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The Effects of Recombinant Human Growth Hormone on Skin, Muscle

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The Effects of Recombinant Human Growth Hormone on Skin, Muscle 2807713108 THE EFFECTS OF RECOMBINANT HUMAN GROWTH HORMONE ON SKIN, MUSCLE AND NERVE. Thesis submitted to the University of London for the degree of Doctor of Philosophy in the Faculty of Medicine. by WOHAIB HASAN MSc BSc (Hons) Division of Endocrinology and Department of Anatomy, Royal Free Hospital School of Medicine February 1997 ProQuest Number: 10046192 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10046192 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 a Abstract This study has investigated the mechanism of growth hormone (GH) action in the skin and its innervation as well as in skeletal muscle. Two main issues have been addressed: (1) To what extent are GH effects on extrahepatic targets the result of direct actions of this hormone, or, indirect effects mediated by local production of insulin-like growth factor I (IGF-I)? (2) Can GH, acting either directly or indirectly, be regarded as a key mediator of neurotrophic functions? These issues have been examined using three approaches: i) Muscle biopsies were taken from adult growth hormone-deficient patients before and after six to twelve months of recombinant human growth hormone (r-hGH) treatment, as part of a double-blind placebo controlled clinical trial. These patients exhibit reductions in muscle bulk and strength which can be reversed with r-hGH treatment. Muscle fibre types and fibre size were examined by light microscopy for an influence of r-hGH therapy. IGF-I message was localised to muscle fibre cytoplasm and fibre- type specific mRNA was quantified by combined non-radioactive in situ hybridisation with computerised image analysis. Circulating IGF-I levels were also assayed, making it possible to compare morphological changes in muscle fibre size with changes in circulating and muscle-derived IGF-I. The results obtained are consistent with a direct effect of GH on skeletal muscle resulting in generation of IGF-I by the muscle fibres. However, the influence of circulating IGF-I could not be dismissed from this scheme. ii) The innervation, morphology and function of eccrine sweat glands was examined in GH-deficient subjects who display reduced sweating, in patients with acromegaly (a GH hypersecretory state with excessive sweating) and in control subjects. Pilocarpine iontophoresis sweat tests were used to assess changes in sweating. An increase in the cholinergic innervation accompanied restoration of sweat rates in r-hGH treated subjects, whilst acromegalics displayed hypertrophy of sweat glands and elevated sweat gland innervation. These data imply an effect of GH on the sweat glands with repercussions for their innervation. A GH-mediated influence on neurotrophic support to the sweat gland nerves can thus be envisaged. iii) Aged rats were utilised to investigate direct effects of r-hGH administration in the vicinity of the footpad eccrine sweat glands, with the aim of minimising the confounding influence of serum IGF-I. Ageing is a state of relative GH deficiency and sweat glands are believed to be targets for GH action. Further aged rats display reductions in sweat gland size and innervation. An immunohistochemical method was utilised to stain for nerves and neurotrophin receptor sites around sweat glands. Due to injection-induced inflammatory effects, the results from this study were not clear, aside fi-om an increase in sweat gland acinar size on r-hGH administration and the demonstration of parallel alterations in neurotrophin receptor expression and periacinar nerve density. These results allow the hypothesis of a direct effect of GH on target tissues to be advanced, resulting in local generation of IGF-I and, perhaps, of other target-derived neurotrophic factors. Acknowledgements In the name o f Allah, the Creator and Sustainer o f the Worlds "Over all those endowed with knowledge is the All-Knowing." "We will show them Our Signs in the universe, and in their own selves, until it becomes manifest to them that this is the Truth." (Al-Qur'an 12:76 & 41:53) I am indebted and extremely grateful to Dr Tim Cowen whose guidance and support were essential throughout this study. Thanks are also due to Dr Pierre Bouloux for his joint supervision and financial support without which this thesis would not have been possible. I acknowledge the help of Dr Philip Barnett and Mr Christopher Thrasivoulou throughout the past few years. I thank "them upstairs" (Patsy Coskeran, Richard Quinton, Priyal D'Zoysa and Véronique Duke) and "them downstairs" (Isabella Gavazzi, Agus Santoso, Marion Leibl, Richard Johnson, Clare