Dual-release hydrocortisone vs conventional glucocorticoids in adrenal insufficiency.

BACKGROUND: Dual-release hydrocortisone (DR-HC) improves metabolism in patients with adrenal insufficiency. The aims of this study were to compare the cardiovascular and metabolic effects of conventional glucocorticoids (GCs) vs. DR-HC and of high vs. low doses of GCs, after 48 months of observation. METHODS: We selected 27 patients on hydrocortisone (mean dose 17.5 ± 4.2 mg/day) and 20 patients on cortisone acetate (mean dose 37.5 ± 12.1 mg/day) who maintained this treatment (group A) and 53 patients switched to DR-HC (mean dose 22 ± 4.8 mg/day) (group B). At baseline and after 48 months, clinical and metabolic parameters and Framingham Risk Score (FRS) were obtained. RESULTS: After 48 months, patients in group A had a significant increase from baseline in BMI (P < 0.001), waist circumference (P = 0.001), systolic blood pressure (P = 0.001), LDL cholesterol (P = 0.018), HbA1c (P = 0.020) and FRS (P = 0.002). By contrast, patients in group B had a significant decrease in BMI (P = 0.002), waist circumference (P = 0.015), diastolic blood pressure (P = 0.031), total (P = 0.006) and LDL cholesterol (P = 0.005), HbA1c (P < 0.001) and FRS (P = 0.015) compared to baseline. No significant differences between high and low doses of both conventional GCs and DR-HC were observed. CONCLUSIONS: DR-HC is associated with an improvement of metabolic parameters and cardiovascular risk compared to conventional GCs, which are associated with a worsening of these parameters, regardless of the dose used.

Insulin sensitivity and secretion and adipokine profile in patients with Cushing's disease treated with pasireotide.

PURPOSE: To evaluate the effect of pasireotide on ß-cell and adipose function in patients with Cushing's disease (CD). METHODS: Clinical and hormonal parameters, insulin secretion evaluated by HOMA-ß and by the area under the curve (AUC2h) of C-peptide during a mixed meal tolerance test and insulin sensitivity, evaluated by the euglycaemic hyperinsulinaemic clamp, were evaluated in 12 patients with active CD, before and after 6 and 12 months of pasireotide. In addition, a panel of adipokines including leptin (Ob), leptin/leptin receptor ratio (Ob/Ob-R ratio), adiponectin, resistin, visfatin, adipocyte fatty acid binding protein (AFABP) and non-esterified fatty acids (NEFAs) was evaluated at baseline and after 12 months of pasireotide. RESULTS: During 12 months of pasireotide treatment, a significant decrease in weight (p = 0.004), BMI (p = 0.008), waist circumference (p = 0.009), urinary free cortisol (p = 0.007), fasting insulinaemia (p = 0.007), HOMA-ß (p = 0.015) and AUC2h c-peptide (p = 0.017), concomitance with an increase in fasting glycaemia (p = 0.015) and HbA1c (p = 0.030), was found. With regard to adipokines, a significant decrease in Ob (p = 0.039), Ob/Ob-R ratio (p = 0.017) and AFABP (p = 0.036) was observed concomitant with a significant increase in Ob-R (p = 0.028) after 12 months of pasireotide. CONCLUSIONS: 12 months of treatment with pasireotide in CD is associated with an impairment of insulin secretion and an improvement of adipose function without any interference in insulin sensitivity.

Pasireotide treatment reduces cardiometabolic risk in Cushing's disease patients: an Italian, multicenter study.

PURPOSE: Patients with Cushing's disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients. METHODS: This is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200-1800 mcg/daily). RESULTS: Before starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h-urinary free cortisol levels (p = 0.003), BMI (p < 0.001), waist circumference (p = 0.001), LDL-cholesterol (p = 0.033), total-cholesterol (p = 0.032), triglycerides (p = 0.030), VAI (p = 0.015), and ATD severity (p = 0.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (p = 0.015) and HbA1c levels (p = 0.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values. CONCLUSIONS: Twelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus.

Efficacy of combined treatment with pasireotide, pegvisomant and cabergoline in an acromegalic patient resistant to other treatments: a case report.

