New etiopathogenetic mechanisms of multisystemic involvement in endocrine diseases and long-term effects of hormonal substitutive treatment

Abstract

The hormones can have different functions and modes of actions. They regulate metabolism, growth, development, puberty and many different tissue functions. One hormone can have multiple effects and target organs and, likewise, one physiological event or target organ can be affected by more than one hormone. For example, the major function of growth hormone (GH) in children is to promote linear growth, but GH has other important physiological effects which influence several key metabolic processes, including body composition, muscle strength, bone mineral density and reproductive capacity (1). Thyroid hormones (TH) are critical for energy metabolism of nutrients and inorganic ions, thermogenesis, and the normal growth and development at critical periods of various tissues, including CNS. In fact, TH regulate neurogenesis, myelination, dendrite proliferation and synapse formation (2). Therefore, TH effect somatic and skeletal growth modulating the action of GH and insulin like growth factors. Endocrine diseases are derived from defects found at any point in the hormonal synthesis, secretion, transport, action, or regulatory control of a hormone, leading a reduction or an increase of hormonal effects. Because the hormones act on multiple target organ, endocrine diseases affect multiple organs and are characterized by multisystemic signs ad symptoms, almost always involving the heart and cardiovascular system. In many case the adaptative cardiac response is physiologically normal and the clinical findings are subtle. Endocrine diseases and, in particular, thyroid dysfunction and growth hormone deficiency in adults are associated with increased cardiovascular morbidity and mortality due to premature atherosclerosis and cardiac abnormalities (3-6). It has established that atherosclerotic disease begins in childhood, however relatelively few studies have shown that some endocrine dysfunction in children and adolescents may be associated with detrimental cardiovascular and metabolic abnormalities, such as alteration of left ventricular mass, low flow-mediated endothelium dependent vasodilatation, abnormal lipid profile and increased homocysteine and inflammatory markers, which place them at higher risk of cardiovascular disease at an early age (8). Hormonal therapy exerts a beneficial effect on cardiovascular abnormalities and metabolic alterations and is likely beneficial in terms of cardiovascular risk. Moreover, sometimes, as for congenital hypothyroidism (CH), the hormonal replacement therapy is necessary for life and during treatment patients may experience periods of over or under-treatment, particularly during adolescence, when the compliance to the treatment becomes less regular, not withstanding an accurate biochemical follow-up and frequent adjustments. These unphysiological fluctuations of hormones levels might place the patients at an increased risk of early cardiovascular and metabolic abnormalities. However, the multisystemic involvement in endocrine disease may be due to an alteration of a signaling pathway shared between endocrine and other systems. It is notable, for example, that many components of the GH receptor (GHR) signalling pathway are also activated by other cytokines and growth factors and defects in these intracellular components may manifest in clinical phenotypes in addition to severe growth failure. Hence, a complex clinical phenotype that includes GH insensitivity with normal GHR would be strongly indicative of post-GHR defects. In fact, in the recent years, defects in intracellular components of GHR and cytokine signalling, such as mutations of gamma chain (γc), Signal Transducers and Activators of Transcription 5b (STAT5b), Nuclear Factor-κB (NF-κB) gene have been observed in patients with complex phenotype characterized by short stature due to GHI and immunodeficiencies (9-12). Aim of this project was to define the multisystemic aspects of the endocrine diseases related to etiopathogenetic mechanisms of molecular and/or anatomical alterations responsible for endocrine dysfunction and the effects of hormonal treatment on various organs and systems. To this aim, we started from 3 model of disease: • Idiopathic Short Stature • Congenital Hypothyroidism • Growth Hormone Deficienc