ethinylestradiol: physical and emotional benefits

Contraception 81 (2010) 49 – 56

Original research article

Efficacy of the low-dose combined oral contraceptive chlormadinone acetate/ethinylestradiol: physical and emotional benefits Marie-Luise S. Heskamp⁎, Georg A.K. Schramm Medical Department, Grünenthal GmbH, 52099 Aachen, Germany Received 5 November 2008; revised 19 May 2009; accepted 11 June 2009

Abstract Background: This study investigated the effects of the low-dose combined oral contraceptive (COC) 2.0 mg chlormadinone acetate (CMA)/ 0.03 mg ethinylestradiol (EE) (Belara®, Balanca®) on cycle-related physical and emotional disorders in women ≥25 years of age. Study Design: A prospective, non-interventional, observational study of 3772 women over six cycles was conducted in 303 office-based gynecological centers throughout Germany. Results: CMA/EE provided high contraceptive efficacy with a Pearl index of 0 (95% confidence interval=0.00–0.22) and was generally well tolerated, with no statistically significant weight changes during the observation period (p=.147). CMA/EE intake resulted in a statistically significant improvement in cycle-related physical and emotional symptoms, with a 67% overall reduction in sum score for number and intensity of cycle-related symptoms per patient. Conclusions: The results of this study in women ≥25 years of age support previous findings that 2.0 mg CMA/0.03 mg EE is an effective low-dose COC, with an excellent tolerability profile, with the additional benefits of significantly reducing both cycle-related physical and emotional symptoms (p≤.001); women with the respective preexisting symptoms may, therefore, benefit from CMA/EE contraceptive treatment. Further research is warranted. © 2010 Elsevier Inc. All rights reserved. Keywords: Ethinylestradiol; Chlormadinone acetate; Combined oral contraceptive; COC; Physical; Emotional

1. Introduction Cycle-related changes in the physical and emotional state are important health concerns for numerous women of reproductive age. These include a series of troublesome physical symptoms, such as mastodynia, headache, abdominal and back pain, tiredness and intermenstrual bleeding, with a variety of emotional changes that are linked to hormonal fluctuations. Often underreported, a great number of women experience mood swings, depressive mood symptoms, nervousness, irritability, lack of energy, anxiety, lack of concentration, decrease of libido and sleep disturbances. Results of a German public survey on emotional symptoms among 515 women aged 25–45 years disclosed

⁎ Corresponding author. Tel.: +49 214 569 2833; fax: +49 241 569 2875. E-mail address: [email protected] (M.-L.S. Heskamp). 0010-7824/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2009.06.011

that more than 60% suffered from mood swings, with approximately 30% suffering these symptoms at least once per month. As expected, the frequency of symptoms increased with age. In contrast to the cumulative incidence of cycle-related mood disorders, only 17% of the women concerned reported these problems to their physician [1]. Many women experience minor physical and mood changes premenstrually; however, when severe, these symptoms may have a negative impact on daily life by impairing work, relationships and social activities. During the menstrual cycle in the absence of hormonal contraception, cycle-related disorders can occur at different stages: at the beginning, mid-cycle, premenstrual or menstrual stages; under hormonal contraception with monophasic pills, cycle-related disorders can occur after withdrawal of the sex hormones during the hormone-free interval, during withdrawal bleeding and/or at the beginning of pill intake from the next blister-strip pack (containing 21 tablets) [2].

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A wide range of oral contraceptives is now available with different therapeutic profiles to meet the needs of individual women. In addition to the reliability and convenience of oral contraceptives, there is increasing awareness that some contraceptive pills may offer additional benefits to health and general well-being. The monophasic, low-dose combined oral contraceptive chlormadinone acetate (CMA) 2.0 mg and ethinylestradiol (EE) 0.03 mg (Belara®, Balanca®) has been shown in clinical trials and non-interventional, observational studies to provide high-level cycle stability, pronounced anti-androgenic effects and benefits in women with dysmenorrhea and other bleeding disorders [3–8]. A non-pooled analysis of the emotional symptom “depressive mood” in four prospective, non-interventional, observational studies of approximately 50,000 women investigated the effects of CMA/EE intake on psychological symptoms and emotional well-being. The results provided clinical evidence of beneficial psychotropic effects, with a notable and statistically significant mood balancing impact on women suffering from depressive mood [9]. The six-cycle observational study reported here was designed to investigate cycle-related emotional and physical symptoms in a selected group of women ≥25 years of age. As the only inclusion criterion was age, a subgroup of women reporting at least one cycle-related physical symptom and at least one cycle-related emotional symptom was created to provide further data on the effects of CMA/EE in women with both physical and emotional symptoms. The aim of this study was to investigate the influence of CMA/EE on intensity and frequency of cycle-related physical and emotional disorders that are highly relevant to the patient but often remain underreported in medical literature. The clinical efficacy and tolerability of CMA/EE in women with both preexisting physical and emotional disorders were also evaluated. 2. Materials and methods

