Reproductive Endocrinology
Read Time: 14 mins

Polycystic Ovary Syndrome as Metabolic Disease: New Insights on Insulin Resistance

Copy Link
Published Online: May 19th 2023 touchREVIEWS in Endocrinology. 2023;19(1):71-7 DOI:
Authors: Alessandro D Genazzani, Andrea R Genazzani
Quick Links:
Article Information

Polycystic ovary syndrome (PCOS) is a very frequent disease that affects reproductive ability and menstrual regularity. Other than the criteria established at the Rotterdam consensus, in these last few years a new issue, insulin resistance, has been found frequently, and at a very high grade, in patients with PCOS.

Insulin resistance occurs for several factors, such as overweight and obesity, but it is now clear that it occurs in patients with PCOS with normal weight, thus supporting the hypothesis that insulin resistance is independent of body weight. Evidence shows that a complex pathophysiological situation occurs that impairs post-receptor insulin signalling, especially in patients with PCOS and familial diabetes. In addition, patients with PCOS have a high incidence of non-alcoholic fatty liver disease related to the hyperinsulinaemia.

This narrative review focuses on the recent new insights about insulin resistance in patients with PCOS, to better understand the metabolic impairment accounting for most of the clinical signs/symptoms of PCOS.


Familial diabetes, hyperinsulinemia, inositols, insulin resistance, lipoic acid, non-alcoholic fatty liver disease, polycystic ovary syndrome


Polycystic ovary syndrome (PCOS) is a very common disease, with an incidence of 5−21% in women during their fertile life (18–45 years of age) worldwide.1 PCOS is clinically diagnosed when two of the three 2003 Rotterdam consensus criteria are met: (i) chronic anovulation disorder (in the form of oligo- or anovulation up to amenorrhoea); (ii) clinical (e.g. acne, hirsutism) or biochemical signs of hyperandrogenism; and (iii) micro-polycystic ovaries, i.e. ≥20 follicles per ovary and/or an ovarian volume ≥10 mL on either ovary (detected using ultrasound transducers with a frequency bandwidth that includes 8 MHz).2–4 Combining these three criteria highlights four distinct phenotypes of PCOS, the most clinically severe of which is the one that is positive for all three criteria.5

Although the overall prevalence of PCOS is similar across all countries, a significant variability due to ethnic factors has been found to influence the phenotypic manifestations of the syndrome; for example, the prevalence of PCOS among Caucasian women ranges from 4.7 to 6.8%.6 Furthermore, it has been reported that, when groups move from one place to another, they retain their ethnic predisposition to PCOS and to impaired metabolism sustained by hyperinsulinaemia and/or diabetes, as observed, for example, in British women of Indian subcontinent Asian origin, who present a higher prevalence of PCOS and type 2 diabetes.6 From these data, we may infer that there is an environmental as well as genetic component to PCOS, because diet, exercise, and lifestyle have wide ethnic variations.

Insulin resistance (IR) is a specific biological adaptation that induces a compensatory hyperinsulinaemia in approximately 70−80% of women with PCOS and central obesity, and in 15−30% of lean women diagnosed with PCOS.3,7,8 IR is frequently found in patients with PCOS, regardless of their body mass index, considering that up to 50% of patients with PCOS are overweight or obese. Notably, overweight and obesity are frequently observed in patients with PCOS phenotype A, the most severe of the four phenotypes.5

Consequently, these metabolic features (i.e. insulin plasma level evaluation, body weight or body mass index computation) should be considered when evaluating patients with PCOS. As such, two alternative types of PCOS have been suggested: the classic reproductive phenotype of PCOS and a new one, with high metabolic risk and impairment, whose proposed name is ‘metabolic reproductive syndrome’.9 Due to the relevance that the metabolic aspects may play in PCOS, this review will focus on the new issues recently highlighted.

Insulin actions and insulin resistance

The role of insulin in mammals is extremely important. In humans, insulin is the main regulator of glucose homeostasis, inducing the uptake of glucose in all tissues, in particular in the adipose tissue, muscles, heart and liver. Insulin also decreases lipolysis, thereby reducing the amount of free fatty acid in the blood, which partly modulates the effects of insulin on glucose production by the liver.10 Other than these metabolic effects, insulin plays a role as a co-gonadotropin. Specifically, it modulates the ovarian function by amplifying the action of the luteinizing hormone (LH) on theca cells, thus participating in the androgen secretion of androstenedione from the ovaries.11 Such co-gonadotropic effects are partly direct and partly indirect since insulin facilitates the expression of its own receptors on the granulosa cells but also on the LH and insulin-like growth factor 1 receptors. When IR occurs, the increased plasma levels of insulin result in excessive stimulation of the ovaries, thus inducing an overproduction of androgens.10,11 It is clear that excess insulin impairs not only ovarian function but also the central and neuroendocrine control of the reproductive axis (Figure 1).

Indeed, recent studies have reported the link between kisspeptin and the gonadotropin-releasing hormone (GnRH)-induced secretion of LH, as evidenced by the concomitant secretion of the pulsatile peaks of both hormones.12,13 Moreover, kisspeptin and LH have been found to be cosecreted in eumenorrheic PCOS but not in oligomenorrheic PCOS.14 In addition, insulin plasma levels were found to significantly correlate with both kisspeptin and LH plasma levels in subjects with PCOS and patients with functional hypothalamic amenorrhoea (FHA).13,15 All these data support the hypothesis that insulin plays a relevant role in the control of reproduction in healthy conditions as well as in physiopathological states such as FHA16 and PCOS in patients who are overweight/obese.15–17 Any excess of insulin can interfere with GnRH secretion at the hypothalamic level through an excess of kisspeptin, thus causing excessive stimulation of the gonadotropin release and LH oversecretion.14 The opposite is true in the case of FHA.15 In fact, patients with FHA show very low levels of insulin that correlate with very low levels of LH.

