ethinyl estradiol triphasic) or other oral contraceptives

Contraception 62 (2000) 289 –295

Original research article

Bleeding patterns of women using Lunelle™ monthly contraceptive injections (medroxyprogesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum® 7/7/7 (norethindrone/ethinyl estradiol triphasic) or other oral contraceptives Roger J. Garceaua,*, Charles J. Wajszczuka, Andrew M. Kaunitzb, Lunelle Study Group a

Pharmacia Corporation, 7000 Portage Road, Kalamazoo, MI 49001 USA Department of Obstetrics and Gynecology, University of Florida Health Science Center, Jacksonville, FL, USA

b

Received 6 October 2000; accepted 16 October 2000

Abstract Persistent and/or unpredictable bleeding is a common reason for discontinuation of hormonal contraceptive methods. An open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of the new, highly efficacious monthly injectable contraceptive containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E2C) (MPA/E2C) (Lunelle™ Monthly Contraceptive Injection) with that of the frequently used norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum® 7/7/7). This report directly compares the bleeding patterns of women on MPA/E2C to those of women on NET/EE and untreated women. Overall, breakthrough bleeding occurred less frequently in women using MPA/E2C than in women using NET/EE (p ⱕ0.01). However, more women using MPA/E2C experienced amenorrhea/missed periods than those on NET/EE (p ⱕ0.01). In addition, the percentage of women experiencing breakthrough bleeding or amenorrhea while using other oral contraceptives is compared to that of women using MPA/E2C. A rapidly reversible method, MPA/E2C, combines the high contraceptive efficacy of surgical sterilization with the convenience of monthly administration. These data suggest that, for a large proportion of women, MPA/E2C offers predictability in bleeding patterns comparable to or greater than that experienced by ovulatory untreated women or those using combination oral contraceptives. © 2001 Elsevier Science Inc. All rights reserved. Keywords: LUNELLE™; Estradiol cypionate; Medroxyprogesterone acetate; Monthly injectable contraception; Ortho-Novum® 7/7/7; Oral contraceptive; Breakthrough bleeding; Withdrawal bleeding

1. Introduction Oral contraceptives (OCs) are currently used by some 10 million US women, or about 27% of those using any method of contraception [1]. Currently available OC formulations are safe, and in consistently perfect pill-takers, highly effective, with a theoretic failure rate of 0.1% noted in clinical trials [2]. However, actual 1-year failure rates in clinical practice are higher. Both the 1988 and 1995 National Surveys of Family Growth found pregnancy rates in women using OCs to be 8% in the first year of use [3,4]. The 1995

* Corresponding author. Tel.: ⫹1-616-833-8031; fax: 1-616-833-0555. E-mail address: [email protected] (R.J. Garceau).

data also found that higher OC failure rates were observed in low-income women and those under age 25 years [4]. These data underscore that, in clinical settings, many women find correct, consistent OC use challenging. A recent prospective cohort study of over 1600 women initiating or switching to a new OC found continuation rates at 6 months of only 68% among new users and 84% among switchers [5]. Almost one-half of OC discontinuation was prompted by side effects, and the most common such side effect was bleeding irregularities, which accounted for 12% of overall pill discontinuation. Bleeding irregularities, including breakthrough bleeding (midcycle spotting requiring sanitary protection) and spotting (not requiring protection) as well as amenorrhea (absence of withdrawal bleeding) represent a major obstacle to OC compliance [6]. Authori-

0010-7824/00/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 0 1 0 - 7 8 2 4 ( 0 0 ) 0 0 1 8 3 - 9