regimen (two to six blister-strip packs, followed by a 7-day pill-free interval). The study was conducted according to the German Drug Law and the quality standards issued by the German Health Authority. 2.2. Efficacy and tolerability evaluation At baseline, demographic and morphometric data were documented, along with age, previous hormonal contraception and thromboembolic risk factors (e.g., obesity, smoking, family history of thromboembolic disease). Efficacy parameters were incidence and intensity of 11 physical symptoms and nine emotional symptoms (Table 1). The documentation comprised cyclic recurrent symptoms during the previous 3 months before baseline visit and during the last 4 weeks before final visit as reported by the patient. Each symptom was ranked according to intensity (“no”, “mild”, “moderate” or “severe”), except for amenorrhea (“yes”/“no”). For the 11 physical disorders and nine emotional disorders, a “sum score” that encompassed the number and intensity of symptoms per patient was used. The underlying assumption was a parity of relevance between all symptoms. A physical, an emotional and a total sum score were used on the basis of four response options (0=“no”, 1=“mild”, 2=“moderate”, 3=“severe”). For amenorrhea, the response option was simply 0 (“no”) or 1 (“yes”). Changes in physical and emotional symptoms were evaluated for the total study population and the subgroup of women reporting at least one preexisting cycle-related physical symptom and one cycle-related emotional symptom at baseline visit, defined as follows: • existence of one or more cycle-related physical symptoms with at least “mild” intensity: ○ headache/migraine, flatulence/dyspepsia, breast tenderness/mastodynia, back pain, (lower) abdominal pain, edema, lack of concentration, sleep disorders, change in appetite and

2.1. Study subjects and design This prospective, non-interventional, observational study collected data from January to December 2006 from 303 office-based gynecological centers throughout Germany, from 3772 women aged ≥25 years who wanted contraception, over six cycles. All participating investigators observed and documented the intake of 2.0 mg CMA/0.03 mg EE during a 6-month period. Two investigations were carried out and documented: one at baseline and the other at the end of the 6-month observation period. The conventional cycle regimen for CMA/EE [21-day pill intake (one blister-strip pack) followed by a 7-day pill-free interval] was used by 3578 (94.9%) women, but this observational study also included 194 (5.1%) women who used an extended cycle

Table 1 Physical and emotional efficacy parameters Physical symptoms Breast tenderness/mastodynia Headache/migraine Tendency towards edema Acne-prone skin Change in appetite (lower) Abdominal pain Back pain Flatulence/dyspepsia Cycle disturbances (e.g., intermenstrual bleeding) Tiredness/asthenia Amenorrhea

Emotional symptoms Depressive mood Mood swings Nervousness/strain Irritability/aggressiveness Loss of energy/excessive demand Anxiety Lack of concentration Decrease of libido Sleep disturbance

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• existence of one or more cycle-related emotional symptoms with at least “mild” intensity: ○

depressive mood, mood swings, nervousness/strain, irritability/aggressiveness, lack of energy/excessive demand, anxiety.

