Hasan, Wohaib; (1997) The effects of recombinant human growth hormone on skin, muscle and nerve. Doctoral thesis (Ph.D), UCL (University College London).

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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 from 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.

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