Suppression of ovarian function by a combined oral contraceptive containing 0.02 mg ethinyl estradiol and 2 mg chlormadinone acetate given in a 24/4-day intake regimen over three cycles J urgen Spona, Ph.D., a Natascha Binder, Ph.D., b Kornelia H oschen, M.Sc., b and Wilfried Feichtinger, Ph.D. c a Vitalogic GmbH, Vienna, Austria; b Gr unenthal GmbH, Aachen, Germany; and c Institute for Sterility Treatment, Vienna, Austria Objective: To describe the suppression of ovarian function with 0.02 mg ethinyl E 2 2 mg chlormadinone acetate administered in a 24/4-day intake regimen in healthy women. Design: Open, uncontrolled, multiple dosing, phase II trial. Setting: Single clinic. Patient(s): Forty women treated. Intervention(s): Treatment for up to three cycles with 0.02 mg ethinyl E 2 2 mg chlormadinone acetate given in a 24/4-day regimen. Main Outcome Measure(s): Assessments of ovarian function classified by the Hoogland and Skouby score, thickness of endometrium, cervical reaction, and sex hormone levels, as well as overall tolerability. Result(s): No ovulation was observed in the per protocol set (N ¼ 36), and one in the full analysis set (N ¼ 38) after vomiting and diarrhea. Absence of ovarian activity, residual ovarian activity, and formation of a luteinized unruptured follicle were observed in 75.0%, 15.9%, and 1.1% of medication cycles, respectively. Endometrial thickness was suppressed to 4 to 5 mm compared with 10 to 12 mm without medication. Cervical reaction was negative. Hormone levels were lower with medication than without, and the medication was well tolerated. Treatment-related adverse events were typical of those associated with hormonal contraceptive use. Conclusion(s): Follicular development, cervical reaction, and endometrial thickness were suppressed profoundly after 0.02 mg ethinyl E 2 2 mg chlormadinone acetate administration in a 24/4-day regimen, resulting in inhibition of ovulation and unfavorable conditions for fertilization, implantation, and thus pregnancy. (Fertil Steril Ò 2010;94:1195 201. Ó2010 by American Society for Reproductive Medicine.) Key Words: Combined oral contraceptive, oral contraception, low-dose ethinylestradiol, chlormadinone acetate, 24/4-day intake regimen, ovarian activity, ovarian function Steroid drugs with contraceptive properties have been available for several decades but are still subject to improvement. One of the most important focal points in the development of combined oral contraceptives (COCs) since their introduction has been the continued reduction of the ethinyl E 2 (EE) component (1 3), with the aim of improving tolerability and minimizing side effects without compromising the ability to suppress pituitary-ovarian activity effectively. The standard dosing regimen of COCs in the past was 21 days intake of the COC followed by a 7-day hormone-free interval, with the aim to reproduce a normal 28-day menstrual cycle with menstrual bleeding. However, in the last few years there has been a trend toward extending the dosing regimen and shortening the hormonefree period to improve COC reliability and tolerability by reducing cycle-related complaints. Received April 17, 2009; revised June 22, 2009; accepted June 25, 2009; published online August 25, 2009. J.S. has nothing to disclose. N.B. has nothing to disclose. K.H. has nothing to disclose. W.F. has nothing to disclose. This study was designed, conducted and funded by Gr unenthal GmbH. The Principle Investigator was Wilfried Feichtinger, M.D., and the Scientific Advisor was J urgen Spona, Ph.D. Reprint requests: J urgen Spona, Ph.D., Vitalogic GmbH, Czerningasse 10, 1020 Vienna, Austria (FAX: 43-1-877-91539; E-mail: juergen.spona@ vitalogic.at). The major contraceptive effect of COCs is to block ovulation. To differentiate various levels of ovarian activity for comparison of different COCs, the grading system according to Hoogland and Skouby combines the ultrasonic examination of follicles with the determination of hormone levels (4 8). As evidenced by the development of follicle-like structures, residual ovarian