Consequently, insulin plasma levels must not be elevated in the blood, and any excess might induce specific effects not only on the metabolic but also on the reproductive side. Insulin’s role is to keep glucose concentrations under control; such a task, however, is accomplished by a highly sophisticated network of hormones and neuropeptides released mainly from the pancreas (i.e. insulin) but also from the brain, liver and intestine, as well as from the adipose and the muscle tissue. Within this network, the pancreas plays a key role by secreting the blood sugar-lowering hormone insulin and its opponent glucagon.18 When such balance between insulin and glucagon is not in equilibrium and plasma insulinemia rises in the presence of normal glucose plasma levels, IR takes place; this means that higher insulin levels are required to maintain a normal level of glucose into the blood flow, to maintain the glucose homeostasis (Figure 2).18,19

IR occurs whenever the ability of insulin to induce its specific metabolic actions is reduced and the metabolic uptake and production of glucose and lipolysis is impaired. Consequently, a compensatory mechanism of releasing higher levels of insulin takes place, and higher levels of insulin are released both in the baseline and after glucose load.8,10

IR has specific negative effects on some organs and tissues. In the liver and skeletal muscle, IR increases lipolysis by the accumulation of non-esterified fatty acids. When lipids are accumulated inside the hepatocytes, they activate the diacylglycerol/protein kinase C and inhibit the insulin receptor.10 Inside the skeletal muscles, IR probably induces the inhibition of both the phosphoinositide-3 kinase and the phosphorylation of insulin receptor substrate 1, thus changing the expression of the glucose transporter-4 (GLUT-4) vesicles and reducing glucose upload.20,21

Notably, IR occurs more frequently in patients with PCOS who are overweight/obese, especially in those with central obesity;4 however, an extensive literature search demonstrated that IR is also possible in normal-weight PCOS, regardless of body mass index.8,22 The evidence that IR occurs in lean patients with PCOS suggests the hypothesis that a post-receptor defect could be affecting glucose upload,8,23,24 rather than an excessive serine phosphorylation of the insulin receptor.8,25 Being overweight or obese is central for the onset of several of the classic PCOS symptoms, as was recently shown by the meta-analysis by Behboudi-Gandevani et al.26 Notably, abnormal glucose control and/or type 2 diabetes have also been observed to develop more rapidly in patients with PCOS than in the control patients.27 This evidence reinforces the suggestion that patients with PCOS should undergo the oral glucose tolerance test (OGTT),28 a method for measuring the body’s response to glucose that lasts at least 2 hours, to disclose the insulin response under metabolic stress. OGTT discloses the patient’s hyperinsulinaemic condition when insulin response is higher than 50 µU/ml within 3090 minutes from the glucose load.19,29

Insulin signalling and insulin resistance: role of inositols

It is a common observation that a high percentage of patients with PCOS undergoing treatment with insulin sensitizers (i.e. metformin) experience significant improvement not only in the metabolic and hormonal parameters, mainly the hyperinsulinaemic state, but also in hyperandrogenic signs, with the recovery of an almost normal ovarian and menstrual function.17,30,31 Unfortunately, metformin dosage depends on both the grade of obesity of the patient and on their hyperinsulinaemic condition; moreover, the higher the dosages are, the more frequent the gastrointestinal side effects.17,30,31 A defect in the inositol phosphoglycan (IPG) second messenger pathway could explain the appearance of hyperinsulinaemia via impairment of the post-receptor insulin-induced signal; this observation is the basis for the proposal of new therapeutical strategies to manage hyperinsulinaemia in patients with PCOS.32,33 Indeed, IPGs represent an essential biological step in the transmission of the specific hormonal and metabolic signals generated after insulin links to its membrane receptor. IPGs are produced at the cellular membrane level after the hydrolysis of glycosyl-phosphatidylinositol lipids located on the internal surface of the cell membrane;34 then, IPGs are part of the post-receptor intracellular mechanism that corresponds to the second messenger. This insulin-induced intracellular mechanism controls the oxidative and non-oxidative metabolism of glucose and the uptake of glucose by GLUT-4 from the extracellular environment.9,35 For this reason, in recent years, inositols have been used consistently as an integrative strategy for improving the cellular response to the metabolic cascades that are activated by insulin binding to its receptor. However, insulin is not the only hormone to use IPG; other peptide hormones, such as thyroid-stimulating and follicle-stimulating hormones, use them as second messengers.34,36

Inositols belong to a family of nine isomers, only two of which are relevant for the mechanisms described above: myo-inositol (MYO) and D-chiro inositol (DCI). Inositols are found in many plants, vegetables such as beans, and fruits. Though belonging to the vitamin group, inositols have a chemical formula similar to glucose and can be produced by our human biology, but most of the inositol comes from food.8,37 Once inositol enters the cells, it is transformed into phosphatidil-myo-inositol and then into inositol-triphosphate, which is the real second messenger of peptide hormones (i.e. insulin, thyroid-stimulating hormones and follicle-stimulating hormones).34,38 According to Larner et al.,39,40 a specific balance is needed between two out of the nine inositol isomers, that is, between MYO and DCI. These inositol isomers differ only in the position of one hydroxyl group, and DCI derives from MYO thanks to the activity of epimerase.40

