Evaluation of Apelin and Insulin Resistance in Patients with PCOS and Therapeutic Effect of Drospirenone-Ethinylestradiol Plus Metformin

Transcription

1 e-issn DOI: /MSM Received: Accepted: Published: Evlution of Apelin nd Insulin Resistnce in Ptients with PCOS nd Therpeutic Effect of Drospirenone-Ethinylestrdiol Plus Metformin Authors Contribution: Study Design A Dt Collection B Sttisticl Anlysis C Dt Interprettion D Mnuscript Preprtion E Literture Serch F Funds Collection G E 1 Xinchng Sun BC 2 Xingguo Wu C 3 Yn Zhou D 4 Xinyn Yu A 5 Wenjun Zhng 1 Deprtment of Physiology, Tishn Medicl University, Tin, Shndong, P.R. Chin 2 Deprtment of Gynecology, The Centrl Hospitl of Tin, Tin, Shndong, P.R. Chin 3 Deprtment of Obstetrics, Affilited Hospitl of Tishn Medicl University, Tin, Shndong, P.R. Chin 4 Center for Reproductive Medicine, The Centrl Hospitl of Tin, Tin, Shndong, P.R. Chin 5 Center for Reproductive Medicine, Affilited Hospitl of Tishn Medicl University, Tin, Shndong, P.R. Chin Corresponding Author: Wenjun Zhng, e-mil: wenjunzhng1119@163.com Source of support: This work ws supported by the development of science nd technology pln of Tin City ( ) Bckground: Mteril/Methods: Results: Conclusions: MeSH Keywords: Full-text PDF: The im of this study ws to determine the relevnce of pelin nd insulin resistnce (IR) with polycystic ovry syndrome (PCOS) nd to ssess the possible therpeutic effect of the combined therpy of drospirenone-ethinylestrdiol (DRSP-EE) combined with metformin. Sixty-three PCOS ptients nd 40 non-pcos infertile ptients were recruited. The fsting serum levels of follicle stimulting hormone (FSH), luteinizing hormone (LH), testosterone (T), prolctin (PRL), estrdiol (E 2 ), glucose (FBG), insulin (FINS), nd pelin t the erly folliculr phse were mesured. To further investigte the reltion between pelin nd IR, we treted the PCOS ptients with DRSP-EE (1 tblet dily, 21 d/month) plus metformin (500 mg tid) for 3 months. All of the bove indices were mesured gin fter tretment. 1) Levels of pelin, LH, LH/FSH, T, nd FINS, s well s homeosttic model ssessment of IR (HOMA-IR) in PCOS ptients, were significntly higher thn in the control group before tretment. 2) These indices significntly decresed fter tretment with DRSP-EE plus metformin. 3) Correltion nlysis showed tht pelin level ws positively correlted with body mss index (BMI), FINS level, nd HOMA-IR. Apelin level significntly incresed in PCOS ptients. The combined therpy of DRSP-EE plus metformin not only decreses IR, but lso improves pelin level. This combintion is superior pproch for PCOS tretment. Body Mss Index Insulin Resistnce Polycystic Ovry Syndrome

2 Sun X. et l.: Evlution of pelin nd insulin resistnce in PCOS Bckground Polycystic ovry syndrome (PCOS) is common endocrine/metbolic disorder [1] mong women of reproductive ge. PCOS is chrcterized by chronic novultion (oligomenorrhe or menorrhe) nd hyperndrogenemi (hirsutism, cne, nd incresed ndrogen hormone plsm level, or combintion of these conditions) [2]. Mny studies indicte tht PCOS is ssocited with metbolic disorders [3,4] tht led to crdiovsculr events, dyslipidemi, nd insulin resistnce (IR) [5,6]. IR with hyperinsulinemi plys n importnt role in the development of hyperndrogenism through the enhncement of ndrogen hormone biosynthesis in the ovries In ddition, IR nd the resultnt hyperinsulinemi rise the risk of long-term metbolic disorders, such s impired glucose tolernce, type 2 dibetes, nd crdiovsculr diseses. Apelin is bioctive peptide originlly identified from bovine stomch extrcts s the endogenous lignd of the G proteincoupled receptor APJ [7]. Apelin hs been recently identified s new dipokine expressed nd secreted by mture dipocytes in both humns nd mice [8,9]. The pelinergic system hs been demonstrted to be involved in the pthogenesis of mny conditions, such s