activity was reported for several COCs (4 8). Thus, extending the active COC pill intake period to beyond 21 days and reducing the hormonefree interval were measures that were taken to reduce rebound effects of FSH and 17b-E 2, maintaining the contraceptive efficacy and the tolerability in low-dose COCs (8 12). The combination of EE and chlormadinone acetate, in a 21-day regimen, already has been used successfully since 1998 as a COC containing 0.03 mg EE 2 mg chlormadinone acetate. A number of publications have reported the contraceptive efficacy and safety of this formulation, as well as its antiandrogenic benefit (13 18). In a phase II trial, the contraceptive and pharmacologic mechanisms were investigated with use of the modified Hoogland and Skouby scale, and the ovarian activity was found to be suppressed effectively (5). Additional contraceptive effects were shown on the cervical mucus and endometrium, resulting in prevention of nidation and conception. Consistent with continuous efforts in the development of new COCs to improve tolerability and minimize side effects by 0015-0282/$36.00 Fertility and Sterility â Vol. 94, No. 4, September 2010 1195 doi:10.1016/j.fertnstert.2009.06.057 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
TABLE 1 Grading of ovarian activity according to the modified Hoogland and Skouby score (7). FLS Hormones Grading of residual ovarian activity Diameter (mm) E 2 (nmol/l) P (nmol/l) 1 No activity %10 2 Potential activity 10 < FLS % 13 3 Nonactive FLS >13 %0.1 4 Active FLS >13 >0.1 %5 5 LUF >13, persistent >0.1 >5 6 Ovulation >13, ruptured >0.1 >5 Note: FLS ¼ follicle-like structure; LUF ¼ luteinized unruptured follicle. reducing the estrogen component EE and shortening the hormone-free interval, the aim of this study was to assess the modulation of ovarian function by a novel COC combining 2 mg chlormadinone acetate with a low dose of 0.02 mg EE given in a 24/4-day intake regimen during three medication cycles. This new COC recently has been demonstrated to provide highly effective contraception, combined with an acceptable bleeding and excellent safety profile comparable with that of current oral contraceptive formulations (19). MATERIALS AND METHODS Trial Design This trial was designed as a line extension of the approved Belara (0.03 mg EE and 2 mg chlormadinone acetate; Gr unenthal GmbH, Aachen, Germany) and performed as a single-center (Vienna, Austria), open, uncontrolled, multiple-dosing, phase II trial in 40 subjects performed between December 2003 and July 2004. The principal endpoint criteria were the influence of 0.02 mg EE 2 mg chlormadinone acetate given in a new 24/4-day intake regimen on ovarian function, sex hormone levels, cervical score, endometrial thickness, and overall safety. The trial was planned to have a maximum duration of 6 months, including a premedication cycle without hormonal or intrauterine contraception (screening phase), three medication cycles (medication phase), a 28-day postmedication phase, and a final examination. Each subject received one daily dose of 0.02 mg EE 2 mg chlormadinone acetate for 24 days, followed by placebo for 4 days in each medication cycle. The protocol was approved by local ethics committees, and the trial was conducted according to the Declaration of Helsinki. All subjects gave their written informed consent before trial participation. Trial Population In total, 40 healthy women were enrolled in this trial. They were aged 18 to 30 years (smokers) or 18 to 35 years (nonsmokers) with a body mass index of 18.5 to 30 kg/m 2, no wish to become pregnant, Papanicolaou status I to II in a cytologic smear, and no administration of oral contraception on admission, and their last three menstrual cycles before admission were regular (i.e., cycle length between 24 and 35 days) according to the inclusion and exclusion criteria to the trial protocol. Subjects were entered in the medication phase of the trial if they had an interval of at least 1 month without hormonal or intrauterine contraception, normal ultrasound scans, and an