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Connective Tissue, Cortisol, the HPA Axis
                      &
        Therapeutic Interventions

         Sport Ex Jou...
Athletes from all sports are the unfortunate recipients of injuries that can curtail racing seasons, delay
training and en...
and osteocytes. It is the arrangement of the different components of connective tissue that determine the
function and all...
sympathetic nerve endings. Protein hormones include insulin, secretin, prolactin and growth hormone.
While the peptides in...
who have a long history of injury and cortisone injections? And how does long term over stimulation of
adrenal response af...
the exact mechanism by which the effect is made is still yet unclear9. It appears that the Parasympathetic
Nervous System ...
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Connective Tissue, Cortisol & HPA Axis

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Connective Tissue, Cortisol & HPA Axis

  1. 1. Connective Tissue, Cortisol, the HPA Axis & Therapeutic Interventions Sport Ex Journal December 2009 Humphrey Bacchus CMT
  2. 2. Athletes from all sports are the unfortunate recipients of injuries that can curtail racing seasons, delay training and end careers. Though we always look to specific incidents and biomechanical causes to explain away the resultant injuries. The more complex mechanism of our reactions and adaptation to internal and external stressors is not something that is explored as readily. The purpose of this article is to create an awareness of the biochemical and physiological responses that the connective tissue makes to stress as well as consider the theory and application of corticosteroid injections to treat injury and sports related inflammation. I am sometimes concerned with the readiness of GP’s to suggest cortisone injections into joints without considerations as to the efficacy or long-term implications for their patients; and are we recognising or developing long-term studies into connective tissue damage due to chronic physical stress. At the forefront of this is the stress response from the Hypothalamic-Pituitary-Adrenal Axis (HPA) that can disturb the body’s fundamental homeostatic balance. It is the major part of the neuro-endocrine system used to regulate stress – it also regulates many other processes including immune system support. Although I want to focus on the steroidal hormone cortisol and its relationship to connective tissue, I think it is important to put its role into context of the wider endocrine system. I also want to consider the use of various therapeutic agents in management of inflammation and cortisol levels that include cortisone injections, nutraceuticals, manual lymphatic drainage and massage. A brief overview of the connective tissue allows us to view it as one piece of material that joins bones to bones, brain to toe, hand to mouth, muscle to ligament, shapes our organs from conception and binds our muscles in a beautiful network that holds the human form together in one entity. The make up of each individual piece of connective tissue contains specific roles in the movement, structure and form of the human body, and directly influences the scope of performance in an athlete. Coupled with this, the environment of the connective tissue nurtures cellular activity, which I will discuss later, and has profound implications on our immunological and metabolic pathways in the body. It is made up of cells including fibroblasts, leukocytes and macrophages, with the fibrous parts being collagen, reticular and elastic fibres – and ground substance making up the basis of the extracellular matrix. Connective tissue is in its essence very diverse. Its properties allow it to form different types including loose connective tissue, dense connective tissue, cartilage and bone. There is not one singular function of the CT in our body since it is so adaptable. The loose connective tissue is in great quantities throughout our body as it joins our skin through to our organs. It also surrounds our organs and allows some movement relationship between them. Dense connective tissue forms the basis of our ligaments and tendons. Cartilage is formed with its own unique properties according to its role within the body. Some may be formed with more elastic qualities than others, while bone is full of very dense extracellular matrix
  3. 3. and osteocytes. It is the arrangement of the different components of connective tissue that determine the function and allow diverse applications throughout the body. There are many ways that that the network is affected by nutritional, hormonal and physical deficiencies as well as administered drugs. These all damage the cellular interaction of the tissue and change the way the body behaves internally with itself and externally with the world. Current research and medical hypotheses are now suggesting that connective tissue functions not only as a network of support and structure to surrounding tissue and organs, but also as a body-wide mechanosensitive signalling network 1. Electrical, cellular and tissue remodelling activity have each been considered as signalling pathways within the connective tissue framework. Cell to cell connections in the form of a fibroblast web have been observed and are the basis of the cellular communication network2. This network could be affected by changes in posture, form, hormonal activity etc and have profound implications on the health of integrated and individual systems alike. CT in this form is an unbroken chain of communication and seems to respond to piezoelectric stimuli. It appears that distortions/inertial fulcrums in the energy body as a result of injury/trauma manifest physically, sometimes along specific acupuncture meridians as trigger points, adhesions and fibrosis. Alternatively if we find the fascia to be healthy, well