As mentioned, a specific balance is needed between MYO and DCI.39,40 Specifically, both MYO and DCI are relevant to controlling the correct transmission of the metabolic signal of insulin after it binds to its membrane receptor. Once insulin binds to a receptor, it activates a specific kinase cascade, which in turn activates the phosphorylation of the protein kinase B/Akt; this determines the translocation of GLUT-4 vesicles on the cell membrane to upload glucose.40 In addition, insulin binding determines another cascade of events that converts MYO to DCI through the activation of the phospholipase and epimerase enzymes.35 DCI induces glycogen synthase in the cytoplasm to transform glucose into glycogen; at the same time, it activates the mitochondrial pyruvate dehydrogenase phosphatase, which induces the oxidation of glucose inside the mitochondria.8,35 It is known that the role of the inositols, MYO and DCI, is relevant from a biological point of view. Maintaining a perfect equilibrium between the two allows for an adequate upload of sugar from the outside of the cell; through the oxidation of glucose inside the mitochondria and the transformation of glucose into glycogen, a gradient of concentration that allows for an additional upload of glucose from outside the cell through the GLUT-4 vesicles is achieved.8

As can be imagined, whatever changes the equilibrium between MYO and DCI impacts the upload of glucose and its transformation into glycogen or oxidation inside the mitochondriaIn particular, events that can negatively affect epimerases reduce DCI production and impair glucose upload, slowing glucose upload and then increasing insulin (i.e. hyperinsulinaemia) to compensate for the impaired MYO-to-DCI conversion.

Indeed, studies conducted on both animals and humans with diabetes reported that higher amounts of MYO are present in urinary excretion, while DCI is reduced.33,41 This finding is suspected to be explained by a reduced expression and/or bioactivity of the epimerase.42 Consequently, these data support the hypothesis that IR occurs due to an abnormal enzymatic expression, rather than due to other putative reasons.8 As a demonstration of abnormal enzymatic expressionvarious studies have focused on the role played by inositols on insulin sensitivity.43 Although MYO effectively reduces IR under OGTT in normal-weight PCOS,22 a differential IR was observed in patients with PCOS who are overweight or obese.19 This finding raises the possibility that specific factors (i.e. the impaired epimerase expression) might be at the basis of the differential activity of the epimerase enzyme. Considering previous reports about altered DCI production and urinary excretion,33,41 a clear biological scenario was observed when DCI was administered to patients with PCOS who are overweight or obese.44 All patients demonstrated reduced insulinaemia under the integrative treatment and improved IR, as shown with the OGTT; however, the subjects that reported the presence of familial diabetes in first-degree relatives (parents and/or grandparents) showed a higher IR with the OGTT and greater improvement under treatment.44 These data support the hypothesis that DCI integration positively corrects a reduced endogenous DCI production in patients with familial diabetes.

Considering that diabetes might represent a serious predisposing factor in reducing insulin sensitivity and increasing IR and hyperinsulinemia, it has been suggested that the administration of inositols may depend on the ability of epimerase to convert MYO into DCI in an adequate quantity.45,46 In the absence of such familial predisposition, the administration of MYO is plausible alone47 or in combination with DCI;48 nonetheless, DCI integration plays a relevant role in the presence of familial diabetes.8,43–46

Alpha-lipoic acid: the silent element that drives insulin sensitivity

Considering the complexity of human biology, it is not possible that only inositols are responsible for controlling the cellular uptake of glucose and, thus, for controlling glycaemia in the biological fluids. Indeed, another compound has very recently been considered relevant for treating IR: alpha-lipoic acid (ALA). In animal models, ALA has been found to modulate and increase glucose use by increasing adenosine monophosphate-activated protein kinase in skeletal muscles, thus increasing GLUT-4.49–51

ALA, also known as thioctic acid, is a naturally occurring substance that is essential for the function of several enzymes in oxidative metabolism.52,53 The first clinical use of ALA was described in 1959 for the treatment of mushroom, especially Amanita phalloides, poisoning.54 ALA is commonly found in vegetables such as spinach and broccoli, and in tomato and meats. In mammals, ALA is synthesized by mitochondria lipoic acid synthase (LASY), which can be downregulated in different clinical conditions, such as diabetes.55 ALA and/or its reduced form, dihydrolipoic acid, have many biochemical functions; they act as biological antioxidants (such as metal chelators), which reduce the oxidized forms of other antioxidant agents (such as vitamin C and E and glutathion), and module the signalling transduction of several pathways (such as insulin and nuclear factor kappa B).51

Among many actions, ALA improves endothelial dysfunction56 and reduces oxidative stress following exercise training,57 protecting against the development of atherosclerosis.57 Due to these actions, ALA could potentially be considered a therapeutic agent for many chronic diseases with a great epidemiological, economic and social impact, such as hypertension,58 Alzheimer’s disease,59 cognitive dysfunction, and diabetes mellitus and its complications.55,60

Consequently, ALA has been proposed as a therapeutic compound for many diseases, especially diabetes and PCOS, since both present an abnormal dysmetabolic profile.61,62