ovulation before cycle day 22. Nursing mothers; subjects with alcohol, medication, or drug dependency; subjects with central nervous system disorders; subjects with hypersensitivity to any of the ingredients; or subjects with chronic illness were excluded from the trial. Women also were excluded if they had a history of menstrual disorders or abnormalities. Additionally, general exclusion criteria for the intake of COCs were applied. Assessments The inhibition of ovarian activity was assessed by the presence, size, and persistence of follicle-like structures with use of an ultrasonic examination of the ovaries. Grading was conducted according to a modified Hoogland and Skouby score (Table 1) (4 8). The Hoogland and Skouby score was determined for each cycle. Changes in endometrial thickness, in the cervix, and in the amount and consistency of the cervical mucus (with use of cervical reaction score) were measured to assess the potential of fertilization and nidation (20, 21). Furthermore, sex hormone levels were measured. The cervical reaction score was calculated by performing cervical smears and taking four variables into account, either quantitatively or qualitatively: the amount and viscosity of the mucus, its ability to crystallize, and the width of the external cervical os (20). Results were classified as either negative (score 1 3), slight (score 4 6), moderate (score 7 9), or full cervical reaction (score 10 12). All described measurements were taken on the even days of the premedication cycle (starting on day 2 of the next menstrual cycle after admission) to form the basis of investigation and establish that the women had regular cycles with an ovulation before day 22. Within the three medication cycles the above measurements were taken on the even days of each 28-day cycle, respectively. Thereafter, the same parameters were assessed on the even days of the 28-day postmedication phase, with a subsequent final examination on day 29 after the last medication cycle, resulting in a total of 14 efficacy assessments per cycle. Statistical Analyses Because of the descriptive design of the trial, no formal sample size was taken. The number of subjects was 40 in the medication phase and is comparable with sample sizes used in other similar ovulation inhibition trials (7, 8, 22). All analyses were exploratory. All subject-related data were analyzed by means of location parameters and measures of dispersion or absolute and relative frequencies as appropriate. The per protocol set and the full analysis set were evaluated. All subjects who took at least one dose of the medication were included in the full analysis set. If single cycles of generally suitable subjects were not in agreement with the definitions for the full analysis set or per protocol set, the cycles rather than the subjects were excluded from the respective analysis. Single cycles were omitted from the per protocol set if more than one pill per medication cycle was missed, diarrhea or vomiting had occurred, and/or antibiotics or other nonpermitted medication were taken. If the above mentioned criteria led to exclusion of all medication cycles of a subject, the respective subject was excluded from the per protocol set. Because the aim of this trial was to demonstrate the effect of 0.02 mg EE 2 mg chlormadinone acetate in a 24/4-day intake regimen on the modulation of ovarian function under compliant conditions, the per protocol set was chosen 1196 Spona et al. Ovulation inhibition by low-dose EE chlormadinone acetate Vol. 94, No. 4, September 2010