hydrated and without pathologies, energy seems to travel a lot quicker and more freely. These ideas are gaining ground at the moment and make sense due to the compensation patterns within fascia. E.g. twisting, pulling and organizing around specific points or fulcrums and groups of points. Three elements of connective tissue that are directly influenced by the HPA axis are the ground substance, osteoblast activity and fibroblast activity. The osteoblast and fibroblast cells synthesise the densely packed fibrils of the skin, bone, tendon and fascia while the ground substance acts as a support and filtration system with its ability to hold water. Each piece of the connective tissue matrix is influenced by varying factors including metabolism, pharmaceuticals, growth hormones, injury repair and dietary input. The involvements of these factors change the biomechanics of the individual due to a change in connective tissue character. The exploration of all the stimulatory factors is beyond our scope here; instead we are looking at the direct influence of cortisol modulation. The Endocrine system is fundamental to maintaining the internal physiology of the body. The system aids us in adapting to constant environmental change as well as changing behaviour.3 Hormones target specific cell receptors and activate strong biochemical responses in the body, including stimulation of the immune response, growth, electrolyte balance, blood nutrient balance and reproduction4. The chemical messengers alter the target cells activity with profound effects at very low concentrations. The active hormones can be divided into three groups: Tyrosine, Protein/Peptide & Steroid. The tyrosine-derived hormones include epinephrine, norepinephrine and thyroxine. Epinephrine and norepinephrine are both produced in the adrenal medulla but also can act as neurotransmitters due to their production at 1 Langevin H, Connective Tissue: A body-wide signalling network? Med Hypothese. 2006;66(6): 1074. Epub 2006 2 Langevin H, Cornbrooks C, Taatjes D. Fibroblasts form a body-wide cellular network. Histochemical Cell Biology. 2004 Jul;122(1):7-15 3 Brook, Charles and Marshall, Nicolas. Endocrinology. Chapter 1. Pp 1-12. 2001 4 Marieb, Elaine. Human Anatomy and Physiology. Pp 604-644. 2004
  4. 4. sympathetic nerve endings. Protein hormones include insulin, secretin, prolactin and growth hormone. While the peptides include corticotrophin-releasing hormone (CRH), oxytocin, gastrin and dopamine (Prolactin inhibiting factor). The steroidal hormones include cortisol, oestrogen, testosterone and aldosterone. This list is not exhaustive but covers the hormones released by the principle endocrine glands. Our focus here is on the behaviour and characteristics of cortisol in the body. The steroid hormones are synthesised from cholesterol. The fat-soluble nature of these hormones means that they can diffuse into the target cells. The stimulation of the adrenal cortex starts with the release of the peptide CRH by the hypothalamus. This triggers adrenocorticotropic hormones that make the adrenal cortex produce corticosteroids. These corticosteroids are important as they help the body in balancing and fighting external/internal stressors. They influence the energy metabolism of most cells and under normal functioning they help to regulate blood sugar levels. They stimulate gluconeogenesis, the glucose formation. The proteins that are broken into glucose are dependent on the role and regulation of cortisol. It directly controls part of our energy metabolism. Cortisol helps to keep glucose levels fairly constant as we regularly eat food. Cortisol also helps to maintain blood volume by preventing a shift of water into the cells. We can theorise that one of the mechanisms of fascial dehydration comes about due to excessive cortisol levels in the body, since it restricts water transfer into tissue cells. This can have long reaching effects since we need to our connective tissue to remain warm, moist and resilient. There 4 main effects that high cortisol levels have in the body: A - depress cartilage and bone formation, B - inhibit inflammation by stabilizing lysosomal membranes and preventing vasodilation, C - depress the immune system and D - promote neural & gastrointestinal function. Cortisol has been used for the treatment of systemic disease to great effect. Rheumatic, Asthma, Intestinal, Malignant and Nervous Disease/Disorder have been treated. Much of these effects come from the histochemical response from the adrenal hormones.5 Cortisol in high levels probably has inhibitory influence on bone formation through decrease of insulin growth factor-I (IGF-I). Cortisol inhibits the activity of fibroblasts (the source of connective tissue). In this way cortisone has been used pharmaceutically in the treatment of fibrosis. These dense connective tissue deposits from chronic strain or trauma are broken down by the application of cortisone. Glucocorticoids (these are hormones themselves) directly inhibit growth hormone as well. Glucocorticoids also have direct effects on the bone, inhibiting osteoblast activity and causing osteoporosis 6 So what can we consider in looking at the long-term application of both corticosteroid applications and chronic stress in the athlete? Local applications of cortisone have been used on tendons; skin diseases and joints to great effect but these applications have been growing steadily. Osteoporosis is a well-known effect of long-term corticosteroid therapy. What might we consider the problems with athletes 5 Iverson, K. Hormonal Influence on Connective Tissue. In: Connective Tissue in Health and Disease. ASBOE-HANSEN, G. (ed.) E.Munksgaard, 1954, pp. 130-150] [ Mancini, R.E. et Al. The Action of ACTH, Cortisone and prednisone on the connective tissue of normal and sclerodermic human skin, J.Invest. Dermat. 1960, 34, 393-326] 6 Chrousos GP, The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro- endocrine and target tissue related causes. Int J Obes Relat Metab Disord. 2000 Jun; 24 Suppl 2: S50-5
