Keywords Hirsutism Hyperandrogenism Insulin resistance Oral contraceptive Polycystic ovary syndrome. Introduction

Transcription

1 DOI /s General Gynecology Comparison of two oral contraceptive forms containing cyproterone acetate and drospirenone in the treatment of patients with polycystic ovary syndrome: a randomized clinical trial Korhan Kahraman Yavuz Emre Şükür Cem Somer Atabekoğlu Can Ateş Salih Taşkın Şerife Esra Çetinkaya Harun Egemen Tolunay Batuhan Özmen Murat Sönmezer Bülent Berker Received: 8 June 2013 / Accepted: 14 March 2014 Springer-Verlag Berlin Heidelberg 2014 Abstract Purpose To compare the effects of combined oral contraceptives (OCs) containing cyproterone acetate and drospirenone in the treatment of polycystic ovary syndrome (PCOS). Methods Fifty-two patients with PCOS were randomized in two groups: group A (n = 26) received mg ethinyl estradiol + 2 mg cyproterone acetate and group B (n = 26) received 0.03 mg ethinyl estradiol + 3 mg drospirenonecontaining OCs for 12 months. Baseline clinical features including body mass index, waist to hip ratio (WHR), and modified Ferriman-Gallwey (mfg) score were noted. Baseline biochemical parameters included androgen profile, carbohydrate metabolism, lipid profile, and oxidative stress. The percentages of changes for all parameters were compared. Results The groups were comparable regarding the baseline characteristics. WHR decreased significantly from baseline ( 4 % [ 31 to 35]) in group B when compared to group A (0 % [ 11 to 14]) (P = 0.033). The total mfg score decreased significantly from baseline ( 35 % [ 71 to 10]) in group A when compared to group B ( 18 % [ 72 to 30]) (P = 0.035). Changes in androgen hormone profile were comparable except DHEA-SO 4 ( 32 % [ 53 to 15] in group B vs. 10 % [ 49 to 63] in group A; K. Kahraman Y. E. Şükür (*) C. S. Atabekoğlu S. Taşkın Ş. E. Çetinkaya H. E. Tolunay B. Özmen M. Sönmezer B. Berker Kadın Hastalıkları ve Doğum Anabilim Dalı, Ankara Üniversitesi Tıp Fakültesi Cebeci Hastanesi, Cebeci, Ankara, Turkey yesukur@yahoo.com C. Ateş Department of Biostatistics, Ankara University School of Medicine, Ankara, Turkey P = 0.046). The effects of the drugs were similar regarding carbohydrate metabolism, lipid profile, and oxidative stress parameters. Conclusions Cyproterone acetate containing OCs seem to be more effective to treat clinical hirsutism in patients with PCOS after 12 months of treatment. Keywords Hirsutism Hyperandrogenism Insulin resistance Oral contraceptive Polycystic ovary syndrome Introduction Polycystic ovary syndrome (PCOS) is one of the most common gynecologic-endocrine disorders of reproductive age women, affecting approximately 5 10 % [1, 2]. It is accepted that PCOS is a complex genetic disease and characterized by hyperandrogenism, chronic oligo/anovulation, and insulin resistance (IR) which clinically may result in menstrual irregularities, hirsutism, acne, infertility and increased risk for diabetes mellitus, cardiovascular disease, and endometrial cancer [3, 4]. The primary etiology of PCOS is unknown [5]. However, IR with hyperinsulinism may have a crucial pathophysiological role in hyperandrogenism of patients with PCOS [6]. Hyperinsulinemia stimulates both ovarian and adrenal androgen production and decreases sex hormone binding globulin (SHBG) synthesis from liver. The increased ovarian androgen levels cause premature follicular atresia and anovulation [7]. Dyslipidemia is also another frequent finding in patients with PCOS independently of the presence of excess weight gain [8, 9]. Combined oral contraceptives (OCs) used in the treatment of PCOS ensure regular menstrual cycles and reduce androgenicity. Combined OCs can also minimize insulin

