ORIGINAL ARTICLE. D Florakis 1, E Diamanti-Kandarakis 2, I Katsikis 1, GP Nassis 3, A Karkanaki 1, N Georgopoulos 4 and D Panidis 1.

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1 (2008) 32, & 2008 Nture Publishing Group All rights reserved /08 $30.00 ORIGINAL ARTICLE Effect of hypocloric diet plus sibutrmine tretment on hormonl nd metbolic fetures in overweight nd obese women with polycystic ovry syndrome: rndomized, 24-week study D Florkis 1, E Dimnti-Kndrkis 2, I Ktsikis 1, GP Nssis 3, A Krknki 1, N Georgopoulos 4 nd D Pnidis 1 1 Second Deprtment of Obstetrics nd Gynecology, Division of Endocrinology nd Humn Reproduction, Medicl School, Aristotle University of Thessloniki, Thessloniki, Greece; 2 First Deprtment of Medicine, Endocrine Section, Medicl School, Liko Hospitl, University of Athens, Athens, Greece; 3 Deprtment of Sports Medicine nd Biology of Physicl Activity, University of Athens, Athens, Greece nd 4 Deprtment of Obstetrics nd Gynecology, Division of Reproductive Endocrinology, University of Ptrs Medicl School, Ptr, Greece Objective: To exmine the effect of hypocloric diet plus sibutrmine on body composition, hormonl nd metbolic prmeters in overweight nd obese ptients with polycystic ovry syndrome (PCOS). Design: Open-lbel, rndomized study t n outptient clinic. Ptients: A totl of 59 overweight nd obese (18 39 yers old) women with PCOS. Mesurements: All ptients were plced in hypocloric diet plus sibutrmine (10 mg per dy) for the first month nd then on hypocloric diet plus sibutrmine (10 mg per dy, group S) or hypocloric diet only (group D) for the subsequent 6 months. Body composition, hormonl nd metbolic fetures nd insulin sensitivity (orl glucose tolernce test, OGTT) were evluted t bseline nd t 3 nd 6 months of tretment. Results: Body weight reduced in both groups but the reduction ws greter with sibutrmine ( 15.4±1.1 vs 11.1±1.9% in groups S nd D, respectively, Po0.05). At 6 months, greter percent of ptients lost more thn 10% of initil body weight in group S thn D (81 vs 52.9%). In both groups, ll women with bnorml OGTT t bseline presented norml glucose tolernce fter 6 months. Free ndrogen index (FAI), glucose re under the curve nd fsting triglyceride (TG) concentrtion were reduced fter 6 months in group S only (Po0.05). No chnges in crdiovsculr risk fctors, prolctin nd heptic enzymes levels were observed in both groups. Conclusion: A hypocloric diet nd diet plus sibutrmine both result in significnt weight loss in overweight nd obese women with PCOS. Ptients who received sibutrmine showed greter weight loss nd improvement in hyperndrogenemi nd insulin sensitivity fter 6 months of tretment. The meliortion of insulin resistnce in this group could not be totlly explined by weight loss. Totl testosterone, FAI nd TG levels reduction could be possible mechnism. Finlly, sibutrmine incresed complince to diet nd it ws well tolerted from these ptients. (2008) 32, ; doi: /sj.ijo ; published online 11 December 2007 Keywords: sibutrmine; hyperndrogenemi; insulin sensitivity; polycystic ovry syndrome Introduction Correspondence: Dr D Florkis, Second Deprtment of Obstetrics nd Gynecology, Division of Endocrinology nd Humn Reproduction, Medicl School, Aristotle University of Thessloniki, 49 Konstndinoupoleos Street, Thessloniki, Greece. E-mil: gnssis@phed.uo.gr Received 11 July 2007; revised 21 October 2007; ccepted 5 November 2007; published online 11 December 2007 The polycystic ovry syndrome (PCOS) is one of the most common hormonl disorders of women of reproductive ge. As syndrome it hs multiple components, such s reproductive (chronic novultion nd infertility), metbolic nd crdiovsculr bnormlities. Although len women present PCOS, obesity is one of the min mnifesttions of this syndrome. PCOS prevlence is 5 7% in women of

