginal bleeding that did not require sanitary protection; ‘bleeding’ was that bleeding that did require use of sanitary protection. The median number of days of scheduled bleeding was 3 days for the first cycle. Subsequent cycles had 2 days of scheduled bleeding and 1 day of scheduled spotting. Unscheduled bleeding and bleeding and spotting (bleeding that occurred on any day of conventional OC pill use) rates are low. On a monthly basis, the median number of unscheduled bleeding-only days was 0.3, compared with 0.3 days every month with conventional 21/7 use.

The impact of the additional EE 10 μg pills can be inferred by comparing the unscheduled bleeding and spotting data seen in the Seasonale study with that reported in the Seasonique trial. While there was no comparative trial between these two agents, their efficacy trials used similar multicenter sites, the same inclusion and exclusion criteria, the same definitions of bleeding and spotting, and the same contemporaneous data-collection technologies. The median number of unscheduled days of spotting or bleeding during the second cycle with Seasonale was 6 compared with 5 days with Seasonique. In the Seasonale study, there was no direct comparison of bleeding-only versus bleeding/spotting days by 91-day intervals. However, it was reported that on an annual basis, 27% of the unscheduled bleeding and spotting days were bleeding-only days, and that that percentage decreased over time [7]. If that percentage were applied to the total days of unscheduled bleeding and spotting seen in the second cycle, one could estimate that there were at least 2 days of unscheduled bleeding during the second 91-day interval. This compares to 1 day of bleeding seen with Seasonique [22].

The other adverse events reported during study drug use included nasopharygitis (7.2%), sinusitis (6.5%), weight increase (5.3%) and acne (5.2%). Clearly, many of these events were not related to use of Seasonique.

Questions may be raised regarding the safety of adding 7 days of ‘unopposed estrogen’ every 3 months. Clearly, this is less unopposed estrogen than the woman would be exposed to during the 3 pill-free weeks using conventional 21/7 regimens. More conclusively, in a randomized trial comparing Seasonique to the conventional 21/7 regimens of the same active pills, endometrial biopsies on therapy and post-treatment demonstrate that Seasonique did not promote any unexpected changes in the endometrium and there were no cases of hyperplasia [24]. Steady-state plasma concentrations of EE after 84 and 91 days were comparable with the steady-state levels found on cycle day 21 of a conventional 21/7 regimen. There is no accumulation of hormones in plasma over time [25].

Conclusion

Monthly bleeding with a combined hormonal contraceptive use is not healthy or medically indicated. It represents an artificial withdrawal bleeding intended to help women accept birth-control pills in the 1960s. Many women suffer discomfort and significant inconvenience during placebo pills. Extended-cycle OC use reduces those problems significantly. The introduction of low-dose EE during the placebo pill softens the impacts of the hormone-free interval and reduces the ovarian activity. This represents a significant improvement in the design of extended-cycle OC use.

Future perspective

As more women are made aware of the safety and convenience of extended-cycle OC use, it will become the standard.

Newer products with longer cycles, or perhaps less rigid schedules of bleeding episodes, may be available and enhance use of these regimens.

Executive summary

Menstruation is an indication of reproductive health in women who are cycling spontaneously.

Menstruation is not necessary for women who are using hormonal contraception.

Monthly bleeding with oral contraceptives cause many of the unpleasant side effects often associated with pill use.

Extended-cycle pill use with the first US FDA-approved product (Seasonale®) reduces the number of scheduled bleeding episodes to four times a year.

The replacement of the 7 placebo pills by 10 μg ethinyl estradiol in the second FDA-approved product (Seasonique®) reduces unscheduled bleeding and spotting after the first cycle of use and better controls ovarian activity.

Footnotes

A Nelson has received a research grant from Barr. She serves as a consultant to Barr/Duramed, is a member of their speakers’ bureau, and has received research supplies from them. Nelson does not have any other relevant financial interests (employment, stock ownership or options, expert testimony, patents or royalties related to this matter).

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