Gynecological Endocrinology, September 2010; 26(9): 690697

PCOS

Metformin versus acarbose therapy in patients with polycystic ovary syndrome (PCOS): a prospective randomised double-blind study

AIDA HANJALIC-BECK1, BORIS GABRIEL1, WOLFGANG SCHAEFER1, HANS-PETER ZAHRADNIK1, MARCUS SCHORIES2, CLEMENS TEMPFER3, CHRISTOPH KECK4, & DOMINIK DENSCHLAG1
Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany, 2Clinic for hormonal disease and diabetes, Basel, Switzerland, 3Department of Obstetrics and Gynecology, Vienna General Hospital, Vienna, Austria, and 4 Pan Institut for Endocrinology and Reproductive Medicine, Cologne, Germany (Received 15 October 2009; accepted 8 February 2010)
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Abstract The objective of this study was to investigate the effect of metformin versus acarbose in terms of ovulation rate, their impact on hormonal and metabolic status and tolerability of both drugs in patients with polycystic ovary syndrome (PCOS). Seventy-ve patients with PCOS were included in this prospective randomised controlled double-blinded clinical study. According to randomisation, patients were allocated to receive either metformin 2550 mg/day (n 37) or acarbose 300 mg/ day (n 38) for 12 weeks. Primary study outcomes were ovulation rate, restoration of a regular menstrual cycle and the incidence of side effects. Secondary outcomes included treatment-related hormonal and metabolic changes. Comparable high rates of regular menstrual cycles as well as ovulation could be achieved in both groups (70% and 73% for metformin vs. 78% and 59% for acarbose, p 0.330 and p 0.185, respectively). In contrast, only in patients treated with metformin a statistically signicant decrease in fasting insulin and cholesterol levels as well as BMI was observed. However, comparing both groups at the end of treatment, no signicant differences in metabolic and/or hormonal parameters could be detected. Regarding side effects, the rate of atulence and/or diarrhoea was signicantly lower for acarbose compared to metformin (38% vs. 80%, p 5 0.001).

Keywords: Polycystic ovary syndrome, insulin resistance, ovulation induction

Introduction Polycystic ovary syndrome (PCOS) as a common endocrine disorder affecting 510% of the population [1], is a clinically heterogeneous disorder characterised by a dysregulation between the central nervous system, the pituitary and adrenal glands, and most important the ovaries. Furthermore, in a large proportion of affected individuals, PCOS is also associated with insulin resistance, obesity and disorders of lipid metabolism as well as infertility [2]. A link between PCOS and disturbed insulin action has been reported by several authors, promoting that insulin resistance is an integral feature of PCOS [3,4]. The associated hyperinsulinemia might cause an increased ovarian androgen secretion leading to an abnormal ovarian follicular development and

therefore dysfunctional menstrual activity [5,6]. Improved understanding of those pathophysiological mechanisms and the recognition of the important role of hyperinsulinemia have provided the rationale for trials evaluating the therapeutic value of insulinsensitising agents, with metformin being the most intensively studied drug [7]. Although effective as shown by numerous studies [7,8], metformin has important side-effects, like nausea, diarrhoea or though rare severe lactic acidosis, which often limit its use [9]. The a-glucosidase inhibitors like acarbose act by slowing the absorption of carbohydrates from the intestines, so minimising the post-prandial rise of blood glucose concentration [10]. Minor gastrointestinal side-effects may require gradual dosage increments over weeks after therapy is initiated, but serious adverse reactions are extremely rare.

Correspondence: Dr. Aida Hanjalic-Beck, Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany. E-mail: [email protected] ISSN 0951-3590 print/ISSN 1473-0766 online 2010 Informa UK Ltd. DOI: 10.3109/09513591003686379

Antidiabetic drugs in PCOS Since Geisthovel et al. [11] were able to demon strate in a pilot study, that hyperinsulinemia and hyperandrogenism can be substantially decreased by acarbose treatment, this observation was conrmed by two randomised controlled trials [12,13]. Moreover, in order to compare metformin treatment with acarbose with a main focus on ovulation rates in patients with PCOS, Sonmez et al. published a small randomised controlled trial including only 30 patients, with inconsistent results showing only a signicant higher ovulation rate in the second month of metformin treatment, in contrast to the rst and third month, where no signicant difference between the groups was observed [14]. The aim of this study was to compare the efcacy of metformin and acarbose therapy in patients with PCOS with respect to ovarian function, metabolic parameters and the incidence of side effects in a larger cohort.

