Posted by: admin on Aug 03, 2016 in News

Inflammation and Infertility:

Ahn SH, Khalaj K, Young SL et al (2016). Immune-inflammation gene signatures in endometriosis patients. Fertil Steril. 2016 Jul 27. pii: S0015-0282(16)61408-5.


To determine if the molecular profiles of endometriotic lesions contain informative measures of inflammation and immune dysfunction that may contribute to better understanding of the interplay between immune dysfunction and inflammation and their contribution to endometriosispathogenesis.


Immune and inflammation transcriptomic analysis with the use of the Nanostring nCounter GX Human Immunology V2 platform (579 human immune and inflammation-related genes and 15 housekeeping genes).


Academic university and teaching hospital.




Stage III-IV endometriosis patients with infertility (n = 8) and fertile disease-free control women undergoing tubal ligation (n = 8). Menstrual stage was matched to secretory phase in all participants.


Immune and inflammation transcriptomics quantification from ectopic endometriotic lesions and matched eutopic endometrium from patients. Endometria of fertile women served as control subjects.


Our results displayed endometriotic lesions as molecularly distinct entities compared with eutopic endometrium and endometrium of control samples; 396 out of 579 screened immune and inflammation-related genes were significantly different in ectopic tissues compared with control endometrium. Most importantly, eutopic endometrium of the patients displayed a unique molecular profile compared with the control endometrium (91/579 genes were significantly different), particularly of genes involved in regulation of cell apoptosis and decidualization.


We characterize differential expression of immune-inflammation genes in endometriosis patients, and show molecular distinction of eutopic endometrium of patients compared with control fertile women.

Keto and inflammation:

Dupuis N1,2, Curatolo N1, Benoist JF et al (2015). Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 56(7):e95-8. doi: 10.1111.

The ketogenic diet (KD) is an established treatment for refractory epilepsy, including some inflammation-induced epileptic encephalopathies. In a lipopolysaccharide (LPS)-induced fever model in rats, we found that animals given the KD for 14 days showed less fever and lower proinflammatory cytokine levels than control animals. However, KD rats exhibited a decrease in circulating levels of arachidonic acid and long-chain n-3 polyunsaturated fatty acids (PUFAs), suggesting that the anti-inflammatory effect of KD was probably not due to an increase in anti-inflammatory n-3 PUFA derivatives. These properties might be of interest in some conditions such as fever-induced refractory epileptic encephalopathy in school-aged children.


Nandivada P1, Fell GL1, Pan AH (2016). Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia. Lipids. 51(6):703-14.*

Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloricketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate-based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each dietgroup were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge,hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-α in the postabsorptive period, with a fivefold higher expression of hepatic NFκB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice.


Ruskin DN1, Kawamura M, Masino SA (2009). Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet. PLoS One. 4(12):e8349. doi: 10.1371.

The ketogenic diet is a high-fat, low-carbohydrate regimen that forces ketone-based rather than glucose-based cellular metabolism. Clinically, maintenance on a ketogenic diet has been proven effective in treating pediatric epilepsy and type II diabetes, and recent basic research provides evidence that ketogenic strategies offer promise in reducing brain injury. Cellular mechanisms hypothesized to be mobilized by ketone metabolism and underlying the success of ketogenic diet therapy, such as reduced reactive oxygen species and increased central adenosine, suggest that the ketolytic metabolism induced by the diet could reduce pain and inflammation. To test the effects of a ketone-based metabolism on pain and inflammation directly, we fed juvenile and adult rats a control diet (standard rodent chow) or ketogenic diet (79% fat) ad libitum for 3–4 weeks. We then quantified hindpaw thermal nociception as a pain measure and complete Freund’s adjuvant- induced local hindpaw swelling and plasma extravasation (fluid movement from the vasculature) as inflammation measures. Independent of age, maintenance on a ketogenic diet reduced the peripheral inflammatory response significantly as measured by paw swelling and plasma extravasation. The ketogenic diet also induced significant thermal hypoalgesia independent of age, shown by increased hindpaw withdrawal latency in the hotplate nociception test. Anti-inflammatory and hypoalgesic diet effects were generally more robust in juveniles. The ketogenic diet elevated plasma ketones similarly in both age groups, but caused slowed body growth only in juveniles. These data suggest that applying a ketogenic diet or exploiting cellular mechanisms associated with ketone-based metabolism offers new therapeutic opportunities for controlling pain and peripheral inflammation, and that such a metabolic strategy may offer significant benefits for children and adults.


