Switching hormonal contraceptives to a chlormadinone acetate-containing oral contraceptive. The Contraceptive Switch Study

Contraception 76 (2007) 84 – 90

Original research article

Switching hormonal contraceptives to a chlormadinone acetate-containing oral contraceptive. The Contraceptive Switch Study Georg Schramm⁎, Birgit Heckes Grünenthal GmbH, Medical Department, 52099 Aachen, Germany Received 5 July 2006; revised 30 March 2007; accepted 30 March 2007

Abstract Purpose: This prospective observational noninterventional study aimed at collecting information on changes in cycle control, dysmenorrhea, androgen-related skin conditions and tolerability in a large cohort of women who switched their oral contraceptive (OC) to 2.0 mg chlormadinone acetate (CMA)/0.03 mg ethinylestradiol (EE) (Belara®). Materials and Methods: In a total of 20,897 women who were enrolled in a four-cycle clinical evaluation at 1597 gynecological practices throughout Germany, there are 16,781 women who switched from another contraceptive. Results: The most frequently mentioned complaint for switching contraceptive was seborrhea/acne (6933/16,781 women; 41.3%). This was followed by cycle irregularities (18.8%), headache (15.9%), breast tension (15.1%), amenorrhea (14.9%), spotting (12.8%) and dysmenorrhea (11.7%). After switching to CMA/EE treatment, these symptoms decreased substantially or even disappeared in a large number of women. The vast majority of study participants scored both tolerability and well-being on CMA/EE intake as ‘very good’ or ‘good’. The results revealed that 13,508 women (80.5%) stated being more satisfied or even much more satisfied on CMA/EE intake compared to their previously used contraceptive; most of them had taken progestins of the nortestosterone type. CMA/EE produced beneficial effects on skin conditions and wellbeing in OC switchers who experienced dissatisfaction with their previous contraceptive regimen. Conclusion: The results of this observational study support that 2.0 mg CMA/0.03 mg EE is well tolerated, provides a reliable cycle stability and is very effective in diminishing dysmenorrhea and other cycle-related complaints. Women suffering from problems on hormonal contraception received benefit from switching to the progesterone derivative CMA-containing OC. © 2007 Published by Elsevier Inc. Keywords: Chlormadinone acetate; Oral contraceptive; Switchers; Cycle control; Dysmenorrhea; Acne

1. Introduction Oral contraceptives (OCs) represent one of the most reliable and globally accepted contraceptive procedures. About 80 million women worldwide are using OCs daily [1]. In Germany, nearly 60% of women aged 20–40 years who do not want to conceive choose the OC method [2]. Most women choose the OC method not only for contraception, but also because it is a convenient and reversible method that offers a reliable tolerability profile as well as additional benefits to general well-being. Detracting adverse symp-

⁎ Corresponding author. Tel.: +49 241 569 1239; fax: +49 241 569 2875. E-mail address: [email protected] (G. Schramm). 0010-7824/$ – see front matter © 2007 Published by Elsevier Inc. doi:10.1016/j.contraception.2007.03.014

toms, such as poor cycle control, dysmenorrhea, acne, weight gain, depressed mood, headache, breast tension and/ or other complaints, often leads to discontinuation or switches in OC preparations [3,4]. An analysis of more than 10,000 women with almost 100,000 patient-years in the German Cohort Study on Women's Health revealed that 93% of ever-users of OCs switched or stopped their OC brand within the observation period [5]. The frequency of switching increased with age and duration of use. Besides the desire to become pregnant, which was the most frequently reported reason for stopping use, side effects such as headache/ migraine and bleeding problems were also shown to be of great importance. In addition, androgen-related skin and hair changes have a major influence on women's decision regarding method compliance as well [6]. All these symptoms reflect common complaints in daily gynecological

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Table 1 Types of contraceptives used before switching to 2.0 mg CMA/0.03 mg EE and duration of previous regimen (N=16,781) % women a