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ties agree that focused counseling regarding menstrual and other side effects at the time of OC initiation as well as during follow-up represents an important approach to improving patients’ success with OCs [6 – 8]. Safety concerns have led manufacturers to reduce the estrogen (ethinyl estradiol) dose of OCs from 50 ␮g or greater to currently used tablets formulated with 20 –35 ␮g. Although 20 ␮g estrogen OC formulations appear to be as effective as higher-estrogen pills, their use may be associated with rates of intermenstrual bleeding and spotting as much as 3 times higher that with 35 ␮g estrogen OCs [9,10]. Two long-acting progestin contraceptives are currently available for use in the United States: depot medroxyprogesterone acetate (DMPA, Pharmacia Corporation, Kalamazoo, MI) and levonorgestrel implants (Norplant®). Because no daily contraceptive activity is required, the contraceptive efficacy of these two methods is extremely high. An important disadvantage of both methods, however, is the menstrual changes associated with their use. Long-term use of DMPA is associated with a high rate of amenorrhea while irregular spotting and bleeding commonly occurs during the first several years of Norplant use [11,12]. One recent US study found that among a cohort of over 500 women initiating DMPA, continuation at 1 year was less than 30% [13]. Menstrual changes played a prominent role in contraceptive discontinuation in this study and others assessing use of DMPA. Other concerns with long-acting progestin contraceptives include removal difficulties with Norplant and delayed return to fertility after discontinuing DMPA injections. A monthly injectable combination of 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E2C) (MPA/E2C) (Lunelle™ Monthly Contraceptive Injection) has been widely studied outside of the US [14,15]. MPA/E2C monthly injections offer users many of the benefits of OCs, including regular menstrual cycles and rapid return to fertility after discontinuation of injections. In addition, since MPA/E2C is administered monthly by injection, the requirement of daily pill-taking is eliminated. Results of trials by the WHO have demonstrated that the contraceptive efficacy of MPA/E2C (estimated life table failure rate of 0.1 per 100 women-years) is comparable to that of DMPA, Norplant, and surgical sterilization [2,15, 16]. As described in a previous communication, a 60-week, open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of MPA/E2C with that of the frequently used norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic OC (Ortho-Novum® 7/7/7) [17]. No pregnancies were reported in the MPA/E2C users, yielding a life table pregnancy rate of 0.0%. In comparison, two pregnancies occurred in the NET/EE users, yielding a life table pregnancy rate of 0.3%. Because the bleeding patterns (e.g., number of bleeding/ spotting episodes per cycle, cycle predictability, incidence of breakthrough bleeding, amenorrhea) of women using

OCs or other contraceptives largely determine method continuation, the purpose of this report is to directly compare the bleeding patterns of women using MPA/E2C to those of women using NET/EE in the same study. Our data suggest that, for a large proportion of women, MPA/E2C offers a level of predictability in bleeding patterns comparable or superior to that of NET/EE and a variety of other currently available OCs. MPA/E2C’s patient acceptability based on convenience, contraceptive efficacy, reversibility, and bleeding patterns suggests that it will be a welcome contraceptive option for women in the United States. 2. Materials and methods 2.1. Subjects For the study comparing MPA/E2C and NET/EE, sexually active women aged 18 to 49 years desiring contraception were enrolled in 42 clinical sites throughout the United States from April 1997 through August 1997. Methodologic details including inclusion and exclusion criteria were described in a prior publication [17]. Briefly, subjects agreed to rely on either MPA/E2C or NET/EE for contraception for at least 60 weeks (15 cycles of 28 days) and were menstruating regularly (cycle length, 25 to 35 days) during the 3 months prior to enrollment or, if postpartum or postabortion, menstruating regularly during the 3 months prior to the pregnancy. 2.2. Treatment plan Women enrolled in the study, all of whom had previously used either hormonal or nonhormonal methods of contraception, were prescribed their choice of either MPA/ E2C monthly injections or triphasic NET/EE, at the discretion of the investigator. Those already using an OC (including NET/EE) were allowed to directly enter the trial and use triphasic NET/EE or to switch to MPA/E2C monthly injections. The MPA/E2C contraceptive injection was administered once every 28 ⫾ 5 days by deep intramuscular injection (0.5 mL), the first injection being administered between days 1 and 5 of the onset of menses. The triphasic NET/EE (provided in a Dialpak® dispenser) was administered orally, 1 tablet daily beginning on day 1 (i.e., onset) of menses. 2.3. Procedures For each month of the study, subjects kept menstrual diary cards on which they recorded their bleeding patterns each day, using the following definitions: none—no bleeding or spotting; spotting—required light pads but no sanitary protection; bleeding—required sanitary protection. 2.4. Bleeding patterns Data from menstrual diaries were used to compare bleeding patterns. Both a 3-cycle/84-day approach and a 1-cycle