FIGURE 1 CONSORT diagram: subjects included in the trial. as the target population for efficacy evaluation. The safety evaluation was based on the safety set including all treated subjects. RESULTS Trial Subjects In total, 54 women were screened for eligibility; 40 were eligible for inclusion and received treatment (safety set), and 38 subjects constituted the full analysis set. Of these, 36 subjects were eligible for the per protocol set (CONSORT diagram, Fig. 1). Baseline demographics and characteristics (per protocol set) are shown in Table 2. The mean age of the women was 26 years, 19 of 36 women (52.8%) were nonsmokers, all women reported regular menstrual cycles (mean length 28.4 days) during the previous 3 months, and 8 of 36 women (22.2%) had used oral contraceptives before the pretreatment phase. was observed in 14 of 88 medication cycles (15.9%); an active follicle-like structure (grade 4) was observed in 13 medication cycles (14.8%), a luteinized unruptured follicle (grade 5) was present in one medication cycle (1.1%), and there was no ovulation (grade 6). Two medication cycles (2.3%) were not gradable according to the modified Hoogland and Skouby score as the value and timing of parameters did not fit in any of the categories. During the postmedication phase the occurrence of ovulation (grade 6) was observed in 22 of 32 cycles (68.8%). The changes in follicle-like structure size, cervical reaction score, and endometrial thickness for the whole trial period are shown in Figure 2A through 2C. During the medication cycles the median maximum diameter of follicle-like structure was <10 mm at each cycle day compared with 19.65 and 20.70 mm during the premedication cycle and postmedication phase, respectively, indicating Contraceptive Efficacy The modified Hoogland and Skouby scores by cycle are shown in Table 3. All 36 women (100%) in the per protocol set ovulated during the pretreatment cycle (grade 6). During the medication phase, in which a total of 88 medication cycles were monitored, 0.02 mg EE 2 mg chlormadinone acetate inhibited ovulation in all women in the per protocol set. One breakthrough ovulation in the full analysis set was caused by episodes of diarrhea and vomiting before the hormone-free interval. The majority of subjects in the per protocol set had Hoogland and Skouby grade 1 ( no activity ) under medication, recorded in 66 of 88 medication cycles (75.0%), with the highest incidences observed in medication cycles 2 (24 of 29 cycles; 82.8%) and 3 (23 of 29 cycles; 79.3%). Nonactive follicle-like structures (grade 3) were observed in one medication cycle (1.1%), and residual ovarian activity (grade 4 or 5) TABLE 2 Baseline demographics and characteristics (per protocol set; N [ 36). Mean age (y) ( SD) 26 ( 4.2) Mean height (cm) ( SD) 169 ( 6.0) Mean weight (kg) ( SD) 63 ( 9.3) Mean body mass index (kg/m 2 )( SD) 21.82 ( 2.8) Mean cycle length (d) (range) 28.4 (27 33) Nonsmoker (n) (%) 19 (52.8) Smoker (n) (%) 14 (38.9) Ex-smoker (n) (%) 3 (8.3) Spona. Ovulation inhibition by low-dose EE chlormadinone acetate. Fertil Steril 2010. Fertility and Sterility â 1197
TABLE 3 Hoogland and Skouby scores of ovarian activity by cycle (per protocol set; absolute and relative frequencies). Time Grade N (%) Pretreatment cycle 1 No activity 0 (0.0) 2 Potential activity 0 (0.0) 4 Active FLS 0 (0.0) 6 Ovulation 36 (100.0) Medication cycle 1 1 No activity 19 (63.3) 2 Potential activity 2 (6.7) 3 Nonactive FLS 1 (3.3) 4 Active FLS 6 (20.0) Ungradable 2 (6.7) Medication cycle 2 1 No activity 24 (82.8) 2 Potential activity 1 (3.4) 4 Active FLS 3 (10.3) 5 LUF 1 (3.4) Medication cycle 3 1 No activity 23 (79.3) 2 Potential activity 2 (6.9) 4 Active FLS 4 (13.8) Postmedication phase 1 No activity 0 (0.0) 2 Potential activity 0 (0.0) 4 Active FLS 4 (12.5) 6 Ovulation 22 (68.8) Ungradable 6 (18.8) Medication cycles 1 3 1 No activity 66 (75.0) 2 Potential activity 5 (5.7) 3 Nonactive FLS 1 (1.1) 4 Active FLS 13 (14.8) 5 LUF 1 (1.1) Ungradable 2 (2.3) Note: FLS ¼ follicle-like structure, LUF ¼ luteinized unruptured follicle. Spona. Ovulation inhibition by low-dose EE chlormadinone acetate. Fertil Steril 2010. successful suppression of follicular development. Estradiol and P levels were measured during each examination for calculation of the Hoogland and Skouby score (4); LH and FSH levels also were determined. Medians of maximum premedication and postmedication E 2 levels were 1.041 and 1.463 nmol/l whereas median maximum values during treatment with 0.02 mg EE 2 mg chlormadinone acetate were <0.28 nmol/l. Similarly, during the medication