2 sensitivity [10, 11]. The estrogen component increases the SHBG and therefore free testosterone levels are decreased [12]. The progestin component inhibits 5α-reductase activity and also acts as antagonist at the androgen receptors [13 15]. In the present study, we compared the effects of two different combined OCs on clinical and biochemical findings of androgen, carbohydrate, and lipid metabolisms in 39 patients with PCOS during a 12-month therapy. These two combined OCs both included ethinyl estradiol (EE) with slightly different dosages and two different forms of anti-androgenic progestins. The OCs analyzed in the present study composed of mg EE + 2 mg cyproterone acetate and 0.03 mg EE + 3 mg drospirenone, respectively. Materials and methods Study design A randomized clinical trial was conducted after obtaining ethical approval from the ethics committee of Ministry of Health of the Republic of Turkey (No. of approval: B-10-0-İEG /2010). cyproterone acetate and drospirenone-containing pills for treatment of PCOS, and to guide us in terms of pre-study power analysis. So, sample size estimation based on to detect a difference of 10 % between the two groups was performed using a two-sided Mann Whitney test. Group sample sizes of 16 and 16 achieved 81 % power with a significance level (alpha) of 0.05 to detect a 10 % difference. The sample sizes were calculated by the package PASS 11; NCSS, LLC [18]. Randomization Figure 1 shows the flowchart of patients assessed, excluded, randomized, treated, and followed up. During the study period, 74 patients with PCOS were assessed for eligibility. However, 13 patients did not meet the inclusion criteria and nine patients refused to participate to the study. After obtaining informed consent, all included patients (n = 52) were randomized into two treatment groups using a computer-generated randomization model. There were two treatment groups: group A (n = 26) received mg EE + 2 mg cyproterone acetate (Diane-35; Schering AG, Istanbul, Turkey) and group B (n = 26) received 0.03 mg Trial population Participants were recruited at the gynecology out-patients clinic of a university-based tertiary care hospital between January 2011 and December PCOS was diagnosed according to the criteria of the Androgen Excess Society, 2006 (hirsutism/hyperandrogenemia and oligo-anovulation/ polycystic ovaries and exclusion of other androgen excess or related disorders) [16]. Patients (age range: years) with oligo-amenorrhea and/or polycystic ovaries diagnosed by ultrasonography and hirsutism and/or laboratory hyperandrogenism were enrolled in the study. Oligomenorrhea was defined as menstrual periods occurring at intervals of >35 days. Hirsutism was defined as 8 at modified Ferriman Gallwey (mfg) scoring system [17]. Laboratory hyperandrogenism was defined as increased levels of free testosterone, DHEA-SO 4, androstenedione and/or increased free androgen index (FAI). The exclusion criteria were presence of any systemic disease associated with hyperinsulinism and hyperandrogenism such as diabetes mellitus, cushing syndrome, congenital adrenal hyperplasia, hyperprolactinemia, and hypothyroidism. Patients who have contraindications to combined OCs and who had history of OC usage within the past 6 months were also excluded. Allocated to Group A (EE+cyproterone acetate) n=26 Discontinuation (n=7) Unwillingness to therapy (n=4) Weight gain (n=2) Breast tenderness (n=1) Assessed for eligibility (n=74) Excluded (n=22) Not meeting the inclusion criteria (n=13) -Hypothyroidism (n=6) - Hyperprolactinemia (n=1) -Age < 18 years (n=3) -OC therapy within 6 months (n=3) Unwillingness to participate (n=9) Allocated to Group B (EE+drospirenone) n=26 Discontinuation (n=6) Unwillingness to therapy (n=3) Removal (n=2) Nausea (n=1) Sample size calculation After 12 months of therapy n=19 After 12 months of therapy n=20 While planning the present study, we were not able to detect any studies in the english literature that compared Fig. 1 Flowchart of the study

