Review Article The Role of Metformin in Metabolic...

Review ArticleThe Role of Metformin in MetabolicDisturbances during Pregnancy Polycystic OvarySyndrome and Gestational Diabetes Mellitus

Joselyn Rojas Mervin Chaacutevez-Castillo and Valmore Bermuacutedez

Endocrine and Metabolic Diseases Research Center School of Medicine University of Zulia 20th Avenue Maracaibo 4004 Venezuela

Correspondence should be addressed to Joselyn Rojas rojasjoselyngmailcom

Received 21 June 2014 Revised 7 November 2014 Accepted 19 November 2014 Published 8 December 2014

Academic Editor Daniela Romualdi

Copyright copy 2014 Joselyn Rojas et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Maintenance of gestation implicates complex function of multiple endocrine mechanisms and disruptions of the global metabolicenvironment prompt profound consequences on fetomaternal well-being during pregnancy and postpartum Polycystic OvarySyndrome (PCOS) and gestational diabetes mellitus (GDM) are very frequent conditions which increase risk for pregnancycomplications including early pregnancy loss pregnancy-induced hypertensive disorders and preterm labor among many othersInsulin resistance (IR) plays a pivotal role in the pathogenesis of both PCOS and GDM representing an important therapeutictarget with metformin being the most widely prescribed insulin-sensitizing antidiabetic drug Although traditional views neglectuse of oral antidiabetic agents during pregnancy increasing evidence of safety during gestation has led to metformin now beingrecognized as a valuable tool in prevention of IR-related pregnancy complications and management of GDM Metformin has beendemonstrated to reduce rates of early pregnancy loss and onset of GDM in women with PCOS and it appears to offer bettermetabolic control than insulin and other oral antidiabetic drugs during pregnancy This review aims to summarize key aspectsof current evidence concerning molecular and epidemiological knowledge on metformin use during pregnancy in the setting ofPCOS and GDM

1 Introduction

Infertility currently affects approximately 485 million ofwomen aged 20ndash44 years around the world [1] with severeimplications in their physical and mental well-being [2]Female fertility entails a complex array of endocrine mech-anisms surrounding the integrity of the hypothalamus-pitu-itary-ovary (HPO) axis which are especially important inmaintenance of a healthy pregnancy particularly due to thedemands of the growing fetus [3] Many conditions maydisrupt this environment and Polycystic Ovary Syndrome(PCOS)mdashan endocrine-metabolic disease that encompassesmultiple hormonal alterations related to female infertilitymdashstands outmainly due to its high prevalence affecting 6-7ofwomen aged 12ndash45 years [4] with aworrisome 70ofwomenestimated to remain undiagnosed [5]

The hallmarks of this gynecoendocrine disease are dis-ruption of ovarian steroidogenesis giving rise to hyper-androgenemia and insulin resistance (IR) [6] A complex

IR-hyperinsulinemia-hyperandrogenemia cycle involved inthe endocrine disruptions in PCOS [7] leads not only to thetypical clinical picture of PCOSmdashfeaturing oligoanovulationand hyperandrogenic manifestationsmdashbut also to diversecardiometabolic comorbidities such as impaired glucosetolerance [8] dyslipidemia [9] hypertension [10] centralobesity [11 12] accelerated atherosclerosis [13] andmetabolicsyndrome [14] which can appear as a myriad of distinctmetabolic phenotypes [15] including mild moderate andsevere forms of PCOS

Insulin resistance is an important component in theetiopathogenesis of PCOS being associated with obesityacanthosis nigricans hirsutism [16] and early pregnancy loss[17] in these women In addition utilizing the HOMA-IRindex as a surrogate for IR quantification Huidobro et al [18]reported this condition to be associated with gestationaldiabetes mellitus (GMD) which supports the notion thatthis pregnancy-related metabolic disorder may be part of

Hindawi Publishing CorporationInternational Journal of Reproductive MedicineVolume 2014 Article ID 797681 14 pageshttpdxdoiorg1011552014797681

2 International Journal of Reproductive Medicine

Table 1 Diagnostic criteria for Polycystic Ovary Syndrome

Clinical or biochemical hyperandrogenism Oligoanovulation US finding of polycystic ovarieslowast

NIH 1990BOTH of the following + +

ESHAREASRM 2003ONLY 2 of the following + + +

AES 2006ALL 3 of the following + + +

NIH = National Institute of Health of the United States ESHRE = European Society of Human Reproduction and Embryology ASRM = American Society ofReproductive Medicine AES = Androgen Excess and PCOS SocietyAll sets of criteria require the exclusion of other etiologies such as congenital adrenal hyperplasia androgen-secreting neoplasms and Cushingrsquos syndromeamong otherslowastUltrasound polycystic ovaries defined as the presence of ge12 follicles of 2ndash9mm width or an increase in ovarian volume (gt10mL) in at least one ovary inwomen not consuming oral contraceptives

the insulin resistance syndrome [14 19] Moreover GDM isobserved in almost 50 of pregnancies in womenwith PCOS[10] which has been described as an independent predictorof the former [20] Although the consequences of PCOS arenot limited to reproductive dysfunction these implicationsoften represent the most critical aspect for both patients andclinicians as it conveys an increase in the risk for pregnancy-induced hypertension preeclampsia and preterm birth [20]

Amidst the metabolic milieu generated by PCOS GDMappears when pancreatic 120573-cell function is unable to com-pensate the converging increase of both PCOS-related IR andnormal gravidic IR [21] Given the profound influence IRexerts on reproduction it has become an important pharma-cological target associated with improvement of ovulationinduction [22] prevention of endocrine-metabolic gesta-tional complications [23] and management of GDM [24] Tothis end oral antidiabetic agents such as metformin havebeen proposed as a valuable tool during pregnancy [25] albeitremaining an FDA Pregnancy Category B drug [26]

The purpose of this review is to describe the phar-macology of metformin during gestation and analyze itsbenefits in metabolically challenged pregnancies such as inwomen with PCOS andor GDM We have compiled severalpeer-evaluated studies both prospective and cross-sectionalwhich aid in the description and analysis of the role ofmetformin during pregnancy including animal models invitro analyses and clinical studiesThese data were organizedper the following reasoning (a) the role of IR in the develop-ment of PCOS and GDM (b) the impact of their endocrine-metabolic derangements in pregnancy and (c) the use ofmetformin in regards to PCOS and pregnancy and in GDM

2 Insulin Resistance as the Key EndocrineDisruption in Polycystic Ovary Syndrome

The etiology of PCOS is complex and multifactorial includ-ing several endocrine disturbances such as (a) increased pul-satile secretion of gonadotropin-releasing hormone (GnRH)and luteinizing hormone (LH) prompting theca cell hyper-stimulation and androgen hypersecretion [27] (b) nonselec-tion of a dominant ovarian follicle mediated by intrinsic andextrinsic ovary factors with follicular cells hyperplasia [28]

(c) genetic predisposition to hyperandrogenemia linked toabnormal in utero androgenic exposure [29] and (d) geneticpredisposition to hyperinsulinemia also linked to prenatalandrogen exposure and pancreatic 120573-cell dysfunction [30]Although it is difficult to establish the relative importanceor chronology of these and subsequent alterations PCOSis characterized by an IR-hyperinsulinemia-hyperandrogene-mia positive feedback circuit (Figure 1) where the latter com-ponent determines themajority of clinicalmanifestations andthe diagnostic criteria for this condition (Table 1) Moreoverobesity is a very common feature in females with PCOSwhich appears to magnify all previous pathophysiologicmechanisms [7]

Insulin resistance defined as a decrease in cellularresponsiveness to insulin signaling [31] triggers increasedinsulin secretion a phenomenon termed ldquocompensatoryhyperinsulinemiardquo [32] Although this mechanism attemptsto maintain lipid carbohydrate and protein metabolismhomeostasis it contributes to multiple aggregate conse-quences such as the cardiovascular PCOS comorbidities [33]and favors hyperandrogenemia through various pathways Inthis respect disruption of the HPO is particularly relevantinsulin has been shown to elevate GnRH and LH secre-tion both dose- and time-dependently [34 35] potentiallymediated through the MAPK pathway [36] This results inincreased frequency and amplitude of GnRH and LH pulsesecretion with increased LHFSH ratio potentiating ovar-ian steroidogenic alterations [6] Other features frequentlyfound in women with PCOS act in synergy with insulintowards enhancing LH release including hyperleptinemia viaAgRPNPY neural pathways and kiss peptidergic signaling[37] and decreased opioidergic tone which appears to sen-sitize pituitary LH-secreting cells to GnRH signaling [38]Hyperinsulinemia has also been associated with diminishedSex Hormone-Binding Globulin (SHBG) levels althoughinsulin appears to be unable to directly inhibit shbg expres-sion instead this effect depends on hyperglycemia-mediatedHepatocyte Nuclear Factor 4-120572 downregulation [39] LowerSHBG synthesis results in increased sex hormone availabilityexacerbating androgenic signaling [40]

Lastly PCOS is also characterized by selective IR inovarian tissue whereinmitogenic pathways are favored while

International Journal of Reproductive Medicine 3

Hyperinsulinemia Hyperandrogenemia

Ovarian cysts-oligoanovulation-hyperandrogenism

Insulin resistance

Obesity Chronicinflammation

Manifestations

Infertility complications during pregnancy

Arterial hypertension-dyslipidemia-metabolic syndrome Type 2 diabetes mellitus and cardiovascular disease

Figure 1 The insulin resistance-hyperinsulinemia-hyperandrogenemia cycle in Polycystic Ovary Syndrome PCOS is dominated by threemajor endocrine disruptions insulin resistance hyperinsulinemia and hyperandrogenemia Although it is difficult to establish whichdisturbance develops first in any given case these components are interconnected by many reinforcing mechanisms constituting a positivefeedback cycle Furthermore obesity and chronic inflammatory statesmdashpresent in both obese and lean women with PCOSmdashamplifypathophysiologic pathways linked to all elements in this triad The cycle leads to the manifestations of PCOS and infertility complicationsduring pregnancy and chronic cardiometabolic comorbidities

metabolic signaling is absent yielding follicular cell hyperpla-sia and potentiation of steroidogenesis [41] Several theoriessurround this concept including cAMP-dependent activa-tion of PKA with subsequent activation of SteroidogenicAcute Regulatory (StAR) protein [42] increased PI3KAktactivity via serine phosphorylation by a hypothetical kinase intheca cells [43] and inositolphosphoglycan signaling whichappears to deviate from insulin-dependent pathways asidefrom being activated by the insulin receptor itself [44] Atany rate IR-hyperinsulinemia activity leads to hyperandro-genemia which in turn induces pro-IR structural and func-tional modifications in key insulin target tissues includingdecreased amount of more oxidative insulin-sensitive type Imuscle fibers and increased amount of more glycolytic lesssensitive type II fibers [40] as well as elevated lipolysis inadipocytes favoring free fatty acid- (FFA-) mediated IR [45]perpetuating the IR-hyperinsulinemia-hyperandrogenemiafeedback [7]

