Comparison of metabolic effects of metformin and rosiglitazone in the management of polycystic ovary syndrome (PCOS): A prospective, parallel, randomized, open-label study

Diabetes & Metabolic Syndrome: Clinical Research & Reviews (2008) 2, 37—46

http://diabetesindia.com/

Comparison of metabolic effects of metformin and rosiglitazone in the management of polycystic ovary syndrome (PCOS): A prospective, parallel, randomized, open-label study Jamal Ahmad *, Nidhi Shukla, Abdur Rahman Khan, Faiz Ahmed, M. Asim Siddiqui Centre for Diabetes and Endocrinology, Faculty of Medicine, Jawahar Lal Nehru Medical College Hospital, Aligarh Muslim University, Aligarh 202002, India KEYWORDS PCOS; Metformin; Rosiglitazone

Summary Background and aims: Effective treatment of polycystic ovary syndrome (PCOS) remains controversial but recently, insulin-sensitizing agents have found usage in PCOS based on the relationship between hyperinsulinemia and ovarian hyperandrogenemia. The present study was undertaken to evaluate and compare the efficacy of metformin versus rosiglitazone on insulin resistance and hyperandrogenemia in women with PCOS. Methods: In this prospective, parallel, randomized, open-label study; insulin resistance and hyperandrogenemia were evaluated in 61 subjects with PCOS, out of which 31 subjects received metformin (850 mg/BD) and 30 subjects received rosiglitazone (2 mg/BD) for 12 months. Evaluation of insulin resistance using the homeostasis model insulin resistance index (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), area under the curve (AUC) for insulin and AUC for glucose; and evaluation of hyperandrogenemia by clinical/biochemical parameters namely, hirsutism, ovulation, resumption of menstrual cycle, and androgen levels were performed at baseline and 3,6 and 12 months, respectively. Results: Clinical manifestations of hyperandrogenemia improved in both groups. Both PCOS groups had normal levels of glucose throughout the study. Insulin levels, at baseline and months 3, 6 and 12 were 13.11  2.45, 9.94  2.41, 9.28  3.25, 8.94  2.39 and 11.38  5.16, 9.55  3.11, 8.22  3.68, 8.02  3.78 mU/ml in metformin and rosiglitazone groups respectively (P < 0.05). Corresponding HOMA values were 4.58  0.22, 3.90  0.19, 3.84  0.20 and 2.76  0.17 in metformin group (P < 0.05), and 4.19  0.24, 2.77  0.22, 2.58  0.20 and 1.90  0.16 in rosiglitazone group (P < 0.05), whereas, QUICKI values were 0.60  0.02, 0.65  0.02, 0.67  0.02

* Corresponding author. Tel.: +91 571 2721173; fax: +91 571 2721544. E-mail address: [email protected] (J. Ahmad). 1871-4021/$ — see front matter # 2007 Diabetes India. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dsx.2007.12.003

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J. Ahmad et al. and 0.66  0.02 in metformin group (P < 0.05) and 0.63  0.02, 0.68  0.02, 0.72  0.03 and 0.70  0.02 in rosiglitazone group (P < 0.05), respectively. Conclusion: Metformin and rosiglitazone improve outcome measures after treatment; rosiglitazone seems to improve insulin resistance relatively earlier; while metformin had an earlier and more sustained benefit on hyperandrogenemia. # 2007 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Introduction Polycystic ovary syndrome (PCOS) is considered to be one of the most common endocrinopathies in women with an estimated frequency between 6.5% [1]. It is characterized by oligo/and or anovulation, symptoms of hyperandrogenism such as hirsutism, acne and in some polycystic ovaries and infertility [2]. Though, there has been considerable controversy about specific diagnostic criteria, two classic features of PCOS are hyperandrogenism and chronic anovulation. Approximately, 60% of women with PCOS display insulin resistance with hyperinsulinemia [3]. Hyperinsulinemia contributes to the hyperandrogenism by increasing ovarian androgen production and by suppressing hepatic production of SHBG with consequent increase in free testosterone levels [4]. Abdominal obesity, hyperinsulinaemia and insulin resistance have been shown to play a central role in the pathogenesis of PCOS [5,6], which predisposes these women to risks of type 2 diabetes mellitus and cardiovascular disease [7,8]. Effective treatment of PCOS remains controversial but needs to be divided into the main requirements of the patient, depending on whether they are seeking restoration of menstrual function, fertility, weight loss, or amelioration of metabolic changes. In the past, therapeutic approaches to PCOS have focused on suppressing ovarian androgen production or ovulation induction. In recent years, so-called insulin-sensitizing agents such as the biguanide metformin and thiazolidinediones have found wide usage in PCOS based on the relationship between hyperinsulinism and ovarian hyperandrogenism. Metformin is an oral hypoglycemic agent that has been shown to be effective in improving insulin sensitivity, menstrual cycle pattern, ovulation and pregnancy outcomes [9—15]. Recently, rosiglitazone, a peroxisome-proliferator-activated receptor-g (PPRAg) agonist belonging to the thiazolidinedione group, increases insulin sensitivity in a novel manner through its effects on PPRAg, has attracted increasing interest in the treatment of type 2 diabetes mellitus. Unlike metformin, rosiglitazone is a ‘true’ insulin sensitizer, which binds to and activates PPRAg, a hormone receptor located in the cell nucleus [16]. By this