Wright C1, Simone NL (2016). Obesity and tumor growth: inflammation, immunity, and the role of a ketogenic diet. Curr Opin Clin Nutr Metab Care.19(4):294-9. doi: 10.1097.*


This article reviews the impact the obese state has on malignancy through inflammation and immune dysregulation using recent excerpts from the medical literature.


The obese state creates a proinflammatory endocrinologic milieu altering cellular signaling between adipocytes, immunologic cells, and epithelial cells, leading to the over-activation of adipose tissue macrophages and the upregulation of compounds associated with carcinogenesis. Obesity correlates with a deficiency in numerous immunologic cells, including dendritic cells, natural killer cells, and T cells. In part, this can be attributed to a recent finding of leptin receptor expression on these immune cells and the upregulation of leptin signaling in the obese state. A number of clinical trials have demonstrated the feasibility of a high-fat, low-carbohydrate diet as an adjuvant treatment for cancer, and current trials are investigating the impact of this intervention on disease outcomes. In preclinical trials, a ketogenic diet has been shown to impedetumor growth in a variety of cancers through anti-angiogenic, anti-inflammatory, and proapoptotic mechanisms.


Obesity is becoming more prevalent and its link to cancer is clearly established providing a rationale for the implementation of dietary interventions as an adjuvant therapeutic strategy for malignancy.

Keto to treat other diseases:

Appavu B1, Vanatta L2, Condie J (2016). Ketogenic diet treatment for pediatric super-refractory status epilepticus. Seizure. 21;41:62-65. doi: 10.1016


We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm.


A retrospective review was performed at Phoenix Children’s Hospital on patients with super-refractory status epilepticus undergoingketogenic diet therapy from 2011 to 2015.


Ten children with super-refractory status epilepticus, ages 2-16 years, were identified. 4/10 patients had immune mediated encephalitis, including Rasmussen encephalitis, anti-N-methyl-d-aspartate receptor encephalitis, and post-infectious mycoplasma encephalitis. Other etiologies included Lennox Gastaut Syndrome, non-ketotic hyperglycinemia, PCDH19 and GABRG2 genetic epilepsy, New Onset Refractory Status Epilepticus, and Febrile Infection-Related Epilepsy Syndrome. 4/10 patients’ EEG features suggested focal with status epilepticus, and 6/10 suggested generalized with status epilepticus. Median hospital length was 61days and median ICU length was 27days. The median number of antiepileptic medications prior to diet initiation was 3.0 drugs, and the median after ketogenic diet treatment was 3.5 drugs. Median duration ofstatus epilepticus prior to KD was 18days. 9/10 patients had resolution of super-refractory status epilepticus in a median of 7days after dietinitiation. 8/9 patients were weaned off anesthesia within 15days of diet initiation, and within 1day of achieving ketonuria. 1/10 patients experienced side effects on the diet requiring supplementation.


Most patients achieved resolution of status epilepticus on KD therapy, suggesting it could be an effective therapy that can be utilized early in the treatment of children with super refractory status epilepticus.


Hall KD, Chen KY, Guo J (2016) Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men Am J Clin Nutr. Jul 6.


The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that “a calorie is a calorie” predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat.


We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition.


Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW).


Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass.


The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. This trial was registered at as NCT01967563.


Maiorana A, Manganozzi L, Barbetti F et al (2015). Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage. Orphanet J Rare Dis. 24;10:120. doi: 10.1186


Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose.


A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs.


We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life.


KD could represent an effective treatment to support brain function in selected cases of CHI.


Storoni M1, Plant GT (2015). The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis. Mult Scler Int. 2015:681289. doi: 10.1155/2015/681289.