Although physical activity and lower caloric intake areconsidered fundamental lifestyle interventions [46] insulin-sensitizing agents are also a hallmark of PCOS manage-ment with metformin being the most frequently usedmolecule [47] Metformin has been described to offer sig-nificant improvement of several parameters including BodyMass Index (BMI) LH androstenedione testosterone [48]DHEAS blood pressure [49] menstrual cyclicity fastinginsulin [50] IR dyslipidemia oxidative stress endothelialdysfunction [51] and several inflammatorymarkers [52]Thisbiguanide has also been reported to improve other featuressuch as anovulation rate and acne [53] as well as BMI and LH[54] in non-IR women with PCOS Moreover it appears to

be beneficial in both obese and lean women with PCOS [53]which may explain the persistent benefits of metformin evenwith several different metabotypes

The subset of leanwomenwith PCOS is particularly inter-esting Although all PCOS phenotypes tend towards a moreldquoapple-likerdquo adipose distribution [55] lean subjects usuallyhave less visceral fat [56] Likewise in these individuals IRand hyperandrogenemia are predominantly related to lowSHBG levels [57] with increased risk for elevated inflamma-tion markers [58] and early vascular disease [59] Althoughboth lean and obese PCOS women tend to exhibit higheroxidative stress [60] they appear to behave differently regard-ing aging and risk of developing type 2 diabetes mellitus(DM2) which seems to be less frequent in lean women withPCOS [61] Indeed women who are able to maintain normalweight with aging appear to boast a healthier metabolicprofile than those who do not [62] These differences mayinfluence the impact of metformin in each group [63]whereas reproductive benefits are observed in both obese andlean PCOS women [64] metabolic advantages such as low-ering of proinsulin and insulin levels are seen predominantlyin the obese and overweight subset [65]

Other antidiabetic drugs have been evaluated to beapplied in PCOS particularly thiazolidinediones (TZD)Despite reports indicating these agents to be more effectivethan metformin at reducing IR in subjects with PCOS[66] their use remains less widespread due to concerns ofincreased cardiovascular risk [67] Indeed despite signif-icantly ameliorating IR glucose homeostasis hyperandro-genic ovarian response and systemic inflammation [68 69]TZD appear to induce several deleterious modifications in


Pregnancy

Insulin resistance Hyperinsulinemia

Obesity

Free fatty acids Glucose

acids

Preferentialmaternal

metabolism

Preferentialfetal

metabolism

Gestational diabetes mellitus

uarr hPL estrogen progesterone cortisol and prolactin

Defective INS-R phosphorylationdarr IRS-1 expression

uarr p85120572 subunit of PI3K expressiondarr GLUT4 expression

uarr Pancreatic 120573-cell massuarr Insulin expression

uarr GSIS

uarr INS-R phosphorylation defectsuarr IRS-1 phosphorylation defects

uarr Chronic inflammation

uarr p70 S6K1 expressiondarr Adiponectin

darr PPAR120574

uarr Free fatty uarr Glucose

Maternal implications uarr weight uarr DM2 risk and other endocrine-metabolic disturbances

Offspring implications worse pregnancy outcomes uarr risk of postpartumendocrine-metabolic disturbances

Figure 2 Mechanisms underlying insulin resistance in normal pregnancy physiology and gestational diabetes mellitus Insulin resistance is aphysiologic state which develops parallel to increased secretion of hPL estrogen progesterone cortisol and prolactin principally Althoughthey favor IR by altering components of peripheral insulin signaling cascades they also activate various mechanisms enhancing 120573-cellfunction The result is an increased release of free fatty acids which are predominantly metabolized by mothers allowing for shunting ofglucose towards fetal metabolism In obesity several pathophysiologic mechanisms worsen IR in target tissues leading to greater free fattyacid levels and dysregulation of glucose homeostasis DM2 type 2 diabetes mellitus GSIS glucose-stimulated insulin secretion hPL humanplacental lactogen INS-R insulin receptor IRS-1 insulin receptor substrate-1 PPAR120574 peroxisome proliferator-activated receptor 120574

cardiac tissue transcriptomes including upregulation of met-alloproteinases implicated in atheromatous plaque rupturepotassium channels required for action potential generationand genes involved in sphingolipid and ceramidemetabolism[70] Beyond these molecular findings the impact of TZD oncardiovascular risk is also reflected in epidemiologic findingswith a higher risk of congestive heart failure in prediabeticand diabetic subjects (RR= 172 95CI 121ndash242119875 = 0002)[71]

3 Exacerbation of Physiologic InsulinResistance as the Fundament of GestationalDiabetes Mellitus

Insulin resistance is a physiologic state during gestationdriven by several maternal hormones such as estrogenprogesterone cortisol and particularly human placental lac-togen (hPL) [72] Target cell modifications include defectivetyrosine phosphorylation of the 120573 subunit of the insulinreceptor [73] and decreased expression of IRS-1 [74] whereasexpression of the p85120572 subunit of phosphoinositol 3-kinase isincreased which interferes with heterodimeric conformationof this enzyme and thus prevents further insulin signaling[72] Similarly GLUT4 expression has been noted to be

decreased in adipose tissue of pregnant females significantlyhindering insulin responsiveness [75] Although the elevatedserum levels of free fatty acids triggered by IR representan important adaptive mechanism in order to increase theglucose offer for fetal metabolism they also serve as a self-reinforcing pathway for IR (Figure 2) [76]

These pro-IR phenomena are counterbalanced by severalpancreatic function-enhancing signals which allow for thetypical over twofold increase in insulin secretion during thesecond and third trimesters of gestation [77] These signalsinclude hPL prolactin and estrogens all of which rise pro-gressively and prominently throughout pregnancy [78] asso-ciated with increases in pancreatic 120573-cell mass and insulintranscription and improve glucose-stimulated insulin secre-tion by promoting glucokinase and GLUT-2 expression aswell as raising glucose utilization and oxidation in pancreatic120573 cells [78] These compensatory pathways are valuable asthey aim to maintain adequate glucose metabolism whilstallowing for increased FFA production [77] Nonethelessthese mechanisms may be intrinsically defective or insuffi-cient in some women leading to the development of GDMdefined as glucose intolerance of onset or first recognitionduring pregnancy [79]

To this end obesity is an important risk factor for GDMwith an OR = 26 95 CI 21ndash34 119875 lt 005 [80] Aside from


enhancing all previously described pro-IR mechanisms [72]obesity favors the development of a systemic inflammatorystate with elevated levels of mediators such as TNF [81] Thiscytokine is implicated in IR by allowing IRS-1 serine phos-phorylation via activation of JNK and NF-120581B pathways [82]Likewise states of nutrient excess have been linked to upreg-ulation of p70 S6K1 an IRS-1 serine kinase which inducesdegradation of this protein and may contribute to IRS-1deficiency in GDM [72] Similarly both obesity and PCOSare associated with decreased expression of GLUT4 [83]

Another important factor is adiponectin a proteic hor-mone with insulin-sensitizing activity whose levels aredecreased in obesity [84] Although adipocytes are the pri-mary site for adiponectin synthesis placental productionof adiponectin appears to be a paramount regulator ofmetabolism homeostasis during gestation [85] Moreovercytokines such as TNF IFN120574 IL-6 and leptin have beenfound to modulate adiponectin and adiponectin receptorexpression in women with GDM [86] harmonizing withreports associating hypoadiponectinemia with postpartumIR 120573-cell dysfunction and dysglycemia [87] Expression ofPPAR120574 is also diminished leading to subdued lipogenic path-ways favoring greater FFA release [88] and disturbance ofproper lipid partition which would enhance lipid depositionin nonprofessional tissues such as skeletal muscle enhancingthe IR cycle [7] Other related metabolic markers have beenindependently associated with higher risk for GDM theCoronary Artery Risk Development in Young Adults (CAR-DIA) Study [89] reported that impaired fasting glucose (OR=474 95 CI 214ndash1051 119875 lt 001) hyperinsulinemia (OR =236 95 CI 120ndash463 119875 lt 001) and low levels of HDL-C(OR = 307 95 CI 162ndash584 119875 lt 001) are associated withGDM risk after adjusting for race age parity and birth order

4 Implications of Gestational DiabetesMellitus on Fetomaternal Health

Gestational diabetes mellitus has been noted to prevail infemales with predisposition to metabolic disturbances withpregnancy acting as stress test on endocrine physiology [90]reflected on both obesity and PCOS representing indepen-dent risk factors for GDM as previously discussed [20 80]This condition entails several consequences on both motherand offspring well-being Maternal implications consist prin-cipally of higher risk for development of DM2 after preg-nancy with approximately 10 of women diagnosed withDM2 shortly after delivery and up to 40 after 10-year follow-up [91] Indeed gestation may reveal or worsen preexistingdefects in 120573-cell function accelerating onset of DM2 andother related conditions [90] This influence is present evenin nonobese women with GDM with findings of endothelialdysfunction and chronic inflammation markersmdashboth asso-ciated with the pathogenesis of DM2 cardiovascular diseaseand metabolic syndromemdashin this population [92] HOMA-IR assessment boasts promising results as predictor of post-partum 120573-cell dysfunction [93]

On the other hand the Hyperglycemia and AdversePregnancy Outcome (HAPO) study [94] has demonstrated

that hyperglycemia during pregnancymdasheven in nondiabeticrangesmdashis associated with increased birth weight and ele-vated cord blood C-peptide serum levels GDM is related togreater risk of macrosomia shoulder dystocia birth injuriesneonatal hypoglycemia hypocalcemia hyperbilirrubinemiarespiratory distress syndrome and polycythemia [95] as wellas teratogenesis particularly in obese subjects [96] Further-more elevated cord-blood insulin concentrations are linkedto glucose intolerance in offspring and children exposed toGDM appear to display various metabolic disturbances wellinto childhood including higher blood pressure and lowerHDL-C [97]

These epidemiological data obey profound disruptionsin embryonic and fetal metabolism and numerous hypothe-ses attempt to explain this panorama The theory of fuel-induced teratogenesis was first outlined by Freinkel [98] whoproposed fuel excess and overgrowth to be the pathogenicbasis of maternal hyperglycemia This notion is founded onfindings of maternal hyperglycemia-induced enhancing fetalinsulin secretion potentiating tissue growthmdashmacrosomiamdashvia fetal IGF-1 [99] Alternatively Hales and Barker [100]have propelled the thrifty phenotype theory suggesting inutero malnutrition to bear a strong influence on postnatalrisk of obesity cardiovascular disease and DM2 and evenrisk of PCOS and future pregnancy complications [101]Thesepremises are complemented by the concept of metabolicmemory related to endocrine-metabolic reprogramming ofoffspring amidst the diabetic environment during pregnancy[102] This notion encompasses fetal inflammation bluntedmyogenesis oxidative stress and disruption of immune sys-tem tolerance among various other alterations [103] Like-wise fetal exposure to diabetes appears to modify hypotha-lamic functionality in animal models associated with hyper-phagic behavior and obesity-proneness after birth [104]

