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.
MAIN OUTCOME MEASURE(S):
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.
Nandivada P1, Fell GL1, Pan AH (2016). Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia. Lipids. 51(6):703-14.*
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.
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.*
PURPOSE OF REVIEW:
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 clinicaltrials.gov 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.
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
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
ĎURAČKOVÁ Z (2009). Some Current Insights into Oxidative Stress. Physiol. Res. 59: 459-469.
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.
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. *
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)).
PRIMARY AND SECONDARY OUTCOME MEASURES:
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.
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.