The above symptoms are defined by the American College of Obstetricians and Gynecologists diagnosis of PMS [10] and the ICD-10 criteria for PMS [11]. Further evaluation parameters were contraceptive efficacy (Pearl index) and the occurrence of adverse drug reactions (ADRs) during CMA/EE intake in the total study population. The ADRs were collected using patient feedback, and any worsening of a preexisting cycle-related disorder or any new occurrence was assessed and documented via an electronic safety reporting form; ADRs were coded according to MedDRA® (version 10.0). 2.3. Statistical analysis Design of the case report form (CRF) impacts the quality of data collected. In this observational study, clinical data were gathered via the Internet on the basis of an electronic CRF (eCRF). This process was accompanied by a program-controlled check during data entry to disclose inconsistencies (simultaneous validation). The following methods were used: date specification, plausibility check and consistency check of mutually dependent information. The electronic patient documentation was closed if the entries were complete and consistent, and eCRFs with data collected retrospectively were excluded from all efficacy analyses and only used for the tolerability assessment. The statistical analysis included descriptive procedures. On the basis of Wilcoxon matched-pairs signed-ranks test, descriptive p values were calculated for changes during the observation period for distribution variables, such as cyclerelated physical and emotional symptoms (including sum score). Possible differences in the sample sizes correspond to missing data. Data validation was performed using SPSS for Windows, Release 12.0.2.

(32.69%) showed at least one risk factor for developing a venous thromboembolic event (VTE): smoking was documented in 992 women (26.30%); 136 women (3.61%) had a positive family history of relevant thromboembolic disease, for example, myocardial infarction, apoplexy, deep vein thrombosis and pulmonary embolism; and obesity (BMI N30 kg/m2) was documented in 132 cases (3.50%). Other risk factors, such as hypertension and diabetes mellitus, were reported in 121 women (3.21%). The age distribution of the study population and risk factors in the age patterns are shown in Fig. 1. 3.1.2. Previous contraception and reasons for switching to CMA/EE At baseline, 401 (10.63%) women had never used a hormonal contraceptive before (“starter”); 1850 (49.05%) women had used hormonal contraception N3 months previous to this study (“restarter”); 1519 (40.27%) women had used an OC during the previous 3 months (“switcher”); and previous contraception data for the two (0.05%) remaining women were missing. More than half of these women had taken a monophasic EE preparation, containing 0.02 mg EE (n=204; 13.43%), 0.03 mg EE (n=583; 38.38%) and 0.05 mg EE (n=19; 1.25%) per tablet. The proportion of women taking multi-phasic preparations was 14.94% (n=227). Within the switcher population, approximately one quarter (n=395; 26.00%) had used the previous contraceptive for N5 years. The most frequently documented reasons for switching hormonal contraception to CMA/EE were “additional benefits needed (e.g., for skin)” (n=649; 42.73%), “no sufficient improvement of cycle-related disorders/bleeding irregularities” (n=494; 32.52%) and “lack of tolerability” (n=430; 28.31%). A total of 392 women (10.39%) switched to or restarted with CMA/EE after pregnancy/breast-feeding; in these patients, the CMA/ EE contraception was started after a median of 4.24 months following childbirth.

3. Results 3.1. Baseline characteristics A total of 3792 women participated in this observational study (safety population); 20 women were excluded due to the following reasons: retrospective documentation (n=3), patient b25 years (n=14) and ADR but incorrect completion of the eCRF (n=3). The efficacy population, therefore, comprised a total of 3772 patients. 3.1.1. Age and thromboembolic risk factors The efficacy population was between 25 and 60 years [mean (SD) age, 32.6 (±5.98) years], with 522 (13.84%) women ≥40 years of age. At study entry, 1233 patients

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Fig. 1. Age distribution and risk factors at baseline.

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3.1.3. Physical and emotional symptoms at baseline Before starting treatment with CMA/EE, 3452 (91.52%) women reported at least one cycle-related physical or emotional symptom of mild, moderate or severe intensity. The most frequently reported preexisting disorders were acne-prone skin (n=2480; 65.75%) and mood swings (n=1776; 47.08%). One or more physical symptoms were documented in 3372 cases (89.40%), and 2457 women (65.14%) admitted the existence of at least one cycle-related emotional symptom. Taking the clinical relevance of symptoms into consideration, “mild” symptoms were not included in the subgroup analysis, which focused on women who graded their symptoms “moderate” or “severe” (except for the amenorrhea question, which could only be answered as “yes” or “no”). On the basis of this severity code, Figs. 2 and 3 reflect the frequencies of the most commonly reported cycle-related symptoms. Further cycle-related disorders of mild to severe intensity that are not illustrated include tendency towards edema (n=1011; 26.80%), back pain (n=813; 21.55%), tiredness/asthenia (n=876; 23.22%), change in appetite (n=788; 20.89%), flatulence/dyspepsia (n=677; 17.95%), sleep disorders (n=1009; 26.75%), lack of concentration (n=880; 23.33%) and anxiety (n=517; 13.71%). 3.2. Contraceptive efficacy The total number of observed cycles was 21,642.25 for both conventional cycle regimen (20,707 cycles) and extended cycle regimen (363 extended cycles=935.25 cycle equivalents at 28 days), with an observation period of 1665 women-years (based on 13 cycles/cycle equivalents at 28 days). The conventional cycle regimen for CMA/EE [21-day pill intake (one blister-strip pack) followed by a 7day pill-free interval] was used by 3578 (94.9%) women, with only a minority of women (n=194; 5.14%) using an extended cycle regimen with a consecutive pill intake of two to six (most often three) blister-strip packs of CMA/EE (n=116; 59.79%) followed by a 7-day pill-free interval.