AMP-dependent kinase (AMPK) a classic target of met-formin action may be an important mediator in this context[105] as it intervenes in processes such as lipogenesis via inhi-bition of acetyl-CoA carboxylase [106] myogenesis throughthe modulation of myocyte enhancer factor 2 [107] cellcycle [108] and appetite pathways [109] Animal models haveshown thatmetformin-inducedAMPK activation yields ben-eficial effects over embryonic implantation [110] fetal inflam-mation [111] maternal liver function [112] and pregnancyoutcomes [113] Notwithstanding that these and other molec-ular pathways remain under research and certain aspectsrequire further characterization metformin has proven tobeat the test of time standing as a promising recourse inmanycircumstances including GDM

5 Metformin Pharmacokineticsduring Pregnancy

Uptake anddistribution ofmetformin towards the circulatorysystem requires the participation of bidirectional transporterslocated in the intestine and liver [114 115] see Figure 3 Inthe apical membrane of enterocytes PMAT (Plasma Mem-brane Monoamine Transporter) and OCT3 (Organic CationTransporters) mediate absorption Mobilization of the drug


Metformin

PMAT

OCT3

OCT2

OCT1

Intestine Liver

BCRP

P-gp

Figure 3 Absorption and distribution of metformin during pregnancy

towards the liver requires OCT1 OCT2 and OCT3 whileOCT2 is needed in order to reach the bloodstream kidneysand excretion [116] Renal clearance of metformin increasesduring mid (723 plusmn 243mLmin 119875 lt 001) and late preg-nancy (625 plusmn 130mLmin 119875 lt 001) [116] relating to aconcentration of the drug in umbilical cord blood at time ofbirth between undetectable levels and 1263 ngmL Placentaltissue expresses OCT2 transporter yet under strict epige-netic control [117 118] underlying ample interindividualdifferences in this aspect However other transporters arealso involved in drug efflux through the placenta Reflectingthe high protectiveness of the human syncytiotrophoblastregarding the fetus this tissue has been described to expressa series of transporters in the apical membrane such as P-glycoprotein (P-gp) Multidrug Resistance-Associated Pro-tein 1 (MRP1) and Breast Cancer Resistance Protein (BCRP)[119ndash122] with metformin being transported mainly via P-gp (58 plusmn 20) and BCRP (25 plusmn 14) [119] Competitionbetween this biguanide and other drugs can also limit theexposure of the fetus further limiting the presence of toxicconcentrations during pregnancy

Animal studies using dosages up to 600mgkg daily havefailed to report evidence of teratogenic effects [123] andextremely high dosages between 900 and 1500mgkg dailyfailed to induce carcinogenicity [124] Furthermore in 2003Gutzin et al [125] reported their results concerning firsttrimester exposure ascertaining no higher rates of majormalformations with an OR of 105 (95 CI 065ndash170) whileneonatal death rendered an OR of 116 (95 CI 067ndash200)Likewise Gilbert et al [126] conducted a meta-analysis on 8studies concerning fetal malformations associated with met-formin use during pregnancy indicating this drug to yield anORof 050 (95CI 015ndash160)mdashrendering aminor protectiveeffect Finally the pooling analysis showed that the controlgroup had a malformation rate of 72 compared to 17 inthe metformin group [126] strongly supporting metforminrsquossafety during pregnancy

Concerning breast milk-related exposure [127] it hasbeen confirmed that metformin can be detected at ranges

between 013 and 028mgmL equivalent to lt05 of themotherrsquos weight-adjusted dosage [106] Other reports havequantified metformin in breast milk at 028ndash108 [128]and 018ndash021 [129] of maternal dose Placental partitioncoefficient formetformin has been calculated at 363 with acord plasma concentration of 01ndash29mgL during labor [130]Such findings confirm that neonatal exposure to metforminis actually quite insignificant and it is not related to glucoseabnormality in infants granting safe use before during andafter pregnancy [128ndash130]

6 Metformin Use in Pregnant Womenwith Polycystic Ovary Syndrome DifferentOutcomes Different Efficacy

Because infertility is one of the main consequences offemale reproduction in patients with PCOS [4 5] ovulationinduction remains the most common intervention dur-ing fertility counseling Current guidelines heavily promotelifestyle modifications and support clomiphene as the first-line agent for ovulation induction while recognizing thatcomplementation with metformin improves ovulation andpregnancy success [131] as reported by Lord et al [22] in theirmeta-analysis concerning effectiveness of this antidiabeticdrug in achievement of ovulation in 15 trials involving 543participants This yielded an OR of 388 (95 CI 225ndash669)for metformin alone and 441 (95 CI 237ndash822) for met-formin combined with clomiphene In addition the resultsfrom Khorram et al [132] showed that two-week treatmentwith insulin reduced insulin levels and IR while improvingSHBG levels and clomiphene-induced ovulation In regardsto metformin and gonadotropin use Palomba et al [133]reported that the biguanide improved live birth rates (OR =195 95 CI 110ndash344 119875 = 0020) and pregnancy success(OR = 225 95 CI 150ndash338 119875 lt 00001)

Early pregnancy loss (EPL) is defined as the interrup-tion of pregnancy before the 20th week of gestation [134]Although chromosomal abnormalities are the principal cause


of EPL [135] they are uncommonly reported in women withPCOS [136] It has been proposed that endocrine disruptionsmay play a role in EPL with elevated androgens being associ-ated with EPL in women with PCOS and with recurrent EPLin women with and without PCOS [21] Additionally severalendometrial molecular alterations have been described dur-ing implantation in PCOS (a) androgen-dependent suppres-sion of glycodelin [137] a cell-adhesion molecule involvedin endometrial receptivity [138] (b) IR-hyperinsulinemiacan also diminish glycodelin expression alongside IGFBP-1key molecules for endometrial preimplantation maturation[139] and (c) a hypofibrinolytic state due to increasedsynthesis of plasminogen activator inhibitor-1 (PAI-1) whichhas been found to be an independent risk factor for EPLin PCOS [140] In this context PCOSpatients prescribedwithmetformin have lower pooled odds ratios for EPL (OR = 03295 CI 019ndash055) and preterm birth (OR = 030 95 CI013ndash068) [141] suggesting that this treatment can reversethe impact of PCOS on implantation success observed in thisgynecoendocrine disease

Other benefits have been attributed to metforminthroughout gestation in women with PCOS but perhaps oneof the most important ones is the 40 reduction of new-onset diabetes in high risk individuals as reported by Salpeteret al [142] In their meta-analysis using 31 trials and 4570subjects the resulting pooled OR was 06 (95 CI 05ndash08)with an absolute risk reduction of 6 (95 CI 4ndash8) duringa period of treatment of 18 years [142] On the other handNawaz et al [143] have described decreased prevalence offetal growth restriction and increased live birth rates as wellas an absence of intrauterine deaths or stillbirths in womentaking metformin during pregnancy in line with claims ofmetformin being unrelated to teratogenicity [144]

Nevertheless metformin during pregnancy appearsunable to significantly reduce rates of preeclampsia andpretermbirth in subjectswith PCOSA randomized placebo-controlled double-blind multicenter study by Vanky et al[145] found that preeclampsia prevalence was 74 in themetformin group and 37 in the placebo group (37 95CI minus17ndash92 119875 = 018) whereas preterm birth prevalencewas 37 in the metformin group and 82 in the placebogroup (minus44 95 CI minus101ndash12 119875 = 012) the inefficacyof metformin at preventing preeclampsia may be due tothe complex etiopathogenesis of this disease Data fromStridsklev et al [146] support this phenomenon in whichreporting metformin treatment did not affect uterine arteryflow during gestation while also describing an associationbetween uterine artery flow and androgens highlightingthe complexity of the mechanisms underlying placentationconservation of uterine artery flow and vessel compliance[147 148]

Indeed despite several mechanisms related to IR-hyper-insulinemia being involved in the etiopathogenesis of pre-eclampsiamdashchronic systemic inflammation increased sym-pathetic tone and vascular smooth muscle growth [149]mdashmetformin may be unable to effectively modify thepathogenic root of this disease which is faulty placentation[150] Similarly although metforminrsquos effects may aid inprevention of preterm birth by ameliorating oxidative stress

and chronic inflammation [151] various elements underlyingpreterm labor may escape the reach of metforminrsquos activityincluding the most common factors associated with thisconditionmdashdefective placentation intrauterine infectionand maternal immunologic receptivity [152]

Still metformin seems to offer other benefits to offspringof women with PCOS even in the postnatal period Inthis scenario metformin throughout pregnancy has beenassociated with diminished neonatal hypoglycemia [153] aswell as normal growth and motor-social development in thefirst 18 months of life [154] Likewise the growth and motor-social skills of breast-fed children of women with PCOStaking metformin have been demonstrated to be similar tothose of formula-fed infants with no abnormalities [155]

7 Metformin in Pregnant Women withGestational Diabetes Mellitus ChallengingInsulin as the Go-To Therapy

Although insulin therapy has been considered the best man-agement option for GDM recent evidence diverges from thispreceptThe firstmajor trial concerning the use ofmetforminandor insulin during pregnancies complicated with GDMwas themetformin in gestational diabetes (MiG) [156] whosegoal was to determine the effects of either drug on preventionof fetal hyperinsulinemia and promotion of lower maternalglycemia This research group ascertained metformin (500ndash2500mgday) with or without supplemental insulin not tobe associated with higher perinatal complications in com-parison to insulin alone [157] findings later corroboratedby Silva et al [158] Furthermore patients tend to prefermetformin over insulin as treatment schemes and wouldrather be prescribed such drug if possible [156] Likewisemetformin use during pregnancy failed to adversely affectmaternal lipid parameters C-reactive protein levels or birthweight [159]

After this emblematic trial several other studies havesupported the effectiveness of metformin in GDM Niro-manesh et al [160] conducted a randomized controlled trialwith 160 pregnant patients with GDM 80 of them treatedwith metformin (500ndash2500mg) and the rest with insulinNPH (02Ukg bedtime) and regular (1 U per 10mgdL over)Results revealed metformin to reduce rates of macrosomiaand maternal weight gain Additionally Rowan et al [161]also ascertained a decline in macrosomia and preeclampsiarates and suggested glycemic goals in GDM should be morerigorous Metformin in GDM has also been described tolower incidence of surgical delivery [162] Notably theseeffects are observed even in spite of lowering of vitamin B12[163] a recognized side effect of the drug [164]

