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Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.

Cushing's disease (CD) is a severe endocrine condition caused by an adrenocorticotropin (ACTH)-pro- ducing pituitary adenoma that chronically stimulates adrenocortical cortisol production and with potentially serious complications if not or inadequately treated. Active CD may produce a fourfold increase in mortality and is associated with significant morbidities. Moreover, excess mortality risk may persist even after CD treatment. Although predictors of risk in treated CD are not fully understood, the importance of early recognition and ade- quate treatment is well established. Surgery with resection of a pituitary adenoma is still the first line therapy, being successful in about 60-70 % of patients; however, recur- rence within 2-4 years may often occur. When surgery fails, medical treatment can reduce cortisol production and ameliorate clinical manifestations while more definitive therapy becomes effective. Compounds that target hypo- thalamic-pituitary axis, glucocorticoid synthesis or adre- nocortical function are currently used to control the deleterious effects of chronic glucocorticoid excess. In this review we describe and analyze the molecular basis of the drugs targeting the disease at central level, suppressing ACTH secretion, as well as at peripheral level, acting as adrenal inhibitors, or glucocorticoid receptor antagonists. Understanding of the underlying molecular mechanisms in CD and of glucocorticoid biology should promote the development of new targeted and more successful therapies in the future. Indeed, most of the drugs discussed have been tested in limited clinical trials, but there is potential ther- apeutic benefit in compounds with better specificity for the class of receptors expressed by ACTH-secreting tumors. However, long-term follow-up with management of per- sistent comorbidities is needed even after successful treatment of CD.

Guidelines for the management of osteoporosis induced by endogenous hypercortisolism are not available. Both the American College of Rheumatology and the International Osteoporosis Foundation recommend to modulate the treatment of exogenous glucocorticoid-induced osteoporosis (GIO) based on the individual fracture risk profile (calculated by FRAX) and dose of glucocorticoid used, but it is difficult to translate corticosteroid dosages to different degrees of endogenous hypercortisolism, and there are no data on validation of FRAX stratification method in patients with endogenous hypercortisolism. Consequently, it is unclear whether such recommendations may be adapted to patients with endogenous hypercortisolism. Moreover, patients with exogenous GIO take glucocorticoids since suffering a disease that commonly affects bone. On the other hand, the correction of coexistent risk factors, which may contribute to increase the fracture risk in patients exposed to glucocorticoid excess, and the removal of the cause of endogenous hypercortisolism, may lead to the recovery of bone health. Although the correction of hypercortisolism and of possible coexistent risk factors is necessary to favor the normalization of bone turnover with recovery of bone mass; in some patients, the fracture risk could not be normalized and specific anti-osteoporotic drugs should be given. Who, when, and how the patient with endogenous hypercortisolism should be treated with bone-active therapy is discussed.

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

ObjectiveAccording to the 2015 American Thyroid Association (ATA) guidelines, thyroid ablation by iodine-131 (I-131) therapy is absolutely recommended only in patients with high-risk differentiated thyroid cancer (DTC). Often distant metastases are not recognized early and they can stay silent for long time. The aim of our study was to retrospectively analyze the prevalence of metastatic disease before and after I-131 and to evaluate the influence of the new ATA guidelines in the management of DTC.MethodsWe retrospectively analyzed 140 patients showing distant metastases. All metastases were detected by whole-body scan after I-131 and confirmed by histology and/or other imaging modalities.ResultsIn 26/140 patients metastases were detected before I-131, while in 114/140 were discovered after I-131. Comparing patients with metastases detected before and after I-131, no differences were demonstrated considering age, sex, histotype, tumor size, multifocality of cancer and metastatic localization. Metastatic DTC discovered before radioiodine had higher thyroglobulin and received a higher radioiodine total activity and number of treatments. Considering patients with distant metastases, according to the 2015 ATA guidelines, 38 patients would have been categorized as high risk, 22 as low risk and 80 as intermediate risk. Among intermediate-risk patients, only in 25 cases (31%) I-131 treatment would have been appropriate according to 2015 ATA recommendations; in the remaining 56 cases (69%), I-131 would not have been recommended.ConclusionsAccording to the 2015 ATA guidelines, most of metastatic patients would not have been treated after surgery, with the risk of late diagnosis and delayed treatment.

In women monitored for thyroid carcinoma, short-term stimulation with rhTSH induced an acute decrease in serum C-telopeptides of type-1 collagen and an increase in serum BALP levels without any effect on OPG production. The inhibitory effect of TSH on bone resorption occurred only in postmenopausal women who showed low BMD and a high bone turnover rate as an effect of L-thyroxine suppressive therapy. INTRODUCTION: It has been recently shown that thyrotropin (TSH) has an inhibitory activity on skeletal remodeling in in vitro conditions. Here, we have aimed at evaluating whether TSH has similar effects in vivo. For this purpose, we have evaluated the sequential profile of serum bone metabolism markers during acute stimulation with recombinant human TSH (rhTSH) in thyroidectomized women monitored for thyroid carcinoma. MATERIALS AND METHODS: The study group included 66 thyroidectomized patients, of whom 38 were premenopausal and 28 postmenopausal, who underwent routine rhTSH-assisted whole body radioactive iodine scanning for differentiated thyroid carcinoma. The patients were sequentially evaluated for TSH, free triiodothyronine (FT3), free thyroxine (FT4), bone alkaline phosphatase (BALP), C-telopeptides of type-1 collagen (CrossLaps), and osteoprotegerin (OPG) levels during rhTSH stimulation. The samples were drawn just before and 2 and 7 days after the first administration of rhTSH. BMD was evaluated by ultrasonography at baseline. Seventy-one healthy women (41 premenopausal and 30 postmenopausal) acted as a control group. RESULTS AND CONCLUSIONS: At study entry, all patients had subclinical thyrotoxicosis as effect of L-thyroxine (L-T4) treatment. The patients had higher serum CrossLaps and OPG levels and lower BMD than healthy subjects. Postmenopausal patients showed comparable serum FT4 and FT3 concentrations with those found in premenopausal patients. However, postmenopausal patients showed higher serum CrossLaps (p < 0.001), OPG (p = 0.03), and BALP (p < 0.001) levels and lower BMD (p < 0.001) than those measured in premenopausal patients. Two days after the first administration of rhTSH, all patients had serum TSH values >100 mUI/liter. At this time, serum CrossLaps levels decreased significantly (p < 0.001) and BALP values increased (p = 0.001) with respect to the baseline values in postmenopausal but not in premenopausal patients. rhTSH did not induce any significant change in serum OPG values either in premenopausal or in postmenopausal patients. One week after the first rhTSH administration, serum CrossLaps values decreased again to values comparable with those measured at baseline, whereas serum BALP values remained high. This study shows that subclinical thyrotoxicosis is accompanied by high bone turnover rate with an increase in serum OPG levels compared with euthyroid healthy subjects. Acute increase in serum TSH levels is accompanied by a reversible inhibition of bone resorption. This effect is characterized by a decrease in serum CrossLaps and an increase in BALP levels without any evident effect on OPG production. The activity of TSH occurs specifically in postmenopausal women in whom the negative effects of L-T4 suppressive therapy on bone mass and metabolism are more marked compared with premenopausal women.