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Methods Eighty-four women with PCOS aged 1843 years were enrolled in the study between September 2002 and November 2004. Due to the trial opening in 2002 before the new Rotterdam criteria were published [15], the recruitment of patients was based on the criteria of the National Institute of Health and Child Health from 1990 requiring the following three conditions for the diagnosis of PCOS: (i) oligomenorrhea (cycles 435 days) or amenorrhea (lack of menstruation for 6 months), (ii) clinical and/or biochemical hyperandrogenemia i.e. total serum testosterone 40.8 ng/ml and (iii) exclusion of other endocrinological disorders. In addition, for inclusion anovulatory cycles had to be conrmed in all patients by serum concentrations of progesterone less than 3.5 ng/ml on two occasions 4 weeks apart within 1 month before randomisation. After performing appropriate blood tests and taking the patients medical history, patients were screened for hyperprolactinemia, thyroid disease, congenital adrenal hyperplasia or liver, kidney and bowel disease, since these disorders were dened as exclusion criteria (Figure 1). Prior to study enrolment patients were requested not to take any hormones (oral contraception, ovulation induction agents, cortisone, etc.), antidiabetic drugs and not to go on any specic diet for at least 6 weeks. The study was approved by the Ethics Committee of the University of Freiburg, and all patients gave their written informed consent prior to entering the study. At screening during early follicular phase (cycle day 25) after spontaneous or progestin-induced bleeding the following measures were performed:

body mass index calculation (BMI weight (kg)/ [height (m)]2), oral glucose tolerance test (OGTT) with 75 g glucose after an overnight fasting including: fasting insulin, fasting glucose (mg/dl) to fasting insulin (mU/ml) ratio with cut-off point 54.5 as a parameter for insulin resistance according to Legro et al. [16], hormone assays (FSH, LH, progesterone, testosterone, androstendione, dehydroepiandrosterone-sulfate (DHEAS), sex hormone-binding globulin (SHBG), 17-hydroxy-progesterone (17-OH-P), cortisole) and metabolic assays (cholesterol and triglyceride). Hormones and metabolic parameters were measured with following intra-assay and interassay coefcients of variation, respectively: 2% and 53% for follicle-stimulating hormone (FSH), 52% and 54% for luteinizing hormone (LH), 53% and 54% for progesterone, 55% and 54% for testosterone, 53% and 55% for SHBG, 52% and 53% for insulin (automated Elecsys Immunoanalyser, Roche Diagnostics, Mannheim, Germany), 510% and 510% for DHEAS, 59% and 59% for cortisole (IMMULITE analyzer, Siemens Medical Solution Diagnostics, Bad Nauheim, Germany), 56% and 510% for androstenedione, 510% and 513% for 17-OH-P (Multi-Kristall Gamma-counter LB 2111, Berthold, Bad Wildbad, Germany), 51% and 53% for cholesterol, 52% and 53% for triglyceride, 52% and 52% for glucose (P-Modull, Roche Diagnostics, Mannheim, Germany). Furthermore, individual menstrual cycle pattern was assessed by interviewing the patients. The patients were randomised in two groups metformin (group I) and acarbose (group II) using a computer generated code. The randomisation list was kept in the examination room. According to the randomisation, the patients received consecutively numbered sealed envelopes including either metformin (group I, Glucophage 500 mg/850 mg MERCK Pharma, Darmstadt, Germany) or acarbose (group II, Glucobay 50 mg/100 mg BAYER Vital, Leverkusen, Germany) in a neutral white tablet form. The envelops were prepared by a nurse, who was not involved in the study. The investigators and the patients were blinded to their assignments. The treatment lasted for 12 weeks in both groups. The patients in group I were treated with metformin starting with 500 mg/day for the rst week, followed by 850 mg/day in the second week, 1700 mg/day in the third week (850 mg twice daily) and for the next 9 weeks the patients were asked to increase the dose up to 2550 mg, if no side effects had occurred. Patients in group II received acarbose 50 mg/day in the rst week, 100 mg/day in the second week, 200 mg/day in the third week (100 mg twice daily) and nally 300 mg/day for the next 9 weeks. During the last 9 weeks patients in both groups were advised to take the maximum dose.

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Figure 1. Flow chart for metformin versus acarbose treatment in patients with PCOS.