mechanism, it influences the transcription of a variety of genes implicated in carbohydrate and lipid homeostasis, thereby increasing peripheral glucose uptake and improving pancreatic b-cell function (either directly or through reduction of insulin resistance. Currently there are only limited short-term data on the use of rosiglitazone in PCOS [15,17—24]. With this background, the present study was aimed to evaluate and compare the efficacy of metformin and rosiglitazone in ameliorating insulin resistance and hyperandrogenism in women with PCOS.

Materials and methods Study population Seventy non-diabetic, euthyroid, normoprolactinemic women aged 18—35 years, attending the outpatient endocrinology clinic with complaints of menstrual irregularities, hirsutism, and/or sterility were recruited. PCOS was diagnosed by the presence of (i) chronic ovulatory dysfunction–—oligomenorrhea (cycle length > 45 days) or amenorrhea (cycle length > 6 months), (ii) evidence of hyperandrogenemia, whether clinical (hirsutism with F—G score of 8) or biochemical (serum concentration of testosterone) and (iii) exclusion of other causes such as CAH, androgen secreting tumors, hyperprolactinemia and Cushing’s syndrome. These criteria are based on the consensus conference sponsored by NICHD, NIH, in April 1990 [25]. In addition to the exclusion of the above-mentioned disorders, subjects who had a history of diabetes mellitus, renal, hepatic or cardiovascular dysfunction were excluded. Subjects who were on medications known or suspected to affect reproductive or metabolic functions (like clomiphene citrate, anti-androgens, OCPs and anti-obesity compounds) within 6 months of study entry as well who had undergone hysterectomy or oopherectomy were excluded from the study.

Study design A prospective parallel randomized, open-label study was designed to evaluate the efficacy of rosiglita-

The efficacy of metformin versus rosiglitazone on insulin resistance and hyperandrogenemia in women with PCOS 39

zone on insulin resistance and hyperandrogenism and to compare it with that of metformin in women with PCOS. Informed consent was taken and study was approved by local ethics committee. Subjects were randomly allocated into two group using random number tables. Group A received metformin 850 mg BID and Group B received rosiglitazone 2 mg BD. All women recruited were instructed not to modify their usual dietary intake as well as their regular exercise pattern during the study. They were advised to use barrier contraception during the study period; further they were advised to stop taking the drug immediately upon confirmation of pregnancy.

mean peak serum progesterone concentration (7.5— 9.8 nmol/l). After baseline evaluation eligible subjects were randomized to receive either metformin or rosiglitazone for 12 months. FSIGTT and all baseline hormone levels (except thyroid, PRL, 17-OH-P and cortisol) were repeated at month 3, month 6, and month 12 of therapy. The outcome measures were evaluation of any clinical/biochemical improvement in hyperandrogenemia (improvement in hirsutism, biochemical parameters), ovulation, menstrual cycles, evaluation of insulin resistance using the homeostasis model insulin resistance index (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and area under the curve (AUC) for insulin and AUC for glucose and androgen levels.