Fig. 2. Number of patients with preexisting cycle-related physical symptoms at baseline (multiple entries were possible).

Fig. 3. Number of patients with preexisting cycle-related emotional symptoms at baseline (multiple entries were possible).

A total of 3276 (86.85%) women declared regular intake of CMA/EE, whereas the remainder missed at least one (n=369) or more (n=127) tablets per cycle/blister-strip packs. Despite these irregularities, no pregnancy occurred during CMA/EE treatment. This resulted in a Pearl index of 0 (95% confidence interval=0.00–0.22). 3.3. Changes in cycle-related symptoms 3.3.1. Total study population After a median of 5.85 months (6 complete cycles), changes in cycle-related physical and emotional symptoms were evaluated. As a result of CMA/EE intake, the total sum score of number and intensity of symptoms was reduced from 8.67 points at baseline to 2.83 points at final visit, with a mean decrease of 3.35 points (change at final visit vs. baseline: p≤.001), equivalent to a 67% overall reduction in symptoms following CMA/EE intake. The separate total sum score for physical symptoms was reduced from 4.86 (baseline) to 1.51 (final visit), resulting in a mean reduction of 3.35 (p≤.001) and, for emotional symptoms, decreased

Fig. 4. Changes in physical symptoms after 6 cycles of CMA/EE treatment.

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symptom), which resolved in 354/371 (95.42%; p≤.001) women, and anxiety (emotional symptom), with 360/517 (69.63%; p≤.001) women being symptom-free at final visit. All symptoms (breast tenderness, headache, tendency towards edema, acne-prone skin, change in appetite, abdominal pain, back pain, flatulence, cycle disturbances, tiredness, amenorrhea, depressive mood, mood swings, nervousness, irritability, lack of energy, anxiety, lack of concentration, decreased libido and sleep disturbance) showed a statistically significant decrease in number and intensity during CMA/EE treatment (p≤.001: change at final visit vs. baseline).

Fig. 5. Changes in emotional symptoms after 6 cycles of CMA/EE treatment.

from 3.81 at baseline to 1.32 at final visit. This implies a mean reduction of 2.48 (p≤.001). Figs. 4 and 5 exemplify the relative numbers of patients with physical and emotional symptoms at baseline (mild, moderate or severe) that increased, remained unchanged, decreased or had completely gone by the final visit. A decrease/increase in symptom was declared if the scoring changed from “severe” to at least “moderate” or from “moderate” to “mild”, and vice versa. The cycle-related symptoms with the highest-resolution rates following CMA/EE intake were amenorrhea (physical

3.3.2. Subgroup of women reporting at least one cyclerelated physical and one cycle-related emotional symptom Within the population of 2039 women (54.06%) who reported at least one cycle-related physical and one cyclerelated emotional symptom at baseline, treatment with CMA/ EE resulted in a marked reduction in cycle-related physical and emotional symptoms, particularly those of moderate to severe intensity. Table 2 provides a comparison between the number of women suffering moderate to severe symptoms in the 3 months prior to intake of CMA/EE and during the last 4 weeks of CMA/EE intake for 6 cycles. 3.4. Tolerability ADRs, as a reason for stopping CMA/EE, were documented in only 104 women (2.76%). A total of 576 (15.27%) women stopped using CMA/EE after six cycles or

Table 2 Women with at least one cycle-related physical and one cycle-related emotional symptom at baseline (N=2039; 100%); number of women with moderate or severe symptoms at baseline and after six cycles of CMA/EE intake Moderate/severe intensity, baselinea, n (%)