Recently, several studies showed the great efficacy of ALA in controlling insulin sensitivity. Indeed, we recently found that ALA administration at a dose as low as 400 mg every day was effective in reducing IR and improving insulin sensitivity in patients with PCOS, as demonstrated by the significant decrease in the homeostasis model assessment index, especially in patients with PCOS with familial diabetes.63 These data support the suggestion that ALA administration overcomes the impairment typically present in familial diabetes that downregulates the expression of LASY inside the mitochondria of mammals and in humans.64,65 Indeed, reduced endogenous ALA synthesis induces a lower glucose uptake in skeletal muscle cells, which are at the basis of IR.65 This defective action decreases adenosine monophosphate-activated protein kinase in skeletal muscles,45 thus reducing induction on GLUT-4.49,65 However, this is not the only benefit. Notably, only patients with familial diabetes showed transaminase plasma levels close to the upper levels of normality and higher than patients with no familial diabetes.66–68 ALA administration to patients with familial diabetes significantly decreased transaminase to normal plasma levels. These data consistently support the hypothesis that the integrative administration of ALA (mimicking endogenous ALA) eliminates most of the metabolic impairment in subjects with PCOS, especially in those with familial diabetes.

The use of ALA as treatment has great clinical significance. A recent review states that non-alcoholic fatty liver disease (NAFLD) is found in a high percentage (from 40 to 70%) of patients with PCOS,69 and the combination of PCOS with obesity and IR is dangerous as it triggers not only NAFLD but also, with a great probability, the occurrence of type 2 diabetes.69,70 The ability of the ALA administration to reduce transaminase levels in patients with familial diabetes confirms its ability in liver protection, as previously reported,54 and suggests that ALA positively affects liver function in patients with PCOS, by reducing the risk of developing a liver impairment such as NAFLD and, later, type 2 diabetes.63 This contradicts another report that did not sustain such effects.71

For these reasons, and considering the benefits of inositols (i.e. MYO and DCI), ALA has been coupled with MYO or DCI to improve the beneficial effects on insulin sensitivity. Various studies have shown that the combination of ALA with MYO or DCI significantly improved both reproductive and metabolic outcomes in patients with PCOS with and without familial diabetes.47,66,67 Indeed, because patients with PCOS with familial diabetes present reduced expression of LASY and of epimerase, the recovery of insulin sensitivity and reproductive function seems to be greatly improved by the combination of ALA with DCI,67 which is greatly effective also in the absence of familial diabetes.67 The combination of ALA and MYO also improves the reproductive axis and metabolic impairment; however, in the case of familial diabetes, it does not overcome the reduced expression/function of epimerase.47,66

Hepatic insulin extraction as an index of hepatic involvement in insulin resistance in polycystic ovary syndrome

A classic silent and asymptomatic hepatic disease is NAFLD. NAFLD is frequently but not always characterized by elevated aminotransferases (i.e. alanine aminotransferase [ALT] and aspartate aminotransferase [AST]),69 which are considered relative indicators of the presence of NAFLD, since they are eventually close to the upper range of normality.46,72 There is growing evidence that NAFLD and PCOS share the same metabolic triggering factors,70 and that NAFLD is related more to IR than to liver fat content.73,74 The incidence of NAFLD in fertile women with PCOS has been shown to be correlated with IR, altered lipid profiles and androgen plasma levels.75–78 Although androgen levels might not differ between patients with PCOS and female patients with NAFLD and without PCOS,79–81 lower levels of sexual hormone-binding globulin have been proposed as a putative mediator between IR and NAFLD; sexual hormone-binding globulin is a steroid transporter and an indicator of the metabolic and nutritional status, whose hepatic production is regulated by insulin.69,82 Therefore, it is clear that there is a close relation between IR and hyperinsulinaemia and the possible occurrence of a hepatic functional impairment, such as NAFLD, which is probably associated with increased transaminase plasma levels.

Consequently, several reports have demonstrated that insulin clearance is impaired in patients who are overweight or obese,83 similarly to patients with PCOS who are overweight or obese.84,85 Recently, our group evaluated the hepatic insulin extraction (HIE) index in patients with PCOS who are overweight or obese and found that this index indicated impairment, specifically when familial diabetes was present in at least one first-degree relative (parents and/or grandparents).84,85

HIE can be computed with various algorithms,73,86 of which the computation of the ratio between insulin and C-peptide plasma levels is the simplest.86 Recent studies reported that reduced liver function and the ability to clear insulin participate in improving IR.73,86,87 From a physiological point of view, HIE reflects insulin kinetics intended as the balance between synthesis from the pancreas and clearance exerted by the liver. Since C-peptide clearance by the liver is almost negligible, C-peptide can be intended to reflect the pancreatic synthesis of insulin.88 Indeed, at the pancreatic level, pro-insulin cleavage generates one insulin molecule and one C-peptide molecule. Although at the pancreatic level the production ratio between insulin and C-peptide is 1, this ratio can be computed using the circulating levels of both peptides. This way, the ratio greatly reflects the balance between insulin hepatic clearance kinetics and insulin pancreatic release, which corresponds to C-peptide concentrations, since its hepatic clearance is very low.89 The liver function, in general, extracts up to 50% of the insulin delivered by the pancreas, while the kidneys extract 30% and the muscles extract approximately 15–35% of what remains in the circulation after the first pass through the liver (Figure 3).83,90–93 The HIE depends on the adequate expression/synthesis of the insulin-degrading enzyme.88,94

