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The serine-threonine kinase Akt/PKB mediates stimuli from different classes of cardiomyocyte receptors, including the growth hormone/insulin like growth factor and the beta-adrenergic receptors. Whereas the growth-promoting and antiapoptotic properties of Akt activation are well established, little is known about the effects of Akt on myocardial contractility, intracellular calcium (Ca(2+)) handling, oxygen consumption, and beta-adrenergic pathway. To this aim, Sprague-Dawley rats were subjected to a wild-type Akt in vivo adenoviral gene transfer using a catheter-based technique combined with aortopulmonary crossclamping. Left ventricular (LV) contractility and intracellular Ca(2+) handling were evaluated in an isolated isovolumic buffer-perfused, aequorin-loaded whole heart preparations 10 days after the surgery. The Ca(2+)-force relationship was obtained under steady-state conditions in tetanized muscles. No significant hypertrophy was detected in adenovirus with wild-type Akt (Ad.Akt) versus controls rats (LV-to-body weight ratio 2.6+/-0.2 versus 2.7+/-0.1 mg/g, controls versus Ad.Akt, P, NS). LV contractility, measured as developed pressure, increased by 41\% in Ad.Akt. This was accounted for by both more systolic Ca(2+) available to the contractile machinery (+19\% versus controls) and by enhanced myofilament Ca(2+) responsiveness, documented by an increased maximal Ca(2+)-activated pressure (+19\% versus controls) and a shift to the left of the Ca(2+)-force relationship. Such increased contractility was paralleled by a slight increase of myocardial oxygen consumption (14\%), while titrated dose of dobutamine providing similar inotropic effect augmented oxygen consumption by 39\% (P

Very little is known about the atherosclerotic risk in patients with childhood-onset growth hormone deficiency (GHD). Such data may be relevant to reconstructing the natural course of the cardiovascular abnormalities associated with GHD. To this end, the intima-media thickness (IMT) of the carotid arteries and the vascular risk factors were evaluated in 14 childhood-onset GHD patients (age 25 +/- 1 yr, BMI 22 +/- 0.6 Kg/m2) and in 14 age-, sex-, and BMI-matched control subjects. IMT was greater in GHD patients (0.83 +/- 0.06 and 0.81 +/- 0.06 mmol/L for the right and left carotid artery) than in controls (0.64 +/- 0.03 and 0.64 +/- 0.04 mmol/L, P < 0.01 and P < 0.02, respectively). Serum total and lipoprotein cholesterol, and serum total triglycerides did not differ between the two groups. However, a significant increase in low density lipid triglycerides was present in GHD patients (0.27 +/- 0.02 mmol/L) compared with controls (0.19 +/- 0.01; P = 0.007). No difference was found in plasma fibrinogen and serum Lp(a) levels. Plasma glucose and insulin concentrations were similar in GHD and control subjects both in the fasted state and after an oral glucose load. In conclusion, young patients with childhood-onset GHD show an increased IMT in the absence of clear-cut abnormalities of the classic vascular risk factors. This suggests a role for GH deficiency per se in increasing the atherosclerotic risk.

The aim of the current study was to evaluate bone metabolism and mass before and after 2 years of GH replacement therapy in adults with childhood or adulthood onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and weight-matched healthy subjects entered the study. Biochemical indexes of bone turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine, of soft tissue formation such as aminoterminal propeptide of type-III and bone mineral density were evaluated. Childhood onset GH deficient patients had significantly decreased bone (osteocalcin: 2.5+/-1.3 vs 6.6+/-4.8 mcg/l, p

Acromegalic patients present an increase of osteoblastic and osteoclastic activity, showing a different effect on the axial and appendicular skeletal structures. At this regard controversial data about bone mineral density (BMD) have been published in literature. In fact an increase of BMD levels in femoral neck and Ward's triangle without any difference in lumbar spine has been described. On the other hand normal BMD levels at forearm and reduced BMD levels at lumbar spine were found. These patients seem to have a reduction of trabecular BMD similar to postmenopausal osteoporotic patients despite normal or slightly elevated cortical BMD. Recently, it has been described that cytokines, in particular tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), are implicated in the pathogenetic mechanism of postmenopausal osteoporosis. Taking into account that growth hormone (GH) can increase TNF-alpha and IL-1 secretion by mononuclear blood cells, the evaluation of possible relationship between the reduced BMD at lumbar spine and circulating cytokines levels was carried out in acromegalic patients. In addition we evaluated the effect of acute octreotide administration on serum TNF-alpha and IL-I concentrations. Eleven patients with active acromegaly and eleven healthy age-, sex-, weight- and heightmatched subjects were enrolled in this study. BMD was significantly reduced at lumbar spine (0.80 +/- 0.29 g/cm2 vs 1.02 +/- 0.11 g/cm2; p < 0.01), but not at femoral neck level or at Ward's triangle level (0.92 + 0.15 g/cm2 vs 0.97 + 0.11 g/cm2, p = NS; and 0.74 +/- 0.16 g/cm2 vs 0.85 +/- 0.1 g/cm2, p = NS) when compared to controls. Baseline serum levels of TNF-alpha and IL-1 were in the normal range both in patients and controls. After acute octreotide administration, no differences in circulating TNF-alpha and IL-1 levels were found. In conclusion, acromegalic patients present a reduced BMD at lumbar spine but not at femoral neck level and Ward's triangle. Circulating cytokines such as TNF-alpha and IL-1 are in the normal range. These data suggest that cytokines are not involved in the pathogenesis of GH-excess induced osteoporosis. The possibility that the GH excess might affect bone turnover inducing an increase of cytokines acting by a paracrine/autocrine mechanism cannot be ruled out.