The primary endpoint was ovulation rate, and reestablishment of a regular menstrual cycle. Thus, during the treatment period serum progesterone (P4) concentration was measured every 2 weeks in order to evaluate for ovulary cycles as considered if a serum level of P4 4 3.5 ng/ml was detected. In addition, all patients were asked to record their menstrual bleeding pattern in order to evaluate for re-establishment of a regular menstrual cycle as dened by a cycle length between 21 and 35 days. Secondary endpoints included differences in hormonal and metabolic parameters, including insulin resistance, differences in BMI as well as the incidence of side effects during metformin and acarbose therapy. Thus, at the end of treatment the following measures were repeated: BMI, OGTT including fasting insulin and fasting glucose (mg/dl) to fasting insulin (mU/ml) ratio as a parameter for insulin resistance, hormone assays (FSH, LH,

testosterone, androstendione, DHEAS, SHBG, 17-OH-P, cortisole) and metabolic assays (cholesterol and triglyceride). Furthermore, individual side effects were rated by subjective scoring. Statistical analysis Statistical Package for the Social sciences, version 13 (SPSS Inc Chicago, IL.) was used for statistical analyses. All data are shown as means (+ SD). For categorical variables Fishers exact test was used. For continuous variables, between-group differences were assessed by the non-parametric MannWhitney U-test for unpaired samples. Continuous variables within each group were assessed for differences using Students t-test for paired samples. p value 5 0.05 was considered statistically signicant. Based on the available literature we assumed an ovulation rate of 50% in patients with PCOS. In

Antidiabetic drugs in PCOS order to detect a clinically meaningful difference of 25% as minimally detectable effect size with a power of 80% (a 0.10) using a 1 to 1 randomisation, a sample size of n 33 in each group was needed. Results Overall 84 women were screened for the study, of whom nine patients did not meet the inclusion criteria (Figure 1). Thus, 75 patients were eligible for intention-to-treat analysis (n 37 in group I and n 38 in group II, Table I). Overall, 13 women had to discontinue the study medication (7 in group I and 6 in group II, n.s.) due to side effects and were therefore excluded for the treated-per-protocol analysis (n 30 in group I and n 32 in group II, Table II).
Table I. Rate of ovulation, regular menstrual cycle, pregnancies and most commonly reported side effects according to treatment (intention to treat analysis). Group I Ovulation Regular menstrual cycle Pregnancy Nausea Flatulence/diarrhoea 59% 62% 8% 30% 76% (22/37) (23/37) (3/37) (11/37) (28/37) Group II 55% 68% 8% 15% 39% (21/38) (26/38) (3/38) (6/38) (15/38) p n.s. n.s. n.s. n.s. 0.001

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n.s. not signicant with p value 4 0.05. Table II. Rate of ovulation, regular menstrual cycle and pregnancies according to treatment (treated per protocol analysis). Group I Ovulation Regular menstrual cycle Pregnancy Nausea Flatulence/diarrhoea 73% 70% 10% 23% 80% (22/30) (21/30) (3/30) (7/30) (24/30) Group II 59% 78% 9% 6% 38% (19/32) (25/32) (3/32) (2/32) (12/32) p n.s. n.s. n.s. 0.049 50.001

The mean age was 28 years in both groups. At baseline, there was no difference between both groups regarding metabolic or hormonal parameters (Table III). Thirty-ve per cent of the patients in the metformin group and 18% of the patients in the acarbose group showed a fasting glucose to fasting insulin ratio 54.5 as a parameter for insulin resistance (p 0.053). The rate of ovulation, regular menstrual cycles and pregnancies did not differ signicantly between both treatment groups as shown in Table I. However, with respect to the most commonly reported side effects, the rate of atulence, diarrhoea and nausea was signicantly higher in group I (metformin) compared to group II (acarbose). After 12 weeks of treatment an improvement of the metabolic situation was observed in group I (decrease of BMI, decrease of fasting insulin, increase of fasting glucose/insulin ratio and reduction of cholesterol levels) (Table III), whereas this trend was not seen in group II. There were no treatment-related changes in hormonal parameters in both groups (FSH, LH, T, cortisol, androstendion, 17-OH-P, SHBG) with the exception of DHEAS showing a slight increase (group I) and decrease (group II) after treatment, which was considered not being clinically relevant, since all values were within normal range. Patients who became pregnant during the therapy (three patients in each group) were excluded from analysis due to pregnancy-induced alterations of hormones and metabolic values. Although signicant differences in terms of insulin resistance and cholesterol levels before and after the treatment were observed in group I, the overall comparison between both groups at the end of treatment did not reveal any signicant difference in metabolic or hormonal parameters (Table III).