BACKGROUND: The approach to acromegalic patients with persistent acromegaly after surgery and inadequate response to first-generation somatostatin receptor ligands (SRLs) should be strictly tailored. Current options include new pituitary surgery and/or radiosurgery, or alternative medical treatment with SRLs high dose regimens, pegvisomant (PEG) as monotherapy, or combined therapy with the addition of PEG or cabergoline to SRLs. A new pharmacological approach includes pasireotide, a second-generation SRL approved for patients who do not adequately respond to surgery and/or for whom surgery is not an option. No reports on efficacy and safety of combined therapy with pasireotide and pegvisomant (PEG) in acromegaly are available. CASE PRESENTATION: Here we report the case of a 41-year-old acromegalic man with a mixed GH/PRL pituitary adenoma post-surgical resistant to first-generation SRLs both alone and in combination with cabergoline and PEG who achieved biochemical and tumor control with the combined triple treatment with pasireotide, PEG and cabergoline without adverse events and with a good compliance to treatment. CONCLUSIONS: Twelve months of therapy with pasireotide, PEG and cabergoline proved to be safe and effective in this particular patient and the clinical improvement of disease resulted in an improved compliance to treatment.

Correlation between adrenal function, growth hormone secretion, and insulin sensitivity in children with idiopathic growth hormone deficiency.

PURPOSE: Patients with growth hormone deficiency (GHD) demonstrate an increased cortisol/cortisone ratio which could potentially explain the metabolic features of GHD, while GH treatment (GHT) could increase the cortisol metabolism. METHODS: In 35 children (27 M, mean age 10.1 years) with idiopathic GHD at baseline and after 12 months of GHT and in 25 controls, in addition to metabolic parameters, we assessed adrenal function by morning serum cortisol, its peak, and its area under the curve (AUCCOR) during insulin tolerance test (ITT). RESULTS: A cortisol peak <18 µg/dl was shown in 22 and 31% of GHD children at baseline and after GHT, respectively. At baseline, GHD children had lower fasting glucose (p < 0.001) and ISI-Matsuda (p = 0.042), with concomitant higher Homa-IR (p = 0.006) and morning cortisol (p = 0.012) than controls. Morning cortisol was negatively correlated with GH (p < 0.001), fasting glucose (p < 0.001) and ISI-Matsuda (p < 0.001) and positively with Homa-IR (p = 0.010). Both cortisol peak and AUCCOR were negatively correlated with GH (all p < 0.001) and ISI-Matsuda (p = 0.016 and p = 0.001, respectively). After 12 months of GHT, a significant increase in fasting glucose (p < 0.001), and Homa-IR (p = 0.011) was documented, with a concomitant decrease in morning cortisol (p = 0.002), AUCCOR (p = 0.038), total (p = 0.003) and LDL-cholesterol (p = 0.016). No significant correlations were found among cortisol levels and all parameters were investigated. CONCLUSIONS: Cortisol levels correlate with GH secretion and with many metabolic parameters in GHD children, while the metabolic effects during GHT are mainly due to GHT per se and less to cortisol reduction.

One-hour post-load plasma glucose level is associated with a worse metabolic profile in children with GH deficiency.

PURPOSE: In children, the plasma glucose value at 1 h (1hPG) during OGTT higher than 132.5 mg/dl is a predictor of alterations in glucose metabolism. We aimed to metabolically characterize GHD children according to 1hPG levels. METHODS: Fifty-one GHD children (35 M, 16 F; mean age 8.6 years), grouped according to 1hPG, were evaluated at diagnosis and after 12 months of GH treatment (GHT) and compared with 50 matched controls at baseline. Auxological parameters, insulin-like growth factor-1 (IGF-1), glucose and insulin during OGTT, lipid profile, the oral disposition index (DIo), the homeostasis model assessment estimate of insulin resistance (Homa-IR), and the insulin sensitivity index (ISI) were evaluated. RESULTS: At baseline, 31.4% of GHD children and 12% of controls (p = 0.016) showed 1hPG ≥ 132.5 mg/dl. The first ones showed higher mean 1hPG (p = 0.025) and LDL cholesterol (p = 0.029) and lower HDL cholesterol (p = 0.014) than controls. GHD with higher 1hPG showed a significant decrease in DIo (p < 0.001) without improvement in lipid profile after GHT, compared with children with lower 1hPG. After 12 months, the higher 1hPG group showed lower ISI Matsuda (p = 0.047) and DIo (p < 0.001) than the lower 1hPG group. 1hPG levels proved to be positively correlated with Homa-IR (p = 0.010) and LDL cholesterol (p = 0.032) and negatively with ISI Matsuda (p = 0.001) and DIo (p = 0.019). The 1hPG value at baseline was the only independent variable significantly associated with DIo at 12 months (p = 0.041). CONCLUSIONS: 1hPG level at baseline may be a useful tool to identify and properly follow up children with enhanced metabolic risk who probably need more surveillance during GHT.