2 reproductive ge, lthough cross-sectionl study in Greece reported prevlence of 9% mong women with hyperndrogenism nd prolonged menstrul cycles. 1 Androgen excess nd insulin resistnce (IR) underline much of the clinicl nd metbolic fetures of the syndrome. The 2003 Rotterdm consensus workshop revised the PCOS dignostic criteri suggesting tht it is syndrome of ovrin dysfunction long with the crdinl fetures hyperndrogenism nd polycystic ovry morphology. 2 Recent evidence suggests tht PCOS ptients hve substntil risk for the development of metbolic nd crdiovsculr bnormlities similr to those presented in the metbolic syndrome. 3 Therefore, PCOS hs been chrcterized s sex-specific form of the metbolic syndrome nd the term syndrome XX hs been suggested. 4 Mny fetures of the metbolic syndrome re common in PCOS, which represents unique model to investigte the ssocition between obesity nd femle reproductive function. Obesity, prticulrly of the bdominl type, is presented in pproximtely hlf of the women with PCOS, lthough studies show tht this rte vry from 30 to 75% nd from 10 to 38% in the Mediterrnen re. 3,5 Severl studies hve demonstrted tht obesity in PCOS women enhnces the clinicl nd metbolic bnormlities of the syndrome. Indeed, obese women with PCOS hve more profound IR or type 2 dibetes mellitus, 6 8 dyslipidemi nd risk of crdiovsculr disese, 9 12 nd greter level of ndrogens due to low levels of sex hormone-binding globulin (SHBG). 13 A modest weight loss (45% of initil body weight) improves ovultion frequency nd conception, reduces miscrrige, hyperlipidemi, hypertension, hyperglycemi nd IR in women with PCOS There re only few studies in the literture on the effect of ntiobesity drug dministrtion on metbolic nd other prmeters in overweight nd obese women with PCOS. Previous studies with orlistt nd metformin showed significnt reduction in body weight, ndrogen levels nd metbolic crdiovsculr risk fctors in PCOS women. 22,23 To our best knowledge, the effect of sibutrmine, serotonin nd norepinephrine reuptke inhibitor (SNRI) pproved s ntiobesity drug, hs been exmined in only one study with obese PCOS women. 24 Given this lck of informtion, the im of the present study ws to investigte ny dditionl effect of sibutrmine combined with hypocloric diet on body composition, hormonl nd lipids prmeters, nd IR in overweight nd obese women with PCOS. Sibutrmine, hyperndrogenemi nd insulin resistnce in PCOS D Florkis et l study. The dignosis of PCOS ws bsed on evidence of hyperndrogenemi (free ndrogen index, FAI45) with history of oligomenorrhe (cycle length o21 or435 dys; o8 cycles per yer). Women with no clssicl 21-hydroxylse deficiency, hyperprolctinemi, drenl or ovrin tumor nd Cushing s disese were excluded by the pproprite tests. Other exclusion criteri were hypertension, thyroid dysfunction, overt dibetes mellitus nd concomitnt tretment, such s ntihypertensive drugs, selective serotonin reuptke inhibitor or other SNRI drug, orl contrceptive pills or ny other ntindrogen tretment (cyproterone cette, spirolctone, luteinizing hormone (LH) relese hormone gonist) nd insulin-sensitizing gents (metformin, pioglitzone, rosiglitzone) tht my interct with insulin sensitivity nd lipid profile. Written informed consent ws obtined from ech womn. The study ws conducted t the Division of Endocrinology nd Humn Reproduction outptient clinic fter receiving pprovl from the Ntionl Ethics Committee of the Hellenic Drug Orgniztion. The tril ws conducted in ccordnce with the guidelines of the Helsinki declrtion. We certify tht ll pplicble institutionl nd governmentl regultions concerning the ethicl use of humn volunteers were followed during this reserch. A totl of 84 women with PCOS were recruited nd 59 of them completed the study (Figure 1). Study design This ws prospective, open-lbel, rndomized, comprtive tril. The study design included three periods; screening period to confirm the PCOS dignosis, run-in period (4 weeks durtion) tht ll ptients received 10 mg per dy sibutrmine plus 600 kcl deficient diet, tretment