Table III. Changes in hormonal and metabolic parameters before and after 12 weeks of treatment (treated per protocol analysis); pregnant patients excluded. Group I (metformin); n 27 Before FSH (U/l) LH (U/l) Testosterone (ng/ml) Cortisole (ng/ml) DHEAS (ng/ml) Androstendione (ng/ml) 17-OH-P (ng/ml) SHBG (nmol/l) BMI (kg/m2) Cholesterol (mg/dl) Triglyceride (mg/dl) Fasting insulin (mU/ml) Fasting glucose/insulin 4.25 + 1.88 5.65 + 3.03 1.08 + 0.36 168.6 + 64.2 2171 + 824 3.32 + 1.47 2.40 + 1.72 68.5 + 59.3 31.6 + 7.77 191.4 + 35.1 134.7 + 75.4 19.5 + 17.7 7.28 + 5.03 After 4.40 + 1.51 7.41 + 5.58 1.04 + 0.31 147.3 + 44.3 2362 + 919 3.29 + 1.68 1.86 + 1.13 52.7 + 41.8 30.6 + 7.39 181.6 + 27.8 116.3 + 55.0 14.3 + 9.8 8.65 + 5.86 p
1

Group II (acarbose); n 29 Before 4.38 + 2.11 6.05 + 3.76 1.12 + 0.32 183.0 + 36.8 2350 + 955 3.31 + 1.13 2.28 + 1.12 48.0 + 24.6 29.0 + 7.52 195.4 + 41.7 123.9 + 93.4 13.0 + 10.2 9.86 + 5.44 After 5.02 + 2.14 6.97 + 7.37 1.09 + 0.32 172.1 + 57.0 2178 + 837 3.62 + 1.77 2.02 + 1.03 48.4 + 32.3 28.4 + 6.91 197.6 + 38.0 129.3 + 78.9 14.2 + 13.7 9.70 + 7.10 p1 n.s. n.s. n.s. n.s. 0.046 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

Group I vs. II after 12 weeks p2 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

n.s. n.s. n.s. n.s. 0.045 n.s. n.s. n.s. 0.000 0.023 0.056 0.013 0.028

Results are shown as mean + SD; n.s.: not signicant; p1 value for Students t-test; p2 value for MannWhitney U test.

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A. Hanjalic-Beck et al. oral biguanid antihyperglycemic drug and has been widely investigated in patients with PCOS. Various studies have been able to show positive effects of metformin in terms of reducing hyperinsulinemia and optimising the metabolic situation, [7,22]. Beside these metabolic effects, metformin seems to have a signicant impact on ovulation rates in anovulatory obese as well as lean patients with PCOS [7,8,21,23 25]. Although, according to a recently published large randomised controlled trial [26], metformin seems to be less effective regarding live birth rate compared to CC in patients with PCOS, a restoration of regular menstrual cycles could be achieved in up to 5091% of the patients [22,27,28]. This positive effect on menstrual cyclicity and ovulation can occur without additional metabolic changes like weight reduction [23,25]. Although the results of previous studies regarding the improvement of hyperandrogenemia under metformin treatment are controversial [7], it appears to be consensus that metformin possesses antiandrogenic properties [22,27,28]. Side effects of metformin include abdominal bloating, atulence, diarrhoea, nausea and vomiting [29,30]. These side effects can be reduced by initially starting the treatment at a low dose, with further slowly increasing the dose according to side effects, and taking the drug after meals. In some patients side effects improve spontaneously. Furthermore, lactic acidosis, as a potentially life-threatening complication of metformin treatment occurs in 1:30,000 patients with diabetes, but has not been reported as a complication in women with PCOS [7]. Acarbose is an antidiabetic drug which reversibly inhibits a-glucosidase activity in the intestinal mucosa decreasing disaccharide digestion, thus delaying glucose entry into the blood stream. It has been widely used for treatment of type 2 diabetes mellitus, as well as for prevention of type 2 diabetes in patients with impaired glucose tolerance [31]. To the best of our knowledge, only ve small trials have been