cycles the P levels were suppressed to median values <6.1 nmol/l, compared with values >54 nmol/l in the premedication cycle and postmedication phase, reflecting the absence of ovulation and thus corpus luteum formation. Median LH and FSH levels detected during the medication phase were below those seen during the premedication cycle and the postmedication phase. During the hormone-free intervals both LH and FSH levels showed a trend toward rebounds, but no follicle-like structure growth was stimulated by these rebounds. Endometrial growth was suppressed during treatment as reflected by median values of 4 to 5 mm of the medication cycles compared with median midcycle values of 10 to 12 mm in the premedication cycle and postmedication phase, indicating that the potential for nidation was suppressed. The cervical reaction score (indicating the likelihood of fertilization) was assessed as negative in all subjects during the medication cycles (Table 4 and Fig. 2B), and no corpus luteum was found in any subject of the per protocol set during the medication phase. Safety Treatment-related adverse events (AEs) were typical of those associated with hormonal contraceptive use. Their incidence is shown in Table 5. The AEs at least possibly related to 0.02 mg EE 2 mg chlormadinone acetate totaled 18 (reported by eight volunteers) and comprised 17.8% of all 101 AEs with 88.9% (16 of 18 at least possibly related AEs) being of mild intensity. The most common of these were headache (in 5 of 40 subjects [12.5%]), breast discomfort (in 3 of 40 subjects [7.5%]), and vaginal discharge (in 3 of 40 subjects [7.5%]). Of all AEs, 92.1% were managed without any countermeasures, and no event led to trial discontinuation. No serious AE occurred, and no AE was judged to be probably or certainly caused by the intake of 0.02 mg EE 2 mg chlormadinone acetate. No clinical or laboratory abnormalities were observed during the trial. There were no pathologic changes in the cervix. Overall the COC was well tolerated. DISCUSSION Modern COC formulations with low EE doses have been administered in new regimens in an effort to improve the tolerance profile and incidence of AEs while maintaining the suppression of pituitary-ovarian activity (8, 9, 11, 23). Accordingly this phase II trial in a population of healthy female subjects describes the modulation of ovarian function by 0.02 mg EE 2 mg chlormadinone acetate, taken in a 24/4-day intake regimen during three medication cycles. Several studies with a similar design, analyzing between 24 and 52 subjects, have been published previously (6, 10, 11, 17). Furthermore, Spona et al. (5) conducted a comparable trial with 0.03 mg EE 2 mg chlormadinone acetate taken in a 21/7-day intake regimen, thus facilitating an optimal and objective comparison with the data described here, that is, the impact on ovarian function of reducing the estrogen content from 0.03 to 0.02 mg per tablet and shortening of the hormone-free interval from 7 to 4 days. During the premedication cycle of the current trial, ovulation was observed in all subjects, whereas, during the medication phase (totaling 88 medication cycles), 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen inhibited ovulation in all women in the per protocol set, which compares well with the results of other ultra-low-dose COCs (8, 9, 11). The impact of prolonging the hormone-free interval was described by Klipping et al. (11) for a COC containing 0.02 mg EE 3 mg drospirenone in a 24/4- day intake regimen. They intentionally prolonged the hormonefree interval by 3 days to simulate noncompliance in current practice and found one breakthrough ovulation among 50 volunteers. Ovarian suppression was comparable with that observed in the current trial (87.8% under 0.02 mg EE 3 mg drospirenone in cycle 2 vs. 82.8% under 0.02 mg EE 2 mg chlormadinone acetate in cycle 2). The intensity of ovulation suppression generally is correlated with the progestogen in COCs (24), but no COC currently available 1198 Spona et al. Ovulation inhibition by low-dose EE chlormadinone acetate Vol. 94, No. 4, September 2010
