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      Does glucocorticoid exposure explain the association between metabolic dysfunction and tendinopathy?

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          Abstract

          Background

          While metabolic health is acknowledged to affect connective tissue structure and function, the mechanisms are unclear. Glucocorticoids are present in almost every cell type throughout the body and control key physiological processes such as energy homeostasis, stress response, inflammatory and immune processes, and cardiovascular function. Glucocorticoid excess manifests as visceral adiposity, dyslipidemia, insulin resistance, and type 2 diabetes. As these metabolic states are also associated with tendinopathy and tendon rupture, it may be that glucocorticoids excess is the link between metabolic health and tendinopathy.

          Objective

          To synthesise current knowledge linking glucocorticoid exposure to tendon structure and function.

          Methods

          Narrative literature review.

          Results

          We provide an overview of endogenous glucocorticoid production, regulation, and signalling. Next we review the impact that oral glucocorticoid has on risk of tendon rupture and the effect that injected glucocorticoid has on resolution of symptoms. Then we highlight the clinical and mechanistic overlap between tendinopathy and glucocorticoid excess in the areas of visceral adiposity, dyslipidemia, insulin resistance and type 2 diabetes. In these areas, we highlight the role of glucocorticoids and how these hormones might underpin the connection between metabolic health and tendon dysfunction.

          Conclusions

          There are several plausible pathways through which glucocorticoids might mediate the connection between metabolic health and tendinopathy.

          Related collections

          Most cited references86

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          Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response.

          The hypothalamo-pituitary-adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition by limbic structures (e.g., hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic, and brainstem circuits. Importantly, an individual's response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur will determine whether an individual's acute or chronic stress responses are adaptive or maladaptive (pathological).
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            The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission.

            Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
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              Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials.

              Few evidence-based treatment guidelines for tendinopathy exist. We undertook a systematic review of randomised trials to establish clinical efficacy and risk of adverse events for treatment by injection. We searched eight databases without language, publication, or date restrictions. We included randomised trials assessing efficacy of one or more peritendinous injections with placebo or non-surgical interventions for tendinopathy, scoring more than 50% on the modified physiotherapy evidence database scale. We undertook meta-analyses with a random-effects model, and estimated relative risk and standardised mean differences (SMDs). The primary outcome of clinical efficacy was protocol-defined pain score in the short term (4 weeks, range 0-12), intermediate term (26 weeks, 13-26), or long term (52 weeks, ≥52). Adverse events were also reported. 3824 trials were identified and 41 met inclusion criteria, providing data for 2672 participants. We showed consistent findings between many high-quality randomised controlled trials that corticosteroid injections reduced pain in the short term compared with other interventions, but this effect was reversed at intermediate and long terms. For example, in pooled analysis of treatment for lateral epicondylalgia, corticosteroid injection had a large effect (defined as SMD>0·8) on reduction of pain compared with no intervention in the short term (SMD 1·44, 95% CI 1·17-1·71, p<0·0001), but no intervention was favoured at intermediate term (-0·40, -0·67 to -0·14, p<0·003) and long term (-0·31, -0·61 to -0·01, p=0·05). Short-term efficacy of corticosteroid injections for rotator-cuff tendinopathy is not clear. Of 991 participants who received corticosteroid injections in studies that reported adverse events, only one (0·1%) had a serious adverse event (tendon rupture). By comparison with placebo, reductions in pain were reported after injections of sodium hyaluronate (short [3·91, 3·54-4·28, p<0·0001], intermediate [2·89, 2·58-3·20, p<0·0001], and long [3·91, 3·55-4·28, p<0·0001] terms), botulinum toxin (short term [1·23, 0·67-1·78, p<0·0001]), and prolotherapy (intermediate term [2·62, 1·36-3·88, p<0·0001]) for treatment of lateral epicondylalgia. Lauromacrogol (polidocanol), aprotinin, and platelet-rich plasma were not more efficacious than was placebo for Achilles tendinopathy, while prolotherapy was not more effective than was eccentric exercise. Despite the effectiveness of corticosteroid injections in the short term, non-corticosteroid injections might be of benefit for long-term treatment of lateral epicondylalgia. However, response to injection should not be generalised because of variation in effect between sites of tendinopathy. None. Copyright © 2010 Elsevier Ltd. All rights reserved.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                March 2020
                21 January 2020
                : 9
                : 3
                : R36-R46
                Affiliations
                [1 ]Physiotherapy Department , Aintree University Hospital NHS Foundation Trust, Liverpool, UK
                [2 ]Department of Surgical and Perioperative Sciences , Umeå Univerisity, Umeå, Sweden
                [3 ]University of Canberra Research Institute for Sport and Exercise (UCRISE) , Canberra, Australian Capital Territory, Australia
                Author notes
                Correspondence should be addressed to T Lewis: trevorlewissky@ 123456sky.com
                Article
                EC-19-0555
                10.1530/EC-19-0555
                7040857
                31967969
                69c3c32c-ea1f-49a1-a010-f7a5a42a9467
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 13 January 2020
                : 21 January 2020
                Categories
                Review

                tendinopathy,glucocorticoids,cortisol,hypothalamic-pituitary-adrenal axis,metabolic health,type 2 diabetes mellitus,visceral adipose tissue

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