Since BMI was not a criterion for the recruitment of patients in our study (BMI range 1746), we performed subsequently a subgroup analysis considering in particular patients with BMI 4 25 kg/m2 (group I, n 19; group II, n 18) which revealed additionally decreased triglyceride levels (group I, p 0.026) and increased FSH levels (group II, p 0.038) after therapy. Again, there was no difference in these parameters between both groups at the end of treatment. DHEAS, BMI and fasting insulin levels were the only parameters showing signicant changes after metformin therapy both for the entire group I and for the subgroup of women with BMI 425 kg/m2 (Table IV). Discussion The rst-line treatment for patients with PCOS with anovulatory infertility is clomiphene citrate (CC) [17]. With CC ovulation rates of up to 80% and pregnancy rates of 3050% [18] can be achieved. However, approximately 1540% of patients with PCOS show a so called clomiphene resistance [18,19]. There is no consensus on the denition of clomiphene resistance, but most clinicians would classify it as a failure to ovulate after three treatment cycles with gradually increasing doses of CC. Especially, patients with PCOS with obesity and severe insulin resistance are more likely to fail to respond to CC [20] contrary to non-obese patients with PCOS, who are able to achieve ovulation rates of up to 67% with CC treatment [21]. Nevertheless the risk of poor response, lower pregnancy rates and potentially higher abortion rates after treatment with CC [21] led to a search for alternatives to this drug. Over the past years, oral antidiabetics like metformin, troglitazone, rosiglitazone or acarbose were increasingly used for the treatment of insulin resistance in patients with PCOS. Metformin is an

Table IV. Changes in hormonal and metabolic parameters for patients with BMI 425 (treated per protocol analysis). Group I (metformin, n 19) Before FSH (U/l) LH (U/l) Testosterone (ng/ml) Cortisole (ng/ml) DHEAS (ng/ml) Androstendione (ng/ml) 17-OH-P (ng/ml) SHBG (nmol/l) BMI (kg/m2) Cholesterol (mg/dl) Triglyceride (mg/dl) Fasting insulin (mU/ml) Fasting glucose/insuline 4.09 + 2.03 5.73 + 2.91 1.12 + 0.36 162.4 + 58.1 2107 + 806 3.30 + 1.52 2.41 + 1.82 45.00 + 39.3 35.5 + 5.62 191.1 + 37.7 159.7 + 74.0 25.6 + 18.5 4.75 + 2.94 After 4.25 + 1.72 6.39 + 4.05 1.11 + 0.29 146.9 + 46.0 2396 + 946 2.95 + 0.87 1.90 + 1.27 32.3 + 15.1 33.99 + 5.51 182.9 + 29.1 131.2 + 58.6 18.4 + 9.4 5.80 + 3.43 p
1

Group II (acarbose, n 18) Before 4.21 + 2.12 5.24 + 3.23 1.13 + 0.36 182.0 + 41.4 2307 + 900 3.13 + 0.98 2.12 + 1.06 41.1 + 19.6 33.5 + 5.50 197.9 + 37.0 145.0 + 102.2 16.9 + 11.5 7.58 + 4.07 After 5.46 + 1.92 5.67 + 3.45 1.14 + 0.35 175.2 + 52.7 2221 + 798 3.46 + 1.84 1.65 + 0.76 37.1 + 19.7 32.5 + 5.00 202.0 + 33.1 146.4 + 88.3 18.5 + 16.3 6.91 + 3.46 p1 0.038 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

Group I vs. II after 12 weeks p2 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

n.s. n.s. n.s. n.s. 0.017 n.s. n.s. n.s. 0.000 n.s. 0.026 0.016 n.s.

Results are shown as mean + SD; n.s.: not signicant; p1 value for Students t-test; p2 value for MannWhitney U-test.