period (for the subsequent 6 months) tht subjects were rndomized in 2:1 rtio to the S group (10 mg per dy of sibutrmine plus hypocloric diet) nd the D group (hypocloric diet only). The run-in period ws dopted by ll ptients, to chieve substntil weight loss nd therefore increse complince to tretments. Diet ws bsed on Hypocloric Diet plus Sibutrmine Group (Group S) STUDY S POPULATION 84 women with PCOS enrolled Hypocloric Diet Group (Group D) 693 Ptients nd methods 56 women enrolled 46 obese 10 overweight 28 women enrolled 19 obese 9 overweight Subjects Outptients, premenopusl, nonpregnnt, nonlctting, overweight nd obese women (body mss index, BMI427), 18 yers of ge nd older with PCOS were recruited for this 42 women completed the study 37 obese 5 overweight Figure 1 Schemtic presenttion of the study popultion. 17 women completed the study 12 obese 5 overweight

3 694 Sibutrmine, hyperndrogenemi nd insulin resistnce in PCOS D Florkis et l individul bsl metbolic rte s defined by the Hrris- Benedict eqution, djusted for moderte physicl ctivity. Before entering the run-in period ll subjects were prescribed n energy-restricted diet contining 50% of energy s crbohydrte, 30% of ft (10% sturted) nd 20% of protein. Subjects were dvised not to modify their eting hbits throughout the study period. The rndomiztion ws performed using seled envelopes prepred in dvnce of the study by reserch ssocite not involved in the study. A rndomiztion tble ws creted using blocks of three numbers with ll possible combintions, to chieve the rndomiztion 2:1 rtio to S nd D groups. A rndom number genertor ws used to keep blnce between tretment groups. Abbott Lbortories Hells provided the study drug. Clinicl mesures Body weight, wist circumference nd fsting blood smples for the determintion of totl testosterone (T), SHBG, dehydroepindrosterone sulfte (DHEAS), ndrostenedione (D4A), 17-hydroxyprogesterone, follicle-stimulting hormone (FSH), LH, thyroid-stimulting hormone, totl cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose nd insulin were tken t bseline s well s t 3 nd 6 months of tretment. At the sme time, n orl glucose tolernce test (OGTT) with 75 g glucose ws performed. Blood smples were collected between 0830 nd 0900 hours, fter n overnight fst, lwys between dys 3 nd 7 of women s menstrul cycle (folliculr phse). IR ws clculted using (1) the homeostsis model of ssessment of insulin resistnce, HOMA-IR (insulin (muml 1 ) glucose (mmol l 1 )/22.5), 25 nd (2) the re under the curve (AUC) for glucose. This re ws clculted from vlues t 0 (fsting), 30, 60, 90 nd 120 min of the OGTT with the trpezoid rule. Monthly, subjects body weight ws recorded, dverse events, hert rte, blood pressure nd study drug complince were determined, nd pregnncy urine test ws crried out. Body weight ws lwys mesured t morning hours with subjects in light clothing. Study mesurements nd ssys methods Plsm glucose concentrtion ws determined with the glucose oxidse method using n utonlyser (Roche/ Hitchi 902; Roche Dignostics GmBH, Mnheim, Germny). LH, FSH, prolctin (PRL), ndrogen nd 17-OH-progesterone (dt not shown) levels were mesured with rdioimmunossy, while SHBG levels were determined with immunordiometric ssy (IRMA) method, using commercil kits (FSH, LH nd PRL: Rdioisotopic Kit, Nichols Institute Dignostics, Sn Jun Cpistrno, CA, USA; T, D4A, DHEA-S, 17-OH progesterone: Rdioisotopic Kit, Dignostic Systems Lbortories, Webster, TX, USA; SHBG: Immunordiometric Assy (IRMA) Kit, Dignostic Systems Lbortories, USA. Serum insulin ws mesured with n enzyme immunossy (ELISA Kit, Mercodi AB, Uppsl, Sweden). The intr-ssy coefficients of vrition (CV) were 1.5% for FSH, 0.7% for LH, 2.7% for PRL, 1.3% for T, 5.9% for D4A, 9.4% for DHEA-S, 5.8% for SHBG nd 3.8% for insulin. The verge inter-ssy CV were 3.2% for FSH, 1.7% for LH, 3.4% for PRL, 2.2% for T, 9.2% for D4A, 12.1% for DHEA-S, 7.8% for SHBG nd 4.4% for insulin. Clcultions Body mss index ws clculted s weight (kg) divided by height (m) squred. Wist nd hip circumferences were mesured in duplicte t the upright position, nd their rtio (WHR) ws clculted. FAI ws clculted s: T (nmol l 1 ) 100/SHBG (nmol l 1 ). 