3 EE + 3 mg drospirenone (Yasmin; Schering AG, Istanbul, Turkey). All of the patients were advised to take a pill daily for 21 days followed by a 7-day rest and to continue the pills for 12 cycles. Seven of 26 patients in group A and six of 26 patients in group B discontinued to the study at the end of 12 months because of adverse effects and some non-medical reasons such as unwillingness to therapy and removal to a different city. The adverse effects that caused discontinuation were weight gain (n = 2) and breast tenderness (n = 1) in group A and nausea (n = 1) in group B. Study protocol A detailed history including menstrual cycles and past medical history was taken. Physical and gynecological examinations with transvaginal and/or abdominal ultrasonography for ovaries were performed during the first visit. Hirsutism scoring by mfg scoring system and acne scoring with a five-category Global Acne Scoring System were performed [19]. These scoring procedures were performed by only two clinicians before and after the treatment period. During mfg scoring, nine body areas were scored from 1 (minimal terminal hairs present) to 4 (equivalent to a hairy man), for a maximum score of 36 [17]. Acne scoring categories were in order of 0, clear; 1, almost clear; 2, mild; 3, moderate and 4, severe [19]. Body weight and height of patients were measured with loose clothes and without shoes and body mass index (BMI) was calculated as weight/height 2 (kg/m 2 ). Waist to hip ratio (WHR) was also calculated for each patient. Blood samples were taken for lipid profile including total cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL), high density lipoprotein (HDL), triglyceride, apolipoprotein A, apolipoprotein B, lipoprotein A, and C-peptide. Fasting blood glucose and insulin, 2-h postprandial glucose level after 75 g oral glucose tolerance test, and insulin-like growth factor 1 (IGF-1) were also obtained for carbohydrate metabolism. Cycle day 3 hormone profile included follicle-stimulating hormone, luteinizing hormone, thyroid stimulating hormone, prolactin, free and total testosterone, SHBG, androstenedione, dehydroepiandrosterone sulfate, and 17-OH progesterone. High sensitive C-reactive protein (hs-crp) and homocysteine levels were also measured as oxidative stress markers. All of the blood samples were repeated after 12 months of treatment. There were two tests which were not performed routinely in our laboratory; SHBG and androstenedione. SHBG was measured by IRMA (immunoradiometric assay) technique (R-CC-100) (ZenTech S.A., Angleur, Belgium). Androstenedione was measured by RIA (radioimmunoassay) technique (KIP0451) (DIAsource Immunoassays S.A., Nivelles, Belgium). The formula used in the calculation of FAI was total testosterone (ng/ml)/shbg (nmol/l) The formula used in the calculation of homeostatic model assessment-insulin resistance (HOMA-IR) was fasting glucose (mg/dl) fasting insulin (μiu/ml)/405. Statistical analyses Shapiro Wilk test was used to test distribution of normality. According to the results, non-parametric tests were preferred. To evaluate the differences between two timedependent measurements, we calculated percent of change in terms of ratios. These ratios and variables severally compared among two groups using Mann Whitney U test. General descriptive statistics were summarized as median (min max). Statistical package for social sciences (SPSS) 15.0 for Windows was used for all these statistical analyses and P value of <0.05 was considered as statistically significant. Results There were 39 patients after 12 months of treatment who completed the study; 19 patients in group A (cyproterone acetate) and 20 patients in group B (drospirenone). The baseline clinical and biochemical features of the patients are listed in Table 1. No statistically significant differences were seen between the two groups in the median age, BMI, WHR, mfg hirsutism scores, or global acne assessment