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approach were used in the analyses. In the 3-cycle approach, the date for each subsequent 3-cycle interval was reset to 1 using the date of injection/first tablet; the theoretic reference period length was 84 days. An 84-day analysis was chosen because of the 28-day administration intervals for the MPA/ E2C and NET/EE arms of the study. This approach permitted the investigators to evaluate whether, once a patient is established on a hormonal contraceptive method for 1 or more 3-cycle periods, predictable bleeding patterns develop [18]. Analyses of the incidence of amenorrhea used the 3-cycle/84-day reference period. The 1-cycle reference period was defined as the interval between injection days (day 1 of a cycle) in consecutive cycles or first tablets of NET/EE in consecutive 28-day courses. The date for each subsequent cycle was reset to 1 using the date of injection/first tablet; the theoretic cycle length for the NET/EE arm was 28 days. Bleeding analysis parameters for both MPA/E2C and NET/EE were based on the pharmacokinetic profile of E2 observed after MPA/E2C administration [19]. The E2 profile exhibits a T1/2 of about 8 days; serum E2 levels return to preovulatory levels (typically ⬃50 pg/mL) by approximately 18 days after the injection. Thus, withdrawal bleeding is expected to occur when serum E2 levels reach baseline value, no longer effective in maintaining the proliferated endometrial tissue. A bleeding/spotting episode was defined as any set of one or more bleeding/spotting days, either consecutive or separated by a single bleeding/spotting-free day. The number of bleeding/spotting episodes per cycle was defined as the number of episodes between injections or pill packs. Bleeding patterns were classified according to the following definitions: 1) missed periods (absence of bleeding or spotting days throughout the 1-cycle reference period); 2) amenorrhea (or the absence of bleeding/spotting episodes over a 3-cycles); 3) withdrawal bleeding, (bleeding/spotting occurring during the withdrawal period); and 4) breakthrough bleeding (any bleeding or spotting episode not classified as withdrawal bleeding). Withdrawal bleeding was defined as any bleeding/spotting episodes starting on cycle days 18 –28 (next injection date), including episodes starting before day 18 (but not before day 15) and continuing into the withdrawal period but not later than 3 days after the next injection/start of new pill pack. Breakthrough bleeding was defined as any bleeding/spotting episode not classified as withdrawal bleeding; i.e., any bleeding/spotting episode occurring between days 0 and 18, excluding those episodes classified as withdrawal bleeding.

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8,920 woman-cycles for the MPA/E2C group and 3,952 woman-cycles for the NET/EE group. The baseline characteristics, disposition, rates of compliance and contraceptive efficacy rates for the treatment groups are provided in an earlier communication [17]. Baseline demographics were similar other than a higher proportion of patients in the MPA/E2C group than in the NET/EE treatment group had 1 or more full-term pregnancies (44.3% and 33.6%, respectively); and the percent of women with abortions (41.3% and 24.3%, respectively). The use of hormonal contraception during the 30 days prior to the study was reported by a higher proportion of women in the NET/EE group (65.1%) than in the MPA/E2C group (43.7%) (p ⱕ0.01). 3.2. Median start day of bleeding/spotting episodes and bleeding classification For both treatment groups, all bleeding and/or spotting episodes were defined as either withdrawal or breakthrough bleeding/spotting according to the cycle day number on which bleeding began. Figure 1 shows the median and range of the start day for bleeding/spotting episodes in cycles 2 and 13 (after 1 year of use) for women in the MPA/E2C and NET/EE treatment groups. The median start day of bleeding/spotting episodes for women treated with MPA/E2C in cycles 2 and 13 was day 22, 2 days earlier than the median start day for patients in the NET/EE treatment group (day 24 in both cycles 2 and 13). For women in the NET/EE treatment group, the 5th to 95th percentile range about the median start day in cycle 13 was 5 days. The ability to predict the start day of normal withdrawal bleeding in subsequent menstrual cycles is important to women choosing a contraceptive method. Although the 5th to 95th percentile range around the median start day for the MPA/E2C users is broad (Figure 1), the onset of a single bleeding/spotting episode in subsequent cycles was predictable in this treatment group. About one-half of the women receiving injections started bleeding/spotting episodes within 2–3 days before or after the same start day of the previous cycle. 3.3. Amenorrhea/missed periods