Type of contraceptive I II III

IV V VI VII VIII IX X XI a

COCs with first-generation progestogens (e.g., norethisterone, lynestrenol) COCs with second-generation progestogens (e.g., levonorgestrel) COCs with third-generation progestogens (e.g., desogestrel, gestodene, norgestimate) COCs with CPA COCs with CMA COCs with DNG COCs with DSP Multiphasic COCs (biphasic and triphasic pills, sequential preparations) Progestin-only pill IUD/IUS Other monophasic 50 μg-EE pills

Duration of previous regimen (years) (mean±SD)

2.9

3.0±2.8

36.0

3.0±3.2

16.6

2.9±3.1

7.9 1.4 12.2 0.5 20.5

3.1±3.4 3.6±4.1 3.0±2.8 3.1±3.0 3.1±3.1

1.3 0.3 1.5

3.2±3.7 2.9±1.8 2.8±3.1

Because of multiple citing within the listed contraceptive categories, the total percentage amounts to just above 100.0%.

practice, and avoidance or reduction of them may be a powerful motivator toward OC continuation. Today, a wide range of OCs are available to meet individual needs. Modern OCs differ from older ones primarily with regard to estrogen dosage and the progestogen component. Most OCs are based on norethindrone or levonorgestrel and may cause androgen-related disorders, such as acne and seborrhea, even though ethinylestradiol (EE) induces hepatic SHBG synthesis and decreases free testosterone [7]. More recently, progestogens with weak or no androgenic effects, or even with anti-androgenic properties, have been developed [8,9], among them the C21progestin chlormadinone acetate (CMA). In contrast to other progestogens derived from the 19-nor-testosterone series, CMA is a derivative of the naturally secreted progesterone. Chlormadinone acetate shows beneficial pharmacological effects on the endometrial transformation. The pharmacokinetic parameters for CMA indicate a mean terminal elimination half-life of 34–38 h after multiple dosing. Steady-state plasma levels are achieved in about 7–8 days of treatment [10]. Belara® is a monophasic combined low-dose OC containing CMA 2.0 mg and EE 0.03 mg per tablet. In clinical trials, this contraceptive was well tolerated and showed reliable contraceptive efficacy (adjusted Pearl index of 0.27) [11], high-level cycle stability and beneficial antiandrogenic effects on both skin and hair [11,12]. Postmarketing surveillance studies reflecting routine clinical use confirm these results in large numbers of patients [13,14]. Of interest was whether the same positive outcome would be found in women who were dissatisfied with their previous OC and therefore switched to the CMA-containing pill. Thus, this observational study was designed to collect information on changes in cycle control, cycle-related complaints like dysmenorrhea, seborrhea/acne and toler-

ability in a large cohort of women switching hormonal contraception to 2.0 mg CMA/0.03 mg EE.

2. Methods 2.1. Study design The prospective observational study was conducted between October 2000 and December 2001, involving 1597 gynaecologists in private practice throughout Germany. The noninterventional design was used to reflect daily gynaecological practice. The main aim of the study was to observe users of OCs, intrauterine devices (IUDs) and intrauterine systems (IUSs) who switched voluntarily and on their own wish to CMA/ EE treatment because of dissatisfaction with their contraceptive regimen and complaints about adverse effects such as cycle instability, dysmenorrhea, headache, breast tension or others. After switching, the intake of the CMAcontaining contraceptive was observed and documented over a period of four cycles. Additionally, women with the first prescription of an OC were included but not in the statistical evaluation. Each woman took one 2.0 mg CMA/0.03 mg EE tablet daily for 21 days per cycle, starting on the first day of withdrawal bleeding, followed by a 7-day pill-free interval. 2.2. Evaluation The following data were collected by using a case report form (CRF): – age, – risk factors (e.g., family history of thromboembolic events, smoking habits, adiposity (BMI N25), – contraceptive preparation used before switching,

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Table 2 Main complaints a for switching the contraceptive regimen to 2.0 mg CMA/ 0.03 mg EE (N=16,781) Reason for switching b19 years of age adolescents

No. of women (% of total)

Seborrhea/acne, a 1863 (46.8%) Cycle irregularities, 819 (20.6%) Headache, a 448 (11.3%) Breast tenderness, a 394 (9.9%) Amenorrhea, 530 (13.3%) Spotting, b 573 (14.4%) Dysmenorrhea, b 634 (15.9%)

6885 (41.0%) 3138 (18.7%) 2658 (15.8%) 2528 (15.1%) 2490 (14.8%) 2147 (12.8%) 1939 (11.6%)

Because of multiple citing, the number of reasons for switching is higher than the number of the study population. a Only for moderate and severe complaints. b Only for frequent spotting and dysmenorrhea.

