Arch Gynecol Obstet DOI 10.1007/s00404-014-3217-5
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 S¸ükür · Cem Somer Atabekog˘lu · Can Ates¸ · Salih Tas¸kın · S¸erife 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 0.035 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-SO4 (−32 % [−53 to 15] in group B vs. −10 % [−49 to 63] in group A; K. Kahraman · Y. E. S¸ükür (*) · C. S. Atabekog˘lu · S. Tas¸kın · S¸. E. Çetinkaya · H. E. Tolunay · B. Özmen · M. Sönmezer · B. Berker Kadın Hastalıkları ve Dog˘um Anabilim Dalı, Ankara Üniversitesi Tıp Fakültesi Cebeci Hastanesi, Cebeci, 06100 Ankara, Turkey e-mail:
[email protected] C. Ates¸ 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
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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 0.035 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-I˙EG-0-15-00-01/2010).
Arch Gynecol Obstet
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 0.035 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 2011. 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: 18–35 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-SO4, 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. Sample size calculation While planning the present study, we were not able to detect any studies in the english literature that compared
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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 A (EE+cyproterone acetate) n=26
Allocated to Group B (EE+drospirenone) n=26
Discontinuation (n=7)
Discontinuation (n=6)
Unwillingness to therapy (n=4)
Unwillingness to therapy (n=3)
Weight gain (n=2)
Removal (n=2)
Breast tenderness (n=1)
Nausea (n=1)
After 12 months of therapy
After 12 months of therapy
n=19
n=20
Fig. 1 Flowchart of the study
Arch Gynecol Obstet
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/height2 (kg/m2). 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) × 100 × 3.47. 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