Moderate/severe intensity, final visitb, n (%)

No symptoms/mild intensity, final visitb, n (%)

Physical symptoms Acne-prone skin Headache/migraine Breast tenderness/mastodynia Cycle disturbances (e.g., intermenstrual bleeding) (lower) Abdominal pain Back pain Edema Change in appetite Amenorrhea Tiredness/asthenia Flatulence/dyspepsia

915 (44.87) 411 (20.16) 405 (19.86) 393 (19.27) 311 (15.25) 242 (11.87) 225 (11.03) 224 (10.99) “yes”: 214 (10.50) 203 (9.96) 137 (6.72)

63 (3.09) 54 (2.65) 36 (1.77) 35 (1.72) 15 (0.74) 17 (0.83) 21 (1.03) 45 (2.21) “yes”: 63 (3.09) 20 (0.98) 13 (0.64)

1976 (96.91) 1985 (97.35) 2003 (98.23) 2004 (98.28) 2024 (99.26) 2022 (99.17) 2018 (98.97) 1994 (97.79) “no” 1976 (96.91) 2019 (99.02) 2026 (99.36)

Emotional symptoms Mood swings Decreased libido Irritability/aggressiveness Nervousness/strain Depressive mood Loss of energy/excessive demand Sleep disorders Lack of concentration Anxiety

501 (24.57) 463 (22.71) 393 (19.27) 387 (18.98) 358 (17.56) 337 (16.53) 294 (14.42) 173 (8.48) 136 (6.67)

43 (2.11) 52 (2.55) 38 (1.86) 42 (2.06) 32 (1.57) 29 (1.42) 27 (1.32) 18 (0.88) 20 (0.98)

1996 (97.89) 1987 (97.45) 2001 (98.14) 1997 (97.94) 2007 (98.43) 2010 (98.58) 2012 (98.68) 2021 (99.12) 2019 (99.02)

Symptom

a b

Last 3 months before baseline visit. Last 4 weeks before final visit.

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Table 3 Number of ADRs during CMA/EE® intake, grouped by the primary SOC; the listing covers all SOCs with an absolute frequency of more than 5 ADRs Primary SOCa

Absolute frequency (n)

Relative frequency (%)

Reproductive system and breast disorders (e.g., metrorrhagia, menorraghia, breast discomfort) Nervous system disorders (e.g., headache, migraine) Investigations (weight increased) Gastrointestinal disorders (e.g., abdominal discomfort, diarrhea, nausea) Psychiatric disorders (e.g., libido decreased, mood swings, nervousness) Skin and subcutaneous disorders (e.g., acne, dry skin)

63

1.66

22

0.58

20 11

0.53 0.29

11

0.29

11

0.29

a

treatment. Improvement of cycle-related symptoms and overall well-being was judged as “very good” or “good” in more than 9 out of 10 women (Table 4). 4. Discussion 4.1. Tolerability and efficacy of CMA/EE

MedDRA® coding (version 10.0).

earlier, the main reason being “no longer a need or wish for contraception” (e.g., desire to have a child, change in life situation) (n=319; 8.46%). Based on the safety population (n=3792), 153 ADRs were reported in 123 patients (3.24%). Of these ADRs, 152 were nonserious and one was serious. Despite the high number of women ≥40 years of age and other risk factors, no VTE and no cardiovascular event occurred during the entire observation period. The most frequently reported ADRs are listed in Table 3, grouped according to the primary System Organ Class (SOC). In one woman, a serious ADR (ovarian cyst) and an associated serious adverse event (adnexitis) were reported; however, symptoms indicating the presence of an ovarian cyst had been present before study entry. The diagnosis and operation proceeded during the period of CMA/EE intake. There were no statistically significant weight changes during the observation period; median body weight decreased from 65.0 kg at baseline to 64.0 kg at final visit (p=.147: change at final visit vs. baseline). A total of 1040 women (27.57%) maintained their weight, 1258 (33.35%) lost weight and 1473 (39.05%) gained weight. In the vast majority of women (81.26%), weight gain ranged between 1 and 2 kg (data for one woman were not available). 3.5. General assessment of therapeutic effects At the end of the observation period, both investigators and patients assessed the therapeutic effects of CMA/EE

