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Context: Colonic polyps occur in 30-40% of acromegalic patients, increasing the risk of colon carcinoma. Although debated, there is emerging evidence that metformin may play a protective role in diabetic and non-diabetic patients with colonic polyps and its use in chemoprevention is currently explored. Objective: Evaluate the prevalence of colonic polyps in acromegalic patients treated or not with metformin and explore its possible protective role. Design: Exploratory cross-sectional study in two tertiary Italian referral centres. Methods: Out of 153 acromegalic patients, we selected 58 patients (36-8 2 years; f: 33) who had at least one colonoscopy performed within the first 2 years of diagnosis. Presence of colonic polyps/cancer and related risk factors, current metformin and acetylsalicylic acid intake, disease duration, therapies for acromegaly, hormonal and metabolic parameters were assessed. Results: An overall prevalence of 36% polyps was found. Based on the presence of polyps, we identified two groups, comparable for age, BMI, disease duration, glucose, insulin, HOMA-IR, HbA1c, GH and IGF-I levels. Of the patients with polyps (including three adenocarcinomas) only 24% were treated with metformin vs 57% of patients without polyps. Multivariate analysis confirmed a significant negative association between colonic polyps and metformin intake (OR: 0.22, 95% CI: 0.06-0.77, P = 0.01), whereas no significant association was found between polyps and age (P = 0.10), overweight/obesity (P = 0.54), smoking (P = 0.15), acetylsalicylic acid intake (P = 0.99), disease duration (P = 0.96), somatostatin analogues treatment (P = 0.70). Conclusions: These findings, though deriving from an exploratory study, could suggest a protective role of metformin on the development of colonic polyps in acromegaly, and need to be confirmed in an extended study population. [ABSTRACT FROM AUTHOR]

Background Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities. Methods This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the "potentially all pairwise rankings of all possible alternatives" (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments. Results One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation. Conclusion NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment. [ABSTRACT FROM AUTHOR]

Background Treatment recommendations for patients with neuroendocrine tumors (NETs) include the use of octreotide long-acting release (LAR) for long-term therapy and immediate-release (IR) as rescue therapy to control the breakthrough symptoms of carcinoid syndrome (CS). High doses of LAR are commonly used in clinical practice. This study aimed to evaluate the real-world utilization of LAR and preceding IR use at the prescription and patient levels. Methods We used an administrative claims database (2009-2018) containing privately insured enrollees. We calculated the normalized LAR dose from pharmacy claims and the initial mean IR daily dose at the prescription level. At the patient level, we conducted a retrospective cohort study that included patients continuously enrolled with ≥1 pharmacy claim of LAR and evaluated the frequency and the clinical reason for dose escalation of LAR. The definition of the above-label maximum dose of LAR was ≥30 mg/4 weeks. Results Nineteen percent of LAR prescriptions had an above-label maximum dose. Only 7% of LAR prescriptions had preceding IR use. There were 386 patients with NETs or CS vs. 570 with an unknown diagnosis. Comparing patients with NETs or CS to those with an unknown diagnosis, 22.3% vs. 11.0 % experienced dose escalations and 29.0% vs. 26.6% had IR use before dose escalation, respectively. LAR dose escalation occurred in 50.9% vs. 39.2% for symptom control, 12.3% vs. 7.1% for tumor progression control, and 16.6% vs. 6.0% for both reasons in NETs/CS and unknown groups, respectively. Conclusion Octreotide LAR dosing above the label-maximum dose is common and IR rescue dosing appears to be underutilized. [ABSTRACT FROM AUTHOR]