Objective The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. Participants The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. Evidence This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. Consensus Process Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system. Conclusions Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.

Background Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting. Objective To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly. Study design Retrospective, longitudinal study including 9 tertiary care endocrine units. Patients and Methods Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ± 13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132). Results During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P Conclusions Bone active drugs may prevent VFs in patients with active acromegaly.

Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for acromegaly is targeted at decreasing GH and insulin-like growth hormone 1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant) and radiotherapy. However, despite all these treatments option, approximately 50% of patients are not adequately controlled.In this paper, the authors discuss: 1) efficacy and safety of current medical therapy 2) the efficacy and safety of the new multireceptor-targeted somatostatin ligand pasireotide 3) medical treatments currently under clinical investigation (oral octreotide, ITF2984, ATL1103), and 4) preliminary data on the use of new injectable and transdermal/transmucosal formulations of octreotide.This expert opinion supports the need for new therapeutic agents and modalities for patients with acromegaly.

Background Bone loss and high risk of fractures have been reported in patients with primary hyperthyroidism, whereas data on skeletal health in TSH-secreting adenoma (TSH-oma) are scant, and the risk of fractures in this specific clinical context has not been investigated so far. In this cross-sectional study, we aimed at evaluating for the first time, to our knowledge, the prevalence and determinants of radiological vertebral fractures (VFs) in patients with TSH-oma. Methods Twenty-two patients (10 males, 12 females; median age 47 years) with TSH-oma and 44 patients (20 males, 24 females; median age 49 years) with nonfunctioning pituitary adenoma (NFPA) were retrospectively evaluated for thoracic VFs using a morphometric approach on lateral chest X-ray routinely performed in the presurgical diagnostic workup. Results The prevalence of VFs was significantly higher in TSH-oma vs NFPA (59.1% vs 22.7%; P = 0.003), the difference being still significant (odds ratio, 10.5; P = 0.005) after correction for the size of pituitary adenomas and biochemical parameters. In TSH-oma, the prevalence of VFs was significantly associated with older age (P = 0.007) and higher serum free T4 values (P = 0.02). In 20 patients, data on presurgical medical therapies of TSH-oma were available. All patients not treated with somatostatin receptor ligands were fractured compared with 25% of those who were treated with these drugs (P = 0.001). No significant (P = 0.25) association between VFs and treatment with methimazole was found. Conclusions This study provides the first evidence, to our knowledge, that patients with TSH-oma may develop VFs in close relationship with severity of hyperthyroidism.

Acromegalic osteopathy is an emerging complication of acromegaly, characterized by high bone turnover, profound deterioration in trabecular and cortical bone microstructure, all of which leading to increased risk of vertebral fractures (VFs). The abnormalities of bone quality in acromegaly are not captured by Dual energy X-ray Absorptiometry (DXA) measurement of bone mineral density (BMD), since VFs may occur even in patients with normal or minimally decreased BMD. The purpose of this article is to provide an update on clinical and therapeutic aspects concerning acromegalic osteopathy.

Vitamin D is a target of chronic exposure to glucocorticoid excess, which is the cause of a severe form of secondary osteoporosis. Glucocorticoids affect Vitamin D metabolism at different levels of the enzymatic cascade, thereby decreasing the synthesis of active Vitamin D and impairing its biological action at the tissue level. Moreover, glucocorticoids may directly counteract peripheral effects of Vitamin D, decreasing intestinal calcium absorption and favoring renal calcium loss with consequent negative calcium balance. Therefore, the use of Vitamin D and calcium is mandatory in patients exposed to glucocorticoid excess, although some peculiarities of this treatment should be taken into account to avoid under-treatment of hypovitaminosis D in the specific clinical context of glucocorticoid-induced osteoporosis. This chapter deals with pathophysiological, clinical, and therapeutic aspects of hypovitaminosis D in patients exposed to glucocortoicoid excess.

Introduction: Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long-standing active acromegaly undergoing treatment with Pegvisomant. Subjects and methods: Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed. Results: Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site. Conclusion: Vertebral fractures are a frequent complication of long-standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism.

Purpose of Review: This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD). Recent Findings: Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term. On the other hand, emerging drugs used in the treatment of CD, such as the novel somatostatin analog pasireotide, may have direct effects on glucose homeostasis regardless of control of cortisol excess. Summary: Diabetes mellitus is a frequent and early complication of CD with important diagnostic, prognostic and therapeutic implications. Specifically, diagnosis of CD in patients with diabetes may be difficult due to potential misinterpretation of markers of cortisol hypersecretion. Moreover, diabetes mellitus is often difficult to be controlled in CD requiring a careful and dedicated therapeutic approach. Finally, the coexistence of diabetes may influence the therapeutic decision making in CD, since drugs used in this setting may variably influence glucose homeostasis regardless of control of hypercortisolism.