Study protocol Laboratory analysis All subjects underwent a baseline clinical, metabolic and hormonal evaluation that included height, body weight, BMI and waist to hip ratio. Hirsutism was clinically assessed by single observer to minimize observer bias and graded by Ferriman—Gallwey scoring [26] with score of 8 indicative of androgen excess. Further the subjects were requested not to use any measures for the removal of unwanted hair such as waxing, plucking, electrolysis etc. Baseline study was performed in the follicular phase of the cycle (day 3—8 of menses) either spontaneous or after progesterone induced withdrawal bleeding. Blood samples were obtained for circulating concentrations of luteinizing hormone (LH), follicular stimulating hormone (FSH), estradiol, prolactin (PRL), testosterone, dehydroepiandrosterone sulfate (DHEAS), cortisol (morning/ evening), TSH, free T4, 17-hydroxy progesterone (17-OH-P) and androstenedione as well as routine investigations were performed (blood counts, electrolytes, lipidogram, hepatic and renal function tests) as a measure of general drug safety and prevent possible metformin related complications (lactic acidosis). A frequently sampled intravenous glucose tolerance test (FSIGTT) was performed between 08:00 and 09:00 h after an overnight fast (12 h) in all subjects. Blood was collected during IVGTT at 30 and 0 min as baseline values; at 0 min time 0.3 g/kg glucose was administered as an i.v. bolus over 1 min. Blood samples were then obtained at 10, 20, 40, 60, 90, and 120 min for glucose and insulin determinations. Insulin resistance was said to be present when there was the presence of at least one of the following criteria (i) BMI > 28.9 kg/m2, (ii) HOMAIR > 4.65, (iii) BMI > 27.5 kg/m2 and HOMA-IR > 3.6 and (iv) BMI > 27.0 kg/m2 and family history of type 2 diabetes mellitus [27]. Ovulation was assessed by

Blood was collected in tubes containing appropriate anticoagulants and preservatives, centrifuged within 2 h and the separated plasma was frozen and stored at 20 8C until assayed. Hormonal assays were done by radioimmunoassay (T4, testosterone, DHEAS, 17-OH-P, cortisol, and insulin) and immunoradiometric assay (TSH, PRL, LH, and FSH). Serum FT4 concentration was measured using the GammaCoat 125I FT4 (two step). Commercial kits were supplied by DiaSorin, Vercelli, Italy (PRL, testosterone, androstenedione, progesterone, & E2); DiaSorin, Minnesota, USA (FT4, & TSH); Beckman Coulter Company, Marseilles, France (17-OH-P); and Diagnostic Products Corporation LA, California (DHEAS). The intra- and inter-assay coefficients of variation were <6.9 and <7.5%, respectively. Blood glucose was estimated by glucose oxidase method. Sensitivity, specificity, inter-assay, and intra-assay coefficients of variation were within the prescribed limits given in the manufacturer’s protocol. Insulin sensitivity was determined by homeostasis model assessment (HOMA) [(fasting insulin in mIU/ l  fasting glucose in mmol/l)/22.5] [28], QUICKI [1/(log glucose + log insulin)] [29], and AUC for glucose and insulin (AUC-G, AUC-I) on FSIGTT using trapezoidal method.

Statistical analysis The Statistics Package for Social Science (SPSS 10.0; SPSS Inc., Chicago, IL) was used for statistical analyses. The results were expressed as mean  S.D. unless specified otherwise. For comparison of all quantitative variables, clinical, biochemical, and hormonal parameters between metformin and rosiglitazone groups at baseline and 12th month, unpaired t-test was used. The ANOVA for repeated measures with Bonferroni post hoc analysis was used

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to compare the clinical, biochemical, and hormonal parameters within each group at 0, 3, 6, 12 months. P value of <0.05 was taken as significant.

acteristics of the PCOS women were also comparable in the two groups (Table 2).

Anthropometric and clinical characteristics

Results Of the 70 subjects recruited (n = 35 in each group), nine subjects dropped out or were excluded (four in the metformin group and five in the rosiglitazone group); two conceived, two had poor compliance, two had incomplete data, and three were lost to follow-up. Sixty-one subjects (31 in metformin group and 30 in rosiglitazone group completed the 12-month follow-up. All subjects received and continued the treatment assigned to them, were available to follow-up and were included in the final analysis.