Genetic syndromes that affect the nervous system may also disrupt testicular function, and the mechanisms for these effects may be interrelated. Most often neurological signs and symptoms predominate and hypogonadism remains undetected and untreated, while in other cases, a thorough evaluation of a hypogonadal male reveals previously unrecognized ataxia, movement disorder, muscle weakness, tremor, or seizures, leading to a syndromic diagnosis. Androgen deficiency in patients with neurological diseases may aggravate muscle weakness and fatigue and predispose patients to osteoporosis and obesity. The purpose of this mini review is to provide a current understanding of the clinical, biochemical, histologic, and genetic features of syndromes in which male hypogonadism and neurological dysfunction may coexist and may be encountered by the clinical endocrinologist. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to develop an open-source and reproducible digital quantitative analysis (DIA) of somatostatin receptor subtype 2a (SST2) staining in formalin-fixed paraffin-embedded tissues of pancreatic neuroendocrine tumors (panNETs) and growth hormone (GH)-secreting pituitary adenomas (GHomas). Design: SST2 immunostaining of 18 panNETs and 39 GHomas was assessed using a novel DIA protocol and compared with a widely used semi-quantitative immunoreactivity score (IRS). Methods: The DIA software calculates the staining intensity/area and the percentage of positive cells (%PC). Four representative images were selected for each sample by two independent selectors (S1 and S2), with the analysis performed by two independent analyzers (A1 and A2). Agreement between observers was calculated using the concordance correlation coefficient (CCC). Results: In panNETs, the CCC ranged 0.935-0.977 for intensity/area and 0.942-0.983 for %PC. In GHomas, the CCC ranged 0.963-0.997 for intensity/area and 0.979-0.990 for %PC. In both panNETs and GHomas, the DIA staining intensity was strongly correlated with the IRS (Spearman rho: 0.916-0.969, P< 0.001), as well as the DIA %PC with the IRS %PC (Spearman rh: 0.826-0.881, P< 0.001). In GHomas, the biochemical response to somatostatin receptor ligands correlated with SST2 expression, evaluated both as DIA intensity/area (Spearman rho: -0.448 to -0.527, P = 0.007-0.004) and DIA %PC (Spearman rho: -0.558 to -0.644, P < 0.001). Conclusions: The DIA has an excellent inter-observer agreement and showed a strong correlation with the widely used semi-quantitative IRS. The DIA protocol is an open-source, highly reproducible tool and provides a reliable quantitative evaluation of SST2 immunohistochemistry. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP‐NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with 68Ga‐DOTATATE positron emission tomography‐computed tomography (PET/CT). We investigated the ability of 68Ga‐DOTATATE PET/CT to predict response to SSA therapy. Materials and Methods: The records of 108 consecutive patients with well‐differentiated grade 1–2 GEP‐NETs on SSA monotherapy who received 68Ga‐DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, 68Ga‐DOTATATE maximum standardized uptake value (SUVmax), and progression‐free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan‐Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression. Results: 68Ga‐DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA‐naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP‐NETs. Conclusion: Low SUVmax on 68Ga‐DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well‐differentiated grade 1–2 GEP‐NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine 68Ga‐DOTATATE PET/CT with very high specificity. Implications for Practice: Based on 68Ga‐DOTATATE positron emission tomography‐computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options. Somatostatin analogs (SSAs) are the frontline antitumor therapy for patients with advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors. This study investigated the ability of 68Ga‐DOTATATE PET/CT to predict response to SSA therapy. [ABSTRACT FROM AUTHOR]

In viral pandemics, most specifically Covid-19, many patients with neuroendocrine neoplasms (NENs), including phaeochromocytomas, paragangliomas and medullary thyroid carcinoma, may develop Covid-19 in a mild or severe form, or be concerned about the influence of viral infection relative to their anti-tumoral therapy. In general, newly presenting patients should be assessed, and patients recently receiving chemotherapy, targeted therapy or radionuclide therapy, or showing tumour growth, should be closely followed. For previously diagnosed patients, who have indolent disease, some delay in routine follow-up or treatment may not be problematic. However, patients developing acute secretory syndromes due to functional neuroendocrine neoplasms (such as of the pancreas, intestine or lung), phaeochromocytomas and paragangliomas, will require prompt treatment. Patients with life-threatening Covid-19-related symptoms should be urgently treated and long-term anti-tumoral treatments may be temporarily delayed. In patients with especially aggressive NENs, a careful judgement should be made regarding the severity of any Covid-19 illness, tumour grade, and the immunosuppressant effects of any planned chemotherapy, immunotherapy (e.g. interferon-alpha), targeted therapy or related treatment. In other cases, especially patients with completely resected NENs, or who are under surveillance for a genetic disorder, a telephone or delayed consultation may be in order, balancing the risk of a delay against that of the possible development of Covid-19. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA‐treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA‐treated patients with NETs. Materials and Methods: A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start. Results: A total of 754 SSA‐treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)‐NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease. Conclusion: We report a high incidence of biliary stone disease particularly in GI‐NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI‐NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned. Implications for Practice: The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI‐NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA‐related biliary stone disease. Biliary stone disease is a common side effect of somatostatin analog treatment for neuroendocrine tumors. This article evaluates incidence, complications, and risk factors for biliary stone disease in a large population of patients treated with somatostatin analogs. [ABSTRACT FROM AUTHOR]