– duration of previous contraception, and – reasons for switching to a CMA/EE-containing pill. The gynaecologists recorded cycle control, dysmenorrhea, weight, androgen-related skin disorders and adverse effects at baseline and after four cycles. Subjective complaints such as headache, breast tension, depressed mood and tiredness were categorized as mild, moderate and heavy, respectively. At the end of the evaluation period, tolerability, well-being, compliance with the medication, premature withdrawal and women's satisfaction compared to the previous contraceptive preparation were assessed as well. A synopsis of the types of contraceptives used before is shown in Table 1. 2.3. Statistical methods Data validation and descriptive statistical analysis were performed using the Statistical Analysis System software package, version 8.0. Results are described by mean average value, standard deviation (SD), median, minimum, maximum, 25% and 75% percentile. The statistical analysis was carried out by the Institut Schauerte (München, Germany). The study was a prospective observational study for which no IRB approval is needed.

(47.6%) aged 20–29 years. The women had a mean height of 167.3 cm (SD ±6.0 cm), mean weight of 63.1 kg (SD± 10.3 kg) and mean body mass index (BMI) of 22.6 kg/m2 (SD ±3.5 kg/m2). The most frequently documented risk factors at baseline for the intake of an OC were smoking (n=5865; 35.0%), adiposity (n=1698; 10.1%) and a family history of thromboembolic diseases (n=317; 1.9%). About 20% of the female smokers admitted to smoking more than 10 cigarettes per day. 3.2. Contraception categories and complaints for switching Concerning the 16,781 switchers, a total of 16,519 women (98.4%) had previously used a combined oral contraceptive (COC), another 1.3% (n=213) switched from a progestin-only pill and 0.3% from an IUD/IUS. Details about the types and duration of previous contraception are shown in Table 1. The majority of women (n=11,082; 66.0%) used their previous contraceptive between 1 and 5 years before switching to CMA/EE treatment. Another 12.1% used their OC brand for less than 1 year and for 9.8% the duration of use of previous regimen was unclear. The most frequently mentioned complaints for discontinuing contraceptive preparation and switching to CMA/EE were seborrhea/acne, menstrual cycle irregularities, headache, breast tension, amenorrhea, spotting and dysmenorrhea. Weight gain was not a complaint for the women in our study. It is noted that for all types of contraceptive preparations, seborrhea/acne was the main complaint for switching. Especially for adolescents and young adults (≤19 years), seborrhea/acne (46.8% of all women at this age), cycle irregularities (20.6%) and dysmenorrhea (15.9%) were revealed to be of greater importance compared to the entire study population (Table 2). In contrast, headache and breast tension became more relevant as a complaint for switching with increasing age.

3. Results 3.1. Baseline characteristics The CRFs returned by 1597 gynaecologists provided data on a total of 16,781 women who switched from OC. Thus, the analysis comprises 68,491 cycles of CMA/EE exposure (5268.5 women-years). Most of the women (80.2%) were observed for a period between 100 and 200 days after switching contraception to CMA/EE (mean observation period: 138.5 days). The mean age of the study population was 25.9 years (SD ±7.3 years), with about one-quarter (23.6%) of the women being aged ≤19 years (they used OCs 1–5 years in a median of 2.2 years. It is not unusual that girls start to use OCs when they are 16 or younger) and one-half

Fig. 1. Women who suffered from irregular cycles on their previous contraceptive regimen: changes in cycle regularity during CMA/EE intake.

