Medical management of metabolic dysfunction in PCOS

Polycystic ovary syndrome (PCOS) is associated with metabolic derangements including insulin resistance, dyslipidemia, systemic inflammation and endothelial dysfunction. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with PCOS. Medications that have been tested in patients with PCOS include metformin, thiazolidinediones, acarbose, naltrexone, orlistat, vitamin D and statins. Metformin decreases hepatic gluconeogenesis and free fatty acid oxidation while increasing peripheral glucose uptake. Early studies in PCOS suggested that metformin indirectly reduces insulin level, dyslipidemia and systemic inflammation; however, recent placebo-controlled trials failed to demonstrate significant metabolic benefit. Thiazolidinediones act primarily by increasing peripheral glucose uptake. Most studies in PCOS have demonstrated that thiazolidinediones reduce insulin resistance; however, effects on dyslipidemia were disappointing. Use of thiazolidinediones is associated with weight gain and major complications. Acarbose reduces digestion of polysaccharides. Studies in PCOS yielded inconsistent effects of acarbose on insulin sensitivity and no significant improvement of dyslipidemia. Naltrexone reduces appetite and modulates insulin release; its use in PCOS may reduce hyperinsulinemia. Orlistat decreases absorption of dietary fats; studies in PCOS suggest beneficial effects on insulin sensitivity. Vitamin D may improve insulin sensitivity but mixed results on lipid profile in PCOS have been reported. Statins are competitive inhibitors of the key enzyme regulating the mevalonate pathway; their effects are related to reduced cholesterol production as well as anti-inflammatory and anti-oxidant properties. In women with PCOS, statins reduce hyperandrogenism, improve lipid profile and reduce systemic inflammation while the effects on insulin sensitivity are variable. Use of statins is contraindicated in pregnancy.     

MitoQ,a mitochondria-targeted antioxidant,delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

Oxidative stress and mitochondrial dysfunction are involved in the progression and pathogenesis of multiple sclerosis (MS). MitoQ is a mitochondria-targeted antioxidant that has a neuroprotective role in several mitochondrial and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Here we sought to determine the possible effects of a systematic administration of MitoQ as a therapy, using an experimental autoimmune encephalomyelitis (EAE) mouse model. We studied the beneficial effects of MitoQ in EAE mice that mimic MS like symptoms by treating EAE mice with MitoQ and pretreated C57BL6 mice with MitoQ plus EAE induction. We found that pretreatment and treatment of EAE mice with MitoQ reduced neurological disabilities associated with EAE. We also found that both pretreatment and treatment of the EAE mice with MitoQ significantly suppressed inflammatory markers of EAE, including the inhibition of inflammatory cytokines and chemokines. MitoQ treatments reduced neuronal cell loss in the spinal cord, a factor underlying motor disability in EAE mice. The neuroprotective role of MitoQ was confirmed by a neuron-glia co-culture system designed to mimic the mechanism of MS and EAE in vitro. We found that axonal inflammation and oxidative stress are associated with impaired behavioral functions in the EAE mouse model and that treatment with MitoQ can exert protective effects on neurons and reduce axonal inflammation and oxidative stress. These protective effects are likely via multiple mechanisms, including the attenuation of the robust immune response. These results suggest that MitoQ may be a new candidate for the treatment of MS.     

Effects of daily walking on subjective symptoms, mood and autonomic nervous function

It is well known that moderate exercise is beneficial to health. However, the effects of exercise on subjective symptoms in relation to mood and autonomic nervous function have not yet been fully examined. The purpose of this study was to investigate the effects of daily walking on subjective symptoms as well as on mood and autonomic nervous function in people who take no medication but have some general physical complaints. We assessed their symptoms by the Cornell Medical Index (CMI), and mood states by a profile of mood states (POMS) and a frontal alpha laterality ratio. Autonomic nervous function was evaluated by a supine rest basal level, reactivity to orthostatic challenge (physiological stimulus) and to a self-programmed videogame (psychophysiological stimulus) of heart rate (HR), heart rate variability (HRV), baroreflex sensitivity and blood pressure (BP). Repeated measures analysis of variance showed no significant group (control and walking group) x time (pre- and post- walking period) interaction of CMI scores. In contrast, the A-H sub-scale (anger and hostility) of POMS and basal HR significantly decreased after a 4-week walking period in a walking group compared to a control group. Negative mood score of POMS reduced, and basal high-frequency component of HRV and reactivity to orthostatic challenge of baroreflex sensitivity increased marginally significantly compared to the control group. Multiple regression analysis revealed a significant contribution of A-H to the physical score of CMI, which showed a marginally significant reduction after the experimental period in the walking group. These results suggest that daily walking can improve mood states and shift autonomic balance to parasympathetic predominance, and may consequently contribute to the reduction of subjective symptoms.     

Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced polycystic ovaries

Despite extensive research on the pathogenesis of polycystic ovary syndrome (PCOS), there is still disagreement on the underlying mechanisms. The rat model for experimentally induced polycystic ovaries (PCO)-produced by a single injection of estradiol valerate-has similarities with human PCOS, and both are associated with hyperactivity in the sympathetic nervous system. Nerve growth factor (NGF) is known to serve as a neurotrophin for both the sympathetic and the sensory nervous systems and to enhance the activity of catecholaminergic and possibly other neuron types. Electro-acupuncture (EA) is known to reduce hyperactivity in the sympathetic nervous system. For these reasons, the model was used in the present study to investigate the effects of EA (12 treatments, approximately 25 min each, over 30 days) by analyzing NGF in the central nervous system and the endocrine organs, including the ovaries. The main findings in the present study were first, that significantly higher concentrations of NGF were found in the ovaries and the adrenal glands in the rats in the PCO model than in the control rats that were only injected with the vehicle (oil or NaCl). Second, that repeated EA treatments in PCO rats resulted in concentrations of NGF in the ovaries that were significantly lower than those in non-EA-treated PCO rats but were within a normal range that did not differ from those in the untreated oil and NaCl control groups. The results in the present study provide support for the theory that EA inhibits hyperactivity in the sympathetic nervous system.     

Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis

The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via α- and β-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor α7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.     

空间环境下肠道菌群失调的研究进展

空间环境中的特殊因素会导致航天员肠道菌群及其代谢产物的失调，对机体会产生系统性的生理影响。本文综述了近年来太空飞行/模拟空间环境对肠道菌群及其代谢产物影响的研究进展。太空飞行/模拟空间环境（space flight/simulated space environment，SF/SPE）可导致侵袭性致病菌的增多及有益菌的减少，肠道炎症加剧与通透性增加，也会引起菌群的有益代谢物减少或有害代谢物增加，进而导致机体内代谢的紊乱，或可诱发其他系统的损伤，从而不利于航天员的健康与工作效率。总结太空飞行/模拟空间环境对肠道菌群产生的影响，可为该领域的后续研究与航天员的在轨健康防护提供科学依据。     

Polycystic ovary syndrome: Challenges in adolescence

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age. PCOS typically develops during adolescence and is a heterogeneous syndrome classically characterized by features of anovulation combined with signs of androgen excess (hirsutism, acne). Increasing obesity in adolescents probably exacerbates signs of PCOS, contributing to its earlier recognition. Recognizing the features of this syndrome can be very challenging in adolescence. Although adolescents’ concerns are often cosmetic, if left untreated these girls are at risk for diabetes, metabolic syndrome, and infertility as they mature. Efforts should be made to diagnose and treat PCOS to minimize the development of symptoms and prevent the onset of cardiovascular and metabolic disturbances.     

Central administration of the peptide alpha-MSH inhibits inflammation in the skin.

Inflammation is generally conceptualized in terms of cells, mediators, and events in the periphery, with no consideration of an influence of the central nervous system (CNS). However, the neuroendocrine peptide alpha-melanocyte stimulating hormone (alpha-MSH) is anti-inflammatory when given systemically and this molecule reaches the brain to exert another effect: fever reduction. Tests on mice indicate that alpha-MSH can act solely within the CNS to inhibit inflammation in the skin. This observation indicates that the central nervous system can inhibit peripheral inflammation via action of alpha-MSH molecules and it further strengthens the idea of neural/endocrine modulation of the host responses.     

