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Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia
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Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia
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Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia
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Polycystic ovary syndrome (PCOS) affects 8–13% of reproductive-aged women, impacts biopsychosocial factors and creates a significant health-related economic burden across the reproductive, metabolic and psychological spectrum of complications. Despite being a heterogenous condition, recent genomic studies indicate that PCOS, regardless of diagnostic criteria and clinical features, shares similar underlying biologic mechanisms. However, recent advances have shown that clinical reproductive and diagnostic features are poorly correlated to genotypes and do not represent true phenotypes. Until we have a better understanding of genetic and epigenetic influences on PCOS and long-term outcomes, targeted treatment is limited.
In the interim, a unified approach to integrate evidence, optimise management and guide future research in PCOS is necessary. This has motivated an international collaboration to develop an International Evidence-Based PCOS Guideline to improve health outcomes in women with PCOS. Dissemination and translation of the guideline into health policy and clinical practice are crucial steps to close the knowledge–-practice gap, guide future research and enhance positive impact on the health of women with PCOS.
Here, we review the (i) understanding of aetiology and genetics of PCOS; (ii) development and translation efforts of the 2018 International Evidence-based PCOS Guideline; (iii) current progress and plans for the guideline update, including the involvement of an early career researcher network to assist with evidence synthesis and (iv) the opportunity to target and guide future research for PCOS.
Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia
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Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia
Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
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Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia
Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
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There is longstanding interest in the role of androgens in the aetiology of prostate cancer, one of the most common malignancies worldwide. In this review, we reflect on the ways that knowledge of prostate development and hormone action have catalysed advances in the management of patients with prostate cancer. The use of hormone therapies to treat prostate cancer has changed significantly over time, including the emergence of androgen receptor signalling inhibitors (ARSI). These compounds have improved outcomes for patients with castration-resistant prostate cancer, which was once considered ‘androgen-independent’ but is clearly still driven by androgen receptor signalling in many cases. There is also a need for new therapies to manage neuroendocrine prostate cancer, which is not responsive to hormonal agents. One of the major gaps is understanding how treatment-induced neuroendocrine prostate cancer emerges and whether it can be re-sensitised to treatment. Patient-derived models, including patient-derived xenografts (PDXs), will be instrumental in facilitating future discoveries in these areas. Developments in the use of PDXs have been fostered by lessons from the field of endocrinology, such as the role of stroma and hormones in normal and developmental tissues. Thus, there is ongoing reciprocity between the discoveries in endocrinology and advances in prostate cancer research and treatment.
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Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver’s prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e. in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g. beta-cell function, insulin secretion, or insulin sensitivity).
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Micronutrients consumed in excess or imbalanced amounts during pregnancy may increase the risk of metabolic diseases in offspring, but the mechanisms underlying these effects are unknown. Serotonin (5-hydroxytryptamine, 5-HT), a multifunctional indoleamine in the brain and the gut, may have key roles in regulating metabolism. We investigated the effects of gestational micronutrient intakes on the central and peripheral serotonergic systems as modulators of the offspring's metabolic phenotypes. Pregnant Wistar rats were fed an AIN-93G diet with 1-fold recommended vitamins (RV), high 10-fold multivitamins (HV), high 10-fold folic acid with recommended choline (HFolRC), or high 10-fold folic acid with no choline (HFolNC). Male and female offspring were weaned to a high-fat RV diet for 12 weeks. We assessed the central function using the 5-HT2C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP), and found that male offspring from the HV- or HFolRC-fed dams were less responsive (P < 0.05) whereas female HFolRC offspring were more responsive to mCPP (P < 0.01) at 6 weeks post-weaning. Male and female offspring from the HV and HFolNC groups, and male HFolRC offspring had greater food intake (males P < 0.001; females P < 0.001) and weight gain (males P < 0.0001; females P < 0.0001), elevated colon 5-HT (males P < 0.01; females P < 0.001) and fasting glucose concentrations (males P < 0.01; females P < 0.01), as well as body composition toward obesity (males P < 0.01; females P < 0.01) at 12 weeks post-weaning. Colon 5-HT was correlated with fasting glucose concentrations (males R2=0.78, P < 0.0001; females R2=0.71, P < 0.0001). Overall, the serotonergic systems are sensitive to the composition of gestational micronutrients, with alterations consistent with metabolic disturbances in offspring.
Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
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Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion Interfaculty Centre, University of Münster, Münster, Germany
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Division of General Medicine, Department of Internal Medicine, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC
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Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
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Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
Clinical Medicine Research Center, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
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The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat domain. Protein–protein interactions act as a ‘pedal or brake’ to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via protein–protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.
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As a key regulator of bone homeostasis, sclerostin has garnered a lot of interest over the last two decades. Although sclerostin is primarily expressed by osteocytes and is well known for its role in bone formation and remodelling, it is also expressed by a number of other cells and potentially plays a role in other organs. Herein, we aim to bring together recent sclerostin research and discuss the effect of sclerostin on bone, cartilage, muscle, liver, kidney and the cardiovascular and immune systems. Particular focus is placed on its role in diseases, such as osteoporosis and myeloma bone disease, and the novel development of sclerostin as a therapeutic target. Anti-sclerostin antibodies have recently been approved for the treatment of osteoporosis. However, a cardiovascular signal was observed, prompting extensive research into the role of sclerostin in vascular and bone tissue crosstalk. The study of sclerostin expression in chronic kidney disease was followed by the investigation of its role in liver–lipid–bone interactions, and the recent discovery of sclerostin as a myokine prompted new research into sclerostin within the bone–muscle relationship. Potentially, the effects of sclerostin reach beyond that of bone alone. We further summarise recent developments in the use of sclerostin as a potential therapeutic for osteoarthritis, osteosarcoma and sclerosteosis. Overall, these new treatments and discoveries illustrate progress within the field, however, also highlight remaining gaps in our knowledge.
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The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin–angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.
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Inflammation is part of the body’s innate immune response and is an essential process that not only defends against harmful bacteria and pathogens but also plays a key role in the maintenance and repair of tissues. Under pathological conditions, there is bilateral crosstalk between immune regulation and aberrant metabolism resulting in persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metainflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve as is evident in metabolic disorders is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients. This review gives an overview of the mechanisms underlying chronic metabolic inflammation, the aberrant metabolic activation of innate immune cells (neutrophils, macrophages, mast cells, dendritic cells), and its role in disease progression using obesity–diabetes as a prime example. Addressing the underlying subclinical metabolic inflammation in addition to achieving glucose control may contribute significantly towards therapeutic interventions aimed at preventing the onset of co-morbidities in diabetic patients.
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Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.
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Glucagon is secreted by the pancreatic alpha cell and has long been known to oppose insulin action. A lyophilized form of the hormone has been available to treat episodes of insulin-induced hypoglycemia in insulin-treated people with diabetes for decades, but the difficulty of use was a barrier to widespread utilization. Newer formulations of glucagon are stable at room temperature in single-use devices that many caregivers find are easier to use than the original glucagon emergency kit. In this review , we will review what is known about the role of glucagon in normal physiology and diabetes and then discuss how the research in this area has been translated into treatment for metabolic conditions.