Until recently, multiple sclerosis has been viewed as an entirely inflammatory disease without acknowledgment of the significant neurodegenerative component responsible for disease progression and disability. This perspective is being challenged by observations of a dissociation between inflammation and neurodegeneration where the neurodegenerative component may play a more significant role in disease progression. In this review, we explore the relationship between mitochondrial dysfunction and neurodegeneration in multiple sclerosis. We review evidence that theketogenic diet can improve mitochondrial function and discuss the potential of the ketogenic diet in treating progressive multiple sclerosis for which no treatment currently exists.


Svensson K1, Albert V1, Cardel B (2016). Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J. 30(5):1976-86. doi: 10.1096

Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KBhomeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α in skeletal muscle, PGC-1α regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC-1α levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC-1α is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1α in muscle enhances systemicketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen-related receptor-α was a partner of PGC-1α in the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal musclePGC-1α in the transcriptional regulation of systemic ketolytic capacity.-Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletalmuscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice.


van der Louw E, van den Hurk D, Neal E (2016). Ketogenic diet guidelines for infants with refractory epilepsy. Eur J Paediatr Neurol. 2016 Jul 17. pii: S1090-3798(16)30098-8. doi: 10.1016.


The ketogenic diet (KD) is an established, effective non-pharmacologic treatment for drug resistant childhood epilepsy. For a long time, the KD was not recommended for use in infancy (under the age of 2 years) because this is such a crucial period in development and the perceived high risk of nutritional inadequacies. Indeed, infants are a vulnerable population with specific nutritional requirements. But current research shows that the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is often achieved and maintained in this specific patient group. There is a need for standardised protocols and management recommendations for clinical use.


In April 2015, a project group of 5 experts was established in order to create a consensus statement regarding the clinical management of the KD in infants. The manuscript was reviewed and amended by a larger group of 10 international experts in the KD field. Consensus was reached with regard to guidance on how the diet should be administered and in whom.


The resulting recommendations include patient selection, pre-KD counseling and evaluation, specific nutritional requirements, preferred initiation, monitoring of adverse effects at initiation and follow-up, evaluation and KD discontinuation.


This paper highlights recommendations based on best evidence, combined with expert opinions and gives directions for future research.

Oxidative Stress and inflammation:

Aggarwal BB, Vijayalekshmi RV, Sung B (2009). Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: Short-Term Friend, Long-Term Foe. Clin Cancer Res.15;15(2):425-30

Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and high-calorie diet have been recognized as major risk factors for the most common types of cancer. All these risk factors are linked to cancer through inflammation. Although acute inflammation that persists forshort-term mediates host defense against infections, chronic inflammation that lasts for long term can predispose the host to various chronic illnesses, including cancer. Linkage between cancer and inflammation is indicated by numerous lines of evidence; first, transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription 3 (STAT3), two major pathways for inflammation, are activated by most cancer risk factors; second, an inflammatory condition precedes most cancers; third, NF-kappaB and STAT3 are constitutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors activate NF-kappaB; fifth, chemotherapeutic agents and gamma-irradiation activate NF-kappaB and lead to chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival, proliferation, invasion, angiogenesis, and metastasis are regulated by NF-kappaB and STAT3; seventh, suppression of NF-kappaB and STAT3 inhibits the proliferation and invasion of tumors; and eighth, most chemopreventive agents mediate their effects through inhibition of NF-kappaB and STAT3 activation pathways. Thus, suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer.


ĎURAČKOVÁ Z (2009). Some Current Insights into Oxidative Stress. Physiol. Res. 59: 459-469.

Oxidative stress is a phenomenon associated with pathogenetic mechanisms of several diseases including atherosclerosis, neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, cancer, diabetes mellitus, inflammatory diseases, as well as psychological diseases or aging processes. Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites, so-called oxidants, and their elimination by protective mechanisms, referred to as antioxidative systems. This imbalance leads to damage of important biomolecules and organs with potential impact on the whole organism. Oxidative and antioxidative processes are associated with electron transfer influencing the redox state of cells and the organism. The changed redox state stimulates or inhibits activities of various signal proteins, resulting in a changed ability of signal pathways to influence the fate of cells. At present, the opinion that oxidative stress is not always harmful, has been accepted. Depending on the type of oxidants, intensity and time of redox imbalance as well as on the type of cells, oxidative stress can play a role in the regulation of other important processes through modulation of signal pathways, influencing synthesis of antioxidant enzymes, repair processes, inflammation, apoptosis and cell proliferation, and thus processes of malignity. Imprudent administration of antioxidants may therefore have a negative impact on the organism.