hypertension, hert filure, glucose intolernce, nd dibetes mellitus [10 12]. Apelin my be key regultor in glucose nd lipid metbolism nd my be ssocited with IR. PCOS is ssocited with the occurrence of IR nd other metbolic disorders, such s dyslipidemi, hypertension, nd therosclerosis. Bsed on these fcts, we conducted this study to determine whether serum pelin levels re different between PCOS women nd helthy women. We lso evluted the therpeutic effects of drospirenone-ethinylestrdiol (DRSP-EE) plus metformin combintion on PCOS. Mteril nd Methods PCOS ptients We recruited 63 PCOS women from the Outptient Center of Reproductive Medicine t the Affilited Hospitl of Tishn Medicl University between Mrch 2014 nd Jnury None of the ptients hd used hormonl preprtions, including orl contrceptives (OC). PCOS ws dignosed ccording to the 2003 Rotterdm Criteri with t lest 2 of the following fetures: oligomenorrhe or menorrhe, clinicl or biochemicl hyperndrogenism, nd polycystic ovries on ultrsound. Ptients with oligomenorrhe or hyperndrogenism cused by ny other clinicl conditions were excluded, such s nonclssicl 21-hydroxylse deficiency, congenitl drenl hyperplsi, hypothyroidism, Cushing s syndrome, or significnt elevtion in serum prolctin (PRL) [13,14]. Control group Forty infertile women with regulr menstrul periods (26 dys menstrul period <35 dys) were recruited s control group t the sme period. All of the controls were crefully evluted to void ny selection bis. None of them hd ny hirsutism or other mnifesttion of hyperndrogenism, sonogrphic evidence of PCOS, sign of glctorrhe, thyroid dysfunction, or dibetes, nor hd ny received hormonl therpy (including orl contrceptives) or ny drug therpy in the lst 3 months. This study ws pproved by the Institutionl Review Bord of Tishn Medicl University. Written informed consent ws obtined from ll prticipnts. PCOS ptients were divided into subgroups A (BMI <25 kg/m 2 ) nd B (BMI ³25 kg/m 2 ) by body mss index (BMI). Similrly, the controls were divided into subgroups C (BMI <25 kg/m 2 ) nd D (BMI ³25 kg/m 2 ). Clinicl nd biochemicl mesurements Serum levels of luteinizing hormone (LH), follicle stimulting hormone (FSH), estrdiol (E 2 ), testosterone (T) nd PRL were mesured during the erly folliculr phse (dys 2 to 5 of the menstrul cycle). Serum smples were collected fter fsting for 12 hours to test pelin, glucose (FBG), nd insulin (FINS), totl cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), nd high-density lipoprotein (HDL) levels. In PCOS ptients, the lst menstrul period ws either spontneous or induced by the dministrtion of dydrogesterone (10 mg/d for 7 dys). FBG ws detected by the oxidse method with n AU640 biochemicl uto-nlyzer (Olympus Compny, Hmburg, Germny). FSH, LH, T, PRL, E 2, T, nd FINS were detected by chemiluminescence immuniztion. Blood lipid levels were mesured using n Ft-7060 precipittion nd enzymtic device (Beckmn Coulter Inc., Glwy, Irelnd). Apelin ws determined by pltinum enzyme-linked immunosorbent ssy (ELISA) kit (ebioscience, North Americ). PCOS ptients were treted with drospirenone-ethinylestrdiol (DRSP-EE, 3 mg DRSP 30 ug EE, 21d/month) plus metformin (500 mg tid) for 3 months. The bove prmeters were recorded t dy 0 nd t 3 months fter tretment. IR expressed s the homeosttic model ssessment of IR (HOMA-IR) ws clculted s fsting glucose fsting insulin/22.5. BMI ws clculted s the weight (kg) divided by the squre of body height (m 2 ). Sttisticl methods Descriptive chrcteristics re reported s men ± stndrd devition (X±SD). The differences in clinicl, hormonl, nd 2548