Antidiabetic drugs in PCOS published so far, investigating the effects of acarbose in patients with PCOS [1114,32]. Positive effects in terms of decreased insulin resistance and hyperandrogenemia, as well as improvement of ovulation rates and menstrual cyclicity were observed. In our study, we observed comparable ovulation rates for metformin and acarbose treatment after 12 weeks of therapy in patients with PCOS. These results should clarify the data previously obtained from a small randomised controlled trial, which revealed inconsistent results showing only a signicantly higher ovulation rate in the second month of metformin treatment compared to acarbose, in contrast to the rst and third months, where no signicant difference between the groups could be observed [14]. However, both studies showed an improvement of ovulation under metformin and acarbose treatment compared to the ovulation rate in patients with PCOS treated with placebo being in a range of 424% [7,8]. Furthermore, in both trials the number of patients with regular menstrual cycles was signicantly increased due to metformin (62 80%) as well as acarbose treatment (6869%), with no statistically signicant difference between both treatment arms. These results regarding restoration of a regular menstrual cycle are in accordance with results of earlier published data on metformin [22,27,28,33], as well as acarbose in obese [13] and/or non-obese hyperinsulinemic patients with PCOS [12]. With respect to metabolic changes, in our study we were not able to demonstrate a signicant difference between metformin and acarbose after 12 weeks of therapy. Analysing the metabolic effects of both treatment arms separately, we found a statistically signicant decrease in fasting insulin and cholesterol levels as well as BMI after 12 weeks of metformin treatment, which was conrmed for fasting insulin and BMI in a subgroup analysis including only patients with a BMI of more than 25 kg/m2. These positive effects of metformin on insulin resistance and dyslipidemia are in accordance to earlier results [7,28]. In contrast, in patients with acarbose treatment, no signicant metabolic changes were observed after 12 weeks of therapy in comparison to baseline. Other investigators have been able to demonstrate positive metabolic effects for acarbose in patients with PCOS in terms of an improved insulin resistance [11,12,14,32] or a decreased BMI [13,14]. It is of note that a direct comparison seems to be difcult in light of the fact that in those studies different denitions, criteria and/or functional tests were used in order to diagnose hyperinsulinaemia. In addition, it is important to mention, that despite randomisation a borderline signicantly higher number of patients with insulin resistance at baseline in the metformin group (35%) compared to the

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acarbose group (18%) was observed. This could partly explain why the positive metabolic effects were only detected in the metformin group. Rather speculative is that metformin might have a stronger metabolic impact in patients with PCOS compared to acarbose, since metformin interacts on different levels of insulin physiology by decreasing intestinal absorption of glucose, increasing peripheral glucose utilisation, inhibiting hepatic gluconeogenesis and enhancing insulin sensitivity of hepatic and peripheral tissue [34], whereas acarbose only acts locally by slowing down the absorption of carbohydrates from the intestine, hence only reducing insulin levels indirectly [10,34]. The effects of metformin and/or acarbose treatment in terms of hyperandrogenemia and/or hirsutism are varying. Whereas some investigators have reported decreased testosterone levels and/or improved hirsutism after acarbose [1114,32] as well as metformin treatment [8,22,28], those effects were not conrmed by other trials [7,25]. According to these variable data, and the results of our study, in which we were not able to demonstrate signicantly decreased androgen levels neither after metformin nor after acarbose treatment, those drugs can not generally be recommended for treatment of hyperandrogenemia and/or hirsutism in patients with PCOS [35]. Typical side effects of metformin include abdominal discomfort and diarrhoea, which occurs in 2030% of the patients, and up to 5% have to discontinue the medication due to the severity of the side effects [34]. In addition, the use of metformin is limited to patients without renal or hepatic disease, respiratory insufciency, severe infections and hypoxemic conditions due to an increased risk of fatal lactic acidosis. Gastrointestinal side effects like abdominal disturbance, atulence and diarrhoea in up to 30% of the patients have also been reported for acarbose treatment [10]. In addition, a transient elevation of serum transaminase concentrations can occur at maximal dose and is completely reversible after discontinuation of treatment [10]. However, in contrast to metformin serious adverse reactions like fatal hypoglycemia or lactic acidosis have not been reported. In general, the dosage of both drugs should be increased gradually in order to reduce the described side effects. Furthermore, those side effects tend to improve spontaneously after several weeks of treatment [34]. In our study treatment with acarbose was associated with signicantly less side effects like atulence, diarrhoea and nausea compared with metformin treatment. However, no differences regarding drop-out rate due to side effects was observed. With respect to the safety during pregnancy, metformin has been documented in several trials to be safe for use in pregnancy, and in fact, even