Background: Most guidelines still recommend active surveillance for patients with asymptomatic, unresectable neuroendocrine tumors (NETs). However, recent findings from several randomized placebo‐controlled trials suggest that most patients would benefit from active treatment. We conducted a meta‐analysis of pooled outcomes from clinical trials in which an active treatment arm was compared with placebo to determine whether active treatment provides a survival advantage. Materials and Methods: This meta‐analysis evaluated six trials that compared a medication with placebo in patients with an asymptomatic, metastatic NET. The trials were heterogenous with regard to the active medication (octreotide, lanreotide, sunitinib, everolimus, Lu‐Dotatate) and tumor localizations (gastrointestinal, pancreas, lung). Overall survival (OS) and progression‐free survival (PFS) for the placebo and active treatment arms were obtained from individual trial data and combined to obtain pooled outcomes. Results: The individual trials all reported significantly better PFS outcomes for active treatment. The pooled data confirmed this advantage. At months 3, 6, 12, 18, and 24, pooled PFS rates for the placebo and treatment arms, respectively, were 92.9% versus 96.9%; 54.3% versus 83.7%; 35.5% versus 68.5%; 25.1% versus 54.7%; and 17.7% versus 61.0%. OS was also higher in the active treatment groups. At months 6, 12, 24, 36, 48, and 60, OS rates (placebo vs. active treatment), respectively, were 88.1% versus 93.4%; 84.1% versus 86.2%; 67.4% versus 76%; 56.6% versus 64.4%; 49.9% versus 61.0%; and 41.7% versus 45.9%. Conclusion: This meta‐analysis confirms findings from recent clinical trials indicating that active treatment yields better survival outcomes than placebo. Importantly, these findings were obtained across a wide range of patient profiles and diverse medical treatments for metastatic NETs. Given the lack of reliable prognostic factors to determine a priori which patients are unlikely to benefit from active treatment, these findings support early treatment in most patients. Implications for Practice: Although most guidelines still recommend active surveillance for patients diagnosed with metastatic neuroendocrine tumors, the results of this meta‐analysis, together with recent data from key clinical trials, suggest that most patients could benefit from upfront active treatment. However, more data are needed to confirm this. Neuroendocrine tumors (NETs) are slow‐growing and often asymptomatic and the optimal upfront management approach is controversial. Despite the lack of evidence‐based data, the watch‐and‐wait strategy is still included in clinical guidelines. The present article reports the results of a meta‐analysis of phase III clinical trials that have compared active treatment to placebo in patients with metastatic NETs. [ABSTRACT FROM AUTHOR]

Advanced adrenocortical carcinoma (ACC) is an aggressive disease with poor prognosis, and the current therapeutic options, such as mitotane or platinum‐based chemotherapy regimens, often offer limited efficacy. Here, we present the first report, to the author's knowledge, of metastatic ACC with positive octreoscan scintigraphy that was successfully treated with octreotide long‐acting release (LAR). A patient with metastatic ACC who showed poor tolerance to mitotane received octreotide LAR because of positive octreoscan scintigraphy. She obtained major partial response to the somatostatin analog. Interestingly, the expression of somatostatin receptor 2 from the previous local recurrence lesion was negative. The next‐generation sequencing‐based circulating tumor DNA analysis in the patient was performed and failed to identify any alterations. These findings suggest that octreotide LAR may be a good option for the treatment of metastatic ACC in selected patients. New therapies for advanced adrenocortical carcinoma are urgently needed. This brief communication describes the case of a patient with metastatic adrenocortical carcinoma with positive scintigraphy, which was successfully treated with octreotide LAR. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors. [ABSTRACT FROM AUTHOR]