Baseline characteristics No significant differences were found in the baseline characteristics of both the groups (Table 1). All the subjects were young (22.81  4.52 years, range 14— 36 years in the metformin group (A); 23.2  3.36 years, range 17—31 years in the rosiglitazone group (B)). Twenty-one (34%) subjects, nine in metformin group and 12 in rosiglitazone group had evidence of polycystic ovaries on transvaginal ultrasonography (P > 0.3). Before treatment 41 subjects had oligomenorrhea (18 in the metformin group and 23 in the rosiglitazone group) and 20 had amenorrhea (13 in the metformin group and 07 in the rosiglitazone group). All subjects were insulin resistant as indicated by HOMA-IR and fasting insulin levels. Other than serum estradiol (E2), all the biochemical char-

Body weight, BMI and waist circumference did not change significantly and remained stable until the end of the study in both groups (Table 3). In particular, metformin treatment decreased the hirsutism score from 10.52  2.63 to 8.63  2.71 at 3 months which further improved to 6.51  1.95 and 6.21  2.74 at 06 and 12 months, respectively (P < 0.05) while the F—G score in the rosiglitazone group was 9.55  2.31, 9.15  1.9, 8.92  1.63 and 8.90  1.71 at baseline and 03, 06 and 12 months respectively. In the metformin group menstrual cycles became regular in 14 (45%) at 03 months, in 28 (90%) at 06 months and in 30 (96%) at 12 months. Ovulation was observed in 8 (26%) at 03 months, in 15 (48%) at 06 months and in 19 (61%) at 12 months. Similar changes were observed in rosiglitazone group with ovulation occurring in 07(23%), 15(50%) and 22(73%) at 03, 06 and 12 months, respectively; and regular menstruation occurring in 10 (33%), 18 (60%) and 28 (90%) subjects at 03, 06 and 12 months, respectively. Two subjects in the rosiglitazone became pregnant on therapy.

Glucose and insulin metabolism Both PCOS groups had normal levels of glucose throughout the study. In metformin group, there was a progressive fall in peak and delta response to FSIGTT, that became significant at 6 and 12 months; where AUC of glucose showed a significant

Table 1 Clinical baseline characteristics for subjects randomized to group A (metformin) and B (rosiglitazone) Parameter

Metformin (Group A)

Rosiglitazone (Group B)

No. of subjects (n) Age (years) Age at menarche (years) Hirsutism score (F—G) Body mass index (kg/m2) >30 25—30 <25 Waist:hip ratio

31 22.81  4.52 12.06  1.34 10.52  2.63 27.66  5.44 10 14 7 0.87  0.06

30 23.20  3.36 11.93  1.11 9.55  2.31 26.94  5.24 9 16 7 0.81  0.02

Menstrual pattern (n) Oligomennorhea Amenorrhea

18 13

23 07

Blood pressure (mmHg) Systolic Diastolic The data were analysed by the unpaired t-test.

124.26  9.98 80.32  7.06

122.33  9.35 77.33  7.60

The efficacy of metformin versus rosiglitazone on insulin resistance and hyperandrogenemia in women with PCOS 41 Table 2 Biochemical baseline characteristics (means  S.D.) for study groups Parameter

Metformin (GroupA)

Rosiglitazone (Group B)

1.06  0.21 3.45  0.27 119.4  14.17 3.09  0.14 11.17  4.91 4.26  1.85 3.21  2.67 10.70  5.41 1.56  0.65 0.95  0.56 177.3  71.58 4.55  2.42

FT4 (ng/dl) TSH (mIU/ml) Estradiol (pg/ml) Progesterone (ng/ml) LH (mIU/ml) FSH (mIU/ml) LH/FSH Prolactin (ng/ml) Testosterone (pg/ml) 17-OH-P (ng/ml) DHEAS (mg/dl) Androstenedione (ng/ml)

1.13  0.28 3.55  0.27 127.1  8.46$ 3.11  0.12 12.60  8.67 4.63  1.54 2.92  1.38 9.10  3.02 1.68  0.54 0.92  0.58 194.0  98.10 5.05  2.50

Plasma glucose (mg/dl) Fasting AUC HOMA-IR

82.68  9.67 13,663  1864 4.58  0.22

79.93  10.01 12,932  1081 4.19  0.24

Insulin (mU/ml) Fasting AUC

13.11  2.45 26,962  7651

11.38  5.16 25,868  9238

The data were analyzed by the unpaired t-test. $P < 0.05, A vs. B.

fall at 3, 6 and 12 months (Table 4). In rosiglitazone group, similar changes were observed in glucose metabolism, however significant changes (P < 0.05) were observed earlier (at 3 months) that persisted at 6 and 12 months of follow-up. In case of insulin metabolism, significant fall was noted in insulin levels in both treatment groups at 3, 6 and 12 months (Table 4). Peak insulin response was also similar both groups. However, delta insulin response was significant at 6 months in metformin group whereas significant response was seen right from months 3 in case of rosiglitazone group. AUC of insulin decreased significantly at 3, 6 and 12 months

in both treatment groups. Measures of insulin resistance/sensitivity like HOMA and QUICKI improved significantly at 3, 6 and 12 months (when compared to baseline) in both treatment groups (Table 4). After treatment, fasting insulin and AUC of glucose was slightly lower in the rosiglitazone group as compared to the metformin group (Fig. 1).