26 Sttisticl nlysis The normlity of distribution ws checked for ll vribles with the Kolmogorov Smirnov test. All vribles were normlly distributed. Sttisticl nlysis ws performed using the bsolute vlues s well s the percentge chnge from bseline t 3 nd 6 months of tretment. Percent chnges from bseline nd the percent chnge difference between groups were evluted with the Student s t-test for independent smples. Comprisons of mens between groups throughout the mesurement time points were performed with repeted mesures two-wy nlysis of vrince. An nlysis of covrince (ANCOVA) ws employed to test the differences in FAI nd glucose AUC. Body weight t ech time point ws used s covrite in the former nlysis nd body weight nd totl testosterone were the covrites in the ltter nlysis. Effect of tretment (time) ws set s the within-subjects fctor, with group (D or S) s the between-subjects fctor. Post hoc nlysis ws performed fter Bonferroni djustment when F ws significnt for the interction. Comprison of frequencies for women losing more thn 10% of their initil body weight in ech group ws performed using w 2 -test. Finlly, the reltions between vribles were tested with the Person s correltion coefficient. All nlyses were performed by the sttisticl pckge SPSS, v.13.0 (SPSS Inc., Chicgo, IL, USA). Two-tiled sttisticl significnce ws set t 5%. Dt re presented s men±stndrd error of the men (s.e.m.). Results Body weight nd body ft distribution Men ge ws 23.5±1.1 (rnge 18 36) yers in group D nd 25.2±0.9 (rnge 18 39) yers in group S. The medin (rnge) BMI ws ( ) kg m 2 nd ( ) kg m 2 in groups D nd S, respectively. At bseline, 5 women were overweight (29.4%) nd 12 obese (70.6%) in group D

4 Sibutrmine, hyperndrogenemi nd insulin resistnce in PCOS D Florkis et l Body weight (kg) ** ** D S Months Androgens Percent chnge from bseline in T nd SHBG t 6 months ws significnt in group S only (Po0.01; Tble 1). FAI ws lower with sibutrmine fter 3 nd 6 months of tretment compred with bseline when n ANCOVA ws employed with body weight t ech mesurement time s covrites (Figure 3). No such decline ws seen in the hypocloric diet group. Finlly, the percent decline in FAI fter 6 months compred with bseline, ws greter in group S thn in D ( 29.7±4.8 vs 2.7±11.6%, respectively, Po0.01). 695 Body weight chnge from bseline (%) months Period 6 months D S * Figure 2 Men body weight (upper prt) nd body weight chnges (lower prt) in overweight nd obese women with PCOS plced on hypocloric diet (D, N ¼ 17) nd hypocloric diet plus sibutrmine (S, N ¼ 42) for 6 months. 1, bseline mesurement; 0, end of run-in period; Po0.001 from bseline; *Po0.05 between groups. **Po0.01 between groups. wheres 5 women were overweight (11.9%) nd 37 obese (88.1%) in group S. Body weight t bseline ws higher in group S thn D (94.5±1.9 vs 87.7±3.4 kg, Po0.01; Figure 2), but this difference disppered t the end of the run-in period (S, 87.6±2.2 kg; D, 83.6±3.8 kg; P ¼ 0.34). Percent chnge in body weight t the end of run-in period did not differ between groups (S, 5.3±0.3%; D, 5.0±0.4%). After 3 nd 6 months of tretment, body weight nd BMI were lower compred with bseline in both groups (Po0.05). However, women who received sibutrmine presented lower (Po0.05) body weight nd BMI t 6 months compred with 3 months mesurement (Figure 2). After 6 months, percent chnge in body weight ws greter in group S thn D ( 15.4±1.1 vs 11.1±1.9%, respectively, Po0.05). A greter percent of women lost more thn 10% of their initil body weight in this 6-month period in group S thn in the group D (81 vs 52.9%, respectively, w 2 ¼ 4.804, d.f. ¼ 1, Po0.05). At the end of study, 15 obese women t bseline becme overweight (40.5% of obese t