Vitamin D across growth hormone (GH) disorders: From GH deficiency to GH excess.

The interplay between vitamin D and the growth hormone (GH)/insulin-like growth factor (IGF)-I system is very complex and to date it is not fully understood. GH directly regulates renal 1 alpha-hydroxylase activity, although the action of GH in modulating vitamin D metabolism may also be IGF-I mediated. On the other hand, vitamin D increases circulating IGF-I and the vitamin D deficiency should be normalized before measurement of IGF-I concentrations to obtain reliable and unbiased IGF-I values. Indeed, linear growth after treatment of nutritional vitamin D deficiency seems to be mediated through activation of the GH/IGF-I axis and it suggests an important role of vitamin D as a link between the proliferating cartilage cells of the growth plate and GH/IGF-I secretion. Vitamin D levels are commonly lower in patients with GH deficiency (GHD) than in controls, with a variable prevalence of insufficiency or deficiency, and this condition may worsen the already known cardiovascular and metabolic risk of GHD, although this finding is not common to all studies. In addition, data on the impact of GH treatment on vitamin D levels in GHD patients are quite conflicting. Conversely, in active acromegaly, a condition characterized by a chronic GH excess, both increased and decreased vitamin D levels have been highlighted, and the interplay between vitamin D and the GH/IGF-I axis becomes even more complicated when we consider the acromegaly treatment, both medical and surgical. The current review summarizes the available data on vitamin D in the main disorders of the GH/IGF-I axis, providing an overview of the current state of the art.

Resistin, visfatin, leptin and omentin are differently related to hormonal and metabolic parameters in growth hormone-deficient children.

PURPOSE: The effect of growth hormone (GH) on adipose tissue and the role of adipokines in modulating metabolism are documented, but with discordant data. Our aim was to evaluate the impact of GH treatment on a series of selected adipokines known to have a metabolic role and poorly investigated in this setting. METHODS: This is a prospective study. Thirty-one prepubertal children (25 M, 6 F; aged 8.5 ± 1.6 years) with isolated GH deficiency treated with GH for at least 12 months and 30 matched controls were evaluated. Auxological and metabolic parameters, insulin sensitivity indexes, leptin, soluble leptin receptor, adiponectin, visfatin, resistin, omentin, adipocyte fatty acid-binding protein and retinol-binding protein-4 were evaluated before and after 12 months of treatment. RESULTS: At baseline, no significant difference in metabolic parameters was found between GHD children and controls, except for higher LDL cholesterol (p = 0.004) in the first group. At multivariate analysis, LDL cholesterol was independently associated with resistin (B 0.531; p = 0.002), while IGF-I was the only variable independently associated with visfatin (B 0.688; p < 0.001). After 12 months, a significant increase in fasting insulin (p = 0.008), Homa-IR (p = 0.007) and visfatin (p < 0.001) was found, with a concomitant decrease in LDL cholesterol (p = 0.015), QUICKI (p = 0.001), ISI Matsuda (p = 0.006), leptin (p = 0.015) and omentin (p = 0.003)]. At multivariate analysis, BMI was the only variable independently associated with leptin (B 0.485; p = 0.040). CONCLUSIONS: GH treatment modifies adipokine secretion and the perturbation of some adipokine levels could contribute to the clinical and metabolic changes observed during the follow-up.

Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance.