Serum androgen levels At baseline (month 0, Table 4), both PCOS groups had elevated levels of testosterone and androstenedione. Metformin caused a significant decrease in

Table 3 Clinical and of anthropometric measurements at specified time intervals during the protocol Baseline Group A (on metformin) BMI (kg/m2) WHR Hirsutism score Regular menstruation (n (%)) Ovulation Group B (on rosiglitazone) BMI (kg/m2) WHR Hirsutism score Regular menstruation (n (%)) Ovulation

Month 0

Month 3

Month 6

Month 12

27.66  5.44 0.87  0.06 10.52  2.63 — —

27.44  5.37 0.86  0.06 8.63  2.71 14 (45%) 8 (26%)

27.35  5.27 0.86  0.06 6.51  1.95 * 28 (90%) 15 (48%)

27.50  5.25 0.86  0.06 6.21  2.74 * 30 (96%) 19 (61%)

26.94  5.24 0.81  0.02 9.52  2.31 —

26.78  5.2 0.81  0.02 9.15  1.9 10 (33%) 07 (23%)

26.58  5.2 0.81  0.02 8.92  1.63 18 (60%) 15 (50%)

27.55  6.0 0.81  0.02 8.90  1.71 28 (90%) 22 (73%)

The data were analysed within groups by the repeated measures ANOVA and Bonferroni’s post hoc analysis. * P < 0.05 is significant.

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Table 4 Metabolic and endocrine profile at specified time intervals during the protocol Month 0

Month 3

Month 6

Month 12

Group A (on metformin) Glucose (mg/dl) Insulin (mU/ml) HOMA QUICKI AUC glucose (mg/dl min) AUC insulin (mU/ml min) Testosterone (pg/ml) DHEAS (mg/ml) Androstendione (ng/ml)

82.68  1.74 13.11  2.45 4.58  0.22 0.60  0.02 13,663  334.8 26,962  1374.1 1.56  0.65 177.3  31.58 3.55  0.42

80.19  1.39 9.94  2.41 * 3.90  0.19 * 0.65  0.02 * 13,311  300.3 20,978  968.5 * 0.96  0.60 * 172.0  35.11 2.63  0.32 *

82.61  1.94 9.28  3.25 * 3.84  0.20 * 0.67  0.02 * 12,662  249.2 * 18,990  895.8 * 0.92  0.33 * 128.0  27.29 2.21  0.85 *

81.94  1.29 8.94  2.39 * 2.76  0.17 * 0.66  0.02 * 12,121  185.8 * 17,553  813.8 * 0.90  0.31 * 120.7  30.1 * 2.11  0.80 *

Group B (on rosiglitazone) Glucose (mmol/l) Insulin (mU/ml) HOMA QUICKI AUC glucose (mg/dl min) AUC insulin (mU/ml min) Testosterone (pg/ml) DHEAS (mg/ml) Androstendione (ng/ml)

79.93  1.83 11.38  5.16 4.19  0.24 0.63  0.02 12,932  197.3 25,868  1687 1.68  0.54 194.0  28.10 3.05  0.50

76.80  1.56 * 9.55  3.11 2.77  0.22 * 0.68  0.02 * 12,003  225.2 * 18,819  1070 * 1.49  0.45 187.78  29.08 3.08  0.69

78.00  2.18 8.22  3.68 * 2.58  0.20 * 0.72  0.03 * 11,434  151.4 * 16,237  1015 * 1.06  0.54 148.31  39.14 2.76  0.45

77.40  1.30 8.02  3.78 * 1.90  0.16 * 0.70  0.02 * 11,250  90.86 * 15,085  813 * 1.01  0.64 * 136.31  19.1 * 2.66  0.41 *

The data were analysed within groups by the repeated measures ANOVA and Bonferronis post hoc analysis. HOMA, homeostasis model assessment; QUICKI, quantitative sensitivity check index; AUC, area under the curve; DHEAS, dehydroepiandrosterone sulphate. * P < 0.05 is significant.

