Bone metabolism, bone mass and structural integrity profile in professional male football players.

BACKGROUND: Physical exercise plays an important role in bone mineralization as well as factors involved in bone metabolism influence the athletic performance. In European countries, soccer is the most popular sport. The aim of the study was to investigate bone metabolism, bone mass and structural integrity profile in professional male adult football players. METHODS: Sixteen professional male football players from a single team of the Second division Italian League (mean age 22.4±0.7 years) were enrolled. Bone biochemical parameters, including serum calcium, phosphorus, albumin, creatinine, alkaline phosphatase, intact plasma PTH, 25-hydroxy-vitamin D (25-OHD), 24-h urinary calcium and phosphorus, and calcaneal quantitative ultrasound (QUS), were evaluated at the beginning (October 2012) and at the end of the League (May 2013). RESULTS: 25-OHD levels were significantly lower at the end of the League compared to the beginning (27.1±5.9 vs. 36.6±9.5 ng/mL, fold change [FC]=0.25, P=0.008), and the prevalence of 25-OHD deficiency increased from 25% to 73%. Moreover, higher rate of previous bone, cartilage or ligament injuries correlated with 25-OHD deficiencies (P=0.014). T-score and Z-score were at the upper limits of the normality ranges, without significant difference between the beginning and end of the League. Phosphaturia was slightly decreased at the end of the League (691.0±364.5 vs. 934.0±274.3 mg/24h, FC=0.26, P=0.06). A significant correlation was found between phosphaturia and BQI (R2=0.28, P=0.03), and both T-s and Z-s (R2=0.28, P=0.03) at the beginning of the League. CONCLUSIONS: With this pilot study, we demonstrated that vitamin D status significantly worsened at the end of the League. Therefore, vitamin D supplementation might be suggested in adult football players in order to prevent vitamin D deficiency and improve the athletic performance.

Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours.

Pituitary tumours express both somatostatin and dopamine receptors. Medical treatment with somatostatin analogues is a cornerstone of GH- and TSH-secreting tumours, while treatment with dopamine agonists is a cornerstone of prolactin-secreting tumours. Dopamine agonists have also demonstrated some efficacy in patients with GH- and TSH-secreting adenomas. Neither ACTH-secreting nor clinically non-functioning tumours have a well-established medical treatment. Nevertheless, some recent results have indicated a potential usefulness of the dopamine agonist cabergoline in patients with pituitary-dependent Cushing's disease. Combination treatment with both somatostatin analogues and dopamine agonists has been poorly investigated. Some studies conducted in small series have documented an additive effect of both drugs in patients with GH-secreting adenomas. Of mention is that none of the studies were randomised and cross-sectional so that the results should be confirmed by other well-designed studies. No data are available in other pituitary tumour histotypes. Preliminary observations in patients with clinically non-functioning adenomas are very promising.

Oral and maxillofacial manifestations of Gardner's syndrome associated with growth hormone deficiency: case report and literature review.

Gardner's syndrome (GS) is a hereditary disorder inherited as autosomal dominant with complete penetrance and variable expression. GS is a variant of familial adenomatous polyposis characterized by extracolonic manifestations including osteomas, dental anomalies, and epidermoid cysts. The association between GS and endocrine abnormalities has been well documented but a direct pituitary involvement has never been reported. We present a case of oral and maxillofacial manifestations in an adult patient affected by GS associated with growth hormone deficiency, a hitherto unreported association. The possible pathogenic mechanisms are discussed.

Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study.