Although various oral hypoglycemic agentsmdashaside frommetforminmdashare known to confer adequatemetabolic controlduring pregnancy compared to insulin [165] metforminseems to be the superior choice offering better control thanglyburide as reported by Silva et al [158]This research grouphas also reported newborns from mothers treated with met-formin to obtain lower weight (3193 g versus 3387 g119875 = 001)and ponderal index results (287 versus 296 119875 = 005) as


well as less maternal weight gain in womenwith GDM whencompared to those treated with glyburide (103 kg versus76 kg 119875 = 002) [166] possibly reducing probabilities ofother weight-related complications such as preeclampsia Onthe other hand data on TZD use during GDM is relativelyscarce and trials conducted to date are considered insufficientto definitively establish these drugs as safe during pregnancy[25] In this context PPAR120574 has been noted to be keyin embryonic development [167] and TZD administrationduring pregnancy has been associated with impaired fetaldevelopment [168] with this drug class remaining within theFDAPregnancyCategory C [169]Therefore further researchis needed to explore the role of TZD in pregnancy and GDM

Beyond evidence supporting metformin use in GDMa key issue regarding pharmacological management of thisdisease is the prediction and selection of the best suitedalternative (insulin alone metformin alone or both com-bined) for each specific patient Insulin remains the mostrecommended option in mild cases of GDM [170] and inwomen with elevated BMI [171] Indeed in women withGDMHOMA-IR values 129ndash289mdashinterpreted as decreasedinsulin secretionmdashhave been proposed to indicate a require-ment of insulin therapy whereas values gt289 are thought tounderline insufficient compensation of IR rendering insulin-sensitizing agents more adequate [172] Likewise womenwith GDM and a fasting glucose result from oral glucosetolerance test below 933mgdL have displayed a probabilityof favorable pharmacological response of 93 to metformin[173] On the other hand early detection of GDM is a pre-dictor for supplemental insulin treatment in women initiallytreatedwithmetformin [174] as well as older age and elevatedserum fructosamine concentration [175]

8 Concluding Remarks

Pregnancies complicated with GDM or with history of PCOSare a challenge for both obstetricians and endocrinologistsrepresenting a halfway point where these specialties mergeand highlighting the importance of multidisciplinary pre-natal management In our experience we have observedthat patients with PCOS who continue with metformintreatment throughout pregnancy and those who receive thisdrug as a pharmacological intervention in GDM yield betterpregnancy outcomes and a better postpartum metabolicprognosis for both mothers and their offspring

Nevertheless further studies are needed to uncover andelucidate the benefits and shortcomings of metformin in thiscontext in both molecular and epidemiological fields Ongo-ing studies concerning these issues include the Metformin toPrevent Late Miscarriage and Preterm Delivery in WomenWith Polycystic Ovary Syndrome Trial (PregMet2) [176] andthe Metformin Treatment in Gestational Diabetes and Non-insulin Dependent Diabetes in Pregnancy in a DevelopingCountry Trial (migdmampt2dm) [177] as well as additionaldata from the MiG trial among many others Indeed thefuture appears compelling and exciting in this aspect withthese sources promising valuable information which mayreshape and refine views onmetformin use during pregnancy

Conflict of Interests

There are no financial or other contractual agreements thatmight cause conflict of interests

Acknowledgments

This work was supported by Research Grant no CC-0437-10-21-09-10 from CONDES University of Zulia and ResearchGrant no FZ-0058-2007 from Fundacite-Zulia

References

[1] H Teede A Deeks and L Moran ldquoPolycystic ovary syndromea complex condition with psychological reproductive andmetabolic manifestations that impacts on health across thelifespanrdquo BMCMedicine vol 8 article 41 2010

[2] M T Sheehan ldquoPolycystic ovarian syndrome diagnosis andmanagementrdquoClinical Medicine amp Research vol 2 no 1 pp 13ndash27 2004

[3] C B Kallen ldquoSteroid hormone synthesis in pregnancyrdquo Obstet-rics and Gynecology Clinics of North America vol 31 no 4 pp795ndash816 2004

[4] J Vrbikova and V Hainer ldquoObesity and polycystic ovarysyndromerdquo Obesity Facts vol 2 no 1 pp 26ndash35 2009

[5] M N Mascarenhas S R Flaxman T Boerma S Vanderpoeland G A Stevens ldquoNational regional and global trends ininfertility prevalence since 1990 a systematic analysis of 277health surveysrdquo PLoS Medicine vol 9 no 12 Article IDe1001356 2012

[6] E Diamanti-Kandarakis ldquoPolycystic ovarian syndrome patho-physiology molecular aspects and clinical implicationsrdquo ExpertReviews in Molecular Medicine vol 10 p e3 2008

[7] J RojasM Chavez L Olivar et al ldquoPolycystic ovary syndromeinsulin resistance and obesity navigating the pathophysiologiclabyrinthrdquo International Journal of Reproductive Medicine vol2014 Article ID 719050 17 pages 2014

[8] S A Arslanian V D Lewy and K Danadian ldquoGlucose intol-erance in obese adolescents with polycystic ovary syndromeroles of insulin resistance and 120573-cell dysfunction and risk ofcardiovascular diseaserdquo The Journal of Clinical Endocrinologyand Metabolism vol 86 no 1 pp 66ndash71 2001

[9] S Robinson A D Henderson S V Gelding et al ldquoDyslip-idaemia is associated with insulin resistance in women withpolycystic ovariesrdquo Clinical Endocrinology vol 44 no 3 pp277ndash284 1996

[10] MW Elting T J M Korsen P D Bezemer and J SchoemakerldquoPrevalence of diabetes mellitus hypertension and cardiaccomplaints in a follow-up study of a Dutch PCOS populationrdquoHuman Reproduction vol 16 no 3 pp 556ndash560 2001

[11] ZHHuang BManickamV Ryvkin et al ldquoPCOS is associatedwith increased CD11c expression and crown-like structuresin adipose tissue and increased central abdominal fat depotsindependent of obesityrdquo The Journal of Clinical Endocrinologyamp Metabolism vol 98 no 1 pp E17ndashE24 2013

[12] S Borruel E Fernandez-Duran M Alpanes et al ldquoGlobaladiposity and thickness of intraperitoneal and mesentericadipose tissue depots are increased in women with polycysticovary syndrome (PCOS)rdquo Journal of Clinical Endocrinology andMetabolism vol 98 no 3 pp 1254ndash1263 2013

[13] R Shroff A Kerchner M Maifeld E J R van Beek D Jagasiaand A Dokras ldquoYoung obese women with polycystic ovary


syndrome have evidence of early coronary atherosclerosisrdquoTheJournal of Clinical Endocrinology amp Metabolism vol 92 no 12pp 4609ndash4614 2007

[14] A J Cussons B G A Stuckey and G F Watts ldquoMetabolicsyndrome and cardiometabolic risk in PCOSrdquo Current DiabetesReports vol 7 no 1 pp 66ndash73 2007

[15] M C Amato V Guarnotta D Forti M Donatelli S Dolcimas-colo and C Giordano ldquoMetabolically healthy polycystic ovarysyndrome (MH-PCOS) andmetabolically unhealthy polycysticovary syndrome (MU-PCOS) a comparative analysis of foursimple methods useful for metabolic assessmentrdquo HumanReproduction vol 28 no 7 pp 1919ndash1928 2013

[16] E Mor A Zograbyan P Saadat et al ldquoThe insulin resistantsubphenotype of polycystic ovary syndrome clinical parame-ters and pathogenesisrdquo The American Journal of Obstetrics andGynecology vol 190 no 6 pp 1654ndash1660 2004

[17] L B Craig R W Ke and W H Kutteh ldquoIncreased prevalenceof insulin resistance in women with a history of recurrentpregnancy lossrdquo Fertility and Sterility vol 78 no 3 pp 487ndash490 2002

[18] A Huidobro A M Prentice A J C Fulford and J RozowskildquoAntropometrıa comopredictor de diabetes gestacional estudiode cohorterdquo Revista Medica de Chile vol 138 pp 1373ndash13772010

[19] CM Clark Jr C Qiu B Amerman et al ldquoGestational diabetesshould it be added to the syndrome of insulin resistancerdquoDiabetes Care vol 20 no 5 pp 867ndash871 1997

[20] C M Boomsma M J C Eijkemans E G Hughes G H AVisser B C J M Fauser and N S Macklon ldquoA meta-analysisof pregnancy outcomes in women with polycystic ovary syn-dromerdquo Human Reproduction Update vol 12 no 6 pp 673ndash683 2006

[21] S Kamalanathan J P Sahoo and T Sathyapalan ldquoPregnancyin polycystic ovary syndromerdquo Indian Journal of Endocrinologyand Metabolism vol 17 pp 37ndash43 2013

[22] J M Lord I H Flight and R J Norman ldquoInsulin-sensitisingdrugs (metformin troglitazone rosiglitazone pioglitazone D-chiro-inositol) for polycystic ovary syndromerdquo Cochrane Data-base of Systematic Reviews vol 3 Article ID CD003053 2003

[23] H C Zisser ldquoPolycystic ovary syndrome and pregnancy ismetformin the magic bulletrdquo Diabetes Spectrum vol 20 no 2pp 85ndash89 2007

[24] M-E Lautatzis D G Goulis and M Vrontakis ldquoEfficacy andsafety of metformin during pregnancy in women with gesta-tional diabetesmellitus or polycystic ovary syndrome a system-atic reviewrdquoMetabolism Clinical and Experimental vol 62 no11 pp 1522ndash1534 2013

[25] D S Feig G G Briggs and G Koren ldquoOral antidiabeticagents in pregnancy and lactation a paradigm shiftrdquo Annalsof Pharmacotherapy vol 41 no 7-8 pp 1174ndash1180 2007

[26] Package Insert for Glucophage httpwwwglucophagexrcompagesdefaultaspx

[27] C RMcCartney CA Eagleson and J CMarshall ldquoRegulationof gonadotropin secretion implications for polycystic ovarysyndromerdquo Seminars in Reproductive Medicine vol 20 no 4pp 317ndash325 2002

[28] M Karoshi and S O Okolo ldquoCommentary Polycystic ovariandisease (PCOD) a misnomer looking for a new namerdquo Inter-national Journal of Fertility and Womenrsquos Medicine vol 49 no4 pp 191ndash192 2004

[29] D H Abbott D A Dumesic and S Franks ldquoDevelopmentalorigin of polycystic ovary syndromemdasha hypothesisrdquo Journal ofEndocrinology vol 174 no 1 pp 1ndash5 2002

[30] D A Dumesic D H Abbott and V Padmanabhan ldquoPolycysticovary syndrome and its developmental originsrdquo Reviews inEndocrine and Metabolic Disorders vol 8 no 2 pp 127ndash1412007

[31] M H Shanik Y Xu J Skrha R Dankner Y Zick and J RothldquoInsulin resistance and hyperinsulinemia is hyperinsulinemiathe cart or the horserdquo Diabetes Care vol 31 supplement 2 ppS262ndashS268 2008

[32] GM Reaven ldquoCompensatory hyperinsulinemia and the devel-opment of an atherogenic lipoprotein profile the price paid tomaintain glucose homeostasis in insulin-resistant individualsrdquoEndocrinology andMetabolismClinics of North America vol 34no 1 pp 49ndash62 2005