PURPOSE: Insulin resistance and compensatory hyperinsulinism are the predominant metabolic defects in polycystic ovary syndrome (PCOS). However, hyperinsulinism, as well as being compensatory, can also express a condition of reduced insulin clearance. Our aim was to evaluate the differences in insulin action and metabolism between women with PCOS (with normal glucose tolerance) and age- and BMI-matched women with prediabetes (without hyperandrogenism and ovulatory disorders). METHODS: 22 women with PCOS and 21 age/BMI-matched women with prediabetes were subjected to a Hyperinsulinemic-euglycemic clamp and an Oral Glucose tolerance Test (OGTT). Insulin sensitivity was assessed by the glucose infusion rate during clamp (M value); insulin secretion by Insulinogenic index, Oral Disposition Index (DIo) and AUC(2h-insulin) during OGTT; and insulin clearance by the metabolic clearance rate of insulin (MCRI) during clamp. RESULTS: Women with PCOS showed significantly higher levels of AUC(2h-insulin) (p < 0.011), Insulinogenic Index (p < 0.001), DIo (p = 0.002) and significantly lower levels of AUC(2h-glucos)e (p = 0.001). No difference was found between the two groups regarding insulin sensitivity (M value). Lower levels of MCRI were found in women with PCOS [420 (IQR 227-588) vs. 743 (IQR 597-888) ml m(-2) min(-1): p < 0.001]. Furthermore, in the PCOS group, a strong independent inverse correlation was only observed between MCRI and AUC(2h-insulin) (PCOS: ß:-0.878; p < 0.001; Prediabetes: ß:-0.501; p = 0.019). CONCLUSIONS: Our study suggests that in normoglycemic women with PCOS there is peripheral insulin sensitivity similar to that of women with prediabetes. What sets PCOS apart is the hyperinsulinism, today still simplistically defined "compensatory"; actually this is mainly related to decreased insulin clearance whose specific causes and dynamics have yet to be clarified.

Serum visfatin levels in acromegaly: Correlation with disease activity and metabolic alterations.

OBJECTIVE: The studies that have extensively evaluated the relation between adipokines and metabolic parameters in acromegaly treatment are quite discordant. We aimed to evaluate and correlate a set of selected adipokines, known to have a metabolic role, with the disease activity, metabolic status and treatment modalities. DESIGN: Data of 56 consecutive acromegalic patients (31 M and 25 F; aged 54 ± 12 years), admitted to the section of Endocrinology of the University of Palermo during the years 2005-2014, including 16 newly diagnosed untreated (ND), 21 during therapy with somatostatin analogues (SA), 12 with pegvisomant (PE) and 7 after surgical treatment (SU), grouped into uncontrolled (group A: No. 33) and controlled (group B: No. 23) were evaluated. Anthropometric and metabolic parameters, insulin sensitivity indexes, visceral adiposity index (VAI), leptin, soluble leptin receptor, adiponectin, visfatin, resistin, adipsin and non-esterified fatty acids (NEFAs) were assessed. In a subgroup of 21 subjects, the insulin sensitivity index (M value) derived from euglycemic clamp was calculated. RESULTS: Group A showed higher Homa-IR (p < 0.001), VAI (p < 0.001), triglycerides (p < 0.001), visfatin (p < 0.001), and NEFAs (p < 0.001) and lower ISI Matsuda (p < 0.001), M value (p < 0.001), HDL cholesterol (p < 0.001) and leptin (p < 0.001) than group B. ND patients showed higher VAI, triglycerides, Homa-IR, and visfatin and lower ISI Matsuda, M-value, and leptin compared to other groups (all p < 0.050), while no differences were found among SA, PE and SU patients. IGF-1 (p = 0.048), M-value (p = 0.0029) and VAI (p = 0.010) were independently associated with visfatin, while only ISI Matsuda (p = 0.019) was associated with leptin. CONCLUSIONS: In acromegaly visfatin could be considered a useful index of disease activity and metabolic alterations, such as insulin resistance and adipose dysfunction, regardless of the type of treatment.

Revaluation of the clinical and metabolic behavior of children with isolated growth hormone deficiency during GH treatment according to newly proposed note 39 of the Italian Medicines Agency (AIFA).

PURPOSE: This study aimed at evaluating the clinical and metabolic behavior of children with isolated growth hormone (GH)-deficiency (GHD), grouped according to the new AIFA criteria for the appropriateness of use and reimbursement of GH treatment in children. METHODS: The clinical and metabolic data of 310 prepubertal children (220 M, 90 F; mean age 10.8 years) grouped, according to new AIFA note 39, into Group A (No. 181 with a peak of GH <8 µg/l), Group B (No. 103 with a peak of GH ≥8 and <10 µg/l) and Group C (No. 26 with a peak of GH >10 µg/l) were retrospectively analyzed. Group A and B, diagnosed as having GHD, were treated with GH for at least 24 months, while Group C was analyzed only at baseline. RESULTS: At baseline, Group A showed higher waist circumference than B (p = 0.031) and C (p = 0.041), while no difference in metabolic parameters was found between the three groups. After 12 and 24 months of treatment, Group B showed lower height velocity (p < 0.001 and p = 0.049, respectively) than Group A. As regards the metabolic parameters, both after 12 and 24 months of treatment, in Group B we found higher fasting glucose (p < 0.001 and p = 0.020), insulin (p = 0.002 and p = 0.011), Homa-ß (p = 0.020 and p = 0.015) and Homa-IR (both p = 0.001) than Group A, with concomitant lower QUICKI (both p < 0.001) and HDL cholesterol (p = 0.020 and p = 0.011), without difference in other lipid parameters. The HbA1c levels, although always within the normal range, were found higher in Group B than Group A after 12 months (p = 0.015). CONCLUSIONS: According to the new AIFA criteria, the reduction of GH cut-off for GHD diagnosis can be supported by auxological and metabolic data. The real benefits from GH therapy in children with higher stimulated GH levels at diagnosis remains to be better understand.

