Impact Of Growth Hormone Deficiency Research Articles

Hypopituitarism and bone disease: pathophysiology, diagnosis and treatment outcomes.

Hypopituitarism is a rare but significant endocrine disorder characterized by the inadequate secretion of one or more pituitary hormones. The intricate relationship between hypopituitarism and bone health is a topic of growing interest in the medical community. In this review the authors explore associations between hypopituitarism and bone health, with specific examination of the impact of growth hormone deficiency, central hypogonadism, central hypocortisolism, and central hypothyroidism. Pathogenesis, diagnosis, and treatment options as well as challenges posed by osteopenia, osteoporosis, and fractures in hypopituitarism are discussed.

P.108 Effects of intermittent fasting on body weight, antioxidant defence system, autonomic nervous system balance and activity in female Wistar rats

The aim of the present study was to investigate the differences in the topological organization of functional brain networks between children with growth hormone deficiency (GHD) and those with idiopathic short stature (ISS).Thirty-one children with GHD and fifty-three children with ISS were recruited based on the results of GH stimulation tests. Resting-state fMRI data were acquired from all children. Whole brain functional connectivity density (FCD) analysis and subsequent seed-based functional connectivity analysis were used to explore the differences in functional brain networks between the children with ISS and GHD. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales and FCD values of different brain regions were applied.Compared with the ISS group, the GHD group exhibited significantly decreased FCDs in the left postcentral gyrus, right precentral gyrus and left cerebellar lobules 7b and 6. The subsequent functional connectivity analysis found decreased functional connectivity between lobules 7b and 6 of the left cerebellum as well as the left postcentral gyrus and right precentral gyrus in the GHD group compared to that in the ISS group. In addition, the FCD values of region 6 of the left cerebellum in the GHD group were negatively correlated with the scores on the Symptom Checklist-90 and Eysenck Personality Questionnaire. The FCD value of the left postcentral gyrus in children with ISS positively correlated with IGFBP-3 levels and was approximately correlated with IGF-1 levels.These findings highlight the impact of growth hormone deficiency on the brain network that mainly involves the somatosensory, somatic motor and cerebellum networks, which may contribute to the behavioural problems observed in these children.

P.553 5-HT4R binding is positively correlated with obsessive-compulsive features: a preliminary analysis in healthy volunteers

The aim of the present study was to investigate the differences in the topological organization of functional brain networks between children with growth hormone deficiency (GHD) and those with idiopathic short stature (ISS).Thirty-one children with GHD and fifty-three children with ISS were recruited based on the results of GH stimulation tests. Resting-state fMRI data were acquired from all children. Whole brain functional connectivity density (FCD) analysis and subsequent seed-based functional connectivity analysis were used to explore the differences in functional brain networks between the children with ISS and GHD. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales and FCD values of different brain regions were applied.Compared with the ISS group, the GHD group exhibited significantly decreased FCDs in the left postcentral gyrus, right precentral gyrus and left cerebellar lobules 7b and 6. The subsequent functional connectivity analysis found decreased functional connectivity between lobules 7b and 6 of the left cerebellum as well as the left postcentral gyrus and right precentral gyrus in the GHD group compared to that in the ISS group. In addition, the FCD values of region 6 of the left cerebellum in the GHD group were negatively correlated with the scores on the Symptom Checklist-90 and Eysenck Personality Questionnaire. The FCD value of the left postcentral gyrus in children with ISS positively correlated with IGFBP-3 levels and was approximately correlated with IGF-1 levels.These findings highlight the impact of growth hormone deficiency on the brain network that mainly involves the somatosensory, somatic motor and cerebellum networks, which may contribute to the behavioural problems observed in these children.

Serum soluble urokinase plasminogen activator receptor (suPAR) in adults with growth hormone deficiency.