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9. Chang CT, Chen YC, Fang JT, Huang CC. Metforminassociated lactic acidosis: case reports and literature review. J Nephrol 2002;15:398402. 10. Coniff RF, Shapiro JA, Robbins D, Kleineld R, Seaton TB, Beisswenger P, McGill JB. Reduction of glycosylated haemoglobin and postprandial hyperglycaemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study. Diabetes Care 1995;18:817824. 11. Geisthovel F, Frorath B, Brabant G. Acarbose reduces elevated testosterone serum concentrations in hyperinsulinaemic premenopausal women: a pilot study. Hum Reprod 1996;11:23772381. 12. Ciotta L, Calogero AE, Farina M, De Leo V, La Marca A, Cianci A. Clinical, endocrine and metabolic effects of acarbose, an alpha-glucosidase inhibitor, in PCOS patients with increased insulin response and normal glucose tolerance. Hum Reprod 2001;16:20662072. 13. Penna IA, Canella PR, Reis RM, Silva de Sa MF, Ferriani RA. Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study. Hum Reprod 2005;20:23962401. 14. Sonmez AS, Yasar L, Savan K, Koc S, Ozcan J, Toklar A, Yazicioglu F, Akgun A, Sut N. Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrom. Hum Reprod 2004;20:175179. 15. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:1925. 16. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:26942698. 17. Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev 2000;(2):CD000056. 18. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3:359365. 19. Pritts EA. Treatment of the infertile patient with polycystic ovarian syndrome. Obstet Gynecol Surv 2002;57:587 597. 20. Barbieri RL. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance. Am J Obstet Gynecol 2000;183:14121418. 21. Palomba S, Orio F, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F. Prospective parallel randomised, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the rst-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:40684074. 22. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M. Metformin effects on clinical features, endocrine and metabolic proles, and insulin sensitivity in polycystic ovary syndrome: a randomised, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139146. 23. Morin-Papunem LC, Koivunem RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998;69:691696. 24. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril 2002;77:101106.

benecial in terms of decreasing the incidence of early pregnancy loss and the development of gestational diabetes, reducing insulin levels and insulin resistance and preventing androgen excess in women with PCOS [36]. The use of acarbose in pregnancy seems to be a good option because it primarily acts in the gut by delaying carbohydrate absorption and is not absorbed, thereby having no systemic effects. However, this drug has not yet been studied well in pregnancy. In a small study by Zarate et al. [37], six pregnant women with moderately elevated levels of fasting and postprandial blood glucose were treated with acarbose, after which, the fasting and postprandial glucose levels normalised. The pregnancies were uneventful and the newborn babies were normal [37]. Although this study shows promising results, it is still a very early and small study on acarbose use in pregnancy, and therefore, no plausible and denitive conclusions can be drawn. In conclusion, we were able to demonstrate a comparable high ovulation rate and improvement regarding regular menstrual cycles for both metformin and acarbose treatment. No signicant differences in terms of metabolic and/or hormonal parameters could be observed between both groups at the end of treatment. Nevertheless this result could be due to short treatment period and heterogeneity of patients in our study. Since acarbose was better tolerated than metformin, we suggest acarbose as an effective alternative to metformin in patients with anovulatory PCOS. References
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Antidiabetic drugs in PCOS

25. Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A, von Wolff M, Hamann A, Strowitzki T. Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2006;91:946952. 26. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551566. 27. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrhoeic women with the polycystic ovary syndrome. Metabolism 1999;48:511519. 28. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogeneamia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647654. 29. Barbieri RL. Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol 2003;101:785793. 30. Stadtmauer L, Oehninger S. Management of infertility in women with polycystic ovary syndrome. Treat Endocrinol 2005;4:279292.

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31. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:20722077. 32. Tugrul S, Kutlu T, Pekin O, Baglam E, Kiyak H, Oral O. Clinical, endocrine and metabolic effects of acarbose, a alphaglucosidase inhibitor, in overweight and nonoverweight patients with polycystic ovarian syndrome. Fertil Steril 2008;90:11441148. 33. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:24742483. 34. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Internal Med 1999;131:281303. 35. Barbieri RL, Ehrmann DA. Metformin for treatment of the polycystic ovary syndrome. UpToDate in Obstetrics, Gynecology and Womens Health 2005. 36. Ho FL, Liew CF, Cunanan EC, Lee KO. Oral hypoglycaemic agents for diabetes in pregnancy an appraisal of the current evidence for oral anti-diabetic drug use in pregnancy. Ann Acad Med 2007;36:672678. 37. Zarate A, Ochoa R, Hernandez M, Basurto L. Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy. Ginecol Obstet Mexico 2000;68:4245.

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