Early lung function abnormalities in acromegaly.

BACKGROUND: Acromegaly is an insidious disorder caused by a pituitary growth hormone (GH)-secreting adenoma resulting in high circulating levels of GH and insulin-like growth factor I (IGF-I). Respiratory disorders are common complications in acromegaly, and can severely impact on quality of life, eventually affecting mortality. OBJECTIVES: The present study aimed to explore structural and functional lung alterations of acromegalic subjects. METHODS: We enrolled 10 consecutive patients (M/F: 5/5) affected by acromegaly. In all patients, magnetic resonance imaging (MRI) revealed the presence of pituitary tumor. All patients underwent clinical, lung functional, biological, and radiological assessments. Ten healthy age-matched subjects also served as controls. RESULTS: No statistically significant differences in lung function were detected between acromegalic and healthy subjects (p ≥ 0.05 for all analyses). However, the diffusing capacity for CO (TLCO) was significantly lower in the acromegalic group than in healthy subjects (TLCO% predicted: 78.1 ± 16 vs. 90 ± 6 %, respectively, p = 0.04; KCO% predicted: 77 ± 16 vs. 93 ± 5 %, p = 0.02, respectively). None of the lung function parameters correlated with duration of the disease, or with inflammatory marker of the airways. In acromegalics, biological (exhaled NO concentrations) and imaging (total lung volume, TLV, and mean lung density, MLD) evaluations were within normal values. The TLV measured by HRCT was 3540 ± 1555 ml in acromegalics, and the MLD was -711 ± 73 HU. None of the lung functional, radiological, and biological findings correlated with GH or IGF-I levels, and no correlation was found with duration of disease. CONCLUSIONS: In the current study, lung function evaluation allowed to detect early involvement of lung parenchyma, as assessed by TLCO and KCO, even in the absence of parenchymal density alterations of the lung by HRCT. These findings suggest to routinely include the carbon monoxide diffusing capacity in the lung function assessment for an early intervention in acromegaly.

Reduction in insulin sensitivity and inadequate ß-cell capacity to counteract the increase in insulin resistance in children with idiopathic growth hormone deficiency during 12 months of growth hormone treatment.

PURPOSE: To evaluate the performance of various indexes of insulin sensitivity and secretion and to identify the most useful indicator of deterioration of glucose metabolism in a cohort of children with growth hormone (GH) deficiency (GHD) during GH treatment. METHODS: In 73 GHD children (55 M, 18 F; mean age 10.5 years) at baseline and after 12 months of treatment, we evaluated a number of surrogate indexes of insulin secretion and sensitivity. In a subgroup of 11 children we also performed an euglycemic hyperinsulinemic clamp. RESULTS: After 12 months, a significant increase in fasting glucose (p < 0.001) and HbA1c levels (p < 0.001) was documented, despite all children remained with a normal glucose tolerance. With regard the insulin secretion, Homa-ß did not show any significant change (p = 0.073), while oral disposition index (DIo) showed a significant decrease (p = 0.031). With regard the insulin sensitivity, Homa-IR significantly increased (p < 0.001) with a concomitant decrease in QUICKI (p < 0.001). ISI Matsuda showed a decrease, although not statistically significant (p = 0.069). In the subgroup of 11 children, the M value derived from clamp showed a significant decrease (p = 0.011) and a significant positive correlation was found between M value and ISI Matsuda both at baseline (ρ 0.950; p = 0.001) and after 12 months (ρ 0.980; p = 0.001) but not with Homa-IR and QUICKI. CONCLUSIONS: 12 months of GH treatment lead to a decrease in insulin sensitivity and impairment in insulin secretion relative to insulin sensitivity even without evident changes in glucose tolerance. DIo has proven to be the most useful indicator of deterioration of glucose metabolism even in cases in which the overt glucose abnormalities have not yet appeared.