BACKGROUND: The pituitary tumour transforming gene (pttg) plays a central role in pituitary tumorigenesis, but PTTG protein expression is poorly documented and its relationship with tumour cell proliferation and the prognosis of pituitary adenomas is unclear. AIM: The aim of this study was to evaluate the immunohistochemical expression of PTTG and Ki-67 in 45 human pituitary adenomas according to the tumour histotype, aggressiveness and persistence/recurrence status. PATIENTS AND METHODS: The tumours comprised 37 macroadenomas and 8 microadenomas. Twenty patients experienced disease persistence or recurrence after transsphenoidal surgery. Disease recurrence was observed in 16 patients, 8-72 months after surgery. RESULTS: No PTTG or Ki-67 expression was detected in normal pituitary tissue. In pituitary adenomas, tumour nuclei were positive for PTTG and Ki-67 in 89 and 98% of samples, respectively, and there was a strong correlation between the expression of the two proteins (P < 0.001). By the ROC curves method, a PTTG score of 3.3% was the best cut-off for distinguishing between recurrent and nonrecurrent pituitary adenomas (P < 0.05; sensitivity 60%; specificity 76%). A 2.9% cut-off was obtained for both PTTG (P < 0.01; sensitivity 77%; specificity 71%) and Ki-67 (P < 0.05; sensitivity 85%; specificity 64%) among patients with more than 1 year of follow-up. Neither PTTG nor Ki-67 expression was influenced by the maximal tumour diameter, tumour grade, age, gender or presurgical medical treatment. Both PTTG and Ki-67 tumour score > 2.9% identified a subgroup of patients with a significantly higher recurrence-free interval (P < 0.01). By multivariate analysis, a > 2.9% Ki-67 tumour score was the best predictor of pituitary tumour persistence/recurrence after surgery (chi(2) = 8.2, P < 0.01). CONCLUSION: PTTG is expressed in approximately 90% of pituitary tumours of different histotypes but with a high variability from one case to another. As expected, PTTG expression parallels that of Ki-67 and both are correlated to a more aggressive behaviour. However, a 2.9% Ki-67 cut-off proved to be the most reliable biological marker for predicting the recurrence potential of these tumours, when an adequate postsurgical follow-up is considered.

Sulfur amino acids in Cushing's disease: insight in homocysteine and taurine levels in patients with active and cured disease.

BACKGROUND: Cushing's syndrome is associated with an increased cardiovascular risk. Although a series of cardiovascular risk factors have been identified, sulfur amino acids (SAAs), recently indicated as independent cardiovascular risk factors, have been poorly investigated in patients with Cushing's syndrome. AIM: The aim of this cross-sectional controlled study was to evaluate serum and urinary levels and urinary excretion rate (ER) of SAAs in patients with Cushing's disease (CD) during the active disease and after long-term disease remission. SUBJECTS AND METHODS: Forty patients with CD (20 with active disease and 20 with cured disease for at least 5 yr) and 40 controls entered the study. Serum and urinary concentrations and urinary ER of SAAs, namely methionine, cystine, homocysteine, and taurine, were measured by means of cationic exchange HPLC. Serum folic acid and vitamin B12 levels were also evaluated in patients and controls and correlated to SAA levels. RESULTS: CD patients with active disease had higher serum and urinary concentrations of cystine and homocysteine, and lower serum and higher urinary concentrations and ER of taurine than cured patients and controls. Vitamin B12 levels were significantly decreased in patients with active disease compared with cured patients and controls, whereas folic acid levels were slightly decreased in patients than in controls. In patients with active CD, urinary cortisol concentrations were significantly and inversely correlated to serum taurine and directly correlated to taurine urinary ER, and fasting serum glucose levels were significantly correlated to taurine urinary ER. At the multiple regression analysis, urinary cortisol concentrations were the best predictors of taurine ER. CONCLUSIONS: CD is associated with hyperhomocysteinemia and hypotaurinemia. Glucocorticoid excess, acting directly or indirectly, seems to be the most responsible for this imbalance in SAA levels. The long-term disease remission is accompanied by normalization of SAA levels. Hyperhomocysteinemia and hypotaurinemia might contribute to the increased cardiovascular risk of CD.

The severity of growth hormone deficiency correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: an observational, case-control study.