Merola B, Longobardi S, Sofia M, Pivonello R, Micco A, Di Rella F, Esposito V, Colao A, Lombardi G. Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency. Effect of 12 months' growth hormone replacement therapy. Eur J Endocrinol 1996;135:553–8. ISSN 0804–4643 We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study. For each subject, evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, record of flow–volume curves, measurement of static lung volumes and lung diffusing capacity. Childhood-onset GH-deficient patients had a significant reduction of maximal inspiratory (p < 0.01) and maximal expiratory (p < 0.05) mouth pressures. Total lung capacity, vital capacity and functional residual capacity were significantly reduced compared to healthy subjects (p < 0.05). Conversely, residual volume and diffusing lung capacity did not show any significant change. No significant change of the ratio between the percentage forced expiratory volume in 1 s and the forced vital capacity was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. Adult-onset GH-deficient patients had only a significant reduction of maximal expiratory pressure compared to healthy subjects (p < 0.05). After 6 months of treatment no significant differences in any of the evaluated parameters were found. After 12 months of treatment patients with childhood-onset GH deficiency show a significant improvement of lung volumes (p < 0.01) and maximal respiratory mouth pressures (p < 0.005), whereas adult-onset GH-deficient patients show a significant improvement of maximal expiratory pressure (p < 0.05). In conclusion, the results of this study showed that adult patients affected with childhood-onset GH deficiency suffer from an impairment of the ventilatory function due to a reduction of lung volumes and a decrease of respiratory pressures probably due to a reduction of respiratory muscle strength. This impairment was reversed after 12 months of treatment with recombinant GH. Conversely, adult-onset GH-deficient patients had only an impairment of the maximal expiratory pressure, probably due to respiratory muscle weakness re-established after 12 months of GH therapy. Gaetano Lombardi, Via G. Santacroce 40/a, 80129 Naples, Italy

At present, the most appropriate method for diagnosing GH deficiency (GHD) in adults remains unclear. Recently, it has been demonstrated that GHD in adults can be identified by insulin tolerance test (ITT). Moreover, it has been described that the GHRH plus pyridostigmine (GHRH+PD) test is more accurate than an arginine, glucagon, levodopa, or GHRH test to diagnose GHD in adults. In the current study, firstly we reevaluated GH secretion by the GHRH+PD test in adults previously diagnosed as GH deficient in childhood. The study included 69 patients and 38 healthy subjects. After the GHRH+PD test, the patients and the healthy subjects had peak GH levels of 10.6 +/- 11.2 and 56.7 +/- 28.1 micrograms/L, respectively (P < 0.001). The patients were divided into two groups, responder patients and nonresponder patients, considering an arbitrary cut-off of 10 micrograms/L as the GH peak after the GHRH+PD test. Thirty-nine patients had GH peak below 10 micrograms/L (1.9 +/- 1.7 micrograms/L), whereas the remaining 30 patients above 10 micrograms/L (21.6 +/- 8.] micrograms/L; P < 0.001). Secondly, we compared the GHRH+PD test and the ITT in diagnosing GHD. Twenty-one of the 39 patients with a GH peak below 10 micrograms/L and 29 of the 30 patients with a GH peak above 10 micrograms/L after the GHRH+PD test underwent an ITT. The GH peak after insulin administration was 2.1 +/- 1.7 micrograms/L in nonresponder patients and 21.1 +/- 9.3 micrograms/L in responder patients after the GHRH+PD test (P < 0.001). Three of the responder patients to the GHRH+PD test were identified as GH deficient by the ITT. The relative diagnostic accuracies of the two tests to discriminate GH-deficient patients from healthy subjects were similar (ITT vs. GHRH test: sensitivity, 100%, specificity, 90%; GHRH+PD vs. ITT; sensitivity, 88%; specificity, 100%). In conclusion, in adults previously diagnosed as GH deficient, it is mandatory to reevaluate GH secretion. GHRH+PD and/or ITT are able to diagnose GHD in adults with similar accuracies. Taking into account the potential side-effects of the ITT, however, the GHRH+PD test is the most reliable and safe test to accurately diagnose GHD status in adults.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1150 Purpose. We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone responsive early breast cancer, within an ongoing phase 3 trial (HOrmonal adjuvant treatment BOne Effects – HOBOE, ClinicalTrial.gov id: [NCT00412022][1]). Patients and M ethods . Patients were randomised to receive tamoxifen or letrozole ± zoledronate. Serum values of 17-b-estradiol, FSH, LH, testosterone, dehydroepiandrosterone-solphate, progesterone, and cortisol were measured at baseline, after 6 and 12 months of treatment. For each hormone, baseline, 6 and 12-month values were compared between treatment groups, by the exact Wilcoxon-Mann-Whitney test. Results. At December 31, 2006, 157 postmenopausal patients had been enrolled into the study; baseline data were available for 139 patients (88.5%), 43 assigned to tamoxifen and 96 assigned to letrozole. Median age was 61 and 62 years in the two groups, respectively. Baseline values were similar between the two groups for all hormones. At 6 and 12 months, levels of 17-b-estradiol were significantly lower with letrozole as compared with tamoxifen (p=0.0003 and p