Objective: Growth hormone (GH) deficiency is related to increased cardiova scular mortality. We studied clinical status, concentration of amino-terminal-pro B-type natriuretic-peptide (NT-proBNP) and echocardiographic parameters during long-term GH replacement (GH-R). Methods: Fifty-one patients (29 females), 45.9 ± 11.3 years (mean ± s.d.), median follow-up 36.2 months, echocardiography and laboratory determinations initially and at 12-months intervals. Results: At the last follow-up (last observation carried forward) (LFU (LOCF)) insulin-like growth-factor-1 standard deviation score (IGF-1 SDS) was ±1 in 92% of the patients. The median NT-proBNP declined signific antly and stabilized (-40.5%) at LFU (LOCF) due to patients with a basal NT-proBNP >125 ng/L (indicative of heart failure). The basal NT-proBNP and the final IGF-1 SDS were significant predictors of the NT-proBNP at LFU (LOCF). Initially left ventricular enddiastolic diameter (LVEDD), left ventricular posterior wall diameter (LVPWD) and ejection fraction (EF) were normal, while interventricular septum diameter (IVSD) and left ventricu lar mass index (LVMi) were slightly increased. LVPWD and IVSD had significantly declined by year three. The LVMi was moderately to severely abnormal in 37.3 and 52.0% of patients initially and at LFU (LOCF). At LFU (LOCF) LVMi and IG F-1 were significantly correlated in the 14 male patients of this subgroup. Conclusion: Long-term GH-R of GHD positively affected ISVD and LVPWD. In a subgroup of patients with severe GHD, LVMi increased concomitantly to the decline in NT-proBNP a nd this was positively correlated to the final IGF-1 concentration. Whether this observation indicates a positive de velopment in a structurally altered heart muscle (reversal of adverse remodelling) or poses a future risk for he art failure needs further follow-up. [ABSTRACT FROM AUTHOR]

Additionally, patients with acromegaly are followed-up sometimes for decades which offers the opportunity to perform longitudinal studies in the frame of regular check-ups for acromegaly, without dedicated site visits or extensive resources. Published by Bioscientifica Ltd. Printed in Great Britain © 2021 European Society of Endocrinology https://eje.bioscientifica.com https://doi.org/10.1530/EJE-21-0067 European Journal of Endocrinology 184:5 C9-C11 D A Niculescu Metformin and colonic polyps in acromegaly Metformin and colonic polyps in acromegaly: is the solution closer than we think?. [Extracted from the article]

Background. Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. Methods. Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016. Results. Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. Conclusion. Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. [ABSTRACT FROM AUTHOR]