In 100 patients with hypopituitarism and 80 sex- and age-matched healthy subjects, we correlated the severity of cardiac impairment to the severity of GH deficiency (GHD). By the GH peak after arginine plus GHRH test (normal > 16.5 microg/liter), the patients were classified as severe GHD (n = 56), partial GHD (n = 27), and non-GHD (n = 17). Compared with controls, decreased left ventricular ejection fraction at rest was found only in severe GHD patients (55.0 +/- 8.8 vs. 63.4 +/- 4.5%, P < 0.001); decreased left ventricular ejection fraction response on effort in severe (-4.6 +/- 17.4 vs. 15.2 +/- 9.1%, P < 0.001) and partial GHD patients (3.6 +/- 6.6 vs. 14.6 +/- 8.3%, P < 0.001); decreased diastolic filling at rest in severe (2.53 +/- 0.68 vs. 3.01 +/- 0.48 end-diastolic volume per second, P < 0.001) and partial GHD (2.61 +/- 0.45 vs. 2.89 +/- 0.54 end-diastolic volume per second, P = 0.004) patients; and decreased exercise duration and capacity in all the patient groups. A normal systolic performance on effort was found in 21.4% of severe GHD, 55.6% of partial GHD, all non-GHD, and 93.7% of controls. A normal diastolic filling at rest was found in 57.1% of severe GHD, 74.1% of partial GHD, 76.5% of non-GHD, and 90% of controls. In conclusion, cardiac performance is correlated with the GH status because significant impairment was found in patients with severe and partial GHD but not in non-GHD hypopituitary patients.

Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency.

OBJECTIVE: To investigate the role of IGF-1 on intima-media thickness (IMT) at common carotid arteries by Doppler ultrasonography. SUBJECTS: Thirty-nine patients (17 women, 22 men, aged 25-70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF-1 levels, and 39 sex-, age- and body mass index (BMI)-matched healthy controls. RESULTS: Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0.88 +/- 0.26 vs. 0.69 +/- 0.14 mm, P < 0.001), and systolic and diastolic peak velocity (P < 0.001) compared to controls. Eight patients (18%) and one control (2.1%, P = 0.04) had well-defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0.78, P < 0.001). In both controls (r = -0.82; P < 0.0001) and patients with GHD (r = -0.84, P < 0.0001), serum IGF-1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH-deficient patients were total cholesterol levels (t = 5.2, P < 0.001), followed by disease duration (t = 2.4, P = 0.02), while in controls the variables most significantly related to IMT were IGF-1 levels (t = -9.9, P < 0.001), followed by low density lipoprotein (LDL)-cholesterol levels (t = -2.3, P = 0.02). Compared to patients with normal IGF-1 levels, those with low IGF-1 levels had lower high density lipoprotein (HDL)-cholesterol levels (1.0 +/- 0.2 vs. 1.3 +/- 0.2 mmol/l, P = 0.0002), and higher glucose (54.3 +/- 6.1 vs. 48.9 +/- 5.9 mmol/l, P = 0.008), insulin (25.2 +/- 6.8 vs. 18.8 +/- 6.0 mUl/l, P = 0.004), total cholesterol (7.1 +/- 1.1 vs. 4.9 +/- 0.6 mmol/l, P < 0.0001), total/HDL-cholesterol ratio (7.2 +/- 1.8 vs. 3.9 +/- 0.7, P < 0.0001), fibrinogen levels (319.8 +/- 56.9 vs. 241.8 +/- 53.0 mg/dl, P < 0.0001) and mean IMT at common carotid arteries (1.05 +/- 0.25 vs. 0.69 +/- 0.07 mm, P < 0.0001). Atherosclerotic plaques were found only in GH-deficient patients with low IGF-1 levels. CONCLUSIONS: GH-deficient patients have alterations in lipid profile with an increase in the total/HDL-cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF-1 deficiency have increased IMT.

Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment.