HIE has been evaluated in patients with PCOS who are overweight or obese, while accounting for whether there was anyone with diabetes among first-degree relatives (i.e. parents and/or grandparents).85 One study found not only that all subjects with PCOS with familial diabetes had higher insulin plasma levels in baseline conditions after overnight fasting, but that they also showed higher HIE than subjects with PCOS without familial diabetes.84 In addition, patients with PCOS with familial diabetes also showed ALT and AST plasma levels at the upper limit of normality and higher than in patients with PCOS without familial diabetes.85 These data let us infer that a specific impairment might be induced by a familial predisposition to diabetes affecting hepatocyte functions. Indeed, patients with PCOS with familial diabetes showed a higher IR than patients with PCOS without familial diabetes when undergoing OGTT.84 As C-peptide response did not differ between the two PCOS groups, HIE resulted higher in patients with PCOS with familial diabetes for almost the whole duration of the OGTT, mainly due to the reduced hepatic clearance of insulin.84 Recently, the integrative approach to treating PCOS using ALA alone63 or in combination with MYO66 or DCI67 demonstrated great efficacy, especially in patients with PCOS with a familial predisposition to diabetes.68

These results support the hypothesis that the familial predisposition to diabetes somehow impairs not only the peripheral insulin sensitivity through the lower/defective expression/synthesis of both epimerase and LASY, but also the hepatic ability to clear insulin. In the absence of familial diabetes, only overweight or obesity are responsible for the peripheral defect in insulin sensitivity, thus inducing a compensatory greater insulin (and C-peptide) production; however, when familial diabetes is present, the impaired function/synthesis of epimerase and LASY is additional to the defect in hepatic clearance, due to a defect of insulin-degrading enzyme function/expression. The combination of these events determines a higher amount of circulating insulin (due to the overproduction and lower clearance) in PCOS with familial diabetes than in PCOS without familial diabetes. The frequent occurrence of elevated (though not pathological) ALT and AST plasma levels has to be attentively taken into consideration, this being a signal of hepatic impairment. The combination of hyperinsulinemia and elevated transaminase has been considered a trigger for NAFLD, which occurs more frequently in patients with PCOS than in the normal population.69

In conclusion, this narrative review recognizes the importance of adopting a precise approach to the treatment of PCOS, not only from a gynaecological perspective but also from an internal medicine perspective. The evidence indicates that there is a greater incidence of dysmetabolic diseases, such as diabetes and dyslipidaemia, together with NAFLD and non-alcoholic steatohepatitis in patients with PCOS, especially in those with familial diabetes; therefore, patients with PCOS deserve a careful evaluation. Every time these patients refer to the gynaecologist for any kind of reproductive impairment or just for menstrual irregularity, a metabolic evaluation has to be done together with the hormonal reproductive profile.

Article Information:

Alessandro D Genazzani and Andrea R Genazzani have no financial or non-financial relationships or activities to declare in relation to this article.

Compliance With Ethics

This article involves a review of literature and does not report on new clinical data, or any studies with human or animal subjects performed by any of the authors.

Review Process

Double-blind peer review.


The named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.


Alessandro D Genazzani, Gynaecological Endocrinology Center, Department of Obstetrics and Gynaecology, University of Modena and Reggio Emilia, Modena, Italy. E:


No funding was received in the publication of this article.


This article is freely accessible at ©Touch Medical Media 2023

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this study.




1. Azziz RWoods KSReyna Ret alThe prevalence and features of the polycystic ovary syndrome in an unselected populationJ Clin Endocrinol Metab2004;89:27459DOI10.1210/jc.2003-032046

2. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and longterm health risks related to polycycstic ovary syndromeFertil Steril2004;81:1925.

3. Fauser BTarlatzis BCRebar RWet alConsensus on women’s health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-sponsored 3rd PCOS consensus workshop groupFertil Steril2012;97:2838. DOI10.1016/j.fertnstert.2011.09.024

4. Teede HJMisso MLCostello MFet alRecommendations from the International evidence-based guideline for the assessment and management of polycystic ovary syndromeHum Reprod2018;33:160218DOI10.1093/humrep/dey256

5. Walters KAGilchrist RBLedger WLet alNew perspectives on the pathogenesis of PCOSNeuroendocrine Origins Trends in Endocrinology & Metabolism2018;12:84152.

6. Escobar-Morreale HFLuque-Ramírez MSan Millán JLThe molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndromeEndocr Rev2005;26:25182DOI10.1210/er.2004-0004

7. Ciampelli MFulghesu AMCucinelli Fet alImpact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndromeMetabolism1999;48:16772DOI10.1016/s0026-0495(99)90028-8

8. Genazzani AInositols: Reflections on how to choose the appropriate one for PCOSGynecol Endocrinol2020;36:10456DOI: 10.1080/09513590.2020.1846697

9. Dunaif AFauser BRenaming PCOS – a two-state solutionJ Clin Endocrinol Metab. 2013;98:43258. DOI10.1210/jc.2013-2040

10. Armanini DBoscaro MBordin LSabbadin CControversies in the pathogenesis, diagnosis and treatment of PCOS: Focus on insulin resistance, inflammation, and hyperandrogenismInt J Mol Sci2022;23:4110DOI10.3390/ijms23084110

11. Diamanti-Kandarakis EDunaif AInsulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev2012;33:9811030DOI10.1210/er.2011-1034

12. Meczekalski BKatulski KPodfigurna-Stopa Aet alSpontaneous endogenous pulsatile release of kisspeptin is temporally coupled with luteinizing hormone in healthy womenFertil Steril. 2016;105:134550DOI10.1016/j.fertnstert.2016.01.029

13. Podfigurna AMaciejewska-Jeske MMeczekalski BGenazzani ADKisspeptin and LH Pulsatility in patients with functional hypothalamic amenorrheaEndocrine2020;70:63543DOI10.1007/s12020-020-02481-4

14. Katulski KPodfigurna ACzyzyk Aet alKisspeptin and LH pulsatile temporal coupling in PCOS patientsEndocrine2018;61:14957. DOI10.1007/s12020-018-1609-1

15. Genazzani ADPodfigurna ASzeliga AMeczekalski BKisspeptin in female reproduction: From physiology to pathophysiologyGynecological and Reproductive Endocrinology and Metabolism2021;2:14855.