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Glucocorticoids modulate the secretion of growth hormone (GH) by various and competing effects on the hypothalamus and pituitary gland. The final effects of this modulation depend on hormone concentrations and the duration of exposure. The traditional hypothesis is that chronically raised levels of glucocorticoids suppress the secretion of GH. However, a functional impairment of the GH reserve might also be observed in patients with low levels of glucocorticoids, such as those with secondary hypoadrenalism, which is consistent with the model of biphasic dose-dependent effects of glucocorticoids on the somatotropic axis. This Review updates our current understanding of the mechanisms underlying the effects of glucocorticoids on the secretion of GH and the clinical implications of the dual action of glucocorticoids on the GH reserve in humans. This Review will also address the potential diagnostic and therapeutic implications of GH for patients with a deficiency or excess of glucocorticoids.

ObjectiveHeart failure (HF) has been associated with increased risk of fragility fractures. Indeed, most literature data on fractures were based on an historical and clinical approach focused on the identification of peripheral fractures, whereas the risk of vertebral fractures in this clinical setting is still unclear.DesignCross-sectional study.AimTo evaluate the prevalence and determinants of radiological thoracic vertebral fractures in patients with HF.MethodsThe study includes 1031 elderly hospitalized patients (491 females and 540 males; median age, 75 years; range, 65–90; 430 patients with HF) who were evaluated for the presence of thoracic vertebral fractures by quantitative morphometric analysis, using chest X-ray routinely performed in the diagnostic work-up of HF.ResultsVertebral fractures were found in 166 patients (16.1%), the prevalence being significantly higher in patients with HF as compared with those without HF, both in females (30.9 vs 15.8%; PP=0.001). The association between HF and vertebral fractures remained statistically significant (odds ratio, 2.14; 95% CI, 1.25–3.66; P=0.01) even after adjustment for age, sex, loop diuretic therapy, anticoagulant therapy, proton pump therapy, coexistent chronic obstructive pulmonary disease, diabetes mellitus, renal insufficiency, and chronic liver diseases. In patients with HF, vertebral fractures were positively correlated with female sex, duration of HF, ischemic heart disease, cigarette smoking, and treatment with anti-osteoporotic drugs, and inversely correlated with left ventricular ejection fraction.ConclusionsHospitalized patients suffering from HF are at higher risk of vertebral fractures than patients without HF in the same clinical context.

Diabetes mellitus is a frequent complication of acromegaly, a disease characterized by chronic hypersecretion of growth hormone (GH) by a pituitary adenoma. Diabetes occurs commonly but not only as a consequence of an insulin-resistant state induced by GH excess. The development of diabetes in patients with acromegaly is clinically relevant, since such a complication is thought to increase the already elevated cardiovascular morbidity and mortality risk of the disease. Emerging data suggest that a specific cardiomyopathy can be identified in acromegaly patients with diabetes. Moreover, the presence of diabetes may also influence therapeutic decision making in acromegaly, since traditional and newly developed drugs used in this clinical setting may impact glucose metabolism regardless of control of GH hypersecretion.

Acromegaly is a rare disease associated with significant morbidity and increased mortality. Treatment of acromegaly aims at controlling growth hormone hypersecretion, improving patients' symptoms and comorbidities and normalizing mortality. The therapeutic options for acromegaly include surgery, medical therapies and radiotherapy. However, despite all these treatment options, approximately one-half of patients are not adequately controlled. Progress in molecular research has made possible to develop new therapeutic strategies to improve control of acromegaly. This article will review the new medical approaches to acromegaly which consist in evolution of traditional therapeutic protocols and development of new molecules with different profiles of activity.

The aim of this longitudinal study was to evaluate the echocardiographic outcome of acromegalic heart disease in patients undergoing different therapeutic approaches, in order to investigate whether SSA could provide therapeutic advantages as compared with neurosurgery. In total of 36, consecutive patients undergoing SSA treatment after neurosurgery were enrolled in this study (Gr.Surg.-SSA). After 12 months of treatment, 21 patients had a controlled disease, while the remaining 15 patients displayed uncontrolled disease. Twelve acromegalic patients who did not undergo SSA treatment due to controlled disease after neurosurgery were enrolled as control group (Gr.Surg). The echocardiographic-Doppler study was performed before neurosurgery and after 12-months of follow-up. After follow-up, a significant reduction in serum GH and IGF-I values, Left Ventricular Mass index (LVMi) and LVH rate with an improvement in diastolic function was observed in both groups of patients. We found a significant reduction of LVMi either in patients with controlled disease or in those with poorly controlled disease undergoing SSA treatment. Diastolic function and of LVH percentage improved in all groups, but significantly so only in controlled patients, no significant difference in any echocardiographic parameters and in the prevalence of the LVH rate were observed between the three groups of patients at the end of follow-up. Therefore, our data appear to show that for echographic parameters medical treatment additive beneficial effects is compared to neurosurgery alone. SSA also appears to contribute to the improvement of acromegalic cardiomyopathy also in patients who did not achieve biochemical control of the disease.

Several recent studies have reported beneficial effects of pegvisomant monotherapy on glucose homeostasis for acromegalic patients resistant to somatostatin analogs (SSA). The aim of our longitudinal study was to test whether these beneficial effects on glucose homeostasis would also occur during combined pegvisomant + SSA treatment amongst partially SSA-resistant acromegalic patients. Ten non-diabetic, partially SSA-resistant acromegalic patients underwent a 12-month SSA+pegvisomant treatment after SSA-only therapy. Glucose homeostasis was evaluated at disease diagnosis, at the end of the SSA treatment and after 6 and 12 months of combined SSA+pegvisomant treatment. The addition of pegvisomant treatment was accompanied by a significant improvement in insulin and glycemic responses to the oral glucose tolerance test, without any significant changes in fasting plasma glucose, glycosylated haemoglobin, homeostatic model assessment-derived insulin resistance index and homeostatic model assessment-derived beta-cell function. Moreover, the number of patients with glucose intolerance did not significantly change during the 12-month combined treatment, notwithstanding the significant decrease in serum IGF-1 values. Therefore, our findings suggest that the combined pegvisomant and SSA treatment may not be able to restore normal clinical and biochemical glycometabolic features occurring in acromegalic patients resistant to SSA, while a slight but significant improvement in some biochemical features may be expected.

Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (1 microg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.

