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

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

Metabolic effects of growth hormone deficiency and GH replacement therapy in children and adolescents

Adults with severe growth hormone (GH) deficiency (GHD) may develop a cluster of cardiovascular risk factors that may contribute to a reduced life expectancy with increased mortality due to cardiovascular disease. In adolescents with severe GHD there is also increasing evidence which suggests that the discontinuation of GH replacement therapy at the completion of linear growth may result in adverse effects on body composition, lipid profile, cardiac morphology and performance. In contrast, relatively few studies have investigated whether or not children with GHD have metabolic and cardiac abnormalities that may place them at higher risk of cardiovascular disease at an early age. This review focuses on the effect of both GHD and GH replacement on cardiovascular risk factors in children and adolescents with GH

Growth hormone deficiency in a patient with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI; MIM 222700) is a rare, autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes the light chain of the cationic amino acids (CAA) transporter y+. The clinical presentation of LPI includes gastrointestinal symptoms, failure to thrive, episodes of coma, hepatosplenomegaly and osteoporosis. However, other findings have also been reported, and these suggest a multisystem involvement. We report a girl with confirmed LPI who presented with severe short stature that was unresponsive to adequate LPI treatment. The girl was found to have a classic growth hormone deficiency (GHD) and responded well to growth hormone (GH) replacement therapy. While it is not known whether the mechanisms involved in the GHD of our patient are related to LPI, this case suggests that GH/IGF-I axis should be investigated in LPI children with persistent growth failure

Serum homocysteine concentrations in children with growth hormone (GH) deficiency before and after 12 months GH replacement.

This open, prospective study was designed to evaluate the effect of growth hormone deficiency (GHD) and GH replacement therapy on serum homocysteine (Hcy) concentration in children with GHD. SUBJECTS: Seventeen prepubertal children with GHD (11 boys and six girls) aged 8.6 +/- 1.9 years were studied before and after 12 months of GH replacement therapy at a dose of GH of 30 microg/kg/day. Seventeen healthy children acted as controls and were matched for age, sex and body mass index (BMI). At study entry, height, weight, blood pressure, serum Hcy, serum IGF-I, total-low density lipoprotein (LDL)- and high density lipoprotein (HDL) cholesterol, triglycerides, free T4, free T3, vitamin B12, folate, glucose and creatinine were measured in all subjects. The atherogenic index (AI) was also calculated as the ratio of total cholesterol/HDL cholesterol (T/HDL). In GHD children these parameters were also revaluated after 12 months of GH therapy. At study entry height and serum IGF-I were significantly lower, as expected, in GHD patients than in controls (P < 0.0001 and P < 0.007, respectively). Serum Hcy levels were significantly higher in GHD patients than in healthy children (8.4 +/- 2.9 vs. 6.0 +/- 2.9 micromol/l; P < 0.03), although the absolute values were within the normal values for age and sex. There were no significant differences at baseline with respect to blood pressure, serum vitamin B12, folate, fT3, fT4, lipid profile, creatinine and glucose levels. After 12 months of GH replacement therapy height and serum IGF-I increased significantly compared to pretreatment values (P < 0.0001); serum Hcy levels decreased significantly (6.0 +/- 3.3 micromol/l; P < 0.002) compared to baseline values, becoming similar to control values. Total cholesterol (3.5 +/- 0.6 mmol/l) and the AI (2.5 +/- 0.8) decreased significantly with respect to both pretreatment (4.2 +/- 1.0 mmol/l; P < 0.0002 and 3.4 +/- 0.8; < 0.002, respectively) and control values (4.2 +/- 0.4 mmol/l; P < 0.0005 and 3.3 +/- 1.1; P = 0.02, respectively). GHD in children is associated with higher serum levels of Hcy compared to controls, without significantly affecting the lipid profile. GH replacement for 12 months significantly decreased the Hcy levels and improved the lipid profile with a decrease of total cholesterol and the total/HDL cholesterol ratio, compared to pretreatment values. Given the small number of patients, further larger studies are needed to clarify whether these results may have significant effects in the prevention of cardiovascular disease in adulthood