3 Sun X. et l.: Evlution of pelin nd insulin resistnce in PCOS CLINICAL RESEARCH Tble 1. Comprison of hormonl chrcteristics mong four groups (X _ ±SD). A (n=40) B (n=23) C (n=20) D (n=20) FSH (IU/L) 5.78± ± ±1.46,b 6.76±1.45,b LH (IU/L) 10.65± ± ±1.89,b 4.55±1.35,b LH/FSH 1.85± ± ±0.30,b 0.69±0.20,b T (ng/dl) 48.48± ± ±10.21,b 28.41±10.69,b PRL (ng/ml) 17.91± ± ± ±8.01 E 2 (pg/ml) 45.75± ± ± ±21.35 Compred with A, P<0.05; b compred with B, P<0.05. Tble 2. Comprison of clinicl, metbolic chrcteristics mong four groups (X _ ±SD). A (n=40) B (n=23) C (n=20) D (n=20) Age 27.45± ± ± ±4.20 Weight (kg) 57.74± ±6.92* 53.30±5.86,b 72.20±4.34 Height (cm) ± ± ± ±4.32 BMI (kg/m 2 ) 21.80± ±3.93* 20.39±2.17,b 27.43±1.76,b,c FBG (mmol/l) 5.31± ± ± ±0.44 FINS (uiu/l) 15.97± ± ±3.42,b 9.96±4.67,b HOMA-IR 3.79± ± ±0.41,b 2.42±0.50,b TC (mmol/l) 4.86± ± ±0.71,b 4.48±0.74 b TG (mmol/l) 1.17± ± ± ±0.87 HDL(mmol/L) 1.25± ± ±0.36,b 1.33±0.31 LDL (mmol/l) 3.00± ± ± 0.66,b 2.92± 0.51 Apelin (ng/ml) 2.09± ±0.86* 0.24±0.08,b 0.48±0.13,b Compred with A, P<0.05; b compred with B, P<0.05; c compred C, P<0.05 biochemicl vribles mong subgroups were evluted by 1-wy nlysis of vrince (ANOVA) on SPSS 15.0 (Chicgo, IL, USA). The modifictions linked to the tretment of PCOS were evluted with the t test for pired dt. Correltion ws nlyzed by Person s test nd multiple stepwise regression nlysis. P<0.05 ws considered s significnt. Results Comprison of clinicl, hormonl, nd metbolic prmeters mong the 4 subgroups before tretment The PCOS group ws not significntly different in ge, height, FBG level, or TG level from the control group, but hd higher pelin level, FINS level, nd HOMA-IR (Tble 2). Comprisons before nd fter combined tretment in PCOS women After the 3-month combined tretment with DRSP-EE plus metformin, the levels of pelin, T, LH, LH/FSH, nd FINS, s well s HOMA-IR, were decresed significntly (P<0.05). The levels of FBG, TC, TG, HDL, LDL, nd FSH did not chnge significntly (P>0.05) (Tbles 3, 4). PCOS ptients nd the controls hd similr E 2 nd PRL levels. However, PCOS women hd significntly higher levels of LH, LH/FSH, nd T thn the controls (Tble 1). 2549

4 Sun X. et l.: Evlution of pelin nd insulin resistnce in PCOS Tble 3. Comprison of hormonl chrcteristics before nd fter tretment (X _ ±SD). Non-obese PCOS group Obese PCOS group Before tretment After tretment Before tretment After tretment FSH (IU/L) 5.78± ± ± ±1.57 LH (IU/L) 10.65± ± ± ±0.84 LH/FSH 1.85± ± ± ±0.31 T (ng/dl) 48.48± ± ± ±8.15 PRL (ng/ml) 17.91± ± ± ±5.48 E 2 (pg/ml) 45.75± ± ± ±13.74 Before nd fter tretment, P<0.05. Tble 4. Comprison of clinicl, metbolic chrcteristics before nd fter tretment (X _ ±SD). Non-obese PCOS group Obese PCOS group Before tretment After tretment Before tretment After tretment BMI 21.80± ± ± ±4.55 FBG (mmol/l) 5.31± ± ± ±0.57 FINS (uiu/l) 15.97± ± ± ±3.54 HOMA-IR 3.79± ± ± ±0.65 TC (mmol/l) 4.86± ± ± ±0.98 TG (mmol/l) 1.17± ± ± ±0.31 HDL(mmol/L) 1.25± ± ± ±0.32 LDL (mmol/l) 3.00± ± ± ±0.64 TC (mmol/l) 4.86± ± ± ±1.27 Apelin (ng/ml) 2.09± ± ± ±0.58 Before nd fter tretment, P<0.05. Tble 5. correltion nlysis of serum Apelin nd the vribles. FSH LH LH/FSH T PRL E 2 r p Weight BMI FBG FINS HOMA-IR TC TG HDL LDL r p < < P<0.01. Correltions Apelin level is positively correlted with BMI, FINS level, nd HOMA-IR (Tble 5). Multiple stepwise regression nlysis showed tht BMI nd HOMA-IR were the independent fctors relted to the level of serum pelin. Discussion PCOS is the most common endocrine cuse of menstrul irregulrities, hirsutism nd cne, but its pthogenesis remins uncler. IR nd its compenstory hyperinsulinemi ply n importnt role in the pthogenesis of PCOS. This study shows tht 2550