This prospective observational study provides data on the efficacy and tolerability of CMA/EE in women ≥25 years of age. The study results support previous findings that CMA/EE is an effective and well-tolerated oral contraceptive. Despite missing tablets in nearly 3% of all cycles, the Pearl index was 0. Incidences of ADRs were low (3.24%) and in line with the known tolerability profile of OC treatment [3–8,12]. The results did not allude to any unexpected side effects. Previous findings from other published studies indicate several non-contraceptive benefits for CMA-containing OCs, for example, marked anti-androgenic properties, sustained cycle stability, substantial relief in dysmenorrhea and improvement of breast pain and migraine/headache [3– 8]. The present study provides evidence of the additional benefits of CMA-containing OCs, with regard to a significant reduction in cycle-related physical and emotional disorders; each of the 20 symptoms investigated declined significantly in intensity and number during CMA/EE intake (p≤.001). These beneficial effects of CME/EE were particularly pronounced for symptoms of moderate to severe intensity and in the subgroup of women reporting at least one preexisting cycle-related physical symptom and at least one emotional symptom. Some cycle-related problems, in particular, emotional symptoms, are typically underreported in daily gynecological practice, although the women concerned endure a high degree of suffering [1]. A non-pooled analysis of four prospective, non-interventional, observational studies with nearly 50,000 women showed a clear potential for alleviating depressive mood during use of a CMA-containing oral contraceptive. These results have been confirmed with 4, 6 and 12 treatment cycles [9]. The findings of the present observational study, in which an extended list of emotional and physical parameters was documented, likewise suggest a positive interaction between CMA/EE intake and neurobiological processes, with depressive mood, mood swings, nervousness, irritability, lack of energy, anxiety, lack of concentration, decreased libido and sleep disturbance all

Table 4 Assessment of treatment with CMA/EE after six cycles, concerning effect on physical symptoms, emotional symptoms and well-being

Effect on physical symptoms Effect on emotional symptoms Well-being

Gynecologists' assessment after six cycles of CMA/EE

Patients' assessment after six cycles of CMA/EE

Very good/Good (%)

Moderate (%)

Poor (%)

Very good/Good (%)

Moderate (%)

Poor (%)

95.37 94.20 95.12

4.08 5.36 4.24

0.56 0.45 0.64

93.74 92.9 93.77

5.04 6.20 5.06

1.22 0.90 1.17

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improved, the most pronounced effect being reduction of anxiety. The pathophysiology and control of mood disorders in women are of increasing interest for research worldwide; nevertheless, only a few studies have investigated the consequences of OC treatment on psychophysiological function [9]. Two placebo-controlled studies [13,14] evaluated the efficacy of 3 mg drospirenone/0.02 mg EE, administered for 24 days in a 28-day cycle, in treating depressive mood problems; both analyses exclusively considered symptoms of premenstrual dysphoric disorder (PMDD). Results supported a significant reduction in mood and physical premenstrual symptoms compared with placebo [13,14]. According to the study authors, the longer period of hormone administration and the reduction in the hormonefree interval may have stabilized both endogenous and exogenous hormone levels, thereby possibly decreasing symptom expression. In contrast to the present study, it is not clear whether these results can be generalized to the large cohort of women who do not meet the criteria for PMDD. Evidence-based, controlled clinical studies to compare the effect of CMA/EE with other progestogen/EE combinations on emotional and physical symptoms would be beneficial and may raise the question of different underlying modes of action of the progestogens. 4.2. Is CMA a modulator of psychophysiological function? Further investigation into the positive psychotropic effect of CMA demonstrated in this study, with a conventional cycle regimen intake (21-day pill intake, followed by a 7-day pill-free interval), would be of interest. Investigations into neuropsychological processes have revealed that the brain gamma-aminobutyric type A (GABAA) receptor complex plays a central role in the regulation of mood and cognitive function in the brain: GABAA receptor agonists modulate neuronal activity by causing hyperpolarization of the cell membrane and reducing neuronal firing [15]. The result is a mood-balancing, anxiolytic, anticonvulsant and sedative effect [16]. Individuals with high circulating levels of GABAA-agonistic steroids display a more relaxed personality and have decreased sensitivity to incoming environmental stimuli [17]. Structure analysis compared the molecular profile of the GABAA agonists, allopregnanolone and epipregnanolone, with the progesterone derivative, CMA, and its metabolites. There was a noticeable congruence between epipregnanolone and the CMA metabolite 5 (M-V), with both steroids displaying almost the same molecular structure. Further investigations into the interaction between GABAA receptors and CMA (CMA metabolites) and of other modes of action are ongoing. 5. Conclusions The results of this 6-month, prospective, observational study provide corroborating evidence for the reliable