scores. There were no patients with hyperprolactinemia, hypothyroidism and/or any systemic disease in either group. The initial biochemical parameters regarding androgen metabolism, carbohydrate metabolism, and lipid profile are also listed in Table 1. There were no statistically significant differences in between the groups regarding day 3 hormone profile, androgen levels, FAI, and SHBG levels. The groups were also statistically comparable regarding the carbohydrate and lipid metabolisms which were tested by fasting blood glucose, insulin, C-peptide, 75 g OGTT, HOMA-IR, IGF-1, cholesterol, triglyceride, and lipoprotein measurements (Table 1). The groups were also comparable in the means of oxidative stress which was assessed by hs-crp and homocysteine measurements (Table 1). The percentages of change in the clinical features after 12 months of treatment are listed in Table 2. The percentages of change in BMI were similar in both groups ( 1 % [ 12 to 6] vs. 1 % [ 9 to 17], respectively; P = 0.789). However, WHR decreased significantly from baseline ( 4 % [ 31 to 35]) in group B when compared to the change in group A (0 % [ 11 to 14]) (P = 0.033). There were no statistically significant percentages of change in between the groups regarding mfg scores except the upper

4 Table 1 Comparison of baseline clinical and biochemical characteristics of patients between the study groups BMI body mass index, WHR waist to hip ratio, mfgscoring modified Ferriman-Gallwey scoring, GASS global acne scoring system, FSH follicle-stimulating hormone, LH luteinizing hormone, TSH thyroid stimulating hormone, DHEA-SO 4 dehydroepiandrosteron sulfate, FAI free androgen index, SHBG sex hormone binding globulin, OGTT oral glucose tolerance test, HOMA-IR homeostatic model assessment-insulin resistance, IGF-1 insulin-like growth factor-1, HDL high density lipoprotein, LDL low density lipoprotein VLDL very low density lipoprotein, hs-crp high sensitive C-reactive protein a Values are given as median (minimum maximum) Group A (n = 19) a Group B (n = 20) a P Clinical parameters Age (years) 21 (18 23) 21.5 (19 34) BMI (kg/m 2 ) ( ) ( ) WHR 0.74 ( ) 0.75 ( ) mfg scoring Upper lip 2 (0 4) 2 (1 3) Chin 3 (0 4) 2 (0 3) Chest 2 (0 3) 1.5 (0 4) Upper abdomen 2 (0 4) 1.5 (0 4) Lower abdomen 3 (0 4) 3 (1 4) Forearm 2 (0 4) 2 (0 3) Thigh 2 (0 4) 2 (1 4) Upper back 1 (0 3) 2 (0 3) 1 Lower back 2 (0 4) 2 (0 3) Total 18 (8 30) 16.5 (8 28) GASS 1 (0 4) 1.5 (0 3) Biochemical parameters FSH (miu/ml) 5.41 ( ) 6.19 ( ) LH (miu/ml) ( ) 9.90 ( ) Estradiol (pg/ml) 48 (30 141) 75.5 (20 276) Prolactin (ng/ml) 12.0 ( ) 16.5 ( ) TSH (μiu/ml) 1.70 ( ) 1.69 ( ) OH progesterone (ng/ml) 1.1 ( ) 1.4 ( ) DHEA-SO 4 (μg/dl) 227 ( ) 231 ( ) Androstenedione (ng/ml) 4.18 ( ) 4.97 ( ) Total testosterone (ng/dl) 49.6 ( ) 55.1 ( ) Free testosterone (pg/ml) 2.40 ( ) 2.20 ( ) FAI 3.65 ( ) 3.97 ( ) SHBG (nmol/l) 40.1 ( ) 55.9 ( ) Fasting glucose (mg/dl) 76 (64 87) 78 (72 86) g OGTT 120 min (mg/dl) 80 (56 120) 87.5 (55 134) HbA1c (%) 5.3 ( ) 5.2 ( ) Fasting insulin (μiu/ml) 13.0 ( ) 15.9 ( ) C-Peptide (ng/ml) 1.79 ( ) 1.71 ( ) HOMA-IR 2.95 ( ) 3.21 ( ) IGF-1 (ng/ml) 326 (93 479) 318 ( ) Total cholesterol (mg(dl) 158 ( ) 173 ( ) HDL (mg(dl) 53 (34 91) 56.5 (31 75) LDL (mg(dl) 90 (44 180) 102 (53 146) VLDL (mg(dl) 12 (4 34) 14 (7 43) Triglyceride (mg(dl) 60 (19 170) 75 (35 217) Apolipoprotein A (g/l) 1.36 ( ) 1.41 ( ) Apolipoprotein B (g/l) 0.65 ( ) 0.62 ( ) Lipoprotein A (g/l) ( ) ( ) Homocysteine (μmol/l) ( ) ( ) hs-crp 1.21 ( ) 0.93 ( ) abdomen and total scores (Table 2). The upper abdomen mfg score significantly decreased from baseline ( 33 % [ 100 to 0]) in group A when compared to the change in group B (0 % [ 75 to 200]) (P = 0.022). Also, the total mfg score decreased significantly from baseline ( 35 % [ 71 to 10]) in group A when compared to the change in