Growth hormone deficiency (GHD) syndrome is associated with adverse levels of several risk factors for cardiovascular diseases (CVD), including metabolic inflammation. However, the impact of GHD and GH treatment on low-grade inflammation is unknown. The aim of the study was to establish the level of the low-grade inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) in adults with GHD and the response to long-term GH treatment. Measurements of suPAR and CRP were performed in bio-bank serum samples from 72 adults, 34 males and 38 females, with GHD before and during at least 5 years of GH treatment. Mean age was 52.5 ± 15.5 years, BMI 27.3 ± 5 kg/m2. Clinical evaluations and blood sampling were performed at routine visits. Data on demography, anthropometry, lab results and clinical events were retrieved from post-marketing surveillance study databases and medical records. suPAR and high-sensitive (hs) CRP were analysed using ELISA and immunochemistry, respectively. At baseline blood pressure, lipid profile and fasting glucose were within the normal reference range. Baseline geometric mean and 95% CI of suPAR was 2.9 (2.7–3.3) ng/mL and of CRP 2.3 (0.6–4.0) mg/L. Mean follow-up was 8 ± 2 years. The suPAR levels remained stable during follow-up, although individual increases were seen on occurrence or presence of co-morbidities. In contrast, levels of CRP decreased. In conclusion, the decrease in CRP and indirectly the absence of an expected increase in suPAR over time indicates a favourable effect of GH on low-grade inflammation.

Differences in the functional connectivity density of the brain between individuals with growth hormone deficiency and idiopathic short stature

PurposeThe aim of the present study was to investigate the differences in the topological organization of functional brain networks between children with growth hormone deficiency (GHD) and those with idiopathic short stature (ISS). MethodsThirty-one children with GHD and fifty-three children with ISS were recruited based on the results of GH stimulation tests. Resting-state fMRI data were acquired from all children. Whole brain functional connectivity density (FCD) analysis and subsequent seed-based functional connectivity analysis were used to explore the differences in functional brain networks between the children with ISS and GHD. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales and FCD values of different brain regions were applied. ResultsCompared with the ISS group, the GHD group exhibited significantly decreased FCDs in the left postcentral gyrus, right precentral gyrus and left cerebellar lobules 7b and 6. The subsequent functional connectivity analysis found decreased functional connectivity between lobules 7b and 6 of the left cerebellum as well as the left postcentral gyrus and right precentral gyrus in the GHD group compared to that in the ISS group. In addition, the FCD values of region 6 of the left cerebellum in the GHD group were negatively correlated with the scores on the Symptom Checklist-90 and Eysenck Personality Questionnaire. The FCD value of the left postcentral gyrus in children with ISS positively correlated with IGFBP-3 levels and was approximately correlated with IGF-1 levels. ConclusionsThese findings highlight the impact of growth hormone deficiency on the brain network that mainly involves the somatosensory, somatic motor and cerebellum networks, which may contribute to the behavioural problems observed in these children.

Growth hormone and hematopoiesis: A retrospective analysis on a large cohort of children with growth hormone deficiency

ObjectiveFew large-scale studies regarding the impact of GH deficiency (GHD) on hematopoiesis in children have been reported. Our aim was to investigate hematopoiesis indices in a large cohort of GHD children at diagnosis and during GH treatment (GHT) and any correlation with hormonal parameters. DesignClinical and biochemical data of children with idiopathic GHD at diagnosis and annually up to 36 months of GHT were retrospectively evaluated. Overall, 255 children reached 12 months, 140 children 24 months and 86 children 36 months of follow-up during GHT. ResultsAt baseline, 18.4% of GHD children and 10.1% of controls showed normocytic anemia. GHD children showed lower hemoglobin (Hb) (p = 0.007), red blood cells (RBC) (p < 0.001) and hematocrit (Ht) (p = 0.001) than controls. During GHT, the percentage of anemic patients decreased from 18.4 to 5.4–3.5 and 4.6% after 12 (p = 0.001), 24 (p < 0.001) and 36 months (p < 0.001) of GHT, respectively. In both anemic and non-anemic patients, a significant increase in Hb (p < 0.001, <0.001 and 0.002), RBC (all p < 0.001) and Ht (all p < 0.001) was found after 12, 24 and 36 months of GHT. The Hb levels were significantly correlated with the GH peak after stimulation test (p < 0.001) at baseline and with IGF-I levels at 36 months of GHT (p = 0.002). ConclusionsA significant improvement in erythropoiesis indices occurs during GHT, regardless of any previous presence of anemia.

Assessing the Impact of Growth Hormone Deficiency (GHD) in Adults: Interpreting Change of the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD).