FIGURE 2 Follicle-like structure size, cervical reaction score, and endometrial thickness (per protocol set; median [quartile 1/quartile 3] time course). For follicle-like structure size, values recorded as <10 mm are replaced by 10 mm in calculations of quartiles. Solid blue line ¼ median course; upper red dashed line ¼ the third quartile; lower red dashed line ¼ the first quartile. completely suppresses ovarian activity (25). Residual ovarian activity under 0.02 mg EE 2 mg chlormadinone acetate (15.9%) given in a 24/4-day intake regimen was found to be in the same range as for 0.03 mg EE 2 mg chlormadinone acetate (14.8%) given in a 21-day intake regimen (5), leading to the assumption that because of the reduction of EE from 0.03 mg to 0.02 mg the expected increase in residual ovarian activity could be compensated by shortening the hormone-free interval from 7 days to 4 days. Compared with other low- and ultra-low-dose COCs, less residual ovarian activity was observed under 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen. Residual ovarian activity with other 0.02 mg EE containing COCs in a 21-day intake regimen has been reported to be between 21% and 30% (24, 26). Follicular development harbors the possible danger of breakthrough ovulations, jeopardizing the reliability of oral Fertility and Sterility â 1199
TABLE 4 Rating of maximum cervical reaction by cycle (per protocol set; absolute and relative frequencies). Negative Slight Moderate Full Time N % N % N % N % Premedication cycle 0 0.0 0 0.0 2 5.6 34 94.4 Medication cycle 1 30 100 0 0.0 0 0.0 0 0.0 Medication cycle 2 29 100 0 0.0 0 0.0 0 0.0 Medication cycle 3 29 100 0 0.0 0 0.0 0 0.0 Postmedication phase 2 6.3 2 6.3 6 18.8 22 68.8 Medication cycles 1 3 36 100 0 0.0 0 0.0 0 0.0 contraceptives (10). Follicular development during treatment with 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen was found to be clearly suppressed reflected by folliclelike structure diameters <10 mm during the medication cycle. However, one breakthrough ovulation in the full analysis set was caused by episodes of diarrhea and vomiting before the hormone-free interval. In the current trial, the endometrial receptivity was suppressed and the cervical reaction score (according to Insler et al. [21]) was negative at each assessment in each medication cycle, reflecting that endometrium, mucus, and morphology of the cervix exerted unfavorable conditions for fertilization under 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen. This also was shown for 0.03 mg EE 2 mg chlormadinone acetate given in a 21- day intake regimen reported by Spona et al. (5) in a trial conducted with comparable design. Two independent trials suggest that follicle-like structures with ovulatory potential may develop during COC use but stress that backup mechanisms such as endometrial thickness and cervical penetrability contribute to the efficacy of a COC, so that contraceptive efficacy is assured even in cases where E 2 rebounds or follicular development during the hormone-free intervals occurs (10, 27). During the medication phase E 2 and P serum levels were far below those observed during the premedication cycle and the postmedication phase. These results reflect published data describing rebounds of endogenous E 2 during 7-day hormone-free intervals TABLE 5 Incidence of treatment-related AEs (at least possibly related). Subjects (N [ 40) AE N % Headache 5 12.5 Breast discomfort 3 7.5 Vaginal discharge 3 7.5 Fatigue 1 2.5 Irritability 1 2.5 Nausea 1 2.5 Spona. Ovulation inhibition by low-dose EE chlormadinone acetate. Fertil Steril 2010. for 0.02 mg EE formulations (7, 24, 26) and for 0.03 mg EE containing COCs (6, 28, 29), which were decreased notably by shortening the hormone-free intervals from 7 to 4 days, as also shown for 0.015 mg EE 0.075 mg gestodene (8). A comparable impact of shortening the hormone-free interval on rebound effects in the hormone-free intervals of cycles with 0.02 mg EE 0.075 mg gestodene also has been observed by comparing a 23-day