[33] J Rojas V Bermudez E Leal et al ldquoInsulinorresistencia ehiperinsulinemia como factores de riesgo para enfermedadcardiovascularrdquo AVFT vol 27 pp 29ndash39 2008

[34] N Sekar J C Garmey and J D Veldhuis ldquoMechanisms under-lying the steroidogenic synergy of insulin and luteinizing hor-mone in porcine granulosa cells joint amplification of pivotalsterol-regulatory genes encoding the low-density lipoprotein(LDL) receptor steroidogenic acute regulatory (stAR) proteinand cytochrome P450 side-chain cleavage (P450scc) enzymerdquoMolecular and Cellular Endocrinology vol 159 no 1-2 pp 25ndash35 2000

[35] E Y Adashi A J W Hsueh and S S C Yen ldquoInsulin enhance-ment of luteinizing hormone and follicle-stimulating hormonerelease by cultured pituitary cellsrdquo Endocrinology vol 108 no 4pp 1441ndash1449 1981

[36] R Salvi E Castillo M-J Voirol et al ldquoGonadotropin-releasinghormone-expressing neurons immortalized conditionally areactivated by insulin implication of the mitogen-activated pro-tein kinase pathwayrdquo Endocrinology vol 147 no 2 pp 816ndash8262006

[37] J W Hill J K Elmquist and C F Elias ldquoHypothalamic path-ways linking energy balance and reproductionrdquo American Jour-nal of Physiology Endocrinology andMetabolism vol 294 no 5pp E827ndashE832 2008

[38] A D Eyvazzadeh K P Pennington R Pop-Busui M SowersJ-K Zubieta and Y R Smith ldquoThe role of the endogenousopioid system in polycystic ovary syndromerdquo Fertility and Ste-rility vol 92 no 1 pp 1ndash12 2009

[39] D M Selva K N Hogeveen S M Innis and G L HammondldquoMonosaccharide-induced lipogenesis regulates the humanhepatic sex hormone-binding globulin generdquo Journal of ClinicalInvestigation vol 117 no 12 pp 3979ndash3987 2007

[40] A Gambineri C Pelusi V Vicennati U Pagotto and RPasquali ldquoObesity and the polycystic ovary syndromerdquo Inter-national Journal of Obesity vol 26 no 7 pp 883ndash896 2002

[41] C-B Book and A Dunaif ldquoSelective insulin resistance in thepolycystic ovary syndromerdquo Journal of Clinical Endocrinologyand Metabolism vol 84 no 9 pp 3110ndash3116 1999

[42] E Mendez N Montserrat and J V Planas ldquoModulation ofthe steroidogenic activity of luteinizing hormone by insulinand insulin-like growth factor-I through interaction with thecAMP-dependent protein kinase signaling pathway in the troutovaryrdquo Molecular and Cellular Endocrinology vol 229 no 1-2pp 49ndash56 2005

[43] A Dunaif J Xia C-B Book E Schenker and Z TangldquoExcessive insulin receptor serine phosphorylation in cultured


fibroblasts and in skeletal muscle a potential mechanism forinsulin resistance in the polycystic ovary syndromerdquo Journal ofClinical Investigation vol 96 no 2 pp 801ndash810 1995

[44] J E Nestler D J Jakubowicz and M J Iuorno ldquoRole ofinositolphosphoglycan mediators of insulin action in the poly-cystic ovary syndromerdquo Journal of Pediatric Endocrinology ampMetabolism vol 13 supplement 5 pp 1295ndash1298 2000

[45] P Arner ldquoEffects of testosterone on fat cell lipolysis Speciesdifferences and possible role in polycystic ovarian syndromerdquoBiochimie vol 87 no 1 pp 39ndash43 2005

[46] L J Moran R Pasquali H J Teede K M Hoeger and R JNorman ldquoTreatment of obesity in polycystic ovary syndromea position statement of the Androgen Excess and PolycysticOvary Syndrome Societyrdquo Fertility and Sterility vol 92 no 6pp 1966ndash1982 2009

[47] L Radosh ldquoDrug treatments for polycystic ovary syndromerdquoAmerican Family Physician vol 79 no 8 pp 671ndash676 2009

[48] A D Genazzani E Chierchia E Rattighieri et al ldquoMet-formin administration restores allopregnanolone response toadrenocorticotropic hormone (ACTH) stimulation in over-weight hyperinsulinemic patients with PCOSrdquo GynecologicalEndocrinology vol 26 no 9 pp 684ndash689 2010

[49] EMVelazquez SMendoza THamer F Sosa andC J GlueckldquoMetformin therapy in polycystic ovary syndrome reduceshyperinsulinemia insulin resistance hyperandrogenemia andsystolic blood pressure while facilitating normal menses andpregnancyrdquoMetabolism Clinical and Experimental vol 43 no5 pp 647ndash654 1994

[50] A Kriplani and N Agarwal ldquoEffects of metformin on clinicaland biochemical parameters in polycystic ovary syndromerdquoTheJournal of Reproductive Medicine vol 49 no 5 pp 361ndash3672004

[51] D Kocer F Bayram and H Diri ldquoThe effects of metforminon endothelial dysfunction lipid metabolism and oxidativestress inwomenwith polycystic ovary syndromerdquoGynecologicalEndocrinology vol 30 no 5 pp 367ndash371 2014

[52] E Diamanti-Kandarakis T Paterakis and H A KandarakisldquoIndices of low-grade inflammation in polycystic ovary syn-dromerdquo Annals of the New York Academy of Sciences vol 1092pp 175ndash186 2006

[53] S Tan S Hahn S Benson et al ldquoMetformin improves poly-cystic ovary syndrome symptoms irrespective of pre-treatmentinsulin resistancerdquo European Journal of Endocrinology vol 157no 5 pp 669ndash676 2007

[54] J Nawrocka and A Starczewski ldquoEffects of metformin treat-ment in women with polycystic ovary syndrome depends oninsulin resistancerdquo Gynecological Endocrinology vol 23 no 4pp 231ndash237 2007

[55] R Horejsi R Moller S Rackl et al ldquoAndroid subcutaneousadipose tissue topography in lean and obese women sufferingfrom PCOS comparison with type 2 diabetic womenrdquo TheAmerican Journal of Physical Anthropology vol 124 no 3 pp275ndash281 2004

[56] J G Dolfing C M Stassen P M M Van Haard B H R Wolf-fenbuttel and D H Schweitzer ldquoComparison of MRI-assessedbody fat content between lean women with polycystic ovarysyndrome (PCOS) and matched controls less visceral fat withPCOSrdquoHuman Reproduction vol 26 no 6 pp 1495ndash1500 2011

[57] J-P Baillargeon andACarpentier ldquoRole of insulin in the hyper-androgenemia of lean women with polycystic ovary syndromeand normal insulin sensitivityrdquo Fertility and Sterility vol 88 no4 pp 886ndash893 2007

[58] R Keskin Kurt A G Okyay A U Hakverdi et al ldquoThe effect ofobesity on inflammatory markers in patients with PCOS aBMI-matched case-control studyrdquo Archives of Gynecology andObstetrics vol 290 no 2 pp 315ndash319 2014

[59] C Celik E Bastu R Abali et al ldquoThe relationship betweencopper homocysteine and early vascular disease in lean womenwith polycystic ovary syndromerdquo Gynecological Endocrinologyvol 29 no 5 pp 488ndash491 2013

[60] S A Blair T Kyaw-Tun I S Young N A Phelan J Gibneyand J McEneny ldquoOxidative stress and inflammation in leanand obese subjects with polycystic ovary syndromerdquo Journal ofReproductive Medicine vol 58 no 3-4 pp 107ndash114 2013

[61] D W Stovall A P Bailey and L M Pastore ldquoAssessment ofinsulin resistance and impaired glucose tolerance in leanwomen with polycystic ovary syndromerdquo Journal of WomenrsquosHealth vol 20 no 1 pp 37ndash43 2011

[62] S Livadas A Kollias D Panidis and E Diamanti-KandarakisldquoDiverse impacts of aging on insulin resistance in lean andobese women with polycystic ovary syndrome evidence from1345 women with the syndromerdquo European Journal of Endocri-nology vol 171 no 3 pp 301ndash309 2014

[63] G Onalan U Goktolga T Ceyhan T Bagis R Onalan and RPabuccu ldquoPredictive value of glucosemdashinsulin ratio in PCOSand profile of womenwhowill benefit frommetformin therapyobese lean hyper or normoinsulinemicrdquo European Journal ofObstetrics Gynecology and Reproductive Biology vol 123 no 2pp 204ndash211 2005

[64] A S Kumari A Haq R Jayasundaram L O Abdel-WarethS A al Haija and M Alvares ldquoMetformin monotherapy inlean women with polycystic ovary syndromerdquo ReproductiveBioMedicine Online vol 10 no 1 pp 100ndash104 2005

[65] A Kruszynska J Słowinska-Srzednicka W Jeske and WZgliczynski ldquoProinsulin adiponectin and hsCRP in reproduc-tive age women with polycystic ovary syndrome (PCOS)mdashtheeffect of metformin treatmentrdquo Endokrynologia Polska vol 65no 1 pp 2ndash10 2014

[66] Q Du Y J Wang S Yang B Wu P Han and Y Y Zhao ldquoAsystematic review and meta-analysis of randomized controlledtrials comparing pioglitazone versus the treatment of polycysticovary syndromerdquo Current Medical Research and Opinion vol28 pp 723ndash730 2012

[67] A Ziaee S Oveisi A Abedini S Hashemipour T Karimzadehand A Ghorbani ldquoEffect of metformin and pioglitazone treat-ment on cardiovascular risk profile in polycystic ovary syn-dromerdquoActaMedica Indonesiana vol 44 no 1 pp 16ndash22 2012

[68] V R Aroda T P Ciaraldi P Burke et al ldquoMetabolic andhormonal changes induced by pioglitazone in polycystic ovarysyndrome a randomized placebo-controlled clinical trialrdquoJournal of Clinical Endocrinology and Metabolism vol 94 no2 pp 469ndash476 2009

[69] T P Ciaraldi V Aroda S R Mudaliar and R R HenryldquoInflammatory cytokines and chemokines skeletal muscle andpolycystic ovary syndrome effects of pioglitazone and met-formin treatmentrdquo Metabolism Clinical and Experimental vol62 no 11 pp 1587ndash1596 2013

[70] K D Wilson Z Li R Wagner et al ldquoTranscriptome alterationin the diabetic heart by rosiglitazone implications for cardio-vascular mortalityrdquo PLoS ONE vol 3 no 7 Article ID e26092008

[71] R M Lago P P Singh and R W Nesto ldquoCongestive heartfailure and cardiovascular death in patients with prediabetesand type 2 diabetes given thiazolidinediones a meta-analysis


of randomised clinical trialsrdquoThe Lancet vol 370 no 9593 pp1129ndash1136 2007