16. Genazzani ADDespini GCzyzyk Aet alModulatory effects of L-carnitine plus l-acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA)Gynecol Endocrinol2017;33:9637DOI10.1080/09513590.2017.1332587

17. Genazzani ADRicchieri FLanzoni CUse of metformin in the treatment of polycystic ovary syndromeWomens Health (Lond)2010;6:57793DOI10.2217/whe.10.43

18. Röder PVWu BLiu YHan WPancreatic regulation of glucose homeostasisExp Mol Med. 2016;48:e219. DOI: 10.1038/emm.2016.6

19. Genazzani ADPrati ASantagni Set alDifferential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients. Gynecol Endocrinol2012;28:96973. DOI10.3109/09513590.2012.685205

20. Petersen MCShulman GIMechanisms of insulin action and insulin resistancePhysiol Rev2018;98:2133223. DOI: 10.1152/physrev.00063.2017

21. Diamanti-Kandarakis EPapavassiliou AGMolecular mechanisms of insulin resistance in polycystic ovary syndromeTrends Mol Med. 2006;12:32432DOI10.1016/j.molmed.2006.05.006

22. Genazzani ADSantagni SRicchieri Fet alMyo-inositol modulates insulin and luteinizing hormone secretion in normal weight patients with polycystic ovary syndromeJ Obstet Gynaecol Res2014;40:135360DOI10.1111/jog.12319

23. Baillargeon JPDiamanti-Kandarakis EOstlund REet alAltered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care2006;29:3005DOI10.2337/diacare.29.02.06.dc05-1070

24. Dunaif AInsulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesisEndocr Rev1997;18:774800DOI10.1210/edrv.18.6.0318

25. Vrbikova JHainer VObesity and polycystic ovary syndromeObes Facts2009;2:2635DOI10.1159/000194971

26. Behboudi-Gandevani SRamezani Tehrani FRostami Dovom Met alInsulin resistance in obesity and polycystic ovary syndrome: Systematic review and meta-analysis of observational studiesGynecol Endocrinol2016;32:34353DOI10.3109/09513590.2015.1117069

27. Celik CTasdemir NAbali Ret alProgression to impaired glucose tolerance or type 2 diabetes mellitus in polycystic ovary syndrome: A controlled follow-up studyFertil Steril2014;101:11238DOI10.1016/j.fertnstert.2013.12.050

28. Legro RSArslanian SAEhrmann DAet alDiagnosis and treatment of polycystic ovary syndrome: An endocrine Society clinical practice guidelineJ Clin Endocrinol Metab2013;98:456592DOI10.1210/jc.2013-2350

29. Legro RSFinegood DDunaif AA fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab1998;83:26948DOI10.1210/jcem.83.8.5054

30. Genazzani ADLanzoni CRicchieri Fet alMetformin administration is more effective when non-obese patients with polycystic ovary syndrome show both hyperandrogenism and hyperinsulinemiaGynecol Endocrinol2007;23:14652DOI10.1080/09513590701214398

31. Pasquali RGambineri AInsulin-sensitizing agents in polycystic ovary syndromeEur J Endocrinol. 2006;154:76375. DOI: 10.1530/eje.1.02156

32. Asplin IGalasko GLarner JChiro-inositol deficiency and insulin resistance: A comparison of the chiro-inositol- and the myo-inositol-containing insulin mediators isolated from urine, hemodialysate, and muscle of control and type II diabetic subjectsProc Natl Acad Sci U S A1993;90:59248DOI10.1073/pnas.90.13.5924

33. Kennington ASHill CRCraig Jet alLow urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitusN Engl J Med. 1990;323:3738DOI10.1056/NEJM199008093230603

34. Porcaro G GGPolycystic ovary syndrome: Features, diagnostic criteria and treatmentsEndocrinol Metab Synd2014;03:2DOI10.4172/2161-1017.1000136

35. Croze MLSoulage COPotential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie. 2013;95:181127. DOI10.1016/j.biochi.2013.05.011

36. Wild RACarmina EDiamanti-Kandarakis Eet alAssessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary ovary syndrome (AE-PCOS) societyJ Clin Endocrinol Metab2010;95:203849.

37. Bizzarri MCarlomagno GInositol: History of an effective therapy for polycystic ovary syndromeEur Rev Med Pharmacol Sci2014;18:1896903.