bseline) nd 7 becme norml (18.9%) in group S. In group D, five obese women t bseline becme overweight (41.7%) nd one obese becme norml (8.3%) t the end of 6 months. Finlly, centrl diposity ws reduced in both groups s indicted by the lower wist circumference t 3 nd 6 months compred to bseline (Po0.05; Tble 1). Insulin, glucose nd insulin resistnce At bseline, 14 of 42 women hd n bnorml OGTT (33.3%) in group S nd 4 of 17 women (23.5%) in group D. At the end of the study, no subject hd n bnorml OGTT in group S wheres only one womn hd n bnorml OGTT in group D. Fsting insulin nd HOMA-IR did not differ between groups (Tble 1). Glucose AUC ws lower fter 6 months of tretment compred with bseline in group S (964.0±25.5 vs 819.7±25.3 mmol per min per l, Po0.05), when ANCOVA ws employed with body weight nd totl testosterone s covrites (Figure 3). Percent chnge in AUC t 6 months, compred to bseline, ws lso greter in group S thn D (Po0.05). Blood lipids, prolctin levels, heptic enzymes nd crdiovsculr risk fctors Blood lipids s well s serum glutmic oxlocetic trnsminse (SGOT), serum glutmic pyruvic trnsminse (SGPT) nd g-glutmyl trnsferse (ggt) concentrtions did not differ between groups t bseline (Tble 1). Percent reduction in TG ws greter in group S thn in D (Po0.05). In ddition, percent chnge from bseline t 6 months ws significnt in group S for TC (Po0.05), HDL-C (Po0.05), SGOT (Po0.05), SGPT nd ggt (Po0.01), systolic (Po0.01) nd distolic (Po0.01) blood pressure (Tble 1). Prolctin levels were unchnged in both groups (Tble 1). Correltions In the sibutrmine group (N ¼ 42), percent decline in body weight fter 6 months ws correlted with percent chnges in FAI (r ¼ 0.337, Po0.05), SHBG (r ¼ 0.467, Po0.01), fsting insulin (r ¼ 0.575, Po0.01), SGOT (r ¼ 0.397, Po0.01) nd ggt (r ¼ 0.35, Po0.05). When dt were nlyzed for the hypocloric diet group (N ¼ 17), percent decline in body weight fter 6 months ws ssocited with the percent chnges in the heptic enzymes only (r ¼ nd for SGPT nd ggt, Po0.05). Subject s complince rte nd dverse events Fourteen women (nine obese nd five overweight) were lost to follow-up during the first 2 months of tretment in group

5 696 Sibutrmine, hyperndrogenemi nd insulin resistnce in PCOS D Florkis et l Tble 1 Anthropometric dt, metbolic nd crdiovsculr vribles t bseline, fter 3 nd 6 months of tretment with hypocloric diet (N ¼ 17) nd hypocloric diet plus sibutrmine (N ¼ 42) in overweight nd obese women with PCOS Vrible Diet plus sibutrmine (group S) Hypocloric diet (group D) Bseline 3 months 6 months Bseline 3 months 6 months Age 25.2± ±1.1 Weight (kg) 94.5±1.9** 82.9± ±2.1,b 87.7± ± ±3.6 Wist circumference (cm) 99.5±1.3** 89.5± ±1.4,b,c 94.1± ± ±2.8,c WHR 0.84± ± ±0.00 c 0.82 ± ± ±0.00 c BMI (kg m 2 ) 34.4± ± ±0.8,b,c 33.0± ± ±1.1,c Fsting insulin (mmol l 1 ) 143.6± ±6.5 84±7.9 c 127± ± ±14.3 c Fsting glucose (mmol l 1 ) 5.87± ± ± ± ± ±0.12 HOMA-IR 5.4± ± ±0.3 c 4.5± ± ±0.6 c Totl testosterone (nmol l 1 ) 2.78± ± ±0.10 c 2.67± ± ±0.15 SHBG (nmol l 1 ) 26.1± ± ±3.0 c 28.3± ± ±2.8 D4A (nmol l 1 ) 9.77± ± ± ± ± ±1.05 DHEA-S (mmol l 1 ) 8.55± ± ± ± ± ±0.65 FSH (U l 1 ) 5.28± ± ±0.29 d 5.22± ± ±0.38 LH (U l 1 ) 7.25± ± ±0.82 d 7.29± ± ±1.40 d PRL (mu l 1 ) 250±14 254±18 254±18 258±28 244±20 294±32 TG (mmol l 1 ) 1.30± ± ±0.06 c 1.04± ± ±0.09 Totl cholesterol (mmol l 1 ) 4.95± ± ±0.13 d 4.7± ± ±0.23 HDL-C (mmol l 1 ) 1.13± ± ±0.03 d 1.18± ± ±0.04 LDL-C (mmol l 1 ) 3.23± ± ± ± ± ±0.20 SBP (mm Hg) 112.7± ± ±1.8 c 106.8± ± ±1.8 c DBP (mm Hg) 75.8± ± ±1.4 d 72.4± ± ±2.6 d HR (bets per min) 78.8± ± ± ± ± ±3.2 SGOT (U l 1 ) 19.1± ± ±0.6 d 19.8± ± ±1.4 SGPT (U l 1 ) 24.6± ± ±1.5 c 22.7± ± ±3.2 d ggt (U l 1 ) 22.5± ± ±1.1 c 22.1± ± ±3.4 Abbrevitions: D4A, ndrostenedione; BMI, body mss index; DBP, distolic blood pressure; DHEA-S, dehydroepindrosterone sulfte; FSH, follicle-stimulting hormone; ggt, g-glutmyl trnsferse; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostsis model ssessment of insulin resistnce; HR, hertrte; LDL-C, low-density lipoprotein cholesterol; LH, luteinizing hormone; PRL, prolctin; SBP, systolic blood pressure; SGOT, serum glutmic oxlocetic trnsminse; SGPT, serum glutmic pyruvic trnsminse; SHBG, sex hormone-binding globulin; TG, triglyceride; WHR, wist-to-hip rtio. Men±s.e.m. Po0.01 from bseline. b Po0.05 from 3 months mesurement. *Po0.05 nd **Po0.01 compred with the hypocloric diet group. c,d Percent chnges re significnt from bseline (Po0.01 nd Po0.05, respectively) D S S (25% drop out rte) nd eleven women (seven obese nd five overweight) in group D (39.2%). No serious dverse effects were reported during the study period. FAI 5 Discussion Glucose AUC (mmol x min/l) Bseline Bseline 3 months 3 months D S 6 months 6 months Figure 3 Free ndrogen index vlues (FAI, upper prt) nd glucose re under the curve (AUC, lower prt) fter 24-week tretment with hypocloric diet (D, N ¼ 17) nd hypocloric diet plus sibutrmine (S, N ¼ 42) in overweight nd obese women with PCOS. Po0.001 from bseline. The min finding of this study ws tht hypocloric diet nd diet supplemented with sibutrmine both reduce body weight within 3 months in overweight nd obese women with PCOS. However, body weight decline ws more pronounced in the group of women who received sibutrmine, while women on diet only showed plteu in the second trimester of tretment. More ptients chieved greter thn 10% weight loss, which is considered of clinicl significnce, when diet ws supplemented with sibutrmine. This could be ttributed to the greter ptient complince with the drug. In the sibutrmine group, hyperndrogenemi nd IR were lso meliorted. This is the first study to compre the effect of low-clorie diet nd diet plus sibutrmine on body composition, hormonl nd metbolic fetures in PCOS women. A previous investigtion in obese ptients with PCOS showed

6 15.5% reduction in body weight fter 6 months of tretment with sibutrmine. 24 However, direct comprison of the present with the bove-mentioned study cnnot be mde due to the different protocols employed. The greter weight loss in the sibutrmine group in the present study could be due to the sibutrmine s mode of ction. Sibutrmine increses stiety, results in greter weight loss compred to diet lone nd thus elevtes subjects motivtion. This could explin the higher complince with sibutrmine, compred to diet only, in the present study. In ddition, sibutrmine exerts thermogenic effect nd this could lso prtilly explin the greter decline in body weight with sibutrmine. 27,28 Another mechnism for the greter reduction in body weight in the sibutrmine compred to the diet group could be the mintennce of plsm leptin levels with sibutrmine, s previously shown. 29,30 Hyperndrogenemi ws reduced in both groups in the present study nd this reduction ws more pronounced in the sibutrmine group, s evidenced by the greter decline in FAI from bseline t 6 months of tretment (Figure 3). In ddition, totl testosterone levels decresed nd SHBG incresed in group S, indicting tht weight loss with diet plus sibutrmine my improve hyperndrogenemi nd hirsutism. These findings re in ccordnce with previous clinicl studies ,23,31,32 The reduction in FAI could be, t lest in prt, due to the greter weight loss in group S thn D. A previous report in PCOS women showed reduction in hyperndrogenemi with sibutrmine tretment in such ptients. 24 It is of note tht ll subjects with glucose intolernce t bseline presented norml OGTT t 6 months of tretment, except for one. This finding is in greement with the view tht weight loss per se is the most importnt fctor for improvement in glucose metbolism in previously obese ptients with bnorml crbohydrte metbolism. An interesting finding of the present study ws tht insulin sensitivity, s exmined with the OGTT AUC, ws improved t 6 months of tretment in S group (Figure 3), nd this effect ws not totlly explined by the reduction in body weight nd totl testosterone levels. The improvement in IR with sibutrmine is in ccordnce with other studies. 