Aim: To evaluate serum osteoprotegerin (OPG) concentrations in relation to age-dependent changes in serum markers of bone metabolism and systemic inflammation. Methods: Two-hundred and eighty-three healthy subjects were evaluated for plasma estimated crea-tinine clearance (Cr-clearance), C-reactive protein (CRP), bone alkaline phosphatase, C-telopeptides of type-1 collagen (CrossLaps), nuclear factor-kappaB ligand (RANKL) and OPG concentrations. Results: In adult subjects (82 cases aged between 27 and 64 years) serum OPG concentrations were significantly and independently correlated with RANKL and Cr-clearance (R2: 0.29), but not with CRP and biochemical markers of bone metabolism. In old subjects who were between 65 and 84 years of age (52 cases) serum OPG concentrations were significantly higher as compared with the adult subjects and correlated independently and significantly with serum RANKL, Cr-clearance and CrossLaps values (R2: 0.63). The highest OPG values were found in the long-lived subjects (149 cases with ages between 85 and 110 years) who also showed increased serum CrossLaps and CRP concentrations as compared with the younger subjects. However, in the long-lived subjects serum OPG concentrations were significantly and independently correlated with Cr-clearance and CRP (R2: 0.45) but not with CrossLaps values. Conclusions: These data would suggest that different factors might be responsible for the age-dependent enhancement of OPG production. Bone metabolism would seem to be the most important factor influencing serum OPG concentrations in old subjects under 85 years of age, whereas in long-lived subjects the circulating values of this cytokine seem to be mainly correlated with serum CRP which could be a marker of inflammation and cardiovascular risk.

This cross-sectional study shows that a high number of untreated adult patients with GHD develop radiological vertebral deformities. Patients undergoing GH replacement treatment showed a significantly lower prevalence of vertebral deformities versus treated patients in the presence of similar BMD, as assessed by DXA. Introduction: In this cross-sectional study, we investigated whether the prevalence and degree of spinal deformities in adults with growth hormone deficiency (GHD) were related to the age of patients, degree of bone turnover, BMD, and recombinant human GH (rhGH) replacement therapy. Materials and Methods: One hundred seven adult hypopituitary patients (67 males and 40 females; mean age, 47 years; range: 16–81 years) with severe GHD and 130 control subjects (39 males, 91 females; mean age: 58.9 years; range: 26–82 years) were evaluated for BMD (DXA) and vertebral deformities (quantitative morphometric analysis). At study entry, 65 patients were on replacement therapy with rhGH, whereas 42 patients had never undergone rhGH. Results: Vertebral fractures were significantly more frequent in GHD patients versus control subjects (63.6% versus 37.7%; χ2 15.7; p < 0.001). The fracture prevalence, as well as the fracture number, was significantly higher in untreated versus treated patients (78.6% versus 53.8%; χ2: 6.7; p = 0.009), although the two groups of patients did not show any significant difference in median T score. In untreated GHD patients, the prevalence of vertebral deformities was correlated with T score (p = 0.002) and duration of disease (p = 0.003). In treated GHD patients, the prevalence of spinal deformities was correlated only with the timing of the beginning of rhGH replacement. Conclusions: This cross-sectional study reports high prevalence of vertebral radiological deformities in adult patients with untreated GHD. The replacement treatment of GHD leads to a significant decrease in fracture rate.

This cross-sectional study shows that high numbers of postmenopausal women with acromegaly develop vertebral fractures in relation to the activity of disease. In patients with active acromegaly, vertebral fractures occur even in presence of normal BMD, whereas in patients with controlled acromegaly, vertebral fractures are always accompanied by a pathological BMD.We studied the frequency of radiological vertebral fractures in a cohort of postmenopausal women with active or controlled acromegaly.Thirty-six postmenopausal acromegalic patients (15 with active and 21 with controlled disease) were evaluated for BMD, bone metabolism (serum 25-hydroxyvitamin D, PTH, bone-specific alkaline phosphatase [BSALP], and urinary deoxypyridinoline [Dpd]), and vertebral quantitative morphometry. Thirty-six nonacromegalic postmenopausal women, matched for age, were selected among the patients consulting the Bone Center as a control group for BMD evaluation and vertebral quantitative morphometry.Vertebral fractures were shown in 19 patients (52.8%) and 11 controls (30.6%; chi2: 3.7; p=0.06). Fractured acromegalic women were older and had higher serum IGF-1, Dpd, and BSALP and lower T score and serum vitamin D values compared with nonfractured patients. Moreover, the fractured women had a longer diagnosis and were in the postmenopausal period for a longer period than the nonfractured women. The fracture rate was significantly higher in active than in controlled acromegaly (80% versus 33.3%; chi2: 7.6; p=0.008). The patients with active acromegaly who fractured (12 cases) had significantly higher serum IGF-1 values (356 ng/ml; range: 212-950 versus 120 ng/ml; range: 84-217; p0.001) and T scores (-1.3 SD, range: -2.9 to +1.3 versus -2.7 SD, range: -3.4 to -1.5, p=0.04) compared with the fractured women whose disease was controlled (7 cases). All fractured women with controlled acromegaly had T scores-1.0 SD (57.1% of them had osteoporosis, and 42.9% were osteopenic). In contrast, 41.7% of women whose fractures were associated with active disease had a normal T score (-1.0 SD), whereas osteopenia and osteoporosis were found only in 33.3% and 25.0% of them, respectively.This cross-sectional study shows that high numbers of postmenopausal women with acromegaly develop vertebral fractures in relation to the activity of disease. Furthermore, our study shows that, in patients with active acromegaly, vertebral fractures occur even in the presence of normal BMD, whereas in patients with controlled acromegaly, vertebral fractures are always accompanied by a pathological BMD.

Cerebrospinal fluid (CSF) levels of rT(3) were evaluated in 21 euthyroid patients with overt Alzheimer's disease (AD) and 18 matched healthy controls. The assessment also included transthyretin and total T(3) and T(4) CSF concentrations. Despite normal circulating thyroid hormone levels, AD subjects showed significantly increased rT(3) levels and an increased rT(3) to T(4) ratio in the face of unchanged CSF total T(4) and transthyretin levels. These results suggest an abnormal intracerebral thyroid hormone metabolism and possibly the occurrence of brain hypothyroidism, either as a secondary consequence of the ongoing process or as a cofactor in the progression of the disease.