5 Sun X. et l.: Evlution of pelin nd insulin resistnce in PCOS CLINICAL RESEARCH FINS level nd HOMA-IR s prmeters of IR in PCOS women re significntly different from the control group. Also, serum T levels re significntly different in PCOS women with nd without obesity compred with the control group. This result suggests tht IR nd hypotestosteronemi re ctively involved in the pthogenesis of PCOS regrdless of obesity. The increse of LH level probbly plys n importnt role in the pthologicl mechnism of the higher ndrogens production in the ovries, which cn interfere with the mturtion of the oocyte. In the present study, the serum LH levels re significntly higher, while FSH level is lower in PCOS women compred with controls. These results further confirm tht high LH level nd reltive insufficiency of FSH re the chrcteristics of PCOS. Apelin is recently discovered peptide tht is designted s n endogenous receptor lignd nd found in severl orgns such s hert, brin, kidneys, nd lungs [15]. Apelin level is relted with the occurrence of obesity nd IR [9]. Recently, vrying expression levels of pelin nd its receptor (APJ) hve been observed in different stges of cttle ovrin follicles [16,17]. There is little dt in the literture regrding chnges in pelin level or its reltion to PCOS, nd even the existing published results re inconsistent. One published reserch study reported lower pelin level in norml-weight PCOS women thn in control subjects [18]. Choi et l. published similr finding of significntly lower serum pelin levels in PCOS women [19]. These 2 studies lso suggest tht serum pelin level is positively correlted with polipoprotein A level, but is negtively correlted with totl testosterone level nd free ndrogen index (FAI) independent of IR. Moreover, serum pelin levels re lower in PCOS women thn in controls [20]. In contrst to this finding, Cekmez et l. [21] reported tht the men level of pelin is higher in PCOS dolescents thn in controls, nd the pelin level is positively correlted with BMI nd HOMA- IR [21]. However, similr pelin levels between women with nd without PCOS were lso reported in other clinicl reserch studies [22]. In our present study, however, serum pelin levels re significntly higher in PCOS women compred with controls. Moreover, we lso observed tht pelin level is significntly nd positively correlted with BMI, HOMA-IR, nd FINS level. These results re consistent with previous study (Cekmez et l.). Discrepnt findings mong the published studies my be ttributed to the differences in ethnicity, ge, study design, smple size, genetic chrcteristics of popultions, nd ssessment methodology. The limittion of our study is tht the size of both groups ws smll, which perhps resulted in inconsistent findings; therefore, further studies re required in lrger cohorts with different genetic bckgrounds. Pnnciulli et l. [23] found the IMT-CCA ws significntly higher in young dult norml-weight, overweight, nd obese glucose-tolernt first-degree reltives of type 2 dibetic ptients compred with control subjects with no fmily history of dibetes. Considering the metbolic fetures of PCOS, such s T2DM, obesity, nd insulin resistnce, fmily-bsed studies re needed to further investigte the ssocition between Apelin nd PCOS. After the 3-month tretment with DRSP-EE plus metformin, PCOS ptients show significntly decresed levels of pelin, FINS, LH, LH/FSH, nd T, s well s HOMA-IR. A multivrite regression nlysis found tht, in ddition to IR, the use of the combined tretment lso reduced pelin level, LH level, nd other prmeters, which indictes tht pelin level is relted to IR. Thus, we speculte tht pelin level reduction cn improve IR nd reduce the risk of crdiovsculr events, dyslipidemi, nd IR ssocited with PCOS. The combintion of metformin nd DRSP-EE might be recommendtion for tretment of PCOS. Conclusions Chinese PCOS women exhibit higher pelin levels thn controls. Serum pelin level is positively correlted with BMI nd HOMA-IR. The tretment with metformin plus drospirenoneethinylestrdiol is effective for the reduction of insulin resistnce, pelin level, nd the improvement of other prmeters linked with higher risk of type 2 dibetes mellitus nd crdiovsculr diseses. Erly recognition, proper intervention, nd long-term monitoring re therefore necessry, nd pelin is cndidte trget for tretment of