Surgical management of metabolic dysfunction in PCOS

Metabolic disturbances are common in women with polycystic ovary syndrome (PCOS). Obesity is the major link in the association of PCOS with diabetes, metabolic syndrome, hypertension, low-grade chronic inflammation and increased body iron stores, among others. Metabolic prevention in PCOS women should start as early as possible, usually meaning at diagnosis. Among preventive strategies, those promoting a healthy life-style based on diet, regular exercising and smoking cessation are possibly the most effective therapies, but also are the most difficult to achieve. To this regard, every effort must be made to avoid weight gain and obesity, given the deleterious impact that obesity exerts on the metabolic and cardiovascular associations of PCOS. Unfortunately, classic strategies that address obesity by life-style modification and dieting are seldom successful on a long-term basis, especially in women with severe obesity. In selected cases, metabolic surgery in severely obese women may resolve signs and symptoms of PCOS restoring insulin sensitivity and fertility, and avoiding the long-term risks associated with PCOS and morbid obesity. Surgical techniques for bariatric surgery have evolved in the past decades and newer procedures do not longer carry the severe side effects associated with earlier bariatric procedures. The choice of bariatric procedure should consider both the severity of obesity and the possibility of future pregnancy, since fertility may be restored by the sustained and marked weight loss usually attained after bariatric surgery. Finally, avoidance of the risks associated with morbid obesity compensate for the possible residual risks for pregnancy derived from the previous bariatric procedure itself.     

Protective effects of lidocaine on polycystic ovary syndrome through modulating ovarian granulosa cell physiology via PI3K/AKT/mTOR pathway

Cytotechnology - Polycystic ovary syndrome (PCOS) is a common endocrine condition in women that causes adverse reproductive and metabolic effects. PCOS is a heterogeneous disorder and its...     

Asprosin,a novel pleiotropic adipokine implicated in fasting and obesity-related cardio-metabolic disease: Comprehensive review of preclinical and clinical evidence

White adipose tissue is a dynamic endocrine organ that releases an array of adipokines, which play a key role in regulating metabolic homeostasis and multiple other physiological processes. An altered adipokine secretion profile from adipose tissue depots frequently characterizes obesity and related cardio-metabolic diseases. Asprosin is a recently discovered adipokine that is released in response to fasting. Following secretion, asprosin acts - via an olfactory G-protein coupled receptor and potentially via other unknown receptor(s) - on hepatocytes and agouti-related peptide-expressing neurons in the central nervous system to stimulate glucose secretion and promote appetite, respectively. A growing body of both in vitro and in vivo studies have shown asprosin to exert a number of effects on different metabolic tissues. Indeed, asprosin can attenuate insulin signalling and promote insulin resistance in skeletal muscle by increasing inflammation and endoplasmic reticulum stress. Interestingly, asprosin may also play a protective role in cardiomyocytes that are exposed to hypoxic conditions. Moreover, clinical studies have reported elevated circulating asprosin levels in obesity, type 2 diabetes and other obesity-related cardio-metabolic diseases, with significant associations to clinically relevant parameters. Understanding the spectrum of the effects of this novel adipokine is essential in order to determine its physiologic role and its significance as a potential therapeutic target and/or a biomarker of cardio-metabolic disease. The present review offers a comprehensive overview of the published literature on asprosin, including both clinical and preclinical studies, focusing on its role in metabolism and cardio-metabolic disease.     

S100‐A9 protein in exosomes derived from follicular fluid promotes inflammation via activation of NF‐κB pathway in polycystic ovary syndrome

Exosomes have recently emerged as key mediators of different physiological and pathological processes. However, there has been few report about proteomic analysis of exosomes derived from human follicular fluid and their association with the occurrence of PCOS. Herein, we used TMT‐tagged quantitative proteomic approach to identify proteomic profiles in exosomes derived from follicular fluid of PCOS patients and healthy controls. We identified 662 proteins in exosomes derived from human ovarian follicular fluid. Eighty‐six differently expressed proteins (P < .05) were found between PCOS and healthy women. The alterations in the proteomic profile were related to the inflammation process, reactive oxygen species metabolic process, cell migration and proliferation. Importantly, we observed that follicular fluid exosomes contain S100 calcium‐binding protein A9 (S100‐A9) protein. Exosome‐enriched S100‐A9 significantly enhanced inflammation and disrupted steroidogenesis via activation of nuclear factor kappa B (NF‐κB) signalling pathway. These data demonstrate that exosomal proteins are differentially expressed in follicular fluid during disease process, and some proteins may play important roles in the regulation of granulosa cell function. These results highlight the importance of exosomes as extracellular communicators in ovarian follicular development.     

