Semih Tugrul, M.D., Tayfun Kutlu, M.D., Oya Pekin, M.D., Elif Baglam, M.D., H useyin Kıyak, M.D., and Ozay Oral, M.D.

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1 Clinical, endocrine, and metabolic effects of acarbose, a a-glucosidase inhibitor, in overweight and nonoverweight patients with polycystic ovarian syndrome Semih Tugrul, M.D., Tayfun Kutlu, M.D., Oya Pekin, M.D., Elif Baglam, M.D., H useyin Kıyak, M.D., and Ozay Oral, M.D. Zeynep Kamil Women s and Children s Hospital, Istanbul, Turkey Objective: To determine the clinical, endocrine, and metabolic effects of acarbose use in overweight and nonoverweight patients with polycystic ovarian syndrome (). Design: Prospective analysis. Setting: Gynecology and infertility clinic of a tertiary care medical center. Patient(s): Seventy-four patients with and 30 healthy women. Intervention(s): Acarbose use. Main Outcome Measure(s): Clinical findings of hyperandrogenism, body mass indices, LH, FSH, DHEAS, total T, PRL, basal insulin, fasting glucose/insulin levels, and lipid profiles. Result(s): Acarbose treatment improved LH/FSH levels, decreased total T, DHEAS, basal insulin, low-density lipoprotein, very low-density lipoprotein, and triglyceride levels, and increased high-density lipoprotein levels in patients with. Basal insulin and fasting glucose/insulin levels reacted more significantly in overweight patients undergoing acarbose treatment. Conclusion(s): Acarbose has been found to improve insulin levels and thus glucose/insulin ratios more effectively in overweight patients compared with nonoverweight patients with. This drug seems to be an effective drug to be used in overweight as well as nonoverweight patients with. (Fertil Steril Ò 2008;90: Ó2008 by American Society for Reproductive Medicine.) Key Words: Acarbose, hyperinsulinemia, Polycystic ovarian syndrome () is a multisystemic disorder characterized by menstrual irregularities, hirsutism, hyperandrogenism, chronic anovulation, increased LH/ FSH ratio, and subfertility (1). Hyperinsulinemic insulin resistance is the universal face of and has a major role in pathogenesis (2). An oral glucose tolerance test (OGTT) of 20% of patients with shows impaired glucose handling (3). Hyperandrogenemia has been shown to be due to induction of thecal and stromal ovarian cells by increased insulin levels (4). Insulin has also been shown to enhance LH release and androgen secretion in hyperinsulinemic overweight and nonoverweight women (1, 5). These data suggest that hyperinsulinemia results in hyperandrogenism in some patients with. Long-term consequences of such as type II diabetes, hypertension, dyslipidemia, cardivascular diseases, gestational diabetes, endometrium, and ovary and breast cancers are important threats to women s health (6). Thus, it is vital to treat to prevent further problems. Reprint requests: Tayfun Kutlu, M.D., Zeynep Kamil Women s and Children s Hospital, Selimiye Kavak Iskele Cad. 16/ , Uskudar, Istanbul, Turkey (FAX: ; tayfunkutlu@gmail.com). Hyperinsulinemia plays a central role in the pathogenesis of ; however, the effectiveness of insulin-decreasing drugs in the treatment of has been challenging. Many agents have been used for this purpose in recent studies (7 10). Acarbose, a a-glucosidase inhibitor, is used in the current study. Acarbose is a common first-line treatment in type II diabetes mellitus. It is a pseudotetrasaccharide that inhibits intestinal a-glucosidase reversibly at the brush border of intestinal mucosa. The transformation of disaccharides to monosaccharides is prevented, the uptake of monosaccharides is retarded, and thus postprandial insulin and glucose levels are reduced (8, 11, 12). Adverse reactions are rare with this drug. Gradual dose increments prevent gastrointestinal side effects. The aim of our study is to understand clinical, endocrine, and metabolic results of acarbose treatment in overweight and nonoverweight patients with. MATERIAL AND METHODS Seventy-eight women with presented to Zeynep Kamil Women s and Children s Hospital between January and December 2006 and were enrolled in the study. There is no Institutional Review Board in our hospital, so we conducted the study under the surveillance of the clinical director, and 1144 Fertility and Sterility â Vol. 90, No. 4, October /08/$34.00 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 patients were asked for consent to participate in this research. None of the authors of this study has a conflict of interest. The following inclusion criteria were established for patients with : chronic anovulation (cycles >35 days or amenorrhea lack of menstruation for