BackgroundThis study’s purpose was to assess the minimal important difference (MID) for the Treatment-Related Impact Measure—Adult Growth Hormone Deficiency (TRIM–AGHD), a patient-reported outcome measure assessing growth hormone deficiency (GHD) impacts. The measure was demonstrated to have adequate psychometric measurement properties, and be reliable and valid. For scores to be interpretable, the TRIM-AGHD must be responsive to treatment benefit and the MID in scores quantified.MethodsA prospective, non-interventional, observational, clinic-based survey study of naïve-to-treatment adult GHD patients (N = 98) was conducted. Key assessments were at baseline and follow-up (between 4 and approximately 8 weeks), with weekly telephone monitoring post-baseline (last n = 34 patients). Responsiveness was evaluated using the effect size of change scores from baseline to follow-up. MID estimates were derived from distribution-based (half standard deviation [0.5 SD], standard error of measurement [SEm]) and anchor-based methods (patient global rating of change [PGRC]) using change scores from baseline to initial report of minimal improvement in GHD severity. Findings from each method were converged to establish an acceptable MID.ResultsPatients were mean age 49.7 years, 65.6% female, and 76.0% Caucasian. The TRIM-AGHD was highly responsive to treatment with the total score effect size being 1.38. For the total score, the 0.5 SD was 8.09 and the SEm was 2.66. The difference found using the PGRC was 20.43. The converged MID value for the total score was 10 points.ConclusionsThe TRIM-AGHD is a highly responsive measure assessing AGHD treatment impacts. A 10-point change score is considered a clinically meaningful improvement.

Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement.

Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood.

WS04.2 Growth hormone deficiency (GHD) in adult patients (pts) with cystic fibrosis (CF)

Introduction CF adult pts complain signs and symptoms that overlap with the GHD: loss of muscle mass, physical function, occurrence of bone fragility, cardiovascular complications and lower stress tolerance. Aim To assess the prevalence of GHD in a cohort of CF adults. Methods 41 pts (30M) with a mean age of 36.9±10.7 yrs were enrolled. Exclusion criteria: liver or lung transplantation, age Results Enrolled subjects had the following characteristics: BMI:21.7±2.8 kg/m 2 FEV1: 61.9±18.3%, FEF25–75 39±23.7%, CVF 78.7±19.5%. All pts with GHD have a severe genotype: have both alleles with mutations of the first 3 classes. Evaluation of the GH-IGF1 axis revealed 34.2% with a GHD: severe in 12.2% and partial in 22%. In severe GHD, mean GH peak was 9.2±1.3 ng/ml and mean IGF1 185.4±51.5 ng/ml, in partial GHD mean GH peak 13.2±1.5, mean IGF1 208±39.7, and in pts with normal GH response, mean GH peak was 51±38.6, mean IGF1 210.6±77.5. All pts with severe GHD showed a ΔF508 mutation (60% in homozygous). We found a significant difference in GHD pts than no GHD: in BMI (23.4±2.4 vs 20.9±2.7) and fasting glucose (115.9±29.1 vs 87.7±13.7) and that these variables are inversely correlated with the GH peak (BMI: R=−0.33, p = 0.04; fasting glucose: R=−0.31, p = 0.05). Discussion To our knowledge there are no studies on the GHD in adults pts CF. You have to follow these pts over time to assess the impact of GHD on general health; should be increased cases in the study to see if this data is confirmed.

Autonomic nervous system and cardiovascular risk assessment during one year of growth hormone replacement therapy in adults with growth hormone deficiency.

This prospective study aimed to evaluate the impact of growth hormone deficiency (GHD) on cardiac autonomic tone and on cardiovascular risk and the changes after 12 months of GH replacement therapy (GHRT). GHD is associated with increased cardiovascular morbidity and mortality. This has been attributed to increased markers of cardiovascular risk and to abnormalities of both the cardiac and peripheral autonomic nervous systems. The autonomic cardiac nervous system (ACNS) can be indirectly evaluated by analysis of heart rate variability (HRV) in clinostatism and orthostatism. We compared 14 GHD patients at baseline and after 12 months of GHRT and 17 healthy controls. We analyzed a number of cardiovascular risk factors and we used analysis of HRV during the Tilt Test that identified high frequency (HF) and low frequency (LF), representing parasympathetic and sympathetic activity, respectively. Compared with the control group, in either clinostatism or in orthostatism our patients showed a significantly lower value of LF (P=0.047; P=0.004, respectively), whereas HF was significantly reduced in orthostatism (P=0.037), and indicatively in clinostatism (P=0.065). These values remained unchanged after 12 months of GHRT. No statistically significant differences were found between the LF/HF ratio in untreated and treated patients. In GHD patients, there was a significant reduction of cardiovascular risk in 12 months of replacement therapy (P=0.002). Our study highlights the absence of sympathovagal imbalance in GHD patients; GHRT does not change ACNS during the first year of GH treatment but it reduces the absolute cardiovascular risk in these patients.