24,33,34 It is difficult to speculte on the effect of sibutrmine on IR. Centrl obesity nd in prticulr the mount of viscerl ft is ssocited with IR in obese ptients. Wist circumference chnge did not differ between conditions in the present study. However, this finding does not exclude the possibility tht viscerl ft reduction might hve been greter in the sibutrmine group, s previously shown with such tretment in obese ptients. 29 The meliortion of hyperndrogenemi nd the reduction in TG concentrtion in group S could be n explntion for the improvement in IR. In the present study, 12 14% reduction in body weight with sibutrmine or diet only did not ffect insulin sensitivity in these ptients, wheres beneficil effect ws observed t bout 15.5% reduction of the initil body weight in the sibutrmine group. This Sibutrmine, hyperndrogenemi nd insulin resistnce in PCOS D Florkis et l percent reduction coincided with 6 months tretment with sibutrmine. Bsed on this observtion we could speculte tht there is criticl weight loss, which seems to be round 15%, to observe significnt improvement in IR in women with PCOS. Given the greter reduction in TG concentrtion with sibutrmine, compred to diet-only in the present study, we could lso speculte tht this reduction contributed to the greter insulin sensitivity observed in the former group. This finding suggests n essentil role of free ftty cids in the pthogenesis of IR in obesity. Prolctin ws unchnged nd this is lso of interest since sibutrmine is wek reuptke inhibitor of dopmine nd prolctin levels my be modertely incresed in PCOS women. 35 However, prolctin levels t bseline were within the norml rnge in these women nd this should be kept in mind when interpreting these dt. It hs been reported tht sibutrmine my cuse mild elevtion in hert rte nd blood pressure. However, studies with sibutrmine hve shown n improvement in blood pressure in obese hypertensive nd normotensive ptients suggesting tht body weight reduction per se my llevite this potentilly hrmful effect of sibutrmine In the present study, the reduction in blood pressure ws significnt from bseline wheres hert rte did not chnge with sibutrmine. It should be noted, however, tht our study popultion ws young normotensive women without preexisting crdiovsculr disese. Fsting leptin levels nd insulin concentrtion during the OGTT were not determined nd these re limittions of this study. In ddition, insulin sensitivity ws evluted with OGTT, which is n indirect method for insulin-sensitivity ssessment. The mechnism for insulin sensitivity improvement with sibutrmine tretment in PCOS women should be explored in future studies. Although the used method for determining testosterone levels is not precise, ll the currently commercilly vilble testosterone RIAs suffer from relibility regrding sensitivity, specificity nd intr-ssy vribility. 39,40 Nevertheless, ll prticipting women to this study hd confirmed dignosis of PCOS bsed on oligomenorrhe, clinicl consequence of chronic novultion, the clinicl hyperndrogenism nd the ppernce of PCO morphology in the ultrsound exmintion. In conclusion, hypocloric diet nd diet plus sibutrmine both result in significnt weight loss in overweight nd obese women with PCOS. However, body weight reduction ws more pronounced in women receiving sibutrmine. Sibutrmine tretment lso resulted in meliortion of hyperndrogenemi nd IR in these women. The improvement in insulin sensitivity in women who received sibutrmine could not be totlly explined by weight loss. Totl testosterone, FAI nd TG levels reduction could be possible dditionl mechnism, but further studies re needed to explore these findings. It seems tht hypocloric diet supplemented with sibutrmine increses the ptients complince to diet. 697

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