testosterone and androstenedione levels at 3 months, this effect persisted at 6 and 12 months. Rosiglitazone, however, caused a marginal decrease in these androgens at 6 months and a significant decrease at 12 months when compared to baseline.

and shown to improve the metabolic and hormonal disturbances of PCOS [9,30,31]. The data on the use of rosiglitazone in the treatment of PCOS is based on limited short-term studies [15,17—24]. Some smal-

Safety profile Both drugs were tolerated well. There was no apparent association of the occasional occurrence of a list of usual side-effects or peculiar symptoms and the different phases of the study. Subjects on metformin noted greater frequency of gastrointestinal disturbances (diarrhea, nausea and abdominal bloating) but not significant enough to warrant discontinuation of the drug. There were no changes from baseline in the serum levels of hepatic transaminases and creatine kinase in either group.

Discussion This study compared the effect of insulin sensitizers in subjects with PCOS who had clinical/biochemical criteria indicating hyperandrogenemia and insulin resistance. Metformin or rosiglitazone were administered to the subjects with PCOS and its effects were observed at three monthly intervals for a period of 1 year on hyperandrogenemia and insulin resistance. Metformin has been extensively used in

Figure 1 Comparison of peak and delta response of glucose (A) and insulin (B) with FSIGTT between women with PCOS who received metformin and those who received rosiglitazone for 12 months.

The efficacy of metformin versus rosiglitazone on insulin resistance and hyperandrogenemia in women with PCOS 43

ler studies have reported improvements in insulin resistance and hyperinsulinemia, hyperandrogenism, and ovulation in obese [17—21] and non-obese [15] PCOS women. The data comparing the effects of metformin and rosiglitazone in women with PCOS are limited [15,23,24,38]. In our study 1 year of treatment with either metformin or rosiglitazone did not cause any significant change in weight, BMI or waist hip ratio. There was no weight gain or increase in BMI appreciated in our subjects on rosiglitazone which is in agreement with most studies using thiazolidinediones in women with PCOS [19,21,22,32,33]; while a few studies have reported a increase in BMI [34,35]. Our results are in agreement with many studies which have shown no statistical decrease in BMI despite improvement in menstrual cyclicity during metformin therapy [9,10,31,35—39]; while some investigators have observed decrease in BMI and an improvement in menstrual function on metformin therapy [9,23,30,33,40—42]. The studies that have shown a statistical decrease in BMI had a larger sample size; thus our study as well as those who have not shown a decrease in BMI had a smaller sample size, which may have led to this finding. In agreement with our results several studies have shown an increase in ovulation and regular menses with no changes in weight, suggesting that the effect is independent of weight loss [9,10,31,34,43]. The waist hip ratio in overweight women with PCOS remained unchanged after 4 months of treatment with rosiglitazone in a study by Rautio et al. [22]; similar results have been reported in some [21,36] but not all studies on use of rosiglitazone in women with PCOS [20,32]. Hirsutism improved in the group treated by metformin while no improvement was noticed at any point of assessment in the group treated with rosiglitazone. Hirsutism scores in women with PCOS remained unchanged (8.92  0.9 vs. 8.45  0.9) after 4 months of rosiglitazone treatment in an earlier study [22]. Another study on early effects of metformin in women with PCOS found no significant change in hirsutism score after 12 weeks of metformin treatment [34]. A similar study had shown that both metformin and rosiglitazone improve ovarian function and hirsutism in patients with PCOS, while rosiglitazone appears better than metformin in the treatment of hirsutism and has better patient tolerance [23]. After 1 year of treatment, both drugs caused a significant decrease in serum levels of testosterone and androstenedione compared to the baseline values; the fall in these levels became significant much earlier (3 months) with metformin. An earlier study found no significant change in serum testos-