Reuter S1, Gupta SC, Chaturvedi MM et al (2010). Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 1;49(11):1603-16. doi: 10.1016.

Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases.Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

Keto and infertility:

Kulak D1, Polotsky AJ (2013). Should the ketogenic diet be considered for enhancing fertility? Maturitas. 74(1):10-3. doi: 10.1016. *

The ketogenic diet was first developed in the 1920s as a treatment for epilepsy in an attempt to create a prolonged physiologic starvation state. Since that time, the diet has been found to have other therapeutic effects, most of which are neurologic. Other diets, mostly based on the principals of caloric restriction, have been shown to improve fertility in certain populations. We explore the data, both clinical and laboratory, for potentialfertility enhancing benefits of the ketogenic diet, beyond just caloric restriction or weight loss.


John C Mavropoulos, William S Yancy, Juanita Hepburn, et al (2005). The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond). 16;2:35.


Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age and is associated with obesity, hyperinsulinemia, and insulin resistance. Because low carbohydrate diets have been shown to reduce insulin resistance, this pilot study investigated the six-month metabolic and endocrine effects of a low-carbohydrate, ketogenic diet (LCKD) on overweight and obese women with PCOS.


Eleven women with a body mass index >27 kg/m2 and a clinical diagnosis of PCOS were recruited from the community. They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks. Participants returned every two weeks to an outpatient research clinic for measurements and reinforcement of dietary instruction. In the 5 women who completed the study, there were significant reductions from baseline to 24 weeks in body weight (-12%), percent free testosterone (-22%), LH/FSH ratio (-36%), and fasting insulin (-54%). There were non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair. Two women became pregnant despite previous infertility problems.


In this pilot study, a LCKD led to significant improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity and PCOS over a 24 week period.


Dimitriadis GK1, Kyrou I, Randeva HS (2016). Polycystic Ovary Syndrome as a Proinflammatory State: The Role of Adipokines. Curr Pharm Des. *


Polycystic Ovary Syndrome (PCOS) is a complex heterogeneous disorder and the most common endocrinopathy amongst women of reproductive age. It is characterized by androgen excess, chronic anovulation and an altered cardiometabolic profile. PCOS is linked to impaired adipose tissue (AT) physiology and women with this disorder present with greater risk for insulin resistance (IR), hyperinsulinemia, central adiposity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) than matched for age and body mass index (BMI) women without PCOS. Hyperandrogenaemia appears to be driving adipocyte hypertrophy observed in PCOS under the influence of a hyperinsulinaemicstate. Changes in the function of adipocytes have an impact on the secretion of adipokines, adipose tissue-derived proinflammatory factors promoting susceptibility to low grade inflammation.


In this article, we review the existing knowledge on the interplay between hyperandrogenaemia, insulin resistance, impaired adipocyte biology, adipokines and chronic low-grade inflammation in PCOS.


In PCOS, more than one mechanisms have been suggested in the development of a chronic low-grade inflammation state with the most prevalent being that of a direct effect of the immune system on adipose tissue functions as previously reported in obese women without PCOS. Despite the lack of conclusive evidence regarding a direct mechanism linking hyperandrogenaemia to pro-inflammation in PCOS, there have been recent findings indicating that hyperandrogenaemia might be involved in chronic inflammation by exerting an effect on adipocytes morphology and attributes.


Increasing evidence suggests that there is an important connection and interaction between pro-inflammatory pathways, hyperinsulinemia, androgen excess and adipose tissue hypertrophy and, dysfunction in PCOS. While lifestyle changes and individualized prescription of insulin-sensitizing drugs are common in managing PCOS, further studies are warranted to eventually identify an adipokine that could serve as an indirect marker of adipocyte dysfunction in PCOS, used as a reliable and path gnomic sign of metabolic alteration in thissyndrome.