[72] L A Barbour C E McCurdy T L Hernandez J P KirwanP M Catalano and J E Friedman ldquoCellular mechanisms forinsulin resistance in normal pregnancy and gestational dia-betesrdquo Diabetes Care vol 30 no 2 pp S112ndashS119 2007

[73] J Shao P M Catalano H Yamashita et al ldquoDecreased insulinreceptor tyrosine kinase activity and plasma cell membraneglycoprotein-1 overexpression in skeletal muscle from obesewomen with gestational diabetes mellitus (GDM) evidence forincreased serinethreonine phosphorylation in pregnancy andGDMrdquo Diabetes vol 49 no 4 pp 603ndash610 2000

[74] P M Catalano S E Nizielski J Shao L Preston L Qiaoand J E Friedman ldquoDownregulated IRS-1 and PPAR120574 in obesewomen with gestational diabetes relationship to FFA duringpregnancyrdquo American Journal of Physiology Endocrinology andMetabolism vol 282 no 3 pp E522ndashE533 2002

[75] S Okuno S Akazawa I Yasuhi et al ldquoDecreased expression ofthe GLUT4 glucose transporter protein in adipose tissue duringpregnancyrdquo Hormone and Metabolic Research vol 27 no 5 pp231ndash234 1995

[76] E Sivan and G Boden ldquoFree fatty acids insulin resistance andpregnancyrdquo Current Diabetes Reports vol 3 no 4 pp 319ndash3222003

[77] P M Catalano L Huston S B Amini and S C Kalhan ldquoLon-gitudinal changes in glucose metabolism during pregnancy inobese women with normal glucose tolerance and gestationaldiabetes mellitusrdquo The American Journal of Obstetrics andGynecology vol 180 no 4 pp 903ndash916 1999

[78] A Nadal P Alonso-Magdalena S Soriano A B Ropero andI Quesada ldquoThe role of oestrogens in the adaptation of islets toinsulin resistancerdquoThe Journal of Physiology vol 587 no 21 pp5031ndash5037 2009

[79] R Kaaja and T Ronnemaa ldquoGestational diabetes pathogenesisand consequences to mother and offspringrdquo Review of DiabeticStudies vol 5 no 4 pp 194ndash202 2008

[80] J L Weiss F D Malone D Emig et al ldquoObesity obstetriccomplications and cesarean delivery ratemdasha population-basedscreening studyrdquo American Journal of Obstetrics amp Gynecologyvol 190 no 4 pp 1091ndash1097 2004

[81] T Tzanavari P Giannogonas and K P Karalis ldquoTNF-120572 andobesityrdquo Current Directions in Autoimmunity vol 11 pp 145ndash156 2010

[82] S E Shoelson J Lee and A B Goldfine ldquoInflammation andinsulin resistancerdquoThe Journal of Clinical Investigation vol 116no 7 pp 1793ndash1801 2006

[83] D Rosenbaum R S Haber and A Dunaif ldquoInsulin resistancein polycystic ovary syndrome decreased expression of GLUT-4 glucose transporters in adipocytesrdquo The American Journal ofPhysiologymdashEndocrinology and Metabolism vol 264 no 2 ppE197ndashE202 1993

[84] J Kawano and R Arora ldquoThe role of adiponectin in obe-sity diabetes and cardiovascular diseaserdquo Journal of the Car-dioMetabolic Syndrome vol 4 no 1 pp 44ndash49 2009

[85] I L M H Aye T L Powell and T Jansson ldquoReview adi-ponectinmdashthemissing link betweenmaternal adiposity placen-tal transport and fetal growthrdquo Placenta vol 34 pp S40ndashS452013

[86] J Chen B Tan E Karteris et al ldquoSecretion of adiponectin byhuman placenta differential modulation of adiponectin and itsreceptors by cytokinesrdquo Diabetologia vol 49 no 6 pp 1292ndash1302 2006

[87] R Retnakaran Y Qi P W Connelly M Sermer A J Han-ley and B Zinman ldquoLow adiponectin concentration duringpregnancy predicts postpartum insulin resistance beta celldysfunction and fasting glycaemiardquo Diabetologia vol 53 no 2pp 268ndash276 2010

[88] TA Buchanan andAHXiang ldquoGestational diabetesmellitusrdquoThe Journal of Clinical Investigation vol 115 no 3 pp 485ndash4912005

[89] E P Gunderson C P Quesenberry Jr D R Jacobs Jr J FengC E Lewis and S Sidney ldquoLongitudinal study of prepregnancycardiometabolic risk factors and subsequent risk of gestationaldiabetes mellitusrdquo The American Journal of Epidemiology vol172 no 10 pp 1131ndash1143 2010

[90] D Williams ldquoPregnancy a stress test for liferdquo Current Opinionin Obstetrics and Gynecology vol 15 no 6 pp 465ndash471 2003

[91] J Lauenborg T Hansen D M Jensen et al ldquoIncreasingincidence of diabetes after gestational diabetes a long-termfollow-up in a Danish populationrdquo Diabetes Care vol 27 no5 pp 1194ndash1199 2004

[92] I Mrizak A Arfa M Fekih et al ldquoInflammation and impairedendothelium-dependant vasodilatation in non obese womenwith gestational diabetesmellitus preliminary resultsrdquo Lipids inHealth and Disease vol 12 article 93 2013

[93] R Retnakaran Y Qi C Ye et al ldquoHepatic insulin resistance isan early determinant of declining120573-cell function in the first yearpostpartum after glucose intolerance in pregnancyrdquo DiabetesCare vol 34 no 11 pp 2431ndash2434 2011

[94] The HAPO Study Cooperative Research Group B E MetzgerL P Lowe et al ldquoHyperglycemia and adverse pregnancyoutcomesrdquo The New England Journal of Medicine vol 358 pp1991ndash2002 2008

[95] J M Perkins J P Dunn and S M Jagasia ldquoPerspectives ingestational diabetes mellitus a review of screening diagnosisand treatmentrdquo Clinical Diabetes vol 25 no 2 pp 57ndash62 2007

[96] HAPO Study Cooperative Research Group ldquoHyperglycemiaand Adverse Pregnancy Outcome (HAPO) Study associationswith neonatal anthropometricsrdquo Diabetes vol 58 pp 453ndash4592009

[97] WH Tam R CWMa X Yang et al ldquoGlucose intolerance andcardiometabolic risk in children exposed to maternal gesta-tional diabetes mellitus in uterordquo Pediatrics vol 122 no 6 pp1229ndash1234 2008

[98] N Freinkel ldquoOf pregnancy and progenyrdquo Diabetes vol 29 no12 pp 1023ndash1035 1980

[99] J Jaksic F Mikulandra M Perisa et al ldquoEffect of insulin andinsulin-like growth factor I on fetal macrosomia in healthywomenrdquo Collegium Antropologicum vol 25 no 2 pp 535ndash5432001

[100] C N Hales and D J P Barker ldquoThe thrifty phenotype hypoth-esisrdquo British Medical Bulletin vol 60 pp 5ndash20 2001

[101] T J Wilkin and L D Voss ldquoMetabolic syndrome maladapta-tion to amodernworldrdquo Journal of the Royal Society ofMedicinevol 97 no 11 pp 511ndash520 2004

[102] A Yessoufou and K Moutairou ldquoMaternal diabetes in preg-nancy early and long-term outcomes on the offspring andthe concept of lsquometabolic memoryrsquordquo Experimental DiabetesResearch vol 2011 Article ID 218598 12 pages 2011

[103] M Du X Yan J F Tong J Zhao and M J Zhu ldquoMaternalobesity inflammation and fetal skeletal muscle developmentrdquoBiology of Reproduction vol 82 no 1 pp 4ndash12 2010


[104] K Franke T Harder L Aerts et al ldquoldquoProgrammingrdquo of orex-igenic and anorexigenic hypothalamic neurons in offspring oftreated and untreated diabetic mother ratsrdquo Brain Research vol1031 no 2 pp 276ndash283 2005

[105] J Rojas N Arraiz M Aguirre M Velasco and V BermudezldquoAMPK as target for intervention in childhood and adolescentobesityrdquo Journal of Obesity vol 2011 Article ID 252817 19 pages2011

[106] R W Brownsey A N Boone J E Elliott J E Kulpa and WM Lee ldquoRegulation of acetyl-CoA carboxylaserdquo BiochemicalSociety Transactions vol 34 no 2 pp 223ndash227 2006

[107] L Al-Khalili A V Chibalin M Yu et al ldquoMEF2 activation indifferentiated primary human skeletal muscle cultures requirescoordinated involvement of parallel pathwaysrdquo The AmericanJournal of PhysiologymdashCell Physiology vol 286 no 6 ppC1410ndashC1416 2004

[108] M M Mihaylova and R J Shaw ldquoThe AMPK signalling path-way coordinates cell growth autophagy and metabolismrdquoNature Cell Biology vol 13 no 9 pp 1016ndash1023 2011

[109] R Stark S E Ashley and Z B Andrews ldquoAMPK and theneuroendocrine regulation of appetite and energy expenditurerdquoMolecular and Cellular Endocrinology vol 366 no 2 pp 215ndash223 2013

[110] P Banerjee R R Bhonde and R Pal ldquoDiverse roles of met-formin during peri-implantation development revisiting novelmolecular mechanisms underlying clinical implicationsrdquo StemCells and Development vol 22 no 22 pp 2927ndash2934 2013

[111] N Desai A Roman B Rochelson et al ldquoMaternal metformintreatment decreases fetal inflammation in a rat model of obesityand metabolic syndromerdquo American Journal of Obstetrics andGynecology vol 209 no 2 pp 136-e1ndash136-e9 2013

[112] H-Y Lee D Wei and M R Loeken ldquoLack of metformin effecton mouse embryo AMPK activity implications for metformintreatment during pregnancyrdquo DiabetesMetabolism Researchand Reviews vol 30 no 1 pp 23ndash30 2014

[113] G S Eng R A Sheridan A Wyman et al ldquoAMP kinaseactivation increases glucose uptake decreases apoptosis andimproves pregnancy outcome in embryos exposed to high IGF-Iconcentrationsrdquo Diabetes vol 56 no 9 pp 2228ndash2234 2007

[114] J J Marin ldquoPlasma membrane transporters in modern liverpharmacologyrdquo Scientifica vol 2012 Article ID428139 15 pages2012

[115] L Gong S Goswami K M Giacomini R B Altman and T EKlein ldquoMetformin pathways pharmacokinetics and pharmaco-dynamicsrdquo Pharmacogenetics and Genomics vol 22 no 11 pp820ndash827 2012

[116] J W Jonker and A H Schinkel ldquoPharmacological and physio-logical functions of the polyspecific organic cation transportersOCT1 2 and 3 (SLC22A1-3)rdquo Journal of Pharmacology andExperimental Therapeutics vol 308 no 1 pp 2ndash9 2004