PCOS nd follow-up. Acknowledgements We re grteful to ll the prticipnts involved in this study. Conflict of interest The uthors hve no conflicts of interest. References: 1. Shyy R, Chng RJ: Reproductive endocrinology of dolescent polycystic ovry syndrome. BJOG, 2010; 117(2): Leo VD, L MA, Petrgli F: Insulin-lowering gents in the mngement of polycystic ovry syndrome. Endocr Rev, 2003; 24(5): Prk HR, Choi Y, Lee HJ et l: The metbolic syndrome in young Koren women with polycystic ovry syndrome. Dibetes Res Clin Prct, 2007; 77(Suppl.1): S Brnov A, Trn TP, Birerdinc A, Younossi ZM: Systemtic review: ssocition of polycystic ovry syndrome with metbolic syndrome nd non-lcoholic ftty liver disese. Aliment Phrmcol Ther, 2011; 33(7):

6 Sun X. et l.: Evlution of pelin nd insulin resistnce in PCOS 5. Sung YA: Insulin resistnce in polycystic ovry syndrome. Koren Dibetes J, 2008; 32: Stnley T, Misr M: Polycystic ovry syndrome in obese dolescents. Curr Opin Endocrinol Dibetes Obes, 2008; 15(1): Ttemoto K, Hosoy M, Hbt Y et l: Isoltion nd chrcteriztion of novel endogenous peptide lignd for the humn APJ receptor. Biochem Biophys Res Commun, 1998; 251: Kleinz MJ, Dvenport AP: Emerging roles of pelin in biology nd medicine. Phrmcol Ther, 2005; 107: Boucher J, Msri B, Dviud D et l: Apelin, newly identified dipokine up-regulted by insulin nd obesity. Endocrinology, 2005; 146: Flcão-PiresI I, Gonçlves N, Henriques-Coelho T et l: Apelin decreses myocrdil injury nd improves right ventriculr function in monocrotline-induced pulmonry hypertension. Am J Physiol Hert Circ Physiol, 2009; 296(6): H Msri B, Knibiehler B, Audigier Y: Apelin signlling: promising pthwy from cloning to phrmcology. Cell Signl, 2005; 17: Li L, Yng G, Li Q et l: Chnges nd reltions of circulting visftin, pelin, nd resistin levels in norml, impired glucose tolernce, nd type 2 dibetic subjects. Exp Clin Endocrinol Dibetes, 2006; 114: Rotterdm ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on dignostic criteri nd long-term helth risks relted to polycystic ovry syndrome. Fertil Steril, 2004; 81(1): Shi Y, Guo M, Yn J et l: Anlysis of clinicl chrcteristics in lrge-scle Chinese women with polycystic ovry syndrome. Neuro Endocrinol Lett, 2007; 28(6): Ricrdo L, João F, Adelino F: The pelinergic system: the role plyed in humn physiology nd pthology nd potentil therpeutic pplictions. Arq Brs Crdiol, 2008; 90: Shimizu T, Kosk N, Murym C et l: Apelin, APJ receptor expression in grnulos, thec cells during different stges of folliculr development in the bovine ovry: Involvement of poptosis nd hormonl regultion. Anim Reprod Sci, 2009; 116: Schilffrth S, Antoni B, Schms D et l: The expression of pelin nd its receptor APJ during different physiologicl stges in the bovine ovry. Int J Biol Sci, 2009; 5: Chng CY, Tsi YC, Lee CH et l: Lower serum pelin levels in women with polycystic ovry syndrome. Fertil Steril, 2011; 95: e Choi YS, Yng HI, Cho S et l: Serum symmetric dimethylrginine, pelin, nd tumor necrosis fctor-levels in non-obese women with polycystic ovry syndrome. Steroids, 2012; 77: Altinky SÖ, Nergiz S, Küçük M, Yüksel H: Apelin levels in reltion with hormonl nd metbolic profile in ptients with polycystic ovry syndrome. Eur J Obstet Gynecol Reprod Biol, 2014; 176: Cekmez F, Cekmez Y, Pirgon O et l: Evlution of new dipocytokines nd insulin resistnce in dolescents with polycystic ovry syndrome. Eur Cytokine Netw, 2011; 22: Olszneck-Glininowicz M, Mdej P, Nylec M et l: Circulting pelin level in reltion to nutritionl sttus in polycystic ovry syndrome nd its ssocition with metbolic nd hormonl disturbnces. Clin Endocrinol, 2013; 79: Pnncciulli N, De Pergol G, Ciccone M et l: Effect of fmily history of type 2 dibetes on the intim-medi thickness of the common crotid rtery in norml-weight, overweight, nd obese glucose-tolernt young dults. Dibetes Cre, 2003; 26(4):