5 Table 2 Effects of treatment methods on clinical features after 12 months Italic values show significant difference BMI body mass index, WHR waist to hip ratio, mfg scoring modified Ferriman-Gallwey scoring, GASS global acne scoring system a Values are given as median (minimum maximum) group B ( 18 % [ 72 to 30]) (P = 0.035). The percentages of change in acne scoring were also similar in both groups (Table 2). Table 3 summarizes the percentages of change in the biochemical parameters after 12 months of treatment. There were no statistically significant different effects on day 3 hormone profile, androgen levels, FAI, and SHBG levels except DHEA-SO 4. DHEA-SO 4 levels decreased significantly from baseline ( 32 % [ 53 to 15]) in group B when compared to the decrease in group A ( 10 % [ 49 to 63]) (P = 0.046). There were no statistically significant percentages of change in between the groups regarding carbohydrate metabolism parameters including fasting glucose, 2-h postprandial glucose, HbA1c, fasting insulin, C-peptide, HOMA-IR, and IGF-1 (Table 3). The percentages of change in lipid profile parameters such as cholesterol and lipoprotein subtypes were also similar in between the groups (Table 3). There were no statistically significant percentages of change in between the groups regarding oxidative stress parameters including homocysteine and hs- CRP (Table 3). Discussion Group A (n = 19) a % change Group B (n = 20) a % change BMI 1 ( 12 to 6) 1 ( 9 to 17) WHR 0 ( 11 to 14) 4 ( 31 to 35) mfg scoring Upper lip 50 ( 100 to 100) 33 ( 100 to 100) Chin 33 ( 100 to 0) 50 ( 100 to 0) Chest 50 ( 100 to 50) 0 ( 100 to 100) Upper abdomen 33 ( 100 to 0) 0 ( 75 to 200) Lower abdomen 33 ( 100 to 200) 0 ( 66 to 100) Forearm 33 ( 100 to 0) 33 ( 66 to 100) Thigh 33 ( 100 to 50) 0 ( 100 to 100) Upper back 33 ( 100 to 100) 50 ( 100 to 100) Lower back 50 ( 100 to 0) 33 ( 66 to 100) Total 35 ( 71 to 10) 18 ( 72 to 30) GASS 50 ( 100 to 100) 66 ( 100 to 0) In the present study the beneficial and adverse effects of two different OCs with cyproterone acetate and drospirenone were compared. As a result, both drugs had P similar effects on lipid profile, carbohydrate metabolism, and oxidative stress parameters. However, cyproterone acetate was found to be more effective to treat hirsutism and drospirenone was found to be more effective to decrease WHR. Androgenicity and hirsutism Both the estrogen and progestin components of the OCs are known to be effective in the treatment of hyperandrogenism. Estradiol increases SHBG levels by stimulating hepatic SHBG synthesis and therefore decreases the circulating free androgen levels [20]. Also, the progestin components of OCs can decrease ovarian androgen synthesis by suppressing gonadotropin release [20]. The OCs also cause a slight reduction in adrenal androgen secretion and a slight blockage in the binding of androgens to their receptors [21]. However, some progestins included in OCs also have androgenic capacity. Cyproterone acetate and drospirenone are the two main anti-androgenic progestins included in OCs. Both of the drugs block peripheral androgen receptors at target organs and cyproterone acetate also increases the hepatic clearance of androgens [22 24]. Previously, Guido et al. [25] concluded that drospirenone may have a more prominent effect on SHBG levels than cyproterone acetate. However, Batukan et al. [20] found similar effects of both drugs on SHBG levels in their study which included 91 hirsute women with or without PCOS. In the recent article which was published after our study had started drospirenone, cyproterone acetate, and desogestrel containing OCs were compared in PCOS patients [26]. The authors reported the maximum increase of SHBG in the cyproterone acetate group and the increase was statistically significant when compared to desogestrel. They also reported that cyproterone acetate showed a statistically significant reduction in FAI when