[117] S Eyal T R Easterling D Carr et al ldquoPharmacokinetics ofmetformin during pregnancyrdquo Drug Metabolism and Disposi-tion vol 38 no 5 pp 833ndash840 2010

[118] J Saito T Hirota N Kikunaga K Otsubo and I Ieiri ldquoInter-individual differences in placental expression of the SLC22A2(OCT2) gene relationship to epigenetic variations in the 51015840-upstream regulatory regionrdquo Journal of Pharmaceutical Sciencesvol 100 no 9 pp 3875ndash3883 2011

[119] M Kovo N Kogman O Ovadia I Nakash A Golan and AHoffman ldquoCarrier-mediated transport of metformin across thehuman placenta determined by using the ex vivo perfusion of

the placental cotyledon modelrdquo Prenatal Diagnosis vol 28 no6 pp 544ndash548 2008

[120] M Maliepaard G L Scheffer I F Faneyte et al ldquoSubcellularlocalization and distribution of the breast cancer resistanceprotein transporter in normal human tissuesrdquo Cancer Researchvol 61 no 8 pp 3458ndash3464 2001

[121] MV St-PierreMA Serrano R I RMacias et al ldquoExpressionofmembers of themultidrug resistance protein family in humanterm placentardquoTheAmerican Journal of PhysiologymdashRegulatoryIntegrative and Comparative Physiology vol 279 no 4 ppR1495ndashR1503 2000

[122] V Ganapathy P D Prasad M E Ganapathy and F H LeibachldquoPlacental transporters relevant to drug distribution acrossthe maternal-fetal interfacerdquo Journal of Pharmacology andExperimental Therapeutics vol 294 no 2 pp 413ndash420 2000

[123] G G Briggs R K Freeman and S J Yaffe Drugs in Pregnancyand Lactation LippincottWilliams ampWilkins Philadelphia PaUSA 2002

[124] Package Insert MetforminHydrochloride Bristol-Myers SquibbNew York NY USA 2009

[125] S J Gutzin E Kozer L A Magee D S Feig and G KorenldquoThe safety of oral hypoglycemic agents in the first trimesterof pregnancy a meta-analysisrdquo Canadian Journal of ClinicalPharmacology vol 10 no 4 pp 179ndash183 2003

[126] C Gilbert M Valois and G Koren ldquoPregnancy outcome afterfirst-trimester exposure tometformin ameta-analysisrdquoFertilityand Sterility vol 86 no 3 pp 658ndash663 2006

[127] G G Briggs P J Ambrose M P Nageotte G Padilla and SWan ldquoExcretion of metformin into breast milk and the effecton nursing infantsrdquo Obstetrics and Gynecology vol 105 no 6pp 1437ndash1441 2005

[128] C J Glueck and P Wang ldquoMetformin before and duringpregnancy and lactation in polycystic ovary syndromerdquo ExpertOpinion on Drug Safety vol 6 no 2 pp 191ndash198 2007

[129] S J Gardiner C M J Kirkpatrick E J Begg M Zhang MPeter Moore and D J Saville ldquoTransfer of metformin intohuman milkrdquo Clinical Pharmacology and Therapeutics vol 73no 1 pp 71ndash77 2003

[130] B Charles R Norris X Xiao andW Hague ldquoPopulation phar-macokinetics ofmetformin in late pregnancyrdquoTherapeutic DrugMonitoring vol 28 no 1 pp 67ndash72 2006

[131] T D R Vause A P Cheung S Sierra et al ldquoOvulationinduction in polycystic ovary syndromerdquo Journal of Obstetricsand Gynaecology Canada vol 32 no 5 pp 495ndash502 2010

[132] O Khorram J P Helliwell S Katz C M Bonpane andL Jaramillo ldquoTwo weeks of metformin improves clomiphenecitrate-induced ovulation andmetabolic profiles inwomenwithpolycystic ovary syndromerdquo Fertility and Sterility vol 85 no 5pp 1448ndash1451 2006

[133] S Palomba A Falbo and G B La Sala ldquoMetformin andgonadotropins for ovulation induction in patients with poly-cystic ovary syndrome a systematic review with meta-analysisof randomized controlled trialsrdquo Reproductive Biology andEndocrinology vol 12 article 3 2014

[134] R G Farquharson E Jauniaux and N Exalto ldquoUpdatedand revised nomenclature for description of early pregnancyeventsrdquo Human Reproduction vol 20 no 11 pp 3008ndash30112005

[135] H B Ford andD J Schust ldquoRecurrent pregnancy loss etiologydiagnosis and therapyrdquo Reviews in Obstetrics and Gynecologyvol 2 pp 76ndash83 2009


[136] P A Essah K I Cheang and J ENestler ldquoThepathophysiologyof miscarriage in women with polycystic ovary syndromeReview and proposed hypothesis of mechanisms involvedrdquoHormones vol 3 pp 221ndash227 2004

[137] E M Tuckerman M A Okon T-C Li and S M Laird ldquoDoandrogens have a direct effect on endometrial function An invitro studyrdquo Fertility and Sterility vol 74 no 4 pp 771ndash7792000

[138] N C Douglas M H Thornton S K Nurudeen M BucurR A Lobo and M V Sauer ldquoDifferential expression of serumglycodelin and insulin-like growth factor binding protein 1 inearly pregnancyrdquo Reproductive Sciences vol 20 no 11 pp 1376ndash1381 2013

[139] D J Jakubowicz P A Essah M Seppala et al ldquoReduced serumglycodelin and insulin-like growth factor-binding protein-1 inwomenwith polycystic ovary syndrome during first trimester ofpregnancyrdquoThe Journal of Clinical EndocrinologyampMetabolismvol 89 no 2 pp 833ndash839 2004

[140] K A Toulis D G Goulis G Mintziori et al ldquoMeta-analysis ofcardiovascular disease risk markers in women with polycysticovary syndromerdquo Human Reproduction Update vol 17 no 6Article ID dmr025 pp 741ndash760 2011

[141] J Zheng P F Shan and W Gu ldquoThe efficacy of metforminin pregnant women with polycystic ovary syndrome a meta-analysis of clinical trialsrdquo Journal of Endocrinological Investiga-tion vol 36 no 10 pp 797ndash802 2013

[142] S R SalpeterN S Buckley J AKahn andE E Salpeter ldquoMeta-analysis metformin treatment in persons at risk for diabetesmellitusrdquo The American Journal of Medicine vol 121 no 2 pp149e2ndash157e2 2008

[143] F H Nawaz R Khalid T Naru and J Rizvi ldquoDoes continuoususe of metformin throughout pregnancy improve pregnancyoutcomes in women with polycystic ovarian syndromerdquo Jour-nal of Obstetrics and Gynaecology Research vol 34 no 5 pp832ndash837 2008

[144] G Koren C Gilbert and M Valois ldquoMetformin use duringthe first trimester of pregnancy is it saferdquo Canadian FamilyPhysician vol 52 pp 171ndash172 2006

[145] E Vanky S Stridsklev R Heimstad et al ldquoMetformin Versusplacebo from first trimester to delivery in polycystic ovarysyndrome a randomized controlledmulticenter studyrdquo Journalof Clinical Endocrinology and Metabolism vol 95 no 12 ppE448ndashE455 2010

[146] S Stridsklev S M Carlsen Oslash Salvesen I Clemens and EVanky ldquoMidpregnancyDoppler ultrasound of the uterine arteryinmetformin- versus placebo-treated PCOSwomen a random-ized trialrdquoThe Journal of Clinical Endocrinology amp Metabolismvol 99 pp 972ndash977 2014

[147] F Sharifzadeh M Kashanian and F Fatemi ldquoA comparison ofserum androgens in pre-eclamptic and normotensive pregnantwomen during the third trimester of pregnancyrdquo GynecologicalEndocrinology vol 28 no 10 pp 834ndash836 2012

[148] T-Y Hsu K-C Lan C-C Tsai et al ldquoExpression of androgenreceptor in human placentas from normal and preeclampticpregnanciesrdquo Taiwanese Journal of Obstetrics and Gynecologyvol 48 no 3 pp 262ndash267 2009

[149] JM Roberts andHGammill ldquoInsulin resistance in preeclamp-siardquo Hypertension vol 47 no 3 pp 341ndash342 2006

[150] J Uzan M Carbonnel O Piconne R Asmar and J-M AyoubildquoPre-eclampsia pathophysiology diagnosis and managementrdquoVascular Health and RiskManagement vol 7 no 1 pp 467ndash4742011

[151] R Menon ldquoSpontaneous preterm birth a clinical dilemma eti-ologic pathophysiologic and genetic heterogeneities and racialdisparityrdquo Acta Obstetricia et Gynecologica Scandinavica vol87 no 6 pp 590ndash600 2008

[152] L Lettieri A M Vintzileos J F Rodis S M Albini and C MSalafia ldquoDoes ldquoidiopathicrdquo preterm labor resulting in pretermbirth existrdquoAmerican Journal of Obstetrics and Gynecology vol168 no 5 pp 1480ndash1485 1993

[153] S Bolton B Cleary J Walsh E Dempsey and M J TurnerldquoContinuation of metformin in the first trimester of womenwith polycystic ovarian syndrome is not associated withincreased perinatal morbidityrdquo European Journal of Pediatricsvol 168 no 2 pp 203ndash206 2009

[154] C J GlueckNGoldenberg J PranicoffM Loftspring L Sieveand P Wang ldquoHeight weight and motor-social developmentduring the first 18 months of life in 126 infants born to 109mothers with polycystic ovary syndromewho conceived on andcontinued metformin through pregnancyrdquo Human Reproduc-tion vol 19 no 6 pp 1323ndash1330 2004

[155] C J Glueck M Salehi L Sieve and P Wang ldquoGrowth motorand social development in breast- and formula-fed infants ofmetformin-treated women with polycystic ovary syndromerdquoJournal of Pediatrics vol 148 no 5 pp 628e2ndash632e2 2006

[156] J A Rowan and MiG Investigators ldquoA trial in progressgestational diabetes Treatment with metformin compared withinsulin (the Metformin in Gestational Diabetes [MiG] trial)rdquoDiabetes Care vol 30 supplement 2 pp S214ndashS219 2007

[157] J A Rowan W M Hague W Gao M R Battin M P Mooreand MiG Trial Investigators ldquoMetformin versus insulin for thetreatment of gestational diabetesrdquo The New England Journal ofMedicine vol 358 no 19 pp 2003ndash2015 2008

[158] J C Silva D R R N Fachin M L Coral and A M BertinildquoPerinatal impact of the use of metformin and glyburide for thetreatment of gestational diabetes mellitusrdquo Journal of PerinatalMedicine vol 40 no 3 pp 225ndash228 2012

[159] H L Barrett K L Gatford C M Houda et al ldquoMaternal andneonatal circulating markers ofmetabolic and cardiovascularrisk in themetformin in gestational diabetes (MiG) trialrdquoDiabetes Care vol 36 no 3 pp 529ndash536 2013