A bstract Stem/progenitor (S/P) cells are special types of cells that have the ability to generate tissues throughout their entire lifetime and play key roles in the developmental process. Androgen and the androgen receptor (AR) signals are the critical determinants in male gender development, suggesting that androgen and AR signals might modulate the behavior of S/P cells. In this review, we summarize the AR effects on the behavior of S/P cells, including self-renewal, proliferation, apoptosis, and differentiation in normal S/P cells, as well as proliferation, invasion, and self-renewal in prostate cancer S/P cells. AR plays a protective role in the oxidative stress-induced apoptosis in embryonic stem cells. AR inhibits the self-renewal of embryonic stem cells, bone marrow stromal cells, and prostate S/P cells, but promotes their differentiation except for adipogenesis. However, AR promotes the proliferation of hematopoietic S/P cells and stimulates hematopoietic lineage differentiation. In prostate cancer S/P cells, AR suppresses their self-renewal, metastasis, and invasion. Together, AR differentially influences the characteristics of normal S/P cells and prostate cancer S/P cells, and targeting AR might improve S/P cell transplantation therapy, especially in embryonic stem cells and bone marrow stromal cells. S tem C ells 2014;32:2299-2308 [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy, also known as Kennedy’s disease, is an adult-onset hereditary neurodegenerative disorder caused by an expansion of the polyglutamine repeat in the first exon in the androgen receptor gene. Pathologically, the disease is defined by selective loss of spinal and bulbar motor neurons causing bulbar, facial and limb weakness. Although the precise disease pathophysiology is largely unknown, it appears to be related to abnormal accumulation of the pathogenic androgen receptor protein within the nucleus, leading to disruption of cellular processes. Using a mouse model of spinal and bulbar muscular atrophy that exhibits many of the characteristic features of the human disease, in vivo physiological assessment of muscle function revealed that mice with the pathogenic expansion of the androgen receptor develop a motor deficit characterized by a reduction in muscle force, abnormal muscle contractile characteristics, loss of functional motor units and motor neuron degeneration. We have previously shown that treatment with arimoclomol, a co-inducer of the heat shock stress response, delays disease progression in the mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis, a fatal motor neuron disease. We therefore evaluated the therapeutic potential of arimoclomol in mice with spinal and bulbar muscular atrophy. Arimoclomol was administered orally, in drinking water, from symptom onset and the effects established at 18 months of age, a late stage of disease. Arimoclomol significantly improved hindlimb muscle force and contractile characteristics, rescued motor units and, importantly, improved motor neuron survival and upregulated the expression of the vascular endothelial growth factor which possess neurotrophic activity. These results provide evidence that upregulation of the heat shock response by treatment with arimoclomol may have therapeutic potential in the treatment of spinal and bulbar muscular atrophy and may also be a possible approach for the treatment of other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The physiologic role of circulating endogenous testosterone and estrogen concentrations in relation to lean body mass (LBM) and muscle strength is not as well documented in postmenopausal women as in elderly men. DESIGN: Three hundred and twenty-nine healthy postmenopausal women were randomly selected from a general practice population-based sample aged between 55 and 85 years. METHODS: Total testosterone and estrogen (TT and TE) and sex hormone-binding globulin (SHBG) were determined and estimates of bioavailable testosterone (free androgen index (TT/SHBG, FAI), calculated free testosterone (cFT), and estrogen (TE/SHBG, ESR) were calculated. Examinations included bone mineral density (BMD) of the spine and femoral neck (FN), LBM, maximum quadriceps extension strength (MES) and maximum handgrip strength (MGS), timed up-and-go test (TUGT), osteocalcin (OC), and urinary deoxy-pyridinoline/creatinine (DPyr). Correlations were assessed using Pearson's correlation coefficient (r). RESULTS: With advancing age, LBM, MES, MGS, BMD, and ESR significantly declined (range r: –0.356 to –0.141) and TUGT, and DPyr significantly increased (range r: 0.135 to 0.282 (P<0.05)). After age-adjustment, LBM, MES, and BMD in spine and FN were significantly related to bioavailable testosterone (range r: 0.146 to 0.193, for cFT, and 0.157 to 0.224, for FAI) and to ESR (range r: 0.162 to 0.273). OC and DPyr were significantly inversely related to ESR (r: –0.154 and –0.144 respectively). CONCLUSIONS: Age-related loss of LBM, MES and BMD in postmenopausal women is partly dependent on the presence of endogenous bioavailable testosterone and estrogen. [ABSTRACT FROM AUTHOR]

Pituitary tumors can cause symptoms of mass effect and hormonal hypersecretion that can be reversed with surgical resection or debulking of the adenoma, radiotherapy, or medical treatment. Medical treatment is the primary choice for prolactinomas because dopamine agonists are very effective in the treatment of these tumors, with rates of control (tumor size reduction and hormone suppression) as high as 80–90% for microprolactinomas and 60–75% for macroprolactinomas. The function of dopamine receptors in other histotypes of pituitary adenoma is still debated. However, new insights into receptor physiology and the introduction of new clinically available, as well as experimental, compounds have reopened a potential role of dopaminergic