The growth hormone receptor and growth hormone sensitivity in man

Sammanfattning: It is well established that the response to endogenous and exogenous growth hormone (GH) varies between individuals. For example, conditions with increased catabolic rate, such as trauma, sepsis and surgery, are believed to be associated with acquired GH insensitivity. To overcome the GH resistance, high doses of GH have therefore been used in attempt to preserve lean body mass in catabolic patients. However, in two recent studies the mortality rate was dramatically increased in critically ill patients given GH, indicating that the patients did not have generalised GH resistance. With the exception of patients with complete GH insensitivity due to GH receptor (GHR) mutations, little is known about the mechanisms behind the variation in GH sensitivity. Detailed studies of GH sensitivity in man have been hampered by the lack of methods sensitive enough to allow measurements in small tissue biopsies. The general aim of this thesis was to study GH sensitivity in man. To measure the expression of the GHR and insulin-like growth factor I (IGF-I) in GH target tissues, novel PCR based methods were developed and used on samples from patients with post surgical catabolism and patients with psoriasis. In addition, the expression of two GHR isoforms (GHR3+ and GHR3-) and 5´-untranslated regions (UTR) of GHR transcripts were examined. The first study showed that the alternative splicing of GHR transcripts, generating GHR3+ and GHR3- isoforms, is regulated in an interindividual rather than a tissue-specific manner and the splicing was not regulated by GH.The effects of surgically induced catabolism on GH sensitivity were investigated in three different studies in patients undergoing elective abdominal surgery. In patients given standardised glucose infusion postoperatively, GHR expression in skeletal muscle was decreased three days after surgery (day 3) compared to the time of surgery (day 0). In two other studies, where the patients were given total parenteral nutrition with or without glutamine postoperatively, GHR expression in skeletal muscle did not change significantly. IGF-I mRNA levels were decreased or not altered in skeletal muscle in response to surgery. Furthermore, GH administration prevented a postsurgical decrease in IGF-I mRNA in skeletal muscle. In one study, where both skeletal muscle and adipose tissue were available, the changes in GHR expression correlated with the changes in IGF-I expression from day 0 to day 3 in both tissues. In contrast to skeletal muscle, IGF-I mRNA levels increased in adipose tissue in response to surgery, suggesting tissue differences in GH sensitivity. This was further investigated in a patient in whom GHR expression increased in adipose tissue and decreased in skeletal muscle after surgery. In this patient, the use of different 5´-UTRs in GHR transcripts differed between skeletal muscle and adipose tissue, suggesting that the tissue-specific variation in GH sensitivity may be explained by differential activation of specific GHR promoter regions. The studies in patients undergoing surgery also demonstrate that the changes in GHR and IGF-I gene expression in GH target tissues are not reflected by similar changes in plasma levels of the corresponding gene products, GH-binding protein and IGF-I.In patients with psoriasis, GHR mRNA levels in epidermis and serum levels of GH-binding protein, IGF-I and IGF-binding protein 3 were similar to those in control subjects, indicating that alterations in the GH/IGF-I axis do not play a major role in the pathogenesis of psoriasis.In contrast to the belief that catabolism is associated with generalised GH insensitivity, data in this study indicate that GH sensitivity can differ between tissues. Therefore, the high doses of GH that are used to prevent muscle breakdown in catabolic patients could result in undesired effects in some tissues, e.g. adipose tissue, where GH sensitivity appears to be increased.