more than 6 months), signs of hyperandrogenism (hirsutism, acne seborrhea, and obesity), elevated LH/FSH ratios, and elevated serum T levels. By transvaginal ultrasound, all patients with showed subcapsular, peripherally located <8 mm follicles and hyperechogenic stroma. All patients were in good health, and none had taken any medication affecting carbohydrate metabolism or gonadal functions in the last 6 months. Thyroid function tests, serum PRL levels, and pubertal and sexual development were recorded as normal. Physical examination was performed; hirsutism was graded according to Ferriman and Gallwey (FG), and body mass index (BMI) was calculated for each woman. The following are the ranges of BMI categories: BMI <18.5 kg/m 2, underweight; kg/m 2, normal; kg/m 2, overweight; and R30 kg/m 2, obese. Serum low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglyceride, and cholesterol levels were measured. All subjects underwent OGTT (75 g glucose; Dextro O.G.-T. Saft, Boerhinger Mannheim, Mannheim, Germany). The results were defined according to the criteria of National Diabetes Group reported in 1979, and only subjects with normal 75 g on OGTTwere included in the study. Insulin levels were sampled after an overnight fasting at 08:00. Insulin resistance was defined as a fasting glucose/insulin ratio <4.5. Thirty patients with were randomly selected for the nontreated. Forty-eight patients were assigned to treatment with acarbose 300 mg/day (Glukobay, Bayer, _Istanbul) for 3 months. Thirty healthy subjects presenting to the gynecology clinic with minor complaints were enrolled in the study as the control. Control and study subjects underwent the same clinical, endocrine, and OGTT evaluations. None of the subjects followed a special diet. Four patients with in the acarbose were finally excluded from the study because of clinical pregnancy. All statistical evaluations were made by the Graphpad Prisma program, version 3 (Graphpad Software, San Diego, CA). Paired t-tests and independent t-tests were used for statistical analysis. P<.05 was considered statistically significant. RESULTS The data of 30 normal women and 74 patients with were studied after the exclusion of four patients from the initial 78 women because of spontaneous pregnancy. Age, gravidity, and parity of study and control s were similar. Patients with had significantly higher BMI (P<.05) and FG scores (P<.001). LH, total T, DHEAS, and basal insulin levels were found to be higher in the with (P<.001). FSH and PRL levels were found to be similar in normal subjects and patients with (P>.05). While serum total cholesterol, HDL, and LDL levels were statistically similar, VLDL and triglyceride levels were found to be higher in the with (P<.01; Table 1). Acarbose and nontreated s were similar for all parameters before treatment (Table 2). TABLE 1 Comparison of with and control. (n [ 74) Control (n [ 30) P Age, years NS Gravidity NS Parity NS FG score <.001 BMI, kg/m <.05 LH, miu/ml <.001 FSH, miu/ml NS Total T, nmol/l <.001 DHEAS, <.001 PRL, ng/ml NS Basal insulin, miu/ml <.001 Total cholesterol, NS HDL, NS LDL, NS VLDL, <.01 Triglyceride, <.01 Note: Data are mean SD. NS ¼ not significant. Tugrul. Acarbose use in. Fertil Steril Fertility and Sterility â 1145

3 All the parameters considered were assessed 3 months after the initiation of acarbose treatment. Total T, LH, DHEAS, basal insulin, LDL, VLDL, and triglyceride levels decreased, and HDL levels increased after acarbose use. But compared with the values of the nontreated, only the decrease of total T and VLDL levels of patients with treated with acarbose (P<.0001) and the increase of HDL levels were found to be statistically significant (P<.01; Table 2). Pretreatment values and the values 3 months later for nontreated patients did not show significant differences. Twelve patients (27.3%) on acarbose treatment reported gastrointestinal complaints such as abdominal pain, distention, and diarrhea. These complaints disappeared when we decreased the dose to 150 mg/day for days and later returned to 300 mg/day. Patients with were divided into overweight and nonoverweight s to evaluate the effects of acarbose treatment on patients with different BMIs. Pretreatment LH and FSH levels in the nonoverweight and basal insulin, total cholesterol, LDL, VLDL, and triglyceride levels in the overweight were found to be significantly higher (Table 3). LH/FSH ratio differences between overweight and nonoverweight s disappeared after acarbose treatment. Total T levels fell in both s, predominantly in the nonoverweight. Total cholesterol, LDL, VLDL, and triglyceride levels were higher