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3.4. Dysmenorrhea At baseline, 4230 women reported rare dysmenorrhea, and another 1939 patients reported frequent dysmenorrhea. In the majority of these women (61.1%), dysmenorrhea resolved completely on CMA/EE intake. In the subgroup of women suffering from frequent dysmenorrhea, only 5.4% (n=104) complained about unchanged symptoms after four cycles of CMA/EE treatment. 3.5. Seborrhea/acne

Fig. 2. Improvement of acne/seborrhea after four cycles of 2.0 mg CMA/ 0.03 mg EE treatment.

A majority of study participants (12,088; 72.0%) complained about seborrhea/acne on their previous hormonal contraceptive regimen. Before and after four cycles of CMA/EE intake, data on this complaint were available from 11,638 patients. In almost half of these women (45.9%), seborrheic symptoms disappeared completely after switching to CMA/EE within a four-cycle treatment. In another 36.5% (n=4248), acne/seborrhea improved. Fig. 2 portrays the characteristics of acne/seborrhea at baseline and at the end of the observation period.

3.3. Cycle control

3.6. Tolerability and compliance

Menstrual cycle irregularities were a frequently reported complaint for switching the contraceptive regimen. The results revealed that 87.0% (n=2731) of all women describing their cycle to be irregular before the switch experienced a regular cycle on CMA/EE intake (Fig. 1). Only in 6.9% (n=217) was irregular cycle seen within the observation period. For 190 patients (6.1%), no details on cycle control were available. During the previously used hormonal contraceptive regimen, 6073 women (36.2%) complained about spotting, and breakthrough bleeding occurred in a total of 2391 contraceptive users (14.2%). After four cycles of CMA/EE treatment, the number of women suffering from these symptoms substantially decreased to 3723 (22.2%) and 692 (4.1%), respectively. The incidence of severe withdrawal bleeding dropped from 7.5% before the start of the study to 0.9% at the end of the evaluation period. A total of 2490 (100%) women switched to the CMA-containing contraceptive because of secondary amenorrhea. On CMA/EE intake, bleeding occurred regularly in 87.6% (n=2180) of these women. If bleeding disorders were newly diagnosed during CMA/ EE treatment, these difficulties mostly occurred in the first two cycles and became less frequent during further treatment. Compared to the entire study population, cycle irregularities, spotting/breakthrough bleeding, severe withdrawal bleeding and amenorrhea before and during study treatment were slightly more often documented in women for whom overweight (BMI N25) was documented. In contrast, the rate of spotting/breakthrough bleeding, amenorrhea and severe withdrawal bleeding at baseline was shown to be marginally below the average in underweight (BMI b20) patients.

Among 16,781 women who participated in the study, a total of 994 (5.9%) adverse events were documented during the observation period. The investigators reported that 288 (1.7%) of them were either possibly or probably related to the use of 2.0 mg CMA/0.03 mg EE. With regard to a possible relationship to CMA/EE treatment, two serious adverse drug reactions occurred: one ovarian cyst and one case of thrombosis in the left lower leg. The thrombosis occurred during the first treatment cycle after switching, leading to premature withdrawal of the CMA-containing OC. In fact, the affected 17-year-old girl was predisposed to thromboembolic events because of APC resistance and a protein S deficiency which was unknown at the start of the OC intake. Subsequently, she recovered from the thrombosis with appropriate treatment. The most frequently reported known adverse events were infrequent intermenstrual bleedings (1.3% of the study population), breast pain (0.5%) and weight gain (0.5%). Within the entire study population, subjective complaints such as moderate or severe headache, breast tension, depressed mood and/or tiredness occurred less frequently after four cycles of CMA/EE intake than before (Fig. 3). Despite the pronounced anti-androgenic effect of CMA [15], changes in libido were observed in only 0.1% of the CMA/ EE users. Baseline body weight was maintained by 47.6% (n=7982) of the women at the end of the 4-month study. The number of women with increase in weight and the number of women with loss of weight are nearly equal so that the mean body weight at baseline (63.1 kg) is equal to the mean body weight at the end of the study (63.1 kg) (Fig. 4). Compliance data were available for 16,530 participants (98.5%). Regular pill intake was reported by 14,911 women

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Fig. 3. Incidence of moderate and severe cycle-related complaints before and after switching from another contraceptive to CMA/EE after four cycles.