In this study, we have investigated in vivo the time-dependent effects of TSH on vascular endothelial growth factor (VEGF) production in patients monitored for thyroid carcinoma. Serum VEGF, thyroglobulin (Tg), and TSH levels were assayed at baseline and 6, 24, 30, 48, 72, and 96 h and 1 wk after administration of recombinant human TSH (rhTSH) in 45 thyroidectomized patients affected by differentiated thyroid carcinoma. At baseline, the patients with metastasis ( 18 cases) showed serum Tg and VEGF values significantly higher than those seen in the cured patients ( 27 cases). During rhTSH stimulation, the mean VEGF levels decreased significantly in both patient groups. In 60% of patients with metastasis, VEGF nadir occurred at the same time as serum TSH reached the highest values, whereas in 85.7% of the cured patients VEGF decreased after the TSH peak ( P = 0.003). In conclusion, we demonstrate for the first time that short-term administration of rhTSH in patients monitored for differentiated thyroid carcinoma induces a significant reduction in serum VEGF values even in the absence of thyroid tissue. This result would suggest that TSH may be able in vivo to regulate VEGF production from tissues other than the thyroid gland

NTRODUCTION: Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. However, this peculiarity may become a weakness in some patients with tumors harboring somatostatin receptors different from the subtype 2. Another clinically relevant aspect related to the use of octreotide LAR and lanreotide ATG is the burden of injectable drug regimen that may adversely impact the quality of life of patients with acromegaly and NETs. AREAS COVERED: The authors review the recently published evidence on novel drugs targeting somatostatin receptors developed for treating acromegaly and NETs. Within this article, the authors discuss: i) the pharmacology of somatostatin and traditional somatostatin analogs; ii) the efficacy and safety of multireceptor-targeted somatostatin analogs in acromegaly and NETs; iii) the efficacy of chimeric molecules in acromegaly and NETs; iv) the preliminary data on the use of new injectable, oral and transdermal formulations of octreotide in acromegaly. EXPERT OPINION: The development of new somatostatin analogs and new formulations has opened a new scenario for treatment of acromegaly and NETs. That being said, even though there have been big steps taken in the development of new therapies for acromegaly, there are still a number of unresolved issues, while more trials are necessary for the use of somatostatin anaologs in the treatment of NETs.

ObjectiveIn this study, we aimed at evaluating the association between radiological vertebral fractures and levo-thyroxine (l-T4) replacement doses in adult patients with hypopituitarism.DesignCross-sectional study.MethodsWe studied 74 adult hypopituitary patients (males, 43; females, 31; mean age, 57 years; and range, 23–79) with central hypothyroidism treated with l-T4 (median daily dose: 1.1 μg/kg). All patients also had severe GH deficiency (GHD) and 38 of them were replaced with recombinant GH. Vertebral fractures were assessed by a quantitative morphometric analysis performed on thoracic and lumbar spine lateral X-ray.ResultsRadiological vertebral fractures were found in 23 patients (31.1%) in association with untreated GHD (P=0.02), higher serum free T4 levels (P=0.03), a higher daily dose of l-T4 (P=0.005), and a longer duration of hypopituitarism (P=0.05). When GHD was treated, the prevalence of vertebral fractures was more frequent (P=0.03) in patients receiving high l-T4 doses (third tertile: >1.35 μg/kg per day) as compared with patients who were treated with lower drug doses (first tertile: l-T4 daily doses. Multivariate analysis showed that untreated GHD (odds ratio: 4.27, 95% CI 1.27–14.33; P=0.01) and the daily dose of l-T4 (odds ratio: 4.01, 95% CI 1.16–14.39; P=0.03) maintained a significant and independent association with vertebral fractures in patients with central hypothyroidism.ConclusionsOur data suggest for the first time that a relative overtreatment with l-T4 may influence the fracture risk in some patients with hypopituitarism.

This study investigated the bone of HIV patients both in terms of quantity and quality. It was found that HIV-infected patients did fracture independently of the degree of bone demineralization as in other forms of secondary osteoporosis.We aimed to determine the prevalence of vertebral fractures (VFs) in HIV patients who were screened by bone mineral density (BMD) and to explore possible factors associated with VFs.This is a cross-sectional study that included HIV-infected patients recruited in the Clinic of Infectious and Tropical Diseases and that underwent BMD measurement by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and hip (Lunar Prodigy, GE Healthcare). For the assessment of VFs, anteroposterior and lateral X-ray examinations of the thoracic and lumbar spines were performed and were centrally digitized. Logistic regression models were used in the statistical analysis of factors associated with VFs.One hundred thirty-one consecutive patients with HIV infection (93 M, 38 F, median age 51 years; range, 36-75) underwent BMD measurement: 25.2 % of patients showed normal BMD, while 45 % were osteopenic and 29.7 % osteoporotic. Prevalence of low BMD (osteopenia and osteoporosis) was higher in females as compared to males (90 vs 69 %) with no significant correlation with age and body mass index. VFs occurred more frequently in patients with low BMD as compared to patients with normal BMD (88.5 vs. 11.4 %; p 0.001) without any significant difference between osteopenia and osteoporosis (43 vs. 46 %; p = 0.073). VFs were significantly associated with older age and previous AIDS events.These results suggest a BMD-1 threshold to identify patients at risk of skeletal fragility and, therefore, good candidates for morphometric evaluation of spine X-ray in line with other forms of secondary osteoporosis with impaired bone quality.

Thyroid autoimmunity and dysfunction are a well known side effect of IFN alpha therapy for viral hepatitis and tumors, while the IFN beta effects on the thyroid gland in neurological patients have not been studied. The aim of this longitudinal study was to look for the appearance of thyroid autoimmunity as well as for the occurrence of overt thyroid disease in the patients affected by multiple sclerosis (MS) treated with IFN beta 1b. Eight patients (4 males, 4 females) undergoing r-IFN beta 1b treatment (8 M.U. every other day for 9 months) for relapsing remitting multiple sclerosis entered the study. We have analyzed thyroid function parameters and auto antibody levels before and after 1, 2, 3, 6 and 9 months of therapy. None of them referred to familiar thyroid pathology or presented clinically overt thyroid disease except for one patient (case 4) who showed TPO-Ab pretreatment positivity and another (case 8) who was in therapy with Levothyroxine 100 microg/die for multinodular goiter. The number of patients with appearance of thyroid antibodies has slowly increased, until the third month of therapy with 3 patients out of 7 positive for TPO-Ab. The only case of overt thyroid dysfunction reported by us appeared after nine months of therapy and consisted of a hypothyroidism. Our data suggest that short-term interferon beta treatment is able to induce thyroid autoimmunity (42.8%) and dysfunction (12.5%).