in the overweight compared with before treatment. Serum HDL levels were increased in both s. Basal insulin levels were found to be higher in overweight patients both before and after acarbose treatment, but there still was an important decline in overweight subjects after treatment. Fasting glucose/insulin levels showed significant difference in overweight and nonoverweight patients. This difference disappeared after treatment owing to an increased fasting glucose/insulin ratio in overweight subjects (Table 3). DISCUSSION Realization of the role of hyperinsulinemia in pathogenesis has brought about the use of insulin-decreasing treatment modalities. Metformin was the first agent to be employed for this purpose in 1994 (7). Troglitazone, diazoxide, and acarbose are the agents that were used later. The various and contradictory results of studies on insulin-decreasing TABLE 2 Comparison of pretreatment values and values after 3 months for acarbose- and nontreated s. Pretreatment After 3 months Acarbose- (n [ 44) Nontreated (n [ 30) P Acarbose- (n [ 44) Nontreated (n [ 30) P BMI, kg/m NS NS FG score NS NS LH, miu/ml NS a NS FSH, miu/ml NS NS Total T, nmol/l NS a <.0001 DHEAS, NS a NS PRL, ng/ml NS NS Basal insulin, NS a NS miu/ml Fasting glucose/ NS NS insulin Total cholesterol, NS NS HDL, NS a <0.01 LDL, NS a NS VLDL, NS a <.0001 Triglyceride, NS a NS Note: NS ¼ not significant. a P<.05 compared with pretreatment values of acarbose-. Tugrul. Acarbose use in. Fertil Steril Tugrul et al. Acarbose use in Vol. 90, No. 4, October 2008

4 TABLE 3 Comparison of pretreatment data and data after 3 months for overweight and nonoverweight acarbose patients with. Pretreatment 3 Months later BMI <25 (n [ 19) BMI R25 (n [ 25) P BMI <25 (n [ 19) BMI R25 (n [ 25) P FG score < <.0001 LH, miu/ml < NS FSH, miu/ml < NS Total T, nmol/l NS <.05 DHEAS, NS NS PRL, ng/ml NS NS Basal insulin, < <.05 miu/ml Total cholesterol, < <.05 HDL, NS NS LDL, < <.01 VLDL, < <.01 Triglyceride, < <.01 Fasting glucose/ insulin < NS Note: NS ¼ not significant. Tugrul. Acarbose use in. Fertil Steril drugs and the rare hematologic and hepatic side effects of these drugs brought about further research studies on new agents. Geisthovel et al. have shown that serum glucose, insulin levels, and androgen production were decreased in premenopausal women with hyperinsulinemia and ovarian hypertestosteronemia after acarbose treatment (8). This study led to the idea that acarbose may be useful in the treatment of patients with who are also hyperinsulinemic and hyperandrogenemic. The first study of acarbose in patients with was carried out in 2001 by Ciotta et al. (9). They reported reduction of acne seborrhea score in hyperinsulinemic patients with treated with acarbose. This improvement was associated with a significant decrease of the insulin response to oral glucose load and of LH and androgen serum concentrations and with a significant rise in sex hormone binding globulin (SHBG) concentration. It was also reported that blood glucose concentrations after OGTT did not change significantly after acarbose treatment, but insulin response to OGTT and the insulinogenic index showed significant decrease. No clinical, metabolic, or hormonal modifications were observed in nontreated patients with. Here we have to remind the reader that all subjects selected had BMI values within the normal range. A similar study on clomiphene citrate (CC)-resistant patients with conducted by S onmez et al. revealed that both CC þ acarbose treatment and CC þ metformin treatment were effective in the treatment of insulin resistance and improving ovulation rates. The increase in the number of eumenorrheic and normoinsulinemic cases and the decrease in the number of insulin-resistant cases were significant in both s. The ovulation rate was greater in the metformin in the second month of therapy Acarbose was found to be an effective agent that could be used in cases with clomiphene-resistant. Reduction in weight and BMI were only significant in the acarbose (10). Penna et al. assessed the effects of low-dose acarbose (150 mg/day) on 30 obese patients with. They concluded that low-dose acarbose administered to obese patients with promotes a reduction in free androgen index and BMI and an increase in SHBG, with improvement of hirsutism and of the menstrual pattern, and is well tolerated by patients (13). Moghetti et al. reported that insulin inhibits 11 b hydroxysteroid dehydrogenase activity and effected adrenal steroidogenesis. The 11 b OH steroid dehydrogenase converts inactive cortisone into active cortisol, and its inhibition results in a decrease of cortisol and subsequently a decrease in central obesity (14). Pretreatment values of our population were similar to values of previous studies in the literature. Serum Fertility and Sterility â 1147

