Adult growth hormone deficiency Outcome and Responsiveness, from clinic to pharmacogenomics (#97)
Hypopituitarism is a complex endocrine deficiency due to a hypothalamic-pituitary disease. It is associated with increased morbidity and mortality, mainly from cardiovascular diseases. These data derives from patients who have received conventional replacement therapy, but not GH. GH replacement in adult hypopituitary patients has demonstrated reduced abdominal obesity, diastolic blood pressure, improved serum lipid profile, reduction in systemic inflammatory markers and improved quality of life. More recently published studies have suggested that the doubled standardised mortality rate seen in previous studies is near normalised in large cohort of patients who have received long-term GH replacement therapy.
The individual treatment response to GH is adults vary considerable. This is to some extent explained by the interaction between GH receptor signalling and sex steroid actions. Oestrogen increases the expression of SOCS2, which attenuates the phosphorylation of JAK2 and thereby attenuates the action of GH. This is most evident at the hepatic level during oral oestrogen replacement therapy that reduces the serum IGF-I response to GH. Testosterone on the other hand augments some of the action of GH such as the protein anabolic response and the increase in extracellular water, but the true mechanisms behind these interactions is not known. Other clinical predictors that have less impact are body mass index and serum insulin concentrations.
As the responsiveness to GH can only be explained to a small extent by clinical predictors genotypes predicting responsiveness have been searched for using target gene approach. Some, but not all studies have demonstrated that the short-form exon-3 deleted GH receptor may be associated with a larger treatment response. Other genotypes related to lipid metabolism, regulation of extracellular fluid and collagen synthesis have been show to be weakly associated with treatment response in adult GH deficiency.
In summary, adult patients with hypopituitarism and GH deficiency is associated with poor cardiovascular metabolic profile and reduced life-expectancy. We have during the last 20 years gathered experience in the overall management of hypopituitary patients including their GH deficiency. We understand more about individual responsiveness to GH and can thereby individualise therapy. Recent data also suggest that the outcome has improved with near normalisation of mortality rate.
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