Corneal thickness in children with growth hormone deficiency: the effect of GH treatment.

OBJECTIVE: The eye represents a target site for GH action, although few data are available in patients with GH deficiency (GHD). Our aim was to evaluate central corneal thickness (CCT) and intraocular pressure (IOP) values in GHD children to assess the role played by GHD or GH treatment on these parameters. DESIGN: In 74 prepubertal GHD children (51M, 23F, aged 10.4±2.4years) we measured CCT and IOP before and after 12months of treatment. A baseline evaluation was also made in 50 healthy children matched for age, gender and body mass index. The study outcome considered CCT and IOP during treatment and their correlations with biochemical and auxological data. RESULTS: No difference in CCT and IOP between GHD children at baseline and controls was found (all p>0.005). GHD children after 12months of therapy showed greater CCT (564.7±13.1µm) than both baseline values (535.7±17µm; p<0.001) and control subjects (536.2±12.5µm; p<0.001), with a concomitantly higher corrected mean IOP (15.6±0.7mmHg; p<0.001) than both baseline (12.5±0.8mmHg; p<0.001) and controls (12.3±0.5mmHg; p<0.001), without correlation with auxological and biochemical parameters. CONCLUSIONS: 12months of GH treatment in children with GHD, regardless of auxological and biochemical data, affect CCT and IOP. Our findings suggest careful ocular evaluation in these patients to prevent undesirable side effects during the follow-up.

Correlation between severity of growth hormone deficiency and thyroid metabolism and effects of long-term growth hormone treatment on thyroid function in children with idiopathic growth hormone deficiency.

BACKGROUND/AIM: The significance of changes in thyroid function in children during growth hormone (GH) treatment remains uncertain. We aimed to evaluate the impact of GH replacement on thyroid status in children with idiopathic GH deficiency (GHD). METHODS: Data of 105 GHD children (82 M, 23 F; aged 11.13 years) during a 36-month follow-up were analyzed. At diagnosis the areas under the curve of GH (AUCGH) were calculated during a GH-releasing hormone + arginine (GHRH-Arg) and insulin tolerance test. RESULTS: A significant ΔfT3 (p < 0.001) was documented at 12 months, without any further change at 24 and 36 months and without fT4 and TSH modifications. Grouping patients according to ΔfT3 at 12 months into those with lower (n = 80, 76%) or greater values than the 75th percentile (n = 25, 24%), the latter showed lower AUCGH and GH peak during a GHRH-Arg (p = 0.018 and 0.014, respectively) and insulin tolerance test (p = 0.023 and 0.020, respectively) at diagnosis. In addition, children with lower GH at diagnosis showed a greater ΔfT3 at 12 months (p = 0.030). CONCLUSIONS: In GHD children, GH treatment is associated with a significant increase in fT3 in the first 12 months, more pronounced in patients with more severe GHD, highlighting the strong correlation between severity of GHD and thyroid metabolism.

High prevalence of hypovitaminosis D in Sicilian children affected by growth hormone deficiency and its improvement after 12 months of replacement treatment.

PURPOSE: Although the correlation between vitamin D and growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis is documented, as of date, few and conflicting studies have prospectively analyzed vitamin D before and after GH treatment. Our aim was to evaluate as to how the condition of GH deficiency (GHD) or GH treatment influences vitamin D in children. METHODS: Eighty Sicilian GHD children (M/F 58/22; mean age 10.3 years), grouped according to the season of evaluation in group A (June-September; 41 children) and group B (November-February; 39 children), were evaluated at baseline and after 12 months of GH treatment. RESULTS: Twenty-eight children (35 %) were vitamin D insufficient and 32 (40 %) deficient at baseline, and lower vitamin D levels were found in group B than in A (17.3 ± 5.3 vs. 31.1 ± 11.1 ng/ml; p < 0.001). A positive correlation between vitamin D and baseline GH levels (p < 0.001) was found. After 12 months, increased vitamin D was found both in all children (34.4 ± 16.4 vs. 24.5 ± 11.1 ng/ml; p = 0.002) and in group A (38.5 ± 14 vs. 31.1 ± 11.1 ng/ml; p < 0.001) and B (30 ± 17.7 vs. 17.3 ± 5.3 ng/ml; p < 0.001). Overall, only 25 (31 %) children remained insufficient and 15 (19 %) deficient, with an increase in prevalence of children with normal levels (p = 0.001). CONCLUSIONS: Our data demonstrated a very high prevalence of hypovitaminosis D in Sicilian GHD children, with an improvement after 12 months of GH treatment. Vitamin D assessment should therefore be considered routinely in GHD children both at diagnosis and during the follow-up.