intake regimen with a 21-day intake regimen: rebounds were less pronounced and occurred later under the 23-day intake regimen (10). In the postmedication phase the incidence of ovulation was 68.8%, and the rebound of all other parameters during the postmedication phase indicates that a conception-favorable state is rapidly reached in most women after withdrawal of 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen. Overall, 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen exerted a favorable safety profile and was well tolerated. The type and incidences of AEs observed were comparable with those observed with another EE chlormadinone acetate contraceptive formulation (5, 15, 17, 22, 30 32) and with COC use in general (9, 23, 33). The incidences of the most frequently reported treatment-related AEs in the current trial were headache (12.5%), breast discomfort (7.5%), and vaginal discharge (7.5%). Klipping et al. (11) also reported headache as the most frequent (15.4%) treatment-related AE, followed by emotional liability (13.5%), nausea (11.5%), and metrorrhagia (11.5%) during intake of 0.02 mg EE 3 mg drospirenone in a 24/4 regimen. Endrikat et al (9, 23, 33) conducted three large clinical trials comparing the efficacy and tolerability of different doses of COC preparations containing 0.02 or 0.03 mg EE in combination with either gestodene, desogestrel, levonorgestrel, or norgestimate (9, 23, 33). As in the current trial, the AEs reported most frequently by the women were headache (15.3 to 20.4%), breast tenderness (7 to 13.7%), and nausea (4.4 to 8.2%). Consequently, the AEs of 0.02 mg EE 2 mg chlormadinone acetate given in a 24/4-day intake regimen in the current trial are comparable with those of other COCs. The combination of 0.02 mg EE and 2 mg chlormadinone acetate, administered in a 24/4-day intake regimen, is a well-tolerated and highly effective COC exhibiting profound modulatory effects on the ovaries, resulting in inhibition of ovulation, as well as of cervical function and endometrial growth. The safety profile for this COC is well known for contraceptives with low EE content. Acknowledgments: The authors thank Zaicom MMC Ltd., Horsham, United Kingdom, for editorial support. 1200 Spona et al. Ovulation inhibition by low-dose EE chlormadinone acetate Vol. 94, No. 4, September 2010
REFERENCES 1. Combined oral contraceptives. A statement by the committee on safety of drugs. Br Med J 1970;2: 231 2. 2. Bettendorf G, Breckwoldtt M, Keller PJ, Kuhl H, Runnebaum B, Braendle W. Recommendations on oral contraception. Der Frauenarzt 1997;38:1058 62. 3. Jeffcoate TN. R.C.O.G. statement on oral contraceptives. Br Med J 1970;2:293. 4. Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993;47:583 90. 5. Spona J, Binder N, H oschen K, Feichtinger W. Contraceptive efficacy and safety of a low-dose oral contraceptive, (0.03 mg ethinyl oestradiol and 2 mg chlormadinone acetate) Belaraâ, over three medication cycles. Eur J Contracept Reprod Health Care 2008;13:39 48. 6. Spona J, Feichtinger W, Kindermann C, Moore C, Mellinger U, Walter F, et al. Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. Contraception 1997;56:185 91. 7. Spona J, Feichtinger W, Kindermann C, Wunsch C, Brill K. Inhibition of ovulation by an oral contraceptive containing 100 micrograms levonorgestrel in combination with 20 micrograms ethinylestradiol. Contraception 1996;54:299 304. 8. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity. Fertil Steril 1999;72:115 20. 9. Endrikat J, Cronin M, Gerlinger C, Ruebig A, Schmidt W, Dusterberg B. Open, multicenter comparison of efficacy, cycle control, and tolerability of a 23- day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 20 microg ethinyl estradiol and 150 microg desogestrel. Contraception 2001;64:201 7. 10. Spona J, Elstein M, Feichtinger W, Sullivan H, Ludicke F, Muller U, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception 1996;54:71 7. 11. Klipping C, Duijkers I, Trummer D, Marr J. Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception 2008;78:16 25. 