compared to desogestrel. According to that study, cyproterone acetate showed a statistically significant reduction in mfg score when compared to both drospirenone and desogestrel [26]. The results of our study support this finding, as cyproterone acetate reduced the mfg score significantly. The difference was more prominent in the upper abdominal area. This increased effect of OCs on upper abdominal hirsutism was also reported previously in two different studies, with OCs including drospirenone [27, 28]. Although it is not statistically significant, we also found a prominent increase in SHBG levels with cyproterone acetate. Certain studies in the literature have shown the effect of combined OCs on adrenal gland [29 31]. Falsetti and Galbignani [29] concluded that cyproterone acetate has an inhibitory effect on adrenal gland function. However, Batukan et al. [20] could not show a significant decline of serum DHEA-SO 4 with neither cyproterone acetate

6 Table 3 Effects of treatment methods on biochemical parameters after 12 months Italic values show significant difference FSH follicle-stimulating hormone, LH luteinizing hormone, DHEA-SO 4 dehydroepiandrosteron sulfate, FAI free androgen index, SHBG sex hormone binding globulin, OGTT oral glucose tolerance test, HOMA-IR homeostatic model assessment-insulin resistance IGF-1 insulin-like growth factor-1 HDL high density lipoprotein LDL low density lipoprotein, VLDL very low density lipoprotein, hs-crp high sensitive C-reactive protein a Values are given as median (minimum maximum) Group A (n = 19) a % change Group B (n = 20) a % change P FSH 35 ( 95 to 66) 9 ( 99 to 152) LH 37 ( 98 to 128) 55 ( 100 to 76) Estradiol 33 ( 85 to 123) 41 ( 89 to 365) DHEA-SO4 10 ( 49 to 63) 32 ( 53 to 15) Androstenedione 18 ( 47 to 52) 29 ( 100 to 25) Total testosterone 16 ( 78 to 125) 39 ( 84 to 43) Free testosterone 42 ( 79 to 164) 50 ( 77 to 85) FAI 77 ( 97 to 510) 79 ( 96 to 56) SHBG +270 (31 to 1,062) +178 ( 57 to 897) Fasting glucose +0 ( 10 to 18) +0 ( 15 to 6) g OGTT 120 min +17 ( 23 to 76) +5 ( 42 to 66) HbA1c +0 ( 10 to 12) 1 ( 10 to 5) Fasting insulin 0 ( 82 to 128) +7 ( 85 to 223) C-Peptide +0 ( 55 to 4,700) +3 ( 33 to 144) HOMA-IR 18 ( 80 to 462) +2 ( 71 to 216) IGF-1 20 ( 66 to 428) 28 ( 77 to 41) Total cholesterol +11 ( 17 to 79) +7 ( 13 to 59) HDL +16 ( 45 to 46) +5 ( 42 to 45) LDL +5 ( 16 to 63) +2 ( 30 to 68) VLDL +62 ( 9 to 262) +50 ( 60 to 414) Triglyceride +53 ( 49 to 502) +43 ( 60 to 180) Apolipoprotein A +21 ( 28 to 65) +19 ( 9 to 117) Apolipoprotein B +4 ( 37 to 91) +14 ( 14 to 150) Lipoprotein A 0 ( 50 to 221) +0 ( 62 to 97) Homocysteine +6 ( 32 to 112) 7 ( 57 to 110) hs-crp +174 ( 96 to 2,656) +31 ( 91 to 8,662) nor drospirenone. In the present study, DHEA-SO 4 was decreased by both drugs but, drospirenone was more effective on adrenal gland when compared to cyproterone acetate (P = 0.046). These incompatible results indicate the necessity of more randomized trials. Carbohydrate metabolism and insulin resistance There is still debate on the metabolic effects of OCs. There are some reports suggesting that OCs may aggravate IR [20, 32]. Thus, Batukan et al. suggested combined OC therapy for PCOS patients without IR [20]. Also, Mastorakos et al. [32] reported increased HOMA-IR after 12 months of treatment with both cyproterone acetate and desogestrel and decreased insulin sensitivity index with cyproterone acetate. In addition, they found that cyproterone acetate was associated with hyperinsulinemia. However, these unfavorable effects are not translated into a clinically relevant major impact [32]. Cagnacci et al. [33] reported improved insulin sensitivity with OCs including cyproterone acetate and impaired insulin sensitivity with OCs including desogestrel. Together with these, in the recent meta-analysis, Halperin et al. [34] reported no association between OC usage and fasting glucose, fasting