No phenotypic differences for polycystic ovary syndrome (PCOS) between women with and without type 1 diabetes mellitus.

CONTEXT: Women with type 1 diabetes mellitus (DM1) have a higher prevalence of polycystic ovary syndrome (PCOS) than the general population. OBJECTIVE: The aim of this study was to clarify, in DM1 women with PCOS (PCOS-DM1), the influence of insulin therapy and glycemic control and evaluate the hormonal and phenotypic differences with age-matched and body mass index (BMI)-matched women with PCOS without diabetes. DESIGN, SETTING, AND PATIENTS: We evaluated 103 DM1 women with and without PCOS treated with intensive insulin therapy; 38 age-matched and BMI-matched women with PCOS without diabetes were compared in a cross-sectional study. OUTCOME MEASUREMENTS: Clinical, anthropometric, and metabolic parameters were evaluated. Hormonal evaluation and ovary ultrasound were performed during the follicular phase of the menstrual cycle. RESULTS: Applying the diagnostic criteria of the Androgen Excess Society, 38 (36.89%) women with DM1 showed PCOS. The 38 PCOS-DM1 women showed no differences in treatment and glycemic control compared with DM1 women without PCOS. The only difference was a higher visceral adiposity index in PCOS-DM1 (1.21±0.70 vs 0.90±0.32; P=.002). PCOS-DM1 showed no phenotypic differences with age-matched and BMI-matched PCOS without diabetes. The hormonal pattern was similar except that higher levels of Δ4androstenedione were found in PCOS-DM1 (12.89±3.49 vs 2.79±1.75 nmol/L; P=.010). CONCLUSIONS: The women with PCOS-DM1 do not exhibit particular phenotypic characteristics compared with nondiabetic women with PCOS. However, this pathological disorder must not be underestimated because it could be an additional cardiovascular risk factor in women with DM1.

The metabolic profile in active acromegaly is gender-specific.

CONTEXT: The sexual dimorphism of the somatotroph axis has been documented, but whether the acromegaly-related metabolic alterations are gender-dependent has never been investigated. OBJECTIVE: The aim of the study was to evaluate the impact of gender on the metabolic parameters in acromegaly. DESIGN: We conducted a retrospective, comparative, multicenter study. PATIENTS: The 307 newly diagnosed acromegalic patients included in the study were grouped by gender: 157 men (aged 48.01 ± 14.28 yr), and 150 women (aged 48.67 ± 14.95 yr; of which 77 were premenopausal and 73 postmenopausal). OUTCOME MEASUREMENTS: We measured each component of the metabolic syndrome (MS), hemoglobin A1c, the areas under the curve (AUCs) of glucose and insulin during 2-h oral glucose tolerance test, basal insulin resistance using the homeostasis model assessment of the insulin resistance index, stimulated insulin sensitivity using the insulin sensitivity index, early insulin-secretion rate using the insulinogenic index, ß-cell function relative to insulin sensitivity using the oral disposition index and the visceral adiposity index (VAI) as the surrogate of visceral fat function. RESULTS: Women showed a higher prevalence of MS (P < 0.001), higher fasting insulin levels (P < 0.001), AUC for insulin (P = 0.002), homeostasis model assessment of the insulin resistance index (P < 0.001), and VAI (P < 0.001) and a lower insulin sensitivity index (P = 0.002) than men, whereas no difference was found in fasting glucose, AUC for glucose, hemoglobin A1c, insulinogenic index, and oral disposition index. In women, fasting glucose and fasting insulin showed a significant trend toward increase (P < 0.001) and decrease (P = 0.004), respectively, from the first to the fourth quartiles of age, whereas VAI showed a trend toward increase in both groups (P < 0.001). A significantly higher prevalence of MS (P < 0.001), increased waist circumference (P < 0.001), low high-density lipoprotein cholesterol (P < 0.001), and overt diabetes mellitus (P < 0.001) was found in postmenopausal women compared with premenopausal women, as well as with men. CONCLUSIONS: The majority of metabolic features in acromegaly are gender-specific. Active acromegaly in women is strongly associated with higher visceral adiposity dysfunction, insulin resistance, and the features of MS. We suggest more accurate metabolic management in acromegalic women, especially in the postmenopausal years.