  5. 5. who have a long history of injury and cortisone injections? And how does long term over stimulation of adrenal response affect the biomechanics, connective tissue generation and tissue repair of an athlete? Studies into the application of corticosteroids by Siraya Chunekamrai PhD showed that treated tissue became hypocellular as well stimulating chondrocyte necrosis. The proteoglycan content of the ground substance was also shown to decrease in both content and synthesis. The ground substance as we touched on earlier is key to the support and function of the connective tissue. It surrounds all our cells. It directly influences the passage of all sorts of gases, nutrients, waste products, hormones, antibodies and white blood cells; while it provides the immediate environment for every cell in the body. To damage or affect the balance of the ground substance is to change the fluidity of our entire connective tissue system. Poor nutrition and all forms of trauma are stress on the body that trigger a response from the HPA axis too. This level of response leads a decrease in ground substance. The decrease allows a build up of toxins; foreign particles and functioning of all cellular activity 7. Depleted levels of ground substance are one of the main factors involved in excessive cortisol levels in the body. Cortisone in some ways just stops the healing process of soft tissue. Masks underlying pathology and allows us to continue pain free without any recognition of the initial injury or damage. One study has showed that the measured decrease in chondrocyte cell count following a cortisone injection decreased a further 25%. This not only has implications for the athlete who returns to sport immediately after injury but to those who are chronically over-trained, tired or who have poor dietary habits. It is possible that this stress has long-term health implications. Long-term term uses of glucocorticosteroids have a catabolic effect on the body – just as stress and excessive cortisol production from internal adrenal cortex stimulation can stimulate as well. Just as people can collapse to the point of exhaustion following the withdrawal of glucocorticosteroids in stressful situations – most of us can relate this to the recovery period following prolonged exposure to stress. Often we find that when a stressor is removed, we are overcome with tiredness and exhaustion. The prolonged production of cortisol also leaves us open to infection; and at the high end of the scale cortisone exposure can also leads to problems like nervousness, sleep disturbance, euphoria and psychosis8 As we can see cortisol affects the immunological, metabolic and structural function of the connective tissue. This warrants a much deeper investigation into the long-term effects of chronic stress on the HPA Axis and the whole connective tissue framework, especially when we consider the recent studies exploring the fibroblast activity and its role in cellular communication. There are three strands of HVA axis management that I would like us to consider. Massage appears to modulate the HPA axis while manual lymphatic drainage (MLD) and nutrition are applicable to the treatment of inflammation in sports injuries. Massage in numerous studies has been shown to have an effect on the levels of cortisol in the body, though 7 Juhan, D. Jobs Body. 2003. pp63-65 8 “Cortisone in Football, Blessing or curse?” - www.fifa.com
  6. 6. the exact mechanism by which the effect is made is still yet unclear9. It appears that the Parasympathetic Nervous System is stimulated which in turn modulates the production of cortisol. Nutrition can have an effect on the inflammatory response of the body in the face of injury and disease. Examples of this are the proinflammatory cytokines that can be suppressed by dietary fish oil10 and turmeric root, which has been shown to have anti-inflammatory and antioxidant effects. In addition functional medicine testing can find deficiency and excess in the production of key hormones, fatty acids, vitamins and amino acids which all have an effect on essential metabolism. Any imbalances can be addressed through dietary plans and supplementation to ensure cellular function is optimal. In the case of MLD, it is particularly useful in treatment of the stagnation of the lymphatic system in inflammatory circumstances. Interstitial fluid circulation is increased and promotes a decrease in fluid retention. These are just a few examples of interventions that can be applied to control a disturbed HPA balance and increased inflammatory response in the body. While none of these can have a singular effective results in the immediate reduction of inflammation with sports injuries (like with cortisone injections) – together they all play a combined role in each athletes health and rehabilitation, without any possible long term damage to CT health and one of the internal communication networks. Short-term gains it seems are all too often taken without long term health in mind, especially when so much evidence is coming to light about the multiple roles of CT in our physiology and function. It may well be more sensible to take a conservative approach to our treatment of injury, inflammation and HPA modulation – until it becomes clearer what consequences are of more direct interventions over longer periods of time. 9 Moraska A, Pollini R, Boulanger K, Brooks MZ, Teitlebaum L. Physiological Adjustments to Stress Measures Following Massage Therapy: A Review of Literature. Evidence Based Complementary Alternative Medicine. 2008 10 Calder P. n-3 Polyunsaturated fatty acids and inflammation: From molecular biology to the clinic. 2003. Lipids. Vol. 38. pp343- 352.

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