Acromegaly is a rare disorder characterized by excess secretion of growth hormone (GH) generally caused by a pituitary macroadenoma and associated with reduced life expectancy if the disease is untreated. This article covers the recent available evidences published on octreotide , the first somatostatin analog introduced into clinical practice for the medical treatment of acromegaly.This article discusses i) pharmacology of somatostatin and octreotide; ii) biochemical effects of regular octreotide and long-acting repeatable formulation; iii) tumor shrinkage effects of octreotide in acromegaly; iv) impact of octreotide on acromegalic clinical manifestations and chronic complications; v) safety of octreotide and vi) place of octreotide in the guidelines for acromegaly treatment. Full-text articles in the English language were selected from a PubMed search spanning 1984 - 2013, for keywords including 'octreotide,' 'acromegaly,' 'GH,' 'IGF-I,' and 'tumor shrinkage.' Reference lists in selected papers were also used to broaden the search.Octreotide is a mature drug with a consolidated favorable benefit versus risks profile in the treatment of acromegaly.

Context: There is experimental but limited clinical evidence that FSH may have direct effects on bone. Objective: The aim of the study was to evaluate the effects of acute FSH stimulation on bone turnover in premenopausal women. Design and Setting: We conducted a prospective study at a referral center. Patients: Twenty-nine infertile women (age range, 30 – 40 yr) undergoing an in vitro fertilization procedure were included in the study. Interventions: Pharmacological suppression of endogenous gonadotropin and estradiol (E2) pro- duction by GnRH analog (leuprolide 1 mg/d sc) was followed by stimulation with recombinant FSH (rFSH; starting dose, 375 IU/d sc). Main Outcome Measures: We measured serum osteocalcin, C-telopeptides of type-1 collagen (-CTX), FSH, and E2 at the beginning of leuprolide administration (T0), at the beginning of rFSH administration (T1), and 3 d (T2) and 10 d (T3) after the first dose of rFSH. Results: At T1, the suppression of FSH and E2 secretion, as an effect of leuprolide administration, led to a significant increase in serum -CTX values vs. T0 (P 0.001). After the administration of rFSH, a rapid increase in serum FSH was observed, whereas serum E2 values increased more slowly. At T2, the increase in serum FSH values above our reference range for early follicular phase (with E2 in the reference range) did not induce any significant change in median serum -CTX values as compared to T1. At T3 (when both FSH and E2 were high), serum -CTX values decreased signif- icantly vs. T1 (P 0.001). Osteocalcin did not change significantly throughout the study period. Conclusions: Our model suggests that FSH does not acutely exert relevant direct effects on bone metabolism in premenopausal women.

BACKGROUND: The long-acting somatostatin analogue octreotide is used either as an adjuvant or primary therapy to lower growth hormone (GH) levels in patients with acromegaly and may also induce pituitary tumor shrinkage. OBJECTIVE: We performed a meta-analysis to accurately assess the effect of octreotide on pituitary tumor shrinkage. DATA SOURCES: A computerized Medline and Embase search was undertaken to identify potentially eligible studies. STUDY ELIGIBILITY CRITERIA: Eligibility criteria included treatment with octreotide, availability of numerical metrics on tumor shrinkage and clear definition of a clinically relevant reduction in tumor size. Primary endpoints included the proportion of patients with tumor shrinkage and mean percentage reduction in tumor volume. DATA EXTRACTION AND ANALYSIS: The electronic search identified 2202 articles. Of these, 41 studies fulfilling the eligibility criteria were selected for data extraction and analysis. In total, 1685 patients were included, ranging from 6 to 189 patients per trial. For the analysis of the effect of octreotide on pituitary tumor shrinkage a random effect model was used to account for differences in both effect size and sampling error. RESULTS: Octreotide was shown to induce tumor shrinkage in 53.0% [95% CI: 45.0%-61.0%] of treated patients. In patients treated with the LAR formulation of octreotide, this increased to 66.0%, [95% CI: 57.0%-74.0%). In the nine studies in which tumor shrinkage was quantified, the overall weighted mean percentage reduction in tumor size was 37.4% [95% CI: 22.4%-52.4%], rising to 50.6% [95% CI: 42.7%-58.4%] with octreotide LAR. LIMITATIONS: Most trials examined were open-label and had no control group. CONCLUSIONS: Octreotide LAR induces clinically relevant tumor shrinkage in more than half of patients with acromegaly.

To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.

Age-related co-morbidities including osteoporosis are relevant in patients responding to combination antiretroviral therapy (cART). Vertebral fractures are common osteoporotic fractures and their diagnosis is useful for managing at-risk individuals. However, there are few data from HIV-infected patients. Therefore, the aim of this study was to determine the prevalence of and factors associated with vertebral fractures in a population of HIV-infected males. A cross-sectional study of 160 HIV-infected patients with available chest X-rays was conducted from 1998 to 2010. One hundred and sixty-three males with comparable age and with no history of HIV infection were recruited as controls. Semi-quantitative evaluation of vertebral heights in lateral chest X-rays and quantitative morphometry assessment of centrally digitized images using dedicated morphometry software were utilized to detect prevalent vertebral fractures. The result showed that the vertebral fractures were detected in 43/160 (26.9%) HIV-infected patients and in 21/163 (12.9%) controls (P = 0.002). In HIV-infected patients with fractures, 27 had two or more fractures and ten patients had severe fractures. The prevalence of any fractures and multiple fractures in HIV-infected patients receiving cART (29.6 and 20.0%) was slightly higher than in HIV-infected patients not exposed to cART (17.1 and 5.7%), but significantly higher than control subjects (12.9 and 3.7%). At multivariable analyses, body mass index and diabetes mellitus were independently correlated with vertebral fractures in HIV-infected patients. We concluded that a significant proportion of HIV-infected males receiving cART showed vertebral fractures. Furthermore, proactive diagnosis of vertebral fragility fractures is particularly relevant in patients who are overweight or suffer from diabetes.