Visceral adiposity index is associated with insulin sensitivity and adipocytokine levels in newly diagnosed acromegalic patients.

CONTEXT: The visceral adiposity index (VAI) has proved to be a marker of visceral adipose dysfunction, strongly associated with insulin sensitivity in both the general and specific populations of patients at metabolic risk. OBJECTIVE: The objective of the study was to test VAI as a useful tool to assess early metabolic risk in acromegaly. PATIENTS: Twenty-four newly diagnosed acromegalic patients (11 women and 13 men, aged 54.9 ± 13.6 yr) were grouped into those with normal (group A, n = 13, 54.2%) and those with high VAI (group B, n = 11, 45.8%). OUTCOME MEASURES: Glucose, hemoglobin A1c, nadir and area under the curve (AUC) of GH (AUC(GH)) during the oral glucose tolerance test, AUC(Cpeptide) during a mixed-meal tolerance test, M value during euglycemic-hyperinsulinemic clamp, oral dispositional index (DIo), each component of the metabolic syndrome, leptin, adiponectin, TNF-α, and IL-6. RESULTS: The VAI value was positively correlated with the age of patients (ρ = 0.408; P = 0.048), tumor volume (ρ = 0.638; P = 0.001), basal GH (ρ = 0.622; P = 0.001), nadir GH (ρ = 0.534; P = 0.007), AUC(GH) (ρ = 0.603; P = 0.002), IGF-I (ρ = 0.618; P = 0.001), TNF-α (ρ = 0.512; P = 0.010), and AUC(Cpeptide) (ρ = 0.715; p<0.001) and negatively with adiponectin (ρ = -0.766; P < 0.001), M value (ρ = -0.818; P < 0.001), and DIo (ρ = -0.512; P = 0.011). Patients with high VAI showed significantly higher basal GH levels (P = 0.018), AUC(GH) (P = 0.047), IGF-I (P = 0.047), AUC(Cpeptide) (P = 0.018), lower M value (P < 0.001), DIo (P = 0.006), and adiponectin levels (P < 0.001), despite the absence of a significantly higher prevalence in the overt metabolic syndrome and glucose tolerance abnormalities. AUC(GH) proved to be the main independent factor influencing VAI. CONCLUSIONS: In acromegaly, VAI appears to be associated with disease activity, adiponectin levels, and insulin sensitivity and secretion and is influenced independently by GH levels. VAI could therefore be used as an easy and useful new tool in daily clinical practice for the assessment of early metabolic risk associated with active acromegaly.

Glycometabolic control in acromegalic patients with diabetes: a study of the effects of different treatments for growth hormone excess and for hyperglycemia.

BACKGROUND: Diabetes mellitus is frequently observed in patients with acromegaly. Current therapies for acromegaly may impact glucose regulation, influencing insulin sensitivity and secretion. The question whether these therapies modify control and progression of diabetes once present is still open. AIM: Aim of our study is to analyze glucose control in acromegalic patients with diabetes, evaluating the relation with treatments for GH excess and for diabetes. METHODS: Seventy patients with acromegaly and diabetes were studied. Duration and treatments of acromegaly and diabetes were recorded, together with clinical and metabolic parameters. RESULTS: Most patients (92.8%) were treated with somatostatin analogs (SSA), either alone or in combination with dopamine-agonists (20%) or pegvisomant (15.7%); 7.1% of patients had been treated by surgery alone. Metformin (65.7%), alone or in combination with other hypoglycemic drugs, was the most frequent treatment for diabetes, followed by insulin (21.5%). Only 15.7% were treated with diet alone. The whole cohort showed a very good control of diabetes and acromegaly. Median glycated hemoglobin was 6.4% (5.9-7). IGF-I was within normal range for age in most patients. No relation was observed between duration of acromegaly or diabetes and metabolic control. SSA had a negative effect on insulin secretion, but these effects did not influence glucose control. Finally, we observed a low prevalence of nephropathy (6%) and retinopathy (20%). CONCLUSIONS: Our study shows that a good control of hyperglycemia can be obtained with success in the majority of acromegalic patients with diabetes, independently of the type of treatment for GH excess.