38. Thomas RMNechamen CAMazurkiewicz JEet alThe adapter protein APPL1 links FSH receptor to inositol 1,4,5-trisphosphate production and is implicated in intracellular Ca (2+) mobilization. Endocrinology. 2011;152:1691701DOI10.1210/en.2010-1353

39. Larner JHuang LCTang Get alInsulin mediators: Structure and formationCold Spring Harb Symp Quant Biol1988;53 Pt 2:96571DOI10.1101/sqb.1988.053.01.111

40. Larner JBrautigan DLThorner MOD-chiro-inositol glycans in insulin signaling and insulin resistanceMol Med2010;16:54352. DOI10.2119/molmed.2010.00107

41. Ortmeyer HKBodkin NLLilley Ket alChiroinositol deficiency and insulin resistance. I. Urinary excretion rate of chiroinositol is directly associated with insulin resistance in spontaneously diabetic rhesus monkeysEndocrinology1993;132:6405DOI10.1210/endo.132.2.8425483

42. Sun THeimark DBNguygen Tet alBoth myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controlsBiochem Biophys Res Commun2002;293:10928DOI10.1016/S0006-291X(02)00313-3

43. Genazzani ADInositols: Reflections on how to choose the appropriate one for PCOSGynecol Endocrinol2020;36:10456. DOI10.1080/09513590.2020.1846697

44. Genazzani ADSantagni SRattighieri Eet alModulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol2014;30:43843DOI10.3109/09513590.2014.897321

45. Genazzani ADInositol as putative integrative treatment for PCOSReprod Biomed Online2016;33:77080DOI10.1016/j.rbmo.2016.08.024

46. Chalasani NYounossi ZLavine JEet alThe diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:200523DOI10.1002/hep.25762

47. Genazzani ADPrati AMarchini Fet alDifferential insulin response to oral glucose tolerance test (OGTT) in overweight/obese polycystic ovary syndrome patients undergoing to myo-inositol (myo), alpha lipoic acid (Ala), or combination of bothGynecol Endocrinol2019;35:108893DOI10.1080/09513590.2019.1640200

48. Dinicola SChiu TTYUnfer Vet alThe rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndromeJ Clin Pharmacol2014;54:107992DOI10.1002/jcph.362

49. Lee WJSong K-HKoh EHet alAlpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscleBiochem Biophys Res Commun2005;332:88591DOI10.1016/j.bbrc.2005.05.035

50. Shen QWZhu MJTong Jet alCa2+ /calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by α-lipoic acid in C2C12 myotubesAm J Physiol Cell Physiol. 2007;293:C1395403DOI10.1152/ajpcell.00115.2007

51. Gomes MBNegrato CAAlpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr2014;6:80DOI10.1186/1758-5996-6-80

52. Golbidi SBadran MLaher IDiabetes and alpha lipoic acidFront Pharmacol. 2011;2:69DOI10.3389/fphar.2011.00069

53. Shay KPMoreau RFSmith EJet alAlpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potentialBiochim Biophys Acta2009;1790:114960DOI10.1016/j.bbagen.2009.07.026

54. Bock ESchneeweiss JEin beitrag zur therapie der neuropathia diabeticMunchner Med Wochenschrift. 1959;43:19112.

55. Padmalayam IHasham SSaxena UPillarisetti SLipoic acid synthase (LASY): A novel role in inflammation, mitochondrial function, and insulin resistanceDiabetes2009;58:6008DOI10.2337/db08-0473

56. Wray DWNishiyama SKHarris RAet alAcute reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension. 2012;59:81824DOI10.1161/HYPERTENSIONAHA.111.189456

57. McNeilly AMDavison GWMurphy MHet alEffect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose toleranceLipids Health Dis2011;10:21722DOI10.1186/1476-511X-10-217

58. Vasdev SFord CAParai Set alDietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive ratsJ Hypertens. 2000;18:56773DOI10.1097/00004872-200018050-00009

59. Moreira PIHarris PLRZhu Xet alLipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblastsJ Alzheimers Dis2007;12:195206DOI10.3233/jad-2007-12210

60. Packer LKraemer KRimbach GMolecular aspects of lipoic acid in the prevention of diabetes complicationsNutrition2001;17:88895. DOI10.1016/s0899-9007(01)00658-x

61. Scaramuzza AGiani ERedaelli Fet alAlpha-lipoic acid and antioxidant diet help to improve endothelial dysfunction in adolescents with type 1 diabetes: A pilot trialJ Diabetes Res2015;2015:474561DOI10.1155/2015/474561

62. Masharani UGjerde CEvans JLet alEffects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndromeJ Diabetes Sci Technol2010;4:35964DOI10.1177/193229681000400218

63. Genazzani ADShefer KDella Casa Det alModulatory effects of alpha-lipoic acid (Ala) administration on insulin sensitivity in obese PCOS patientsJ Endocrinol Invest2018;41:58390DOI10.1007/s40618-017-0782-z

64. Morikawa TYasuno RWada HDo mammalian cells synthesize lipoic acid? Identification of a mouse cDNA encoding a lipoic acid synthase located in mitochondriaFEBS Lett2001;498:1621DOI10.1016/s0014-5793(01)02469-3

65. Padmalayam IHasham SSaxena UPillarisetti SLipoic acid synthase (LASY): A novel role in inflammation, mitochondrial function, and insulin resistanceDiabetes2009;58:6008DOI10.2337/db08-0473

66. Genazzani ADDespini GSantagni Set alEffects of a combination of alpha lipoic acid and myo-inositol on insulin dynamics in overweight/obese patients with PCOSEndocrinol Metab Syndr2014;03:3DOI10.4172/2161-1017.1000140

67. Genazzani ADPrati ASimoncini TNapolitano AModulatory role of D-chiro-inositol and alpha lipoic acid combination on hormonal and metabolic parameters of overweight/obese PCOS patientsEur Gynecol Obstet2019;1:2933.

68. Genazzani ADExpert’s opinion: Integrative treatment with inositols and lipoic acid for insulin resistance of PCOSGynecol Reprod Endocrinol Metab2020;1:14657.