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contraceptive efficacy and an excellent tolerability profile of 2.0 mg CMA/0.03 mg EE (Belara®, Balanca®). Interestingly, CMA/EE also provided non-contraceptive benefits on multiple, cycle-related, physical and emotional symptoms that exceeded the well-known positive effects on skin, cycle stability and dysmenorrhea. In addition to alleviation of headache, dyspepsia, mastodynia, tendency towards edema, lack of concentration, sleep disturbance and change in appetite, there is evidence to suggest that CMAcontaining contraceptives also have psychophysiological effects. Women with the respective preexisting symptoms may, therefore, benefit from CMA/EE contraceptive treatment. Further research is warranted. Acknowledgment The study was conducted and sponsored by Grünenthal GmbH, Germany. The authors would like to thank all of the 303 participating investigators. References [1] Society of Consumer Goods Research (Gesellschaft für Konsumgüterforschung). Survey on prevalence of depressive mood and other psychical disorders in German women. Dec 2005–Jan 2006. unpublished. [2] Sangthawan M, Taneepanichskul S. A comparative study of monophasic oral contraceptives containing either drospirenone 3 mg or levonorgestrel 150 microg on premenstrual symptoms. Contraception 2005;71:1–7. [3] Bock K, Heskamp ML, Schramm G. Influence of chlormadinone acetate on dysmenorrhea and other cycle-related complaints (original in German language). Gyne 2008;8:219–25. [4] Schramm G, Steffens D. Contraceptive efficacy and tolerability of chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (Belara®). Clin Drug Invest 2002;22:221–31. [5] Schramm G, Steffens D. A 12-month evaluation of the CMAcontaining oral contraceptive Belara®: efficacy, tolerability and antiandrogenic properties. Contraception 2003;67:305–12. [6] Schramm G, Heckes B. Switching hormonal contraceptives to a chlormadinone acetate-containing oral contraceptive. The Contraceptive Switch Study. Contraception 2007;76:84–90. [7] Zahradnik HP, Goldberg J, Andreas JO. Efficacy and safety of the new antiandrogenic oral contraceptive Belara®. Contraception 1998;57: 103–9. [8] Worret I, Arp W, Zahradnik HP, Andreas JE, Binder N. Acne resolution rates: results of a single-blind, randomised, controlled, parallel phase III trial with EE/CMA (Belara®) and EE/LNG (Microgynon®). Dermatology 2001;203:38–44. [9] Huber JC, Heskamp MLS, Schramm GAK. Effect of an oral contraceptive with chlormadinone acetate on depressive mood. Analysis of data from four observational studies. Clin Drug Invest 2008;28:783–91. [10] American College of Obstetricians and Gynecologists (ACOG). Premenstrual syndrome. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2000 [Apr. 9 (ACOG practice bulletin; no. 15) (reaffirmed 2005)]. [11] Connolly M. Premenstrual syndrome: an update on definitions, diagnosis and management. Adv Psychiatr Treat 2001;7:469–77. [12] Merki-Feld GS. Cardiovascular risks associated with low-dose combined oral contraceptives. Ther Umsch 2001;58:564–9.

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[13] Pearlstein TB, Bachmann GA, Zacur HA, et al. Treatment of premenstrual dysphoric disorder with a new drospirenonecontaining oral contraceptive formulation. Contraception 2005; 72:414–21. [14] Yonkers KA, Brown C, Pearlstein TB, et al. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 2005;106:492–501.

[15] Mehta AK, Ticku MK. An update on GABAA receptors. Brain Res Rev 1999;29:196–217. [16] Zinder O, Dar DE. Neuroactive steroids: their mechanism of action and their function in the stress response. Acta Physiol Scand 1999;167: 181–8. [17] Epperson CN, Wisner KL, Yamamoto B. Gonadal steroids in the treatment of mood disorders. Psychosom Med 1999;61:676–97.