Reyes-Muñoz E, Ortega-González C, Martínez-Cruz N, et al (2016). Association of obesity and overweight with the prevalence of insulin resistance, pre-diabetes and clinical-biochemical characteristics among infertile Mexican women with polycystic ovary syndrome: a cross-sectional study. BMJ Open 6(7):e012107. doi: 10.1136.


To study the association of obesity and overweight with the prevalence of insulin resistance (IR), pre-diabetes and clinical-biochemical characteristics among infertile Mexican women with polycystic ovary syndrome (PCOS).


Retrospective cross-sectional study.


Level-three medical institution, an infertility clinic in Mexico City.


We included infertile Mexican women with diagnosis of PCOS according to the Rotterdam criteria: group 1 (n=83), normal weight (body mass index (BMI) 18.5-24.9 kg/m(2)); group 2 (n=217), overweight (BMI 25-29.9 kg/m(2)); and group 3 (n=238), obese (BMI≥30 kg/m(2)).


IR was determined by homeostatic model assessment (HOMA) >2.5 and pre-diabetes by fasting glucose between 5.6 and 6.9 mmol/L and/or glucose value between 7.8 and 11 mmol/L at 2 hours during an oral glucose tolerance test. We compared clinical-biochemical characteristics among groups.


Prevalence of IR for groups 1, 2 and 3 was 19.3%, 56.2% and 78.2%; overweight and obesity increase the IR OR (CI 95%) to 5.3 (2.9 to 9.8) and 14.9 (8.0 to 28), respectively. Prevalence of pre-diabetes for groups 1, 2 and 3 was 7.2%, 17.5% and 31.5%; overweight and obesityincrease the pre-diabetes OR (CI 95%) to 2.7 (1.1 to 6.7) and 5.9 (2.4 to 14), respectively. Acanthosis nigricans was more frequent in group 3 than group 1. Free Androgen Index (FAI) and thyroid-stimulating hormone (TSH) levels were lower in group 1 than in groups 2 and 3. Progesterone and sex hormone-binding globulin (SHBG) levels were higher in group 1 than in groups 2 and 3. Dehydroepiandrosterone sulfate (DHEA-S) was higher in group 1 than group 3.


Obese and overweight infertile Mexican women with PCOS, attending to an infertility clinic, have a higher prevalence of IR andpre-diabetes compared with normal-weight women with PCOS. Therapeutic interventions should include those that improved metabolic functioning prior to attempting pregnancy in these groups of women.


Polak, K., Czyzyk, A., Simoncini, T. et al (2016) New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest. doi:10.1007/s40618-016-0523-8.

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in women of repro- ductive age. The diagnostic criteria include two out of three features: hyperandrogenism, polycystic ovaries on ultrasound and menstrual irregularities (Rotterdam Crite- ria 2003). PCOS patients are more vulnerable to develop diabetes, cardiovascular diseases and metabolic syndrome. Insulin resistance (IR) is prevalent in women with PCOS independently of obesity and is critically involved in repro- ductive and metabolic complications of the syndrome. Sev- eral tests have been developed to measure IR, some very reliable but complex like the hyperinsulinemic euglyce- mic glucose clamp and others less precise but easier and less invasive like HOMA-IR. New markers are needed to reach a more reliable assessment of insulin resistance. To date, several surrogate markers have been proposed in the literature to facilitate and improve the determination of IR. Many new proteins are strongly involved with PCOS physiopathology and IR, such as some adipocytokines (adiponectin, visfatin, vaspin and apelin), copeptin, irisin, PAI-1 and zonulin. Many other proteins have been pro- posed as potential new markers of IR in PCOS, such as resistin, leptin, RBP4, kisspetin and ghrelin, but their role is still controversial. In this review, we provide a short characterization of these new markers, recently studied as indicators of metabolic state.


Yuehui Zhang, Xue Sun, Xiaoyan Sun, et al (2016). Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus. Scientific Reports 6, Article number: 30679.

Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients.

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