5 triglyceride and HDL levels were high in our study. DHEAS levels were also higher than in the healthy control. This finding is parallel with the finding of Martikainen et al., who performed selective adrenal gland vein catheterization and reported increased adrenal hormones in patients with. It was also found that adrenal androgen levels correlated well with serum insulin levels (15). In this study, we found that acarbose was able to reduce serum LH, androgens, and VLDL and to increase HDL levels in patients with. These effects were associated with a decrease in basal insulin levels. Reduction of LH seems to be related to decreased insulin levels during acarbose therapy. On the other hand, decreased LH concentrations contribute to the decline in LH-dependent adrenal androgen secretion. To our knowledge, our study is the first to compare the different effects of acarbose treatment on overweight and nonoverweight patients with. This study has confirmed that acarbose treatment decreases LH/FSH ratios in both overweight and nonoverweight s. This could be the indirect result of decreased LH concentrations related to lowered serum insulin levels. The decline in T levels is also explained by the reduction in insulin in hyperinsulinemic patients. Basal insulin levels fell especially in overweight subjects after treatment. We know that insulin resistance is more pronounced in overweight patients with (16). Accordingly fasting glucose/insulin levels were increased predominantly in overweight patients with acarbose therapy. In conclusion, acarbose has been found to improve insulin levels and thus glucose/insulin ratios more effectively in overweight patients than in nonoverweight patients with. Correction of hyperinsulinemia is central to the treatment of, and acarbose seems to be an effective drug to be used in overweight patients with. These results bring about an expectation of improvement in clinical aspects of such as fertility rates, hirsutism, acne seborrhea, and BMI as well as metabolic aspects of the syndrome in overweight patients with. REFERENCES 1. Franks S. Polycystic ovary syndrome. N Eng J Med 1995;333: Nestler JE. Role of the hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome and its clinical implications. Semin Reprod Endocrinol 1997;15: Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Endocrinol Metab 1996;81: Ehrmann DA. Insulin-lowering therapeutic modalities for polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28: Nestler JE, Jacubowicz D. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335: Legro RS, Kunselman AR, Donson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84: Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43: Geisthovel F, Frorath B, Brabant G. Acarbose reduces elevated testosterone serum concentrations in hyperinsuliaemic premenopausal women: a pilot study. Hum Reprod 1996;11: Ciotta L, Calogero AE, Farina M, De Leo V, La Marca A, Cianci A. Clinical, endocrine and metabolic effect of acarbose, an alpha-glucosidase inhibitor, in patients with increased insulin response and normal glucose tolerance. Hum Reprod 2001;16: Sonmez AS, Yasar L, Savan K, Koc S, Ozcan J, Toklar A, et al. Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome. Hum Reprod 2005;20: Laube H. Acarbose: an update therapeutic use in diabetes treatment. Clin Drug Invest 2000;22: Salvatore T, Giugliano D. Pharmacokinetic-pharmacodynamic relationships of acarbose. Clin Pharmacokinet 1996;30: Penna IA, Canella PR, Reis RM, Silva De Sa MF, Ferriani RA. Acarbose in obese patients with polycystic ovarian syndrome: a doubleblind, randomized, placebo-controlled study. Hum Reprod 2005;20: Moghetti P, Tosi F, Castello R, Magnani CM, Negri C, Brun E, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 1996;81: Martikainen H, Salmela P, Nuojua-Huttunen S, Perala J, Leinonen S, Knip M, et al. Adrenal steroidogenesis is related to insulin in hyperandrogenic women. Fertil Steril 1996;66: Meirow D, Yossipowitch O, Rosler A. Insulin resistant and nonresistant polycystic ovary syndrome represent two separate clinical and endocrinologic subs. Hum Reprod 1995;10: Tugrul et al. Acarbose use in Vol. 90, No. 4, October 2008

Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome

Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome FERTILITY AND STERILITY VOL. 69, NO. 4, APRIL 1998 Copyright 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Metformin therapy improves