3. Results

The incidence of amenorrhea in women using MPA/E2C ranged from 1– 4%. The proportion of women in the NET/EE treatment group who experienced amenorrhea was ⬍1%. Women experiencing a missed period during a given cycle 2nd through 12th period among Lunelle-treated women was 14.6% compared to 3.3% for ON7/7/7 users (p ⱕ0.01).

3.1. Study population

3.4. Withdrawal bleeding

Vaginal bleeding data were available for a total of 1,103 women (782 MPA/E2C; 321 NET/EE), providing a total of

At the end of the third month, 80.4% of women using MPA/E2C had withdrawal bleeding without any break-

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Fig. 1. Median start day of bleeding/spotting episodes.

through bleeding/spotting (Fig. 2), 73.5% had a single withdrawal bleeding episode, 4.5% of women had 2 withdrawal episodes (separated by ⬎1 day without bleeding or spotting). The number of women with only withdrawal bleeding remained constant during the study at about 75– 80%. The average length of each withdrawal bleeding episode for MPA/E2C users was approximately 6 days. In comparison, the incidence of withdrawal bleeding without breakthrough bleeding in the NET/EE treatment group at cycle 2 was 86.8% (Fig. 2). This percent remained fairly constant between 85–93% for the remainder of the study. The average length of each withdrawal episode was about 5 days. 3.5. Average length of withdrawal bleeding/spotting episodes and bleeding/spotting-free intervals The average length of withdrawal bleeding/spotting episodes for women using MPA/E2C or NET/EE remained relatively constant at around 6 days and 5 days, respectively, throughout the course of the study. The average length of bleeding/spotting-free intervals for the MPA/E2C and NET/EE treatment groups was 22 days

Fig. 2. Participants with only withdrawal bleeding.

and 23 days, respectively. Mean bleeding/spotting-free intervals were somewhat shorter during the first cycle for participants using MPA/E2C since treatment was begun during menstrual bleeding days. 3.6. Breakthrough bleeding/spotting As shown in Fig. 3, the incidence of breakthrough bleeding/spotting for women in the MPA/E2C treatment group was 8% in cycle 2, decreasing to approximately 4% by cycle 8 and the remainder of the study. The incidence of breakthrough bleeding/spotting for the NET/EE treatment group was around 11% in cycle 2, and decreasing to around 6% for the remainder of the first year. In the 2nd through 12th cycle of treatment, 6.1% of cycles in Lunelle-treated women compared to 8.0% of cycles in NET/EE-treated women (p ⱕ0.01) had breakthrough bleeding/spotting. 3.7. BMI (body mass index) and bleeding patterns A possible relationship between BMI (body mass index) and bleeding patterns was examined. Fewer women in the MPA/E2C treatment group in cycle 13 with BMI ⬎ 27.3 had

Fig. 3. Incidence of breakthrough bleeding/spotting.

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Fig. 4. Incidence of intermenstrual or breakthrough bleeding/spotting—selected oral contraceptives.

a single withdrawal bleeding pattern than women with BMI ⱕ 27.3 (64.3% vs. 79.9%). More women with BMI ⬎ 27.3 (23.8%) than women with BMI ⱕ 27.3 (11.1%) had an absence of bleeding or spotting during a single month by cycle. In contrast, no such pattern was seen with NET/EE users. These trends were consistent throughout the course of the study from cycle 2 through 13 (1 year).