The aim of this study was to correlate dopamine receptors and D(2) isoform expression with the cabergoline effect on alpha-subunit secretion in vitro and tumor mass in vivo in clinically nonfunctioning pituitary tumors. Eighteen patients were subjected to neurosurgery, and a tumor sample was used for dopamine receptor and D(2) isoform expression evaluation by RT-PCR and the in vitro functional studies. After neurosurgery, nine of 18 patients with persistent tumor were treated with cabergoline and tumor mass was evaluated before and after 1 yr treatment. D(2) receptor was expressed in 67% of cases. D(2long) was found in 50%, D(2short) in 17%, and both D(2) isoforms in 33% of cases. D(4) receptor was also expressed in 17% of cases. The in vitro inhibition of alpha-subunit concentration was found in 56% of cases and was associated with D(2) expression (chi(2) = 5.6; P < 0.05). After 1 yr of cabergoline treatment, tumor shrinkage was evident in 56% of patients and was associated with D(2) expression (chi(2) = 5.6; P < 0.05). The expression of D(2short) rather than D(2long) isoform is associated with the most favorable response of the tumor to cabergoline treatment. In conclusion, this study demonstrates D(2) receptor expression and function in nearly 70% of cases, suggesting a role of this drug in the treatment schedule of clinically nonfunctioning pituitary tumors.

Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing's disease during active disease and 1 year after disease remission.

Cardiovascular accidents represent the most important cause of death in patients with Cushing's syndrome. This prospective study aims at evaluating carotid arteries by echo-Doppler ultrasonography and clinical and metabolic markers of atherosclerosis in 25 patients with Cushing's disease (CD) before and after 1 yr of remission. Thirty-two sex- and age-matched subjects (control-1) and 32 body mass index-matched subjects (control-2) served as controls. At diagnosis, CD patients had higher body mass index, waist to hip ratio (WHR), total, low-density lipoprotein-cholesterol and total/high-density lipoprotein (HDL) ratio, glucose and insulin, as well as lower HDL-cholesterol than control-1; they had higher WHR and total/HDL ratio and lower HDL-cholesterol than control-2. They also had higher intima-media thickness (IMT), and lower systolic lumen diameter and distensibility coefficient (DC) than either control group. Atherosclerotic plaques were detected in 31.2% of patients, 0 control-1, and 6.2% of control-2 subjects. One year after remission, WHR, LDL-cholesterol, and IMT significantly decreased, whereas systolic lumen diameter and DC significantly increased. However, all of the above parameters were still abnormal compared with control-1, but not control-2. A significant correlation was found between WHR, glucose and insulin levels, and right and left carotid IMT. WHR was the best predictor of left IMT and left DC in active, but not in cured, patients. The duration of hypercortisolism was the best predictor of right DC in active but not in cured patients. In conclusion, patients with CD have severe atherosclerotic damage. The persistence of a metabolic syndrome, vascular damage, and atherosclerotic plaques after cortisol level normalization makes these subjects still at high cardiovascular risk despite disease remission.

Somatostatin analogs in treatment of non-growth hormone-secreting pituitary adenomas.

Besides well-known effects in GH-secreting adenomas, somatostatin analogs such as octreotide and lanreotide have been used in TSH-secreting adenomas and in the so-called clinically nonfunctioning adenomas. The rationale for their use is based on the evidence that both these tumor types express large amounts of somatostatin receptor subtypes 2 and 5, which are preferentially bound by octreotide and lanreotide. However, whether in TSH-secreting adenomas the results are excellent in the nonfunctioning type, the results are controversial. Some preliminary results showing a very rapid recovery of the visual field have not been confirmed subsequently. No evident effect of tumor shrinkage has been reported. At present, the use of somatostatin analogs in clinically nonfunctioning adenomas is questioned.

Nephrolithiasis in Cushing's disease: prevalence, etiopathogenesis, and modification after disease cure.