insulin, fasting glucose to insulin ratio, HOMA-IR, and M-value in euglycemic hyperinsulinemic clamp test. WHR and BMI have positive correlation with HOMA, hyperinsulinemia, and IR [33]. As it provides information about both IR and glucose intolerance, OGTT is suggested to be the best simple office test to evaluate PCOS patients [35]. In the present study, there were no significant differences between cyproterone acetate and drospirenone regarding carbohydrate metabolism parameters except WHR. Drospirenone caused a more prominent reduction in WHR when compared to cyproterone acetate ( 4 vs. 0 %, respectively; P = 0.033) and this finding may reflect a decreased IR with drospirenone when compared to cyproterone acetate. However, this finding was not supported by biochemical evaluation as the fasting insulin, C-peptide, and HOMA-IR levels did not change significantly by drospirenone-containing OC. The low number of subjects as a limitation may be the reason of this contradiction. Also, the WHR can be influenced by some variables such as alcohol consumption and physical activity. However, as a limitation of the present study, these

7 parameters could not be documented. In conclusion, the metabolic effects of OCs in PCOS patients require further investigations. Lipid profile In the recent meta-analysis by Halperin et al. [34], OC usage was found to be associated with increased HDL cholesterol and triglyceride levels. However, it was not associated to changes in total cholesterol and LDL cholesterol levels [34]. Mastorakos et al. [36] compared desogestrel and cyproterone acetate containing OCs in PCOS patients after 12 months of follow-up [34]. They found that total cholesterol and LDL increased in both groups. They reported similar impacts on lipid profile, although the cyproterone acetate containing OCs increased levels of triglycerides more. Drospirenone-containing OCs were also associated with increased total cholesterol, triglyceride, VLDL and HDL levels and decreased LDL levels [25, 28, 37, 38]. Our results were in accordance with the literature as triglyceride and VLDL levels were increased almost 50 % with both cyproterone acetate and drospirenone-containing OCs. The changes in other lipid profile parameters were less (Table 3). We also found that, the impact of both drugs on lipid profile did not show any statistically significant difference. Oxidative stress Alteration of inflammatory status in combined OC users can affect the risk of cardiovascular diseases (CVD) and venous thromboembolism [39]. In various studies, there was a raise in hs-crp with OCs that represents increased low grade inflammatory status and metabolic and cardiovascular risks [39 41]. In the present study, we also found prominent increases of hs-crp in both groups. However, the difference between the impacts of cyproterone acetate and drospirenone-containing OCs on hs-crp was not statistically significant (Table 3). Similarly, increased homocysteine is also related to cardiovascular disease and thrombosis risks [39]. Previously, raise in homocysteine levels were reported by OC usage [41, 42]. In the present study, we could not show a significant change between pretreatment and posttreatment homocysteine levels with neither cyproterone acetate nor drospirenone-containing OCs (Table 3). However, we should not forget that PCOS itself is characterized by greater odds for elevated CVD markers and long term use of OCs increase the risk of CVD and thromboembolism risk [43, 44]. Bird et al. reported a twofold increased risk of venous thromboembolism among women with PCOS who were taking OCs and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives [44]. Conclusions In conclusion, cyproterone acetate and drospirenone-containing OCs have similar effects regarding lipid metabolism and oxidative stress parameters. 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