4. Discussion The bleeding patterns in women using MPA/E2C showed a similar pattern to that of untreated women [18]. A woman using these monthly injections can anticipate a single 6-day bleeding episode, with its onset approximately day 22, with day 0 being the day of each injection. After 1 year of use, the bleeding pattern is fairly consistent with each subsequent withdrawal bleeding/spotting episode occurring at approximately (⫾3 days) the same time after each injection. NET/EE users will experience approximately 4 –5 bleeding/ spotting days with an interval of 23 days between bleeding/ spotting episodes. Withdrawal bleeding in studies with OC is usually defined by the pill-free period ⫾3 days. Breakthrough (or intermenstrual) bleeding is usually defined as any bleeding other than withdrawal bleeding. In the present study, the definition of withdrawal bleeding was based on pharmacokinetics of MPA/E2C. This difference in definitions expands the time allowed for meeting the criteria for withdrawal bleeding by 3 days each cycle. The incidence of intermenstrual bleeding/spotting varies widely among oral contraceptives and ranges from a low of ⬍10% to as high as 50% in some reports. MPA/E2C has a very favorable intermenstrual/breakthrough bleeding/spotting rate of ⬃4% at 1 year.

The observed breakthrough (intermenstrual) bleeding/ spotting rate for NET/EE users in the current study is lower than previously reported [26]. This may be partially explained by the fact that a common definition of withdrawal bleeding was used in the current study to make the comparison between MPA/E2C and NET/EE as fair as possible. Even with the broader definition of breakthrough bleeding/ spotting, this undesirable phenomenon occurred more often with the study oral contraceptive than with MPA/E2C. This observation, which may be surprising to some, underscores the favorable bleeding pattern noted with use of this monthly combination injectable contraceptive. Figure 4 summarizes the incidence of breakthrough or intermenstrual bleeding/spotting measured in studies of women using a variety of other OC formulations [20 –26]. Although the studies differed in the use of terms and time periods to describe abnormal bleeding/spotting, the terms intermenstrual bleeding/spotting and breakthrough bleeding/spotting generally refer to bleeding or spotting not classified as withdrawal bleeding and thus are comparable to the breakthrough bleeding/spotting classification used to compare MPA/E2C and NET/EE. Examining Figs. 3 and 4 together suggests that the incidence of breakthrough bleeding/spotting observed in participants using MPA/E2C compares very favorably with the wide range of breakthrough or intermenstrual bleeding rates (less than 10% to as high as 50%) reported for women using other OCs. MPA/E2C has a very favorable intermenstrual/breakthrough bleeding/spotting rate of ⬃4% at 1 year. In this study, intermenstrual bleeding/spotting occurred significantly less often (p ⱕ0.01) among MPA/E2C users than NET/EE users. Figure 5 summarizes the rates of amenorrhea observed in studies of women using a variety of other OC formulations. The length of these studies ranged from 4 to 30 cycles. For

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Fig. 5. Incidence of amenorrhea—selected oral contraceptives.

most of these OC formulations, amenorrhea occurred in less than 5% of cycles. These rates are comparable to the rates of amenorrhea observed in women using MPA/E2C (4%) or in healthy, untreated women [18]. Approximately 14% of women using MPA/E2C will experience missed menses during each injection cycle. There was also a negative correlation with BMI with those women who had BMI ⬎27.3, therefore, more likely to experience missed periods and have less regular periods. The increased missed periods or a less regular bleeding pattern noted in women with BMI ⬎27.3 may be related to the pharmacokinetics of E2. After administration of MPA/E2C, E2 (released from E2C by esterases) distributes throughout the body (particularly adispose tissue). As a result, the expected serum E2 peak profile may not increase enough in some heavier women to provide endometrial stimulation/proliferation resulting in withdrawal bleeding. No perfect contraceptive choice exists for all women. A rapidly reversible contraceptive, Lunelle (MPA/E2C) offers women the convenience of monthly dosing, very high efficacy, and a monthly bleeding/spotting pattern similar to that of an “untreated” woman. In this trial, use of Lunelle (MPA/ E2C) was found to be associated with less breakthrough bleeding/spotting than Ortho-Novum® 7/7/7 (NET/EE) with 75– 80% women having regular monthly withdrawal bleeding. However, MPA/E2C users also were more likely to experience an absence of bleeding during each cycle of use. As with any contraceptive method, counseling MPA/E2C candidates regarding menstrual changes and other side effects will enhance the successful use of this convenient and highly effective method of birth control.

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