IMPRODA, NICOLA (2021) NEW INSIGHTS IN CHILDHOOD-ONSET GROWTH HORMONE DEFICIENCY: FROM DIAGNOSIS TO LONG-TERM OUTCOMES. [Tesi di dottorato]

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Although rare, GHD is an important diagnosis to make correctly. In fact, GH replacement therapy (GHRT) in GHD is highly efficacious so amissed diagnosis will result in a poor outcome. Equally, a false positive diagnosis will lead to many years of unnecessary daily subcutaneous injections, with significant wasted expenses and exposure to potential adverse effects. Unfortunately, many aspects regarding diagnosis and treatment of GHD during childhood and adolescence are still subject of much controversy (4). While the diagnosis of GHD in the context of MPHD and/or organic pathologies of the CNS generally appears straightforward, differentiating idiopathic GHD from non-GH deficient short children can be more challenging, especially in patients in the peripubertal phase or with delayed puberty, which may exhibit transient growth deceleration or short stature. Although an integrated assessment of history and physical examination, stature, growth velocity and bone age represents is the most reliable diagnostic element, provocative GH testing continues to play a primary role in the diagnosis of GHD. Nevertheless, there are significant issues concerning the validity and reproducibility of GH testing, regarding optimal provocative stimuli, appropriate cut-off levels specific to GH assay and other factors such as BMI and pubertal status, utility of sex steroid priming, and standardization of testing protocols (4). Indeed, the vast majority of patients diagnosed with GHD in childhood and with no structural pituitary abnormality on MRI will have adequate GH secretion when retested in late adolescence or adulthood (66%–85% depending on the test and cutoff used) (5,6). The presence of structural abnormalities of the hypothalamus-pituitary region, such as an ectopic posterior pituitary, has been previously reported to predict the development of severe GHD, but its role in predicting the evolution of endocrine deficits in MPHD or the persistence of GHD is still debated (7, 1). Although recombinant human (rh) GH has been available since the 1980s, many clinical aspects related to GHD or to GH treatment itself still need to be defined. It has been consistently shown that adults with untreated GHD have impaired cardiac performance, adverse metabolic profile and increased atherogenic risk, which can be restored by GH replacement therapy (GHRT) (8, 9). Moreover, in adults with GHD body composition is altered, with increased fat mass (FM) and decreased lean body mass (LBM), causing diminished muscle strength and physical fitness (10). There is usually an increase in muscle 7 mass in response to GH but whether this change results in increased strength is still debated (11-12). Nonetheless, overall data in adults suggest that GH treatment significantly improves aerobic exercise capacity and physical performance (13). This topic is relevant even in childhood since, in addition to promoting linear growth, GH also exerts beneficial effects on early risk factors involved in the development of CV morbidity (14). Nonetheless, in childhood and adolescence the effects of GHD and GHRT on functional outcome measures characterizing the patient's physical fitness, such as cardiopulmonary functional capacity, muscle strength, flexibility, and endurance are still poorly delineated. Given the controversies regarding diagnosis and long-term outcomes of GHD, improved specificity of diagnostic testing, as well as a better understanding of the role of GHD and GHRT on metabolic and functional parameters are required in order to develop tailored therapeutic approaches. Indeed, functional parameters represent important therapeutic outcomes, as they are the most relevant for the patient's physical, motor and psychosocial development, thus significantly influencing the patient's quality of life. Therefore, the present Ph.D. thesis aimed to investigate: - Usefulness of priming with sex steroids in improving the diagnostic accuracy of GHST in the diagnosis of GHD. - Endocrine morbidity and final height of children with MPHD and SOD. - Metabolic profile, body composition, vascular morphology and function in children with GHD treated with rhGH. - The effects of GHD and GHRT on functional parameters contributing to the health related fitness (exercise capacity, and muscle strength and flexibility).

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