terone or androstenedione levels after 3 months of metformin treatment in women with PCOS [34]. Rautio et al. found a significant decrease in androstenedione level after 4 months of treatment with rosiglitazone (16.6 vs. 13.9 nmol/l) and no change in testosterone concentration (2.7 vs. 2.7 nmol/l) in overweight women with PCOS [22]. Some other studies have reported a decrease in serum testosterone in PCOS women with thiazolidinediones in association with improvements in hyperinsulinemia [19,21,32,36] and/or direct effects of these agents on ovarian steroidogenesis [35,44,45]. The levels of all androgens (testosterone, androstenedione, and DHEA-S) decreased significantly with rosiglitazone and with metformin at 12 months in our study. Other studies have revealed both unchanged [18,20] and decreased [19,21] androgen levels with rosiglitazone. Similar to our study Mitkov et al. have shown that metformin treatment influences better hyperandrogenemia while rosiglitazone affects more pronouncedly insulin resistance and hyperinsulinemia [38]. We found a significant improvement in glucose disposal on FSIGTT with both drugs; the effect became significant at third and sixth month of study in subjects treated with rosiglitazone and metformin, respectively, and persisted to the end of the study. This is in agreement with the results of other studies which showed improved glucose tolerance with rosiglitazone [18,21]. Rautio et al. reported that fasting plasma glucose concentrations were significantly lower (5.2  0.1 vs. 5.5  0.1 mmol/ l) at 4 months of treatment with rosiglitazone than with a placebo in a cohort of overweight PCOS women; the concentrations were similar at the start of treatment in rosiglitazone and placebo treated women (5.4  0.2 vs. 5.4  0.1 mmol/l) [22]. The measures of insulin sensitivity (AUC of insulin, HOMA-IR, and QUICKI) showed significant improvements from the basal values at all assessment points (3, 6, and 12 months) in women treated with either drug in our study. Interestingly, the improvement in insulin sensitivity occurred without any change in BMI in subjects treated with either of the drugs showing that improvement in insulin sensitivity was independent of adiposity. The possibility that redistribution of fat (at least with rosiglitazone) could be the basis for improved insulin sensitivity is unlikely as there was no change in waist hip ratio from the baseline value in either group. Other studies have also reported improved insulin sensitivity in thiazolidinedione treated PCOS women independent of any decrease in BMI or waist hip ratio [21,22]. Yilmaz et al. have found that both metformin and rosiglitazone increased insulin sensitivity in obese patients with PCOS and in lean

44 patients; further they found that rosiglitazone seems to be more effective in decreasing the androgen level and in achieving slightly greater improvement in menstrual disturbance then metformin [23]. In our study, we have seen that insulin resistance had an early and more benefit by the administration of rosiglitazone while metformin causes far more decrease in hyperandrogenemia. In a recent trial by Rouzi et al. [24], they have compared rosiglitazone and clomiphene citrate with metformin and clomiphene citrate; which have resulted in increased rates of ovulation and pregnancy and decreased hyperinsulinemia and hyperandrogenism. OrtegaGonzalez et al. [32] studied 52 females with PCOS and compared the response of serum androgen and insulin resistance to metformin and pioglitazone. They revealed that pioglitazone was more effective in improving insulin resistance while metformin had a greater effect on androgen level. Their findings are in accordance to our study. Mitkov et al. [38] had a prospective open-labelled study consisting of 30 females with PCOS in whom metformin and rosiglitazone given. At the end of the third month they concluded that the much better decrease in the level of testosterone and free androgen index was established in group treated with metformin, while the indices of insulin resistance were better influenced in the group treated with rosiglitazone. Baillergeon et al. [15] compared metformin and rosiglitazone alone and in combination in non-obese women with normal levels of insulin sensitivity; they found out that metformin was more effective in improving ovulation, systolic blood pressure, serum insulin levels and insulin sensitivity indices. A limitation of their study was the high drop-out rate in the rosiglitazone group because of unexpected delay in the availability of rosiglitazone. The discordant changes in insulin sensitivity and testosterone levels in two study groups could be explained in several ways (i) studies have shown a direct effect of metformin in reducing androgen production in theca cells of ovary [46,47]. Insulin has been shown to stimulate androgen production by thecal cells [48,49] as well as increasing levels of free testosterone by decreasing production of SHBG [50]. At the level of the adrenal gland hyperinsulinemia increases ACTH-stimulated adrenal androgen production [51]; therefore metformin decreases androgen levels both directly by suppressing androgen production by theca cells and indirectly by decreasing insulin levels, (ii) inter-group variation in indices of insulin sensitivity and (iii) inadequate dosage of the prescribed drug rosiglitazone. In conclusion, both metformin and rosiglitazone improved the metabolic parameters and clinical expressions of hyperandrogenism in women with

J. Ahmad et al. PCOS. Rosiglitazone have early benefit on insulin sensitivity while metformin have early and more sustained benefit on serum androgen levels. Such studies and more long-term studies on different insulin-sensitizing agents in women with PCOS are required to clarify the important questions surrounding the selection of a particular agent in a given clinical situation.

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