Underwood and David Kelly) for their help and intellectual discourse, and for keeping me sane! Dr Shiyu Yang and Mr Tjeu Gysbers assisted with in situ hybridisation and photography respectively, and their expertise is gratefully appreciated. This thesis is dedicated to my parents Dr Suhaib Hasan and Mrs Shakila Khatoon whose constant encouragement has been my inspiration. I thank Api, Liaquat bhai, Hamdi, Shazra, Usama, Salma, Hafsa, Shahar and Mujahid for being the best family ever. The kindness and support of my parents-in-law, Mr & Mrs Bashir Butt, is duly acknowledged. In addition, I express my gratitude to Naeem, Saeed, Abdul Haq, Abdul Malik, and all the members of the Royal Free Islamic Society. Finally, a huge thanks to my wife Rizwana and my daughters Sana and Safana for putting up with a husband and father whose fleeting appearances were so rarely accompanied by a smile! Contents Page Title 1 Abstract 2 Acknowledgements 4 Contents 5 List of figures and legends 12 Tables and Charts 12 Figures 12 Plates 18 List of abbreviations 19 Chapter 1-General Introduction 22 AI 1. Growth hormone; a historical perspective 23 AI 2 Adult growth hormone deficiency syndrome 23 AI.3. Acromegaly 24 AI.4. Growth hormone; structure, binding proteins and receptor 25 AI.5. Growth hormone; secretion and control 27 AI.6. Insulin-like growth factor I; structure, secretion, function and control 30 AI.7. Growth hormone, insulin-like growth factor I and the nervous system 33 AI.7.1. Growth hormone and the nervous system 33 AI.7.2. Insulin-like growth factor I in neuronal development 35 AI.7.3. Insulin-like growth factor I and the mature nervous system 36 AI . 8 . Aims of the investigation 38 Chapter 2-An investigation into recombinant human growth hormone treatment of growth hormone-deficient adults. 40 Chapter 2-Tntroduction BI. 1. Diagnosis of adult growth hormone deficiency 41 BI.2. Growth hormone, insulin-like growth factor I and thyroid hormones 41 BI 3 Growth hormone, insulin-like growth factor I and bone metabolism 42 BI 4. Aims of the investigation 42 Methods BM. 1. Growth hormone-deficient patients 44 BM.2. Administration of recombinant human growth hormone 44 BM.3. Serum insulin-like growth factor I assay 45 BM.4. Serum free 3,5,3'-triiodothyronine and free thyroxine assay 45 BM.5. Urinary total pyridinoline crosslinks assay 45 BM 5 1. Collagen pyridinium as a marker of bone metabolism 45 BM.5.2. Methodology 45 BM 6 Acknowledgments 46 Results BR. 1. Patient responses to recombinant human growth hormone therapy 47 BR.2. Serum insulin-like growth factor I 47 BR.3. Thyroid hormones 55 BR.3.1. Serum free 3,5,3'-triiodothyronine 55 BR.3.2. Serum free thyroxine 56 BR.4. Urinary total pyridinoline crosslinks 65 Discussion BD. 1. Patient responses to recombinant human growth hormone therapy 70 BD.2. Serum insulin-like growth factor I 70 BD 3 Serum free 3,5,3'-triiodothyronine and free thyroxine 72 BD.4. Urinary total pyridinoline crosslinks 74 BD 5 Synopsis of the investigation 76 Chapter 3-An investigation into the thermoregulatory apparatus in adult growth hormone deficiency and acromegaly. 77 Introduction Cl. The regulation of body temperature 78 CI.l. Central control of thermoregulation 78 CL2. Sweat glands; eccrine and apocrine 78 CL 3. Eccrine sweat gland innervation, neurotransmitters and functional tests 80 CI.4. Developmental changes in the innervation to eccrine sweat glands 84 CL 5. Neuropeptides in skin 85 CL5.1. Vasoactive intestinal polypeptide; distribution and function in the skin 86 CL5.2. Other neuropeptides in the skin 89 CL6. Abnormalities of sudomotor innervation in clinical conditions 90 CL 7. Growth hormone and thermoregulation 90 CL 8 . Growth hormone and the skin 91 CL 9. Aims of the investigation 92 Methods CM 1. Patient characteristics 95 CM.2. Pilocarpine iontophoresis-induced sweat production 95 CM. 3. Sweat gland morphology and innervation 95 CM 3.1. Skin biopsy and tissue processing 95 CM.3.2. Acetylcholinesterase histochemistry 96 CM 3 3 Immunohistochemistry 96 CM 3 4 Microscopy and image analysis for skin innervation 97 CM.3.4.1. Microscopy and image input 97 CM.3.4.2. Sweat gland size and innervation measurements 98 CM.3.4.3. Epidermal-dermal junction innervation measurements 98 Results CR. 1. Pilocarpine iontophoresis-induced sweat production 99 CR.2. Acetylcholinesterase histochemistry 104 CR 3 Vasoactive intestinal polypeptide immunoreactive nerve density 110 Chapter 3-Results (contd.) CR 4 Protein gene product 9.5 immunoreactive nerve density 114 CR 5 Protein gene product 9.5 immunoreactive nerves in the epidermal-dermal junction 118 CR 6 Eccrine sweat gland acinus perimeter 121 CR 7 Tyrosine hydroxylase distribution 124 Discussion CD.
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