(88.9%), while 1202 (7.2%) and 417 (2.5%) women admitted to forgetting CMA/EE intake once or several times. These irregularities in contraceptive pill intake mainly occurred in the first two cycles after switching from the previous regimen. A total of 15,306 women (91.2%) completed the four cycles of CMA/EE treatment. Only 1173 patients (7.0%) stopped the OC prematurely (e.g., bleeding disorder, desire for children), and for 302 women (1.8%), no details were documented. During the observation period, pregnancy occurred in 19 (0.1%) women. The unadjusted (with intake mistakes) Pearl index on the basis of 68,491 cycles was calculated to be 0.360 (95% CI, 0.231– 0.563). The adjusted Pearl index was found to be 0.133 (95% CI, 0.064–0.274). At the end of the study, the women and gynaecologists assessed the overall tolerability of the CMA-containing OC (‘very good’, ‘good’, ‘moderate’ or ‘poor’). A very good or good result was stated by 90.8% of the patients and only 0.4% of the women rated the tolerability of CMA/EE as poor. Where tolerability assessment is concerned, patients and gynaecologists agreed unanimously. 3.7. Well-being and satisfaction score After switching contraception to CMA/EE, well-being during the study period was evaluated in terms of very good,

Fig. 4. Changes in body weight during four cycles of CMA/EE treatment.

Fig. 5. Women's assessment on well-being in comparison to previously used contraceptive regimen after switching to 2.0 mg CMA/0.03 mg EE.

good, moderate and poor. Well-being was rated by 14,418 women (85.9%) on CMA/EE intake as very good or good, 6.1% (n=1018) rated it as moderate and only 1.6% (n=266) noted a poor well-being. For 6.4% (n=1079), well-being rating was unfortunately not documented. Compared to their previously used contraceptive regimen. 13,508 patients (80.5%) reported being more satisfied or even much more satisfied on CMA/EE treatment. No difference was found by 10.8% (n=1824), and for 3.8% (n=644) of the women a worsening was documented (Fig. 5). For 4.9% (n=815), the documentation was missing.

4. Discussion This observational study was designed to collect data about changes in cycle control, dysmenorrhea, seborrhea/ acne and tolerability after switching hormonal contraception to the CMA-containing OC Belara® in routine gynaecological practice. The observation period was limited to four cycles of CMA/EE treatment because the question of continuing or stopping an OC will usually be decided within the initial 3–4 months after starting a new contraceptive regimen based on clinical experiences. The observational study involved 1597 investigators, representing more than one-sixth of all gynecologists in private practice in Germany, and a large study population of nearly 16,800 women switching OC to the CMA-containing pill. The study population profile within the various subgroups of previous contraception appeared to be typical of OC users in Germany [14]. All women participating in the study switched to 2.0 mg CMA/0.03 mg EE because of adverse experiences with their previous contraceptive regimen. More than one-third of the study population reported seborrhea/acne as a reason for switching contraception. This is probably connected with the