[160] S Niromanesh A Alavi F R Sharbaf N Amjadi S Moosaviand S Akbari ldquoMetformin compared with insulin in themanagement of gestational diabetes mellitus a randomizedclinical trialrdquo Diabetes Research and Clinical Practice vol 98no 3 pp 422ndash429 2012

[161] J A Rowan W Gao W M Hague and H D McIntyreldquoGlycemia and its relationship to outcomes in the metformin ingestational diabetes trialrdquo Diabetes Care vol 33 no 1 pp 9ndash162010

[162] H Ijas M Vaarasmaki L Morin-Papunen et al ldquoMetforminshould be considered in the treatment of gestational diabetesa prospective randomised studyrdquo An International Journal ofObstetrics and Gynaecology vol 118 no 7 pp 880ndash885 2011

[163] K L Gatford C M Houda Z X Lu et al ldquoVitamin B12

and homocysteine status during pregnancy in the metforminin gestational diabetes trial responses to maternal metformincompared with insulin treatmentrdquo Diabetes Obesity andMetabolism vol 15 no 7 pp 660ndash667 2013

[164] R Obeid ldquoMetformin causing vitamin b12 deficiency a guiltyverdict without sufficient evidencerdquoDiabetes Care vol 37 no 2pp e22ndashe23 2014


[165] J S Dhulkotia B Ola R Fraser and T Farrell ldquoOral hypo-glycemic agents vs insulin in management of gestational dia-betes a systematic review and metaanalysisrdquo American Journalof Obstetrics amp Gynecology vol 203 no 5 pp 457e1ndash457e92010

[166] J C Silva C Pacheco J Bizato B V De Souza T E Ribeiroand A M Bertini ldquoMetformin compared with glyburide forthe management of gestational diabetesrdquo International Journalof Gynecology and Obstetrics vol 111 no 1 pp 37ndash40 2010

[167] Y Barak M C Nelson E S Ong et al ldquoPPAR120574 is required forplacental cardiac and adipose tissue developmentrdquo MolecularCell vol 4 no 4 pp 585ndash595 1999

[168] J Sevillano I C Lopez-Perez E Herrera M Del Pilar Ramosand C Bocos ldquoEnglitazone administration to late pregnant ratsproduces delayed body growth and insulin resistance in theirfetuses and neonatesrdquo Biochemical Journal vol 389 no 3 pp913ndash918 2005

[169] P Froment and P Touraine ldquoThiazolidinediones and fertility inpolycystic ovary syndrome (PCOS)rdquo PPAR Research vol 2006Article ID 73986 8 pages 2006

[170] J Gui Q Liu and L Feng ldquoMetformin vs insulin in themanagement of gestational diabetes a meta-analysisrdquo PLoSONE vol 8 no 5 Article ID e64585 2013

[171] V W Wong and B Jalaludin ldquoGestational diabetes mellituswho requires insulin therapyrdquo Australian and New ZealandJournal of Obstetrics and Gynaecology vol 51 no 5 pp 432ndash436 2011

[172] A Sokup B Ruszkowska-Ciastek K Goralczyk M Walen-towicz M Szymanski and D Rosc ldquoInsulin resistance asestimated by the homeostaticmethod at diagnosis of gestationaldiabetes estimation of disease severity and therapeutic needsin a population-based studyrdquo BMC Endocrine Disorders vol 13article 21 2013

[173] A Corbould F Swinton A Radford J Campbell S McBeathand A Dennis ldquoFasting blood glucose predicts response toextended-release metformin in gestational diabetes mellitusrdquoAustralian and New Zealand Journal of Obstetrics and Gynae-cology vol 53 pp 125ndash129 2013

[174] C P Spaulonci L S Bernardes T C Trindade M Zugaib andR P Francisco ldquoRandomized trial of metformin vs insulin inthe management of gestational diabetesrdquo American Journal ofObstetrics amp Gynecology vol 209 no 1 pp 34e1ndash34e7 2013

[175] K Tertti U Ekblad P Koskinen T Vahlberg andT RonnemaaldquoMetformin vs insulin in gestational diabetes A randomizedstudy characterizing metformin patients needing additionalinsulinrdquo Diabetes Obesity and Metabolism vol 15 no 3 pp246ndash251 2013

[176] Identifier NCT01587378 Metformin to Prevent Late Miscar-riage and Preterm Delivery in Women with Polycystic OvarySyndrome Trial (PregMet2) ClinicalTrialsgov Bethesda MdUSA National Library of Medicine 2012 httpclinicaltrialsgovshowNCT01855763

[177] National Library of Medicine ldquoMetformin treatment in ges-tational diabetes and noninsulin dependent diabetes in preg-nancy in a developing country (migdmampt2dm)rdquo ClinicalTri-alsgov NCT01855763 National Library of Medicine BethesdaMd USA 2013 httpclinicaltrialsgovshowNCT01855763

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Diagnostic criteria for Polycystic Ovary Syndrome

Clinical or biochemical hyperandrogenism Oligoanovulation US finding of polycystic ovarieslowast

NIH 1990BOTH of the following + +

ESHAREASRM 2003ONLY 2 of the following + + +

AES 2006ALL 3 of the following + + +

NIH = National Institute of Health of the United States ESHRE = European Society of Human Reproduction and Embryology ASRM = American Society ofReproductive Medicine AES = Androgen Excess and PCOS SocietyAll sets of criteria require the exclusion of other etiologies such as congenital adrenal hyperplasia androgen-secreting neoplasms and Cushingrsquos syndromeamong otherslowastUltrasound polycystic ovaries defined as the presence of ge12 follicles of 2ndash9mm width or an increase in ovarian volume (gt10mL) in at least one ovary inwomen not consuming oral contraceptives

the insulin resistance syndrome [14 19] Moreover GDM isobserved in almost 50 of pregnancies in womenwith PCOS[10] which has been described as an independent predictorof the former [20] Although the consequences of PCOS arenot limited to reproductive dysfunction these implicationsoften represent the most critical aspect for both patients andclinicians as it conveys an increase in the risk for pregnancy-induced hypertension preeclampsia and preterm birth [20]

Amidst the metabolic milieu generated by PCOS GDMappears when pancreatic 120573-cell function is unable to com-pensate the converging increase of both PCOS-related IR andnormal gravidic IR [21] Given the profound influence IRexerts on reproduction it has become an important pharma-cological target associated with improvement of ovulationinduction [22] prevention of endocrine-metabolic gesta-tional complications [23] and management of GDM [24] Tothis end oral antidiabetic agents such as metformin havebeen proposed as a valuable tool during pregnancy [25] albeitremaining an FDA Pregnancy Category B drug [26]

The purpose of this review is to describe the phar-macology of metformin during gestation and analyze itsbenefits in metabolically challenged pregnancies such as inwomen with PCOS andor GDM We have compiled severalpeer-evaluated studies both prospective and cross-sectionalwhich aid in the description and analysis of the role ofmetformin during pregnancy including animal models invitro analyses and clinical studiesThese data were organizedper the following reasoning (a) the role of IR in the develop-ment of PCOS and GDM (b) the impact of their endocrine-metabolic derangements in pregnancy and (c) the use ofmetformin in regards to PCOS and pregnancy and in GDM

2 Insulin Resistance as the Key EndocrineDisruption in Polycystic Ovary Syndrome

The etiology of PCOS is complex and multifactorial includ-ing several endocrine disturbances such as (a) increased pul-satile secretion of gonadotropin-releasing hormone (GnRH)and luteinizing hormone (LH) prompting theca cell hyper-stimulation and androgen hypersecretion [27] (b) nonselec-tion of a dominant ovarian follicle mediated by intrinsic andextrinsic ovary factors with follicular cells hyperplasia [28]

(c) genetic predisposition to hyperandrogenemia linked toabnormal in utero androgenic exposure [29] and (d) geneticpredisposition to hyperinsulinemia also linked to prenatalandrogen exposure and pancreatic 120573-cell dysfunction [30]Although it is difficult to establish the relative importanceor chronology of these and subsequent alterations PCOSis characterized by an IR-hyperinsulinemia-hyperandrogene-mia positive feedback circuit (Figure 1) where the latter com-ponent determines themajority of clinicalmanifestations andthe diagnostic criteria for this condition (Table 1) Moreoverobesity is a very common feature in females with PCOSwhich appears to magnify all previous pathophysiologicmechanisms [7]

Insulin resistance defined as a decrease in cellularresponsiveness to insulin signaling [31] triggers increasedinsulin secretion a phenomenon termed ldquocompensatoryhyperinsulinemiardquo [32] Although this mechanism attemptsto maintain lipid carbohydrate and protein metabolismhomeostasis it contributes to multiple aggregate conse-quences such as the cardiovascular PCOS comorbidities [33]and favors hyperandrogenemia through various pathways Inthis respect disruption of the HPO is particularly relevantinsulin has been shown to elevate GnRH and LH secre-tion both dose- and time-dependently [34 35] potentiallymediated through the MAPK pathway [36] This results inincreased frequency and amplitude of GnRH and LH pulsesecretion with increased LHFSH ratio potentiating ovar-ian steroidogenic alterations [6] Other features frequentlyfound in women with PCOS act in synergy with insulintowards enhancing LH release including hyperleptinemia viaAgRPNPY neural pathways and kiss peptidergic signaling[37] and decreased opioidergic tone which appears to sen-sitize pituitary LH-secreting cells to GnRH signaling [38]Hyperinsulinemia has also been associated with diminishedSex Hormone-Binding Globulin (SHBG) levels althoughinsulin appears to be unable to directly inhibit shbg expres-sion instead this effect depends on hyperglycemia-mediatedHepatocyte Nuclear Factor 4-120572 downregulation [39] LowerSHBG synthesis results in increased sex hormone availabilityexacerbating androgenic signaling [40]

Lastly PCOS is also characterized by selective IR inovarian tissue whereinmitogenic pathways are favored while




Insulin resistance


Manifestations










Pregnancy


Obesity


acids


metabolism

Preferentialfetal

metabolism






uarr GSIS




darr PPAR120574























Metformin

PMAT

OCT3

OCT2

OCT1

Intestine Liver

BCRP

P-gp




























Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Insulin resistance


Manifestations










Pregnancy


Obesity


acids


metabolism

Preferentialfetal

metabolism






uarr GSIS




darr PPAR120574























Metformin

PMAT

OCT3

OCT2

OCT1

Intestine Liver

BCRP

P-gp




























Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Pregnancy


Obesity


acids


metabolism

Preferentialfetal

metabolism






uarr GSIS




darr PPAR120574























Metformin

PMAT

OCT3

OCT2

OCT1

Intestine Liver

BCRP

P-gp




























Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Metformin

PMAT

OCT3

OCT2

OCT1

Intestine Liver

BCRP

P-gp




























Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Metformin

PMAT

OCT3

OCT2

OCT1

Intestine Liver

BCRP

P-gp




























Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























Acknowledgments


References


































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Date post:	25-Aug-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Review Article The Role of Metformin in Metabolic...

Documents