多囊卵巢综合征并发抑郁症的研究现状

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是育龄女性最常见的内分泌疾病之一,表现为生殖和代谢异常。近些年来,越来越多的人群学研究发现,PCOS病人患精神心理疾病,尤其是抑郁症的发生率高于正常人群。本文概述了PCOS并发抑郁症的相关危险因素和可能机制,并简要论述了PCOS的治疗药物对抑郁症作用的最新研究进展。     

Stress and immunity: an integrated view of relationships between the brain and the immune system

The old notion that stress exacerbates the progression of physical illness via its corticosteroid-mediated immunosuppressive effects must be revised. Experimental and clinical studies demonstrate that both laboratory and natural stressors alter the activities of lymphocytes and macrophages in a complex way that depends on the type of immune response, the physical and psychological characteristics of the stressor and the timing of stress relative to the induction and expression of the immune event. The influences of stress on immunity are mediated not only by glucocorticoids but also by catecholamines, endogenous opioids and pituitary hormones such as growth hormone. Sensitivity of the immune system to stress is not simply fortuitous but is an indirect consequence of the regulatory reciprocal influences that exist between the immune system and the central nervous system. The immune system receives signals from the brain and the neuroendocrine system via the autonomic nervous system and hormones and sends information to the brain via cytokines. These connections appear to be part of a long-loop regulatory feedback system that plays an important role in the coordination of behavioral and physiological responses to infection and inflammation.     

Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth?

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disturbance among women of reproductive age and is proposed to be linked with size at birth and increased prevalence of cardiovascular disease. A disturbance in the sympathetic nervous system may contribute to the etiology of PCOS. This study evaluates sympathetic outflow in PCOS and its relation to size at birth. Directly recorded sympathetic nerve activity to the muscle vascular bed (MSNA) was obtained in 20 women with PCOS and in 18 matched controls. Ovarian ultrasonographic evaluation, biometric, hormonal, and biochemical parameters were measured, and birth data were collected. Women with PCOS had increased MSNA (30 +/- 8 vs. 20 +/- 7 burst frequency, P < 0.0005) compared with controls. MSNA was positively related to testosterone (r = 0.63, P < 0.005) and cholesterol (r = 0.55, P = 0.01) levels in PCOS, which, in turn, were not related to each other. Testosterone level was a stronger predictor of MSNA than cholesterol. Birth size did not differ between the study groups. This is the first study to directly address sympathetic nerve activity in women with PCOS and shows that PCOS is associated with high MSNA. Testosterone and cholesterol levels are identified as independent predictors of MSNA in PCOS, although testosterone has a stronger impact. The increased MSNA in PCOS may contribute to the increased cardiovascular risk and etiology of the condition. In this study, PCOS was not related to size at birth.     

Mouse models of altered CRH-binding protein expression

CRH is the key physiological mediator of the endocrine, autonomic, and behavioral responses to stress. The recent characterization of urocortin, a new mammalian CRH-like ligand, adds to the complexity of the CRH system. Both CRH and urocortin mediate their endocrine and/or synaptic effects via two classes of CRH receptors. Similarly, both CRH and urocortin bind to the CRH-binding protein (CRH-BP). This secreted binding protein is smaller than the CRH receptors, but binds CRH and urocortin with an affinity equal to or greater than that of the receptors, and blocks CRH-mediated ACTH release in vitro. Several regions of CRH-BP expression colocalize with sites of CRH synthesis or release, suggesting that this binding protein may have a profound impact on the biological activity of CRH (or urocortin). While in vitro and in vivo studies have characterized the biochemical properties and regulation of the CRH-BP, animal models of altered CRH-BP expression can provide additional information on the in vivo role of this important modulatory protein. This review focuses on three mouse models of CRH-BP overexpression or deficiency. These animal models show numerous physiological changes in the HPA axis and in energy balance, with additional alterations in anxiogenic behavior. These changes are consistent with the hypothesis that CRH-BP plays an important in vivo modulatory role by regulating levels of "free" CRH and other CRH-like peptides in the pituitary and central nervous system.     