Data on osteoporotic fractures in hyperprolactinemia are limited. An increased prevalence of radiological vertebral fractures was recently observed in women with prolactin (PRL)-secreting adenoma, whereas it is unknown whether this observation may reflect a more general increased risk of fractures in this disease and whether the prevalence of fractures in males is affected by gonadal status. Thirty-two males (median age 47 years, range: 22-79) with PRL-secreting pituitary adenoma (10 with microadenoma and 22 with macroadenoma) and 64 control males, with normal PRL values and with comparable age to patients with hyperprolactinemia, were evaluated for vertebral fractures by a morphometric approach and for bone mineral density (BMD) by a dual-energy X-ray absorptiometry at lumbar spine. Vertebral fractures were shown in 12 patients with PRL-secreting adenoma (37.5%) and in 5 controls (7.8%, P < 0.001). Fractured patients had lower BMD T-score (P = 0.007) and longer duration of disease (P < 0.001) as compared to patients who did not fracture. Fractures occurred more frequently (P = 0.03) in patients with untreated hyperprolactinemia versus patients treated with cabergoline whose frequency of vertebral fractures was still higher than control subjects. The prevalence of vertebral fractures was not significantly different between eugonadal and hypogonadal patients (33.3% vs. 38.5%; P = 0.8). Moreover, no significant (P = 0.4) difference in serum testosterone values was found between fractured and not fractured males. Hyperprolactinemia is associated with high prevalence of radiological vertebral fractures in men with PRL-secreting adenoma. These findings would also suggest that PRL excess may produce negative skeletal effects independently of hypogonadism.

ObjectiveIn this study, the effect of high-dose octreotide LAR on glucose metabolism in patients with acromegaly was investigated.DesignA post-hoc analysis of a clinical trial enrolling 26 patients with acromegaly not controlled by standard maximal somatostatin analog (SSAs) dose and randomized to receive high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection (octreotide LAR) for 6 months.MethodsGlucose metabolic status was defined as worsened when a progression from normoglycemia to impaired fasting glucose (IFG) or from IFG to diabetes occurred or when an increase of HbAlc by at least 0.5% was demonstrated. An improvement of glucose metabolism was defined in the presence of a regression from IFG to normoglycemia and/or when HbAlc decreased by at least 0.5%.ResultsGlucose metabolic status remained unchanged in a majority of patients (16/26 patients, 65.3%), worsened in six patients, and improved in four patients. Pre-existing metabolic status did not predict worsening of glucose metabolism, which, conversely, was significantly related to persistent biochemical activity of the disease. In fact, patients with worsened glucose metabolism exhibited a less frequent decrease in serum GH and IGF1 levels, compared with patients with improved or unchanged glucose metabolism (2/6 vs 18/20; P=0.01).ConclusionAn increase in octreotide LAR dose or frequency did not impact on glucose metabolism in most patients. Worsening of glucose metabolic status occurred in close relation with persistently uncontrolled acromegaly.

Hyperprolactinemia may cause bone loss but data on fractures are scanty. The aim of this study was to evaluate the prevalence of vertebral fractures in women with prolactin (PRL)-secreting adenoma. In this cross-sectional study, 78 women (median age 45.5 years, range: 20-81) with PRL-secreting pituitary adenoma (66 with microadenoma and 12 with macroadenoma) and 156 control subjects, with normal PRL values and with comparable age to patients with hyperprolactinemia, were evaluated for vertebral fractures by a morphometric approach and for bone mineral density (BMD) by a dual-energy X-ray absorptiometry at lumbar spine. Vertebral fractures were shown in 25 patients with PRL-secreting adenoma (32.6%) and in 20 controls (12.8%, P < 0.001). Fractured patients were significantly older (P < 0.001) and had lower BMD T-score (P < 0.001), longer duration of disease (P < 0.001), higher serum PRL (P = 0.004) and lower serum IGF-I (P < 0.001) values as compared to patients who did not fracture. The prevalence of vertebral fractures was significantly (P < 0.001) higher in post-menopausal women with PRL-secreting adenoma as compared to pre-menopausal patients. Fractures occurred more frequently (P = 0.01) in patients with untreated hyperprolactinemia versus patients treated with cabergoline. Logistic regression analysis demonstrated that duration of disease maintained a significant correlation with vertebral fractures (odds ratio 1.16, C.I. 95% 1.02-1.33) even after correction for age, menopausal status, treatment with cabergoline, BMD, serum IGF-I and serum PRL values. Hyperprolactinemia is associated with high prevalence of radiological vertebral fractures in women with PRL-secreting adenoma.

Acromegaly is frequently complicated by fragility vertebral fractures and diabetes mellitus. Since type 2 diabetes mellitus is a cause of secondary osteoporosis in the general population, in this cross-sectional study we aimed at investigating the association between diabetes mellitus and vertebral fractures in males with acromegaly. Fifty-seven patients (median age 47 years, range: 24-85) with active (21 cases) and controlled (36 cases) acromegaly and 57 control subjects were evaluated for bone mineral density (BMD) by DXA and vertebral fractures by a quantitative morphometric analysis. Diabetes mellitus was found in 18 patients and 18 control subjects. The prevalence of vertebral fractures was higher in acromegalic patients as compared with the control subjects (50.9 vs. 10.5%; χ(2): 21.8; P < 0.001). Acromegalic patients with fractures had serum IGF-I values significantly higher (P = 0.009), longer duration of active disease (P < 0.001) and higher prevalence of active acromegaly (P = 0.007) and diabetes mellitus (P = 0.04) as compared to patients who did not fracture. When acromegaly was active, the prevalence of vertebral fractures was high independently of the coexistent diabetes mellitus. On the contrary, when acromegaly was controlled the prevalence of vertebral fractures was significantly higher in patients with diabetes as compared to patients without diabetes (62.6 vs. 28.0%; P = 0.04). In both diabetic and non diabetic patients, vertebral fractures occurred independently of BMD. In conclusion, this study suggests that diabetes mellitus may be associated with an increased prevalence of vertebral fractures in males with acromegaly. However, this effect seems to be relatively attenuated in the presence of persistent GH hypersecretion.