12. Rapkin AJ, Sorger SN, Winer SA. Drospirenone/ ethinyl estradiol. Drugs Today (Barc) 2008;44: 133 45. 13. Plewig G, Cunliffe WJ, Binder N, Hoschen K. Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled phase III trial. Contraception 2009;80:25 33. 14. Schramm G, Steffens D. Contraceptive efficacy and tolerability of chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (Belara). Results of a post-marketing surveillance study. Clin Drug Invest 2002;22:221 31. 15. Schramm G, Steffens D. A 12-month evaluation of the CMA-containing oral contraceptive Belara: efficacy, tolerability and anti-androgenic properties. Contraception 2003;67:305 12. 16. Winkler U, Daume E, Sudik R, Oberhoff C, Bier U, Hallmann C, et al. A comparative study of the hemostatic effects of two monophasic oral contraceptives containing 30 mu(g) ethinylestradiol and either 2 mg chlormadinone acetate or 150 mu(g) desogestrel. Eur J Contracept Reprod Health Care 1999;4:145 54. 17. Zahradnik HP, Goldberg J, Andreas JO. Efficacy and safety of the new antiandrogenic oral contraceptive Belara. Contraception 1998;57:103 9. 18. Zahradnik HP, Hanjalic-Beck A. Efficacy, safety and sustainability of treatment continuation and results of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg chlormadinone acetate, in long-term usage (up to 45 cycles) an open-label, prospective, noncontrolled, office-based Phase III study. Contraception 2008;77:337 43. 19. Brucker C, Hedon B, The HS, H oschen K, Binder N, Christoph A. Long-term efficacy and safety of a monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4-day regimen. Contraception 2010;81:501 9. 20. Insler V, Glezerman M, Bernstein D. Diagnosis and treatment of the cervical factor of infertility. Reproduccion 1981;5:295 300. 21. Insler V, Melmed H, Eichenbrenner I, Serr D, Lunenfeld B. The cervical score. Int J Gynaecol Obstet 1972;10:223 8. 22. Worret I, Arp W, Zahradnik HP, Andreas JO, Binder N. Acne resolution rates: results of a singleblind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology 2001;203:38 44. 23. Endrikat J, Cronin M, Gerlinger C, Ruebig A, Schmidt W, Dusterberg B. Double-blind, multicenter comparison of efficacy, cycle control, and tolerability of a 23-day versus a 21-day low-dose oral contraceptive regimen containing 20 microg ethinyl estradiol and 75 microg gestodene. Contraception 2001;64: 99 105. 24. Ludicke F, Sullivan H, Spona J, Elstein M. Dose finding in a low-dose 21-day combined oral contraceptive containing gestodene. Contraception 2001;64:243 8. 25. Baerwald AR, Pierson RA. Ovarian follicular development during the use of oral contraception: a review. J Obstet Gynaecol Can 2004;26:19 24. 26. Fitzgerald C, Feichtinger W, Spona J, Elstein M, Ludicke F, Muller U, et al. A comparison of the effects of two monophasic low dose oral contraceptives on the inhibition of ovulation. Adv Contracept 1994;10:5 18. 27. Killick SR. Ovarian follicles during oral contraceptive cycles: their potential for ovulation. Fertil Steril 1989;52:580 2. 28. Cohen BL, Katz M. Pituitary and ovarian function in women receiving hormonal contraception. Contraception 1979;20:475 87. 29. Duijkers IJ, Klipping C, Verhoeven CH, Dieben TO. Ovarian function with the contraceptive vaginal ring or an oral contraceptive: a randomized study. Hum Reprod 2004;19:2668 73. 30. Bitzer J. Belara proven benefits in daily practice. Eur J Contracept Reprod Health Care 2005;10(Suppl 1):19 25. 31. Curran MP, Wagstaff AJ. Ethinylestradiol/chlormadinone acetate. Drugs 2004;64:751 60. discussion 61 2. 32. Zahradnik HP. Belara a reliable oral contraceptive with additional benefits for health and efficacy in dysmenorrhoea. Eur J Contracept Reprod Health Care 2005;10(Suppl 1):12 8. 33. Endrikat J, Hite R, Bannemerschult R, Gerlinger C, Schmidt W. Multicenter, comparative study of cycle control, efficacy and tolerability of two low-dose oral contraceptives containing 20 microg ethinylestradiol/100 microg levonorgestrel and 20 microg ethinylestradiol/500 microg norethisterone. Contraception 2001;64:3 10. Fertility and Sterility â 1201