The pathogenesis of nephrolithiasis in Cushing's syndrome is still not completely clarified. The current study aimed at investigating prevalence of nephrolithiasis and role of different lithogenic factors in Cushing's disease (CD). Forty-six CD patients (24 with active and 22 with cured disease) and 46 sex- and age-matched controls entered the study. Body mass index, blood pressure, fasting glucose and insulin, serum and urinary creatinine, urea, uric acid, electrolytes, and cystine, urinary volume, pH, oxalate, and citrate levels, and renal ultrasonography (US) were performed in all patients and controls. Nephrolithiasis was found in 50% of active patients, 27.3% of cured patients, and 6.5% of controls (P < 0.001). Compared with controls, patients with active disease had a significantly increased prevalence of obesity, arterial hypertension, diabetes mellitus, hypercalciuria, hypocitraturia, and hyperuricosuria, significantly higher levels of serum and urinary cystine, urinary creatinine, urea, uric acid, potassium, calcium, phosphorus, and oxalate, significantly lower levels of urinary citrate levels. Compared with controls, patients cured from CD had a significantly increased prevalence of obesity, systemic arterial hypertension, and diabetes mellitus, whereas urinary citrate was significantly decreased. At multivariate analysis, a significantly increased risk to develop kidney stones was independently associated with urinary excretion of uric acid (odds ratio = 1.6, confidence interval = 1.0-2.5) and systemic arterial blood pressure (odds ratio = 2.6, confidence interval = 1.1-6.6). In conclusion, patients with active CD have an increased prevalence of nephrolithiasis compared with general population, which decreases but not disappears in patients successfully cured from the disease. This complication is likely caused by the synergic effect of different hypercortisolism-dependent metabolic and hemodynamic abnormalities, among which systemic arterial hypertension and excessive urinary uric acid excretion seem to play a pivotal role.

Effect of growth hormone (GH) and/or testosterone replacement on the prostate in GH-deficient adult patients.

The prostate is a target organ of the GH and IGF-I axis because prostate hypertrophy is found in acromegaly, reduced prostate size is found in GH deficiency (GHD) patients, and additionally, IGF-I is reported to be a positive predictor factor of prostate cancer. To investigate whether GH replacement therapy in adult patients with GHD has adverse effects on the prostate, we studied the effect of 12-month GH or GH plus testosterone replacement on prostate pathophysiology in 24 adult patients with GHD (11 euandrogenemic and 13 hypoandrogenemic), compared with 24 age-matched healthy controls. At study entry, GHD patients had lower prostate volume than controls (19.4 +/- 1.7 vs. 24.9 +/- 1.7 ml; P = 0.03). After 12 months of treatment, all hypoandrogenemic patients achieved normal testosterone levels, and prostate volume increased in the patients to the same level as controls (25.0 +/- 1.9 ml). The percentage increase in prostate volume was greater in hypoandrogenemic patients receiving both GH and testosterone replacement (51 +/- 11%) than in those receiving GH replacement alone (15 +/- 3%; P < 0.0009). At baseline, prostate volume was similar in GHD patients below or above 60 yr of age (16.8 +/- 1.3 vs. 23 +/- 3.6 ml; P = 0.08), whereas after treatment it was higher in the latter patients (21.8 +/- 1.2 vs. 29.5 +/- 3.9 ml; P = 0.04). Prostate-specific antigen (PSA) and free PSA did not change, whereas PSA density was significantly reduced after treatment in hypoandrogenemic patients; there was also no change in calcifications, cysts, or nodules. In conclusion, GH replacement restores prostate size to normal in both young and elderly patients, with no increase in prostate abnormalities. Because the simultaneous treatment with GH and testosterone induces an increase of prostate size by 50% of baseline on average, care is suggested in elderly patients with prostate hyperplasia to avoid any risk of prostate symptoms. In these cases, GH replacement might be performed sequentially to reduce the hypertrophic effect of combining GH and testosterone.

Influence of growth hormone on cardiovascular health and disease.

Experimental and clinical studies indicate that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are involved in heart development. Impaired cardiovascular function, as recently demonstrated, could potentially reduce life expectancy both in GH deficiency (GHD) and excess. Patients with childhood- or adult-onset GHD may have both cardiac structural and functional abnormalities, i.e. reduced cardiac mass, reduced diastolic filling, and impaired left ventricular response to peak exercise. In addition, GHD patients may present with an increase in vascular intima-media thickness and a higher occurrence of atheromatous plaques that can further aggravate the hemodynamic conditions and contribute to the increased cardiovascular and cerebrovascular risk. However, some evidence has been provided to show that cardiovascular abnormalities can be partially reversed after somatropin (recombinant GH) therapy in patients with GHD. Recently, somatropin administration was shown to induce improvement in hemodynamics and clinical status in some patients with heart failure. Although these data need to be confirmed in more extensive studies, such promising results open new perspectives for somatropin therapy. The role of GH secretagogues in heart failure is still unknown.