ObjectiveGH deficiency (GHD) and glucocorticoid excess are associated with increased risk of fragility fractures. We aimed to evaluate whether the prevalence of vertebral fractures may be influenced by glucocorticoid over-replacement in hypopituitary males with GHD.DesignCross-sectional study.MethodsFifty-one adult hypopituitary patients (all males; mean age 55 years, range: 23–81) with severe adult-onset GHD (replaced in 21 patients and untreated in 30 patients) and glucocorticoid deficiency on replacement treatment were studied for vertebral fractures using a radiological and morphometric approach.ResultsVertebral fractures were observed in 31 patients (60.8%) in correlation with untreated GHD, urinary cortisol values, and cortisone doses. Patients were stratified according to treatment of GHD, and current and cumulative cortisone doses. In untreated GHD, vertebral fractures occurred more frequently in patients who had received higher (greater than median) cumulative and current doses of cortisone compared with patients who had received lower (less than median) drug doses (95.2 vs 50.0%, P=0.009 and 90.5 vs 55.6%, P=0.04 respectively). In untreated GHD, fractured patients had significantly higher urinary cortisol values compared with patients without vertebral fractures (84 μg/24 h, range: 24–135 vs 49 μg/24 h, range: 30–96; P=0.04). In treated GHD patients, by contrast, the prevalence of vertebral fractures was not influenced by cumulative and current cortisone doses and urinary cortisol values.ConclusionsGlucocorticoid over-replacement may increase the prevalence of vertebral fractures in patients with untreated GHD. However, treatment of GHD seems to protect the skeleton from the deleterious effects of glucocorticoid overtreatment in hypopituitary patients.

Background: Somatostatin analogs (SSA) may influence glucose metabolism, but the clinical relevance of this effect is uncertain because trials performed so far are limited in terms of number of patients and heterogeneity for length and type of follow-up. Purpose: The purpose of the study was to assess, via the metaanalysis of acromegaly studies, the clinical impact of SSA on glucose metabolism. The outcomes analyzed were fasting plasma glucose, fasting plasma insulin, hemoglobin A(1c), and plasma glucose concentrations during oral glucose tolerance test. Study Selection: Eligibility criteria were: 1) duration of SSA treatment of at least 3 wk; 2) available numerical data for at least one of the four biochemical outcomes investigated; 3) measurement of the outcomes before and after SSA treatment; and 4) no selection of acromegalic patients for their responsivity to SSA. After revision, only 31 studies fulfilled eligibility criteria and were therefore selected for data extraction and analysis. Data Synthesis: SSA treatment was found to induce statistically significant decrease in fasting plasma insulin [effect size −0.45, 95% confidence interval (CI) from −0.58 to −0.32, P < 0.001], without any significant change of fasting plasma glucose (effect size +0.04, 95% CI from −0.07 to +0.15, P = 0.52) and hemoglobin A(1c) (effect size +0.11, 95% CI from −0.02 to +0.23, P = 0.09). Serum glucose values during the oral glucose tolerance test were shown to significantly change during SSA treatment (effect size +0.31, 95% CI from +0.17 to +0.45, P < 0.001), although with high inconsistency among trials. Conclusions: Our data suggest that modifications of glucose homeostasis induced by SSA may have an overall minor clinical impact in acromegaly.

Background Sensitivity to pegvisomant therapy is highly variable in patients with acromegaly but determinants of this variability are still unknown. Lack of exon 3 (d3-) of the growth hormone (GH) receptor (GHR) has been associated with increased biological activity of GH. Objective To assess whether the presence of d3-GHR haplotype may have a role in predicting dose regimen and response to pegvisomant in acromegaly. Design Case series. Setting Institutional referral center at a tertiary care hospital. Patients Ninenteen acromegalic patients with active disease after unsuccessful neurosurgery and somatostatin analog therapy. Measurements before and 1, 3, 6 and 12 months after treatment with pegvisomant, IGF-I; GH receptor genotype, determined from peripheral blood by polymerase chain reaction. All patients started treatment with pegvisomant at 10 mg/daily and then increased the dose, according to a fixed schedule, during a 12-month follow-up until normalization of IGF-I levels. Results d3-GHR patients required a significant lower dose of pegvisomant and shorter treatment time to normalize IGF-I. Conclusion the GHR genotype could be useful in predicting dose and individual response to pegvisomant in acromegaly.

Data on osteoporotic fractures in acromegaly are limited. An increased prevalence of radiological vertebral fractures was already observed in postmenopausal women with active acromegaly. It is unknown whether this observation may reflect a more general increased risk of fractures in acromegaly.This was a cross-sectional study.The study was conducted at referral centers.Subjects included 40 males with acromegaly (25 patients with controlled disease and 15 patients with active disease) and 31 control males, with age and gonadal status comparable with the patients.Evaluation of vertebral fractures (quantitative morphometric analysis) and bone mineral density (BMD) at lumbar spine and total hip (dual energy X-ray absorptiometry) was done.Vertebral fractures were assessed.Although BMD was not significantly different between acromegalic patients and control subjects, the prevalence of vertebral fractures was higher in acromegalic patients as compared with the control subjects (57.5 vs. 22.6%; chi(2): 8.7; P = 0.003). Fractured and nonfractured acromegalic patients showed no significant difference in age and BMD Z-score. However, acromegalic patients with fractures had serum IGF-I values significantly higher and duration of active disease significantly longer with respect to patients without fractures. Moreover, patients with fractures showed significantly longer untreated hypogonadism as compared with patients without fractures. In a multivariate logistic regression analysis, the duration of active acromegaly was the only risk factor significantly correlated with the occurrence of fractures (odds ratio 1.1, confidence interval 1.04-1.6).This study reports for the first time a high prevalence of osteoporotic vertebral fractures in an unselected acromegalic male population generally considered at low risk of osteoporosis, suggesting that complicated osteoporosis is an important comorbidity of acromegaly.