Metabonomics reveals plasma metabolic changes and inflammatory marker in polycystic ovary syndrome patients

Polycystic ovary syndrome (PCOS) is a common, clinically heterogeneous endocrine disorder affecting women of reproductive age, associated with endocrinopathy and metabolic abnormalities. Although some metabolic parameters have been investigated, very little information has been reported on the changes of small metabolites in biofluids. The aim of this study was to establish the metabolic profile of PCOS and compare it with that of controls. In this cross-sectional study of 34 women with PCOS and 36 controls, contents of small metabolites and lipids in plasma samples were measured using nuclear magnetic resonance (NMR)-based techniques and analyzed using multivariate statistical methods. Significant decrease (P < 0.05) in the levels of amino acids (leucine, isoleucine, methionine, glutamine, and arginine), citrate, choline, and glycerophosphocholine/phosphocholine (GPC/PC), and increase (P < 0.05) in the levels of lactate, dimethylamine (DMA), creatine, and N-acetyl glycoproteins were observed in PCOS patients compared with the controls. Subgroups of patients with obesity, metabolic syndrome, or hyperandrogenism exhibited greater metabolic deviations than their corresponding subgroups without these factors. PCOS patients have perturbations in amino acid metabolism, the tricarboxylic acid (TCA) cycle, and gut microflora, as well as mild disturbances in glucose and lipid metabolism. The elevated level of N-acetyl glycoproteins demonstrates the existence of low-grade chronic inflammation in PCOS patients.     

Rodent models for human polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most frequent female endocrine disorder, affecting 5%-10% of women, causing infertility due to dysfunctional follicular maturation and ovulation, distinctive multicystic ovaries and hyperandrogenism, together with metabolic abnormalities including obesity, hyperinsulinism, an increased risk of type 2 diabetes, and cardiovascular disease. The etiology of PCOS is unclear, and decisive clinical studies are limited by ethical and logistic constraints. Consequently treatment is palliative rather than curative and focuses on symptomatic approaches. Hence, a suitable animal model could provide a valuable means with which to study the pathogenesis of the characteristic reproductive and metabolic abnormalities and thereby identify novel and more effective treatments. So far there is no consensus on the best experimental animal model, which should ideally reproduce the key features associated with human PCOS. The prenatally androgenized rhesus monkey displays many characteristics of the human condition, including hyperandrogenism, anovulation, polycystic ovaries, increased adiposity, and insulin insensitivity. However, the high cost of nonhuman primate studies limits the practical utility of these large-animal models. Rodent models, on the other hand, are inexpensive, provide well-characterized and stable genetic backgrounds readily accessible for targeted genetic manipulation, and shorter reproductive life spans and generation times. Recent rodent models display both reproductive and metabolic disturbances associated with human PCOS. This review aimed to evaluate the rodent models reported to identify the advantages and disadvantages of the distinct rodent models used to investigate this complex endocrine disorder.     

Leptin, a neuroendocrine mediator of immune responses, inflammation, and sickness behaviors

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Effective immune responses are coordinated by interactions among the nervous, endocrine, and immune systems. Mounting immune, inflammatory, and sickness responses requires substantial energetic investments, and as such, an organism may need to balance energy allocation to these processes with the energetic demands of other competing physiological systems. The metabolic hormone leptin appears to be mediating trade-offs between the immune system and other physiological systems through its actions on immune cells and the brain. Here we review the evidence in both mammalian and non-mammalian vertebrates that suggests leptin is involved in regulating immune responses, inflammation, and sickness behaviors. Leptin has also been implicated in the regulation of seasonal immune responses, including sickness; however, the precise physiological mechanisms remain unclear. Thus, we discuss recent data in support of leptin as a mediator of seasonal sickness responses and provide a theoretical model that outlines how seasonal cues, leptin, and proinflammatory cytokines may interact to coordinate seasonal immune and sickness responses.