Assessing the Impact of Growth Hormone Deficiency and Treatment in Adults: Development of a New Disease-Specific Measure

Approximately 50 000 adults in the United States are diagnosed with GH deficiency, which has negative impacts on cognitive functioning, psychological well-being, and quality of life. This paper presents development and validation of a patient-reported outcome measure (PRO), the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD). The TRIM-AGHD was developed to measure the impact of GH deficiency and its treatment. The development and validation of the TRIM-AGHD was conducted according to the Food and Drug Administration guidance on the development of PROs. Concept elicitation, conducted in three countries included interviews with patients, clinical experts, and literature review. Qualitative data were analyzed based on grounded theory principles, and draft items were cognitively debriefed. The measure underwent psychometric validation in a US clinic-based population. An a priori statistical analysis plan included assessment of the measurement model, reliability, and validity. Item functioning was reviewed using item response theory analyses. Forty-eight patients and six clinical experts participated in concept elicitation and 169 patients completed the validation study. TRIM-AGHD was measured. Factor analysis resulted in four domains: energy level, physical health, emotional health, and cognitive ability. The item response theory confirmed adequate item fit and placement within their domain. Internal consistency ranged from 0.82 to 0.95 and test-retest ranged from 0.80 to 0.92. All prespecified hypotheses for convergent validity and all but two for discriminant validity were met. The final 26-item TRIM-AGHD can be considered a reliable and valid PRO of the impact of disease and treatment for adult GH deficiency.

Growth Hormone Deficiency During the Transition Phase

The growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis has several roles. While achievement of a satisfactory height is probably the most important and well-known, it is now clear that it also affects body composition, metabolism, muscle mass, and bone density during the transition period. Recombinant-growth hormone (Rec-GH) therapy is normally administered to GH-deficient children to achieve a reasonable final height. Retesting with a provocative test (insulin tolerance test or growth-hormone-releasing hormone + arginine test) is necessary during the transition period, after measuring IGF-1 levels. If the patient is still GH-deficient, rec-GH therapy should be restarted at 0.2–0.5 mg/day up to a final dosage of 0.8–1.0 mg/day (albeit there is no general consensus on the dosage). In fact, there is widespread literature evidence of the negative impact of GH-deficiency during the transition period, which provokes increased visceral fat and waist/hip ratio, decreased muscle mass and bone density and increased cardiovascular morbidity and mortality.

Growth Hormone Deficiency During the Transition Phase

The growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis has several roles. While achievement of a satisfactory height is probably the most important and well-known, it is now clear that it also affects body composition, metabolism, muscle mass and bone density during the transition period. Recombinant-growth hormone (Rec-GH) therapy is normally administered to GH-deficient children to achieve a reasonable final height. Retesting with a provocative test (insulin tolerance test or growth-hormone-releasing hormone + arginine test) is necessary during the transition period, after measuring IGF-1 levels. If the patient is still GH-deficient, rec-GH therapy should be restarted at 0.2–0.5 mg/day up to a final dosage of 0.8–1.0 mg/day (albeit there is no general consensus on the dosage). In fact, there is widespread literature evidence of the negative impact of GH-deficiency during the transition period, which provokes increased visceral fat and waist/hip ratio, decreased muscle mass and bone density and increased cardiovascular morbidity and mortality.

Evaluation of the Components of the Insulin-like Growth Factors System in GH-deficient Adults: Effects of Twelve-month rhGH Treatment

The impact of GH deficiency and rhGH replacement therapy on IGF-I, IGFBP-3 and ALS levels has been widely studied. There is less information available on IGF-II levels, the component of the ternary complex poorly dependent on GH. We investigate the components of IGFs system in 36 GHD adults (28M, 8F, age 45 +/- 14 yrs) before and after 12 months of rhGH therapy (mean dose 0.3 +/- 0.1 mg/day). One-hundred healthy sex- and age-matched subjects were studied for comparison. At baseline, GHD patients showed IGF-I and IGF-II levels and IGFs to IGFBP-3 molar ratios that were lower than controls. During therapy, IGF-I levels increased (p < 0.01) to normal range. IGF-II levels, though higher than at baseline (p < 0.01), remained lower than in controls (p < 0.01). ALS and IGFBP-3 significantly increased (p < 0.001). These modifications resulted in normalization in IGF-I to IGFBP-3 ratio, while no change in IGF-II to IGFBP-3 ratio was observed. In conclusion, the increase of serum IGF-II levels during rhGH treatment in GHD patients probably reflects the increase in the other components of ternary complex (ALS and IGFBP-3). However, serum IGF-II levels as well as IGF-II to IGFBP-3 ratio, although increased, were definitely lower than in controls. This last result, given the increasing evidences of a direct implication of IGF-II in cancer, may further confirm the safety of rhGH replacement in adults with severe GHD as diagnosed by appropriate stimulation tests.

Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA): Comparison of Normative Reference Data for the General Population of England and Wales with Results for Adult Hypopituitary Patients with Growth Hormone Deficiency

Background/Aim:Age- and gender-specific reference values for the quality of life (QoL) measures used in assessing the impact of growth hormone deficiency (GHD) are important. The objective of this study was to develop such data for the QoL-AGHDA instrument for the population of England and Wales and to demonstrate the QoL deficit in patients with GHD. Methods: For the purpose of this study, a questionnaire was developed that contained the EurQoL EQ-5D, QoL-AGHDA, questions recording an individual’s general situation and social functioning, and a self-reported five-point rating scale of general health. The questionnaire was mailed out to a sample of 1,190 individuals drawn from the general population of England and Wales. Corresponding data for 836 patients were retrieved from KIMS (Pfizer International Metabolic Database). The postal survey data were weighted to ensure that they were representative of the general population. Results: The mean weighted QoL-AGHDA scores for the general population were 6.2 and 7.1 for men and women, respectively, compared with 13.6 and 15.7 for patients. For both males and females the differences in mean QoL-AGHDA scores between the general population and patients were statistically significant for all age categories (p < 0.01). In the general population the mean QoL-AGHDA score for each category of self-assessed health status increased progressively, indicating a poorer QoL as health status declined. Conclusions: This study reports QoL-AGHDA normative values for the population of England and Wales and confirms the extent of QoL impairment in patients with GHD in comparison with the general population.

Serum lipid levels in growth hormone-deficient men

To evaluate the impact of growth hormone deficiency (GHD) on lipid metabolism, serum lipid and apolipoprotein concentrations were measured in 64 GHD adult males (mean age, 27.1 ± 4.7 years). Results were compared with those obtained from an age- and sex-matched control group. Total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein (apo) B levels were significantly higher in GHD patients ( P < .001). In 14 patients (23%), total cholesterol concentration exceeded the 95th percentile for healthy adults. Total and LDL cholesterol were inversely related to plasma insulin-like growth factor-I (IGF-I). Apo B also tended to be negatively correlated with IGF-I; however, statistical significance was not reached ( P = .054). High-density lipoprotein (HDL) cholesterol and plasma triglyceride concentrations were within normal limits, whereas apo A-1 and A-2 levels were only slightly different from normal. We conclude that GHD in adulthood is associated with mild hypercholesterolemia due to an increased LDL cholesterol level. An inverse relationship was established between LDL cholesterol concentration and GH secretory status.

EFFECT OF TESTOSTERONE ON BONE MINERAL DENSITY (BMD) IN GROWTH HORMONE (GH) DEFICIENT RATS

The contribution of GH and sex steroids to attainment of peak bone mass are not clear and require longitudinal studies. We are examining the interactions between testosterone and GH on BMD using the GH deficient and GH sufficient rat models (Lewis strain). In the first part of study, forty male GH deficient rats were included with half the rats castrated at age 4 weeks and half remained as controls. All rats received identical diet and housing. BMD of total body, femur and lumbar spine (L1-L4) were measured from early adulthood at age 12 and 36 weeks, using Dual Energy X-ray Absorptiometry (DEXA, LUNAR) equipped with special software for small animals. This DEXA software was validated for small animals prior to the study. There was strong agreement between bone mineral content and ash weight for total body (r2=0.90) and femur (r2=0.83) in 17 rats with weight ranging from 146 to 212 grams. At age 12 weeks, there was no difference in total body, femur and L1-L4 BMD between two groups. However at 36 weeks, the castrated rats had significantly lower L1-L4 BMD compared to the controls (data not shown). From age 12 to 36 weeks, rats of both groups had significant increase in total body and femur BMD (left). The castrated group had no increase in L1-L4 BMD, which is significantly different from the control rats. We conclude that testosterone, even in the presence of GH deficiency, is critical for maintaining BMD of lumbar spine, which is predominantly trabecular bone. The impact of GH deficiency on BMD will be examined in the second part of study with GH deficient and sufficient models.