69. Macut DBožić-Antić IBjekić-Macut JTziomalos KPolycystic ovary syndrome and nonalcoholic fatty liver diseaseEur J Endocrinol. 2017;177:R14558.

70. Bae JCRhee EJLee WYet alCombined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetesDiabetes Care2011;34:7279DOI10.2337/dc10-1991

71. Laganà ASMonti NFedeli Vet alDoes alpha-lipoic acid improve effects on polycystic ovary syndrome? Eur Rev Med Pharmacol Sci. 2022;26:12417DOI10.26355/eurrev_202202_28116

72. Loria PAdinolfi LEBellentani Set alPractice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian association for the study of the liver (AISF) expert CommitteeDig Liver Dis2010;42:27282DOI10.1016/j.dld.2010.01.021

73. Utzschneider KMKahn SEPolidori DCHepatic insulin extraction in NAFLD is related to insulin resistance rather than liver fat contentJ Clin Endocrinol Metab2019;104:185565DOI10.1210/jc.2018-01808

74. Macut DTziomalos KBožić-Antić Iet alNon-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndromeHum Reprod2016;31:134753DOI10.1093/humrep/dew076

75. Vassilatou ELafoyianni SVryonidou Aet alIncreased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndromeHum Reprod2010;25:21220DOI10.1093/humrep/dep380

76. Jones HSprung VSPugh CJAet alPolycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistanceJ Clin Endocrinol Metab. 2012;97:370916DOI10.1210/jc.2012-1382

77. Anstee QMTargher GDay CPProgression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosisNat Rev Gastroenterol Hepatol2013;10:33044DOI10.1038/nrgastro.2013.41

78. Birkenfeld ALShulman GINonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetesHepatology2014;59:71323DOI10.1002/hep.26672

79. Qu ZZhu YJiang Jet alThe clinical characteristics and etiological study of nonalcoholic fatty liver disease in Chinese women with PCOSIran J Reprod Med2013;11:72532.

80. Gangale MFMiele LLanzone Aet alLong-term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight patients with polycystic ovarian syndromeClin Endocrinol (Oxf)2011;75:5207DOI10.1111/j.1365-2265.2011.04093.x

81. Dawson AJSathyapalan TSmithson JAJet alA comparison of cardiovascular risk indices in patients with polycystic ovary syndrome with and without coexisting nonalcoholic fatty liver diseaseClin Endocrinol2014;80:8439DOI10.1111/cen.12258

82. Pascal NAmouzou EKSSanni Aet alSerum concentrations of sex hormone binding globulin are elevated in kwashiorkor and anorexia nervosa but not in marasmusAm J Clin Nutr2002;76:23944DOI10.1093/ajcn/76.1.239

83. Koh H-CCao CMittendorfer BInsulin clearance in obesity and type 2 diabetesInt J Mol Sci. 2022;23:596. DOI: 10.3390/ijms23020596

84. Genazzani ADBattipaglia CPetrillo Tet alHIE (hepatic insulin extraction) index in overweight/obese. PCOS patients with or without familial diabetesGynecol Reprod Endocrinol Metab. 2022;3:5768. DOI10.3390/endocrines3020024

85. Genazzani ADBattipaglia CSemprini Eet alFamilial diabetes in obese PCOS predisposes individuals to compensatory hyperinsulinemia and insulin resistance (IR) also for reduced hepatic insulin extraction (HIE)Endocrines2022;3:296302DOI10.3390/endocrines3020024

86. Genazzani ADPrati AGenazzani ARet alSynergistic effects of the integrative administration of acetyl-L-carnitine, L-carnitine, L-arginine and N-acetyl-cysteine on metabolic dynamics and on hepatic insulin extraction in overweight/obese patients with PCOSGynecol Reprod Endocrinol Metab2020;1:5663.

87. Finucane FMSharp SJHatunic Met alLiver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individualsDiabetol Metab Syndr2014;6:43DOI10.1186/1758-5996-6-43

88. Fosam ASikder SAbel BSet alReduced insulin clearance and insulin-degrading enzyme activity contribute to hyperinsulinemia in African AmericansJ Clin Endocrinol Metab2020;105:e183546DOI10.1210/clinem/dgaa070

89. Tura ALudvik BNolan JJet alInsulin and C-peptide secretion and kinetics in humans: Direct and model-based measurements during OGTT. Am J Physiol Endocrinol Metab2001;281:E96674DOI10.1152/ajpendo.2001.281.5.E966

90. Rabkin RSimon NMSteiner SColwell JAEffect of renal disease on renal uptake and excretion of insulin in manN Engl J Med1970;282:1827DOI10.1056/NEJM197001222820402

91. Ferrannini EWahren JFaber OKet alSplanchnic and renal metabolism of insulin in human subjects: A dose-response studyAm J Physiol. 1983;244:E51727DOI10.1152/ajpendo.1983.244.6.E517

92. Eggleston EMJahn LABarrett EJHyperinsulinemia rapidly increases human muscle microvascular perfusion but fails to increase muscle insulin clearance: Evidence that a saturable process mediates muscle insulin uptakeDiabetes2007;56:295863DOI10.2337/db07-0670

93. Chamberlain MJStimmler LThe renal handling of insulinJ Clin Invest1967;46:9119DOI10.1172/JCI105597

94. Leissring MAGonzález-Casimiro CMMerino Bet alTargeting insulin-degrading enzyme in insulin clearanceInt J Mol Sci. 2021;22:2235DOI10.3390/ijms22052235

Further Resources

Share this Article
Related Content In Reproductive Endocrinology
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72