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proven and well-known anti-androgenic profile of the progesterone-derivative 2.0 mg CMA/0.03 mg EE [11–14]. Animal experiments, untransferable to human beings, show that the anti-androgenic property of CMA is equal to that of dienogest (DNG) and averages one third of the antiandrogenic property of cyproterone acetate (CPA) [16]. Muhn et al. [17] compared the anti-androgenic property of CPA and drospirenone (DSP) in rats. Drospirenone was about a third as anti-androgenic as CPA [17]. A great amount of women also described cycle irregularities (spotting, amenorrhea), headache, breast tension and dysmenorrhea as a complaint for switching. All preceding symptoms had been confirmed to be important factors in determining compliance by other studies as well [5,18,19]. Seborrheic symptoms are the most common skin disorder and nearly 85% of people 12–25 years old will experience some degree of acne [20]. On CMA/EE treatment, a major benefit was seen in women with preexisting androgenrelated disorders. The percentage of women complaining about seborrhea/acne decreased substantially by more than 80% after study medication (Fig. 2). Cycle disorders represent a key concern for women in the reproductive years. OCs are frequently prescribed for their beneficial effects on menstrual bleeding patterns. They decrease menstrual flow, shorten the duration of bleeding, treat dysfunctional bleeding and reduce the incidence of iron-deficiency anemia [21,22]. In this observation study, more than 50% of all women suffered from intermenstrual bleeding with their previous contraceptive. After switching to CMA/EE treatment, a consistent reduction in the prevalence of spotting and breakthrough bleeding by almost one-half was demonstrated. Women having the most frequent bleeding irregularities showed the greatest benefit. Among those patients who experienced irregular cycles at baseline, this complaint disappeared in over 80%. This is probably linked to the progesterone-derivative CMA, which shows well-defined beneficial effects on the endometrium [23,24]. Dysmenorrhea is an important menstrual cycle inconvenience. Studies have reported that about 60% of all teenage girls report dysmenorrhea and up to 14% miss school days because of the complaint [25]. Dysmenorrhea is presumably based on increased prostaglandin production and a thinning of the endometrial lining [21,22,26]. Zahradnik and Breckwoldt [23] found a 2.5 times higher menstrual excretion of prostaglandin F2α (PGF2α) in the dysmenorrheic women compared to the control groups. Increased uterine production of PGF2α amplifies uterine contractility, whereas prostacyclin (PGI2) has been shown to relax myometrial tissue. The ratio of PGF2α/PGI2 is impaired in dysmenorrheic women resulting in an increased contractility and a reduced relaxation of the myometrium. These findings are causally related to a shift in the prostaglandin biosynthesis resulting in a relative progesterone deficiency and an increased PGF2α formation, which can be balanced by an intrauterine application of progesterone [23,27].

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Consistently, within the large population of this observational study, dysmenorrheic symptoms were a frequently reported complaint. More than one-third of the participants suffered from this difficulty with their previous contraceptive regimen. After switching to CMA/EE treatment, dysmenorrhea resolved completely in more than 60% of these women. The greatest benefit was documented in women who complained about frequent dysmenorrhea. In 95% of these women, this difficulty was reported less frequently or even disappeared on CMA/EE intake. The pronounced beneficial effects on dysmenorrhea during CMA/EE treatment — even in women already having used other OCs — cannot only be explained by a thinning of the endometrial lining but also by the close similarity of CMA to progesterone [27]. The low rate of bleeding problems during CMA/EE intake is consistent with previous observations [11,13,14]. Amenorrhea is another problematic issue because of the association with the fear of being pregnant. Of 2490 women who reported secondary amenorrhea before switching to the CMA-containing contraceptive, 87.6% (n=2180) had regular cycles after 4 months of CMA/EE treatment (Fig. 2). This may be causally related to CMA being a progesterone derivative with beneficial effects on the endometrium and to the balanced ratio of EE to CMA. As expected, substantial reductions in headache, breast tension, depressed mood and tiredness turned out to be a further noncontraceptive beneficial effect produced by CMA/EE intake due to the CMA component (Fig. 3). The studied OC, 2.0 mg CMA/0.03 mg EE, is well tolerated, as highlighted by the small number of withdrawals and the high percentage of women and investigators rating tolerability as good or very good. In the present observational study, the documented adverse events reflect the spectrum of complaints usually observed with the intake of an OC. As previously reported by other observation studies, the adverse events rates fell during further treatment [13,14]. One of the most frequently described adverse events in the literature is weight gain with the use of an OC [18,28– 30]. Against this background, the present study found no change in mean weight during CMA/EE treatment. The results of this observational study suggest that the CMA-containing pill 2.0 mg CMA/0.03 mg EE provides an effective means of reducing the incidence of menstrual disorders, seborrhea/acne, migraine/headache, breast tension and other subjective complaints of women who have had these difficulties with other OC regimens. Accordingly, the vast majority of women scored both tolerability and wellbeing on CMA/EE intake as very good or good. More than 80% of all patients claimed to be more satisfied or even much more satisfied with CMA/EE treatment compared to their previously used contraceptive regimen. In conclusion, this prospective observational evaluation substantiates the results of previous clinical trials and postmarketing studies that the COC containing EE 0.03 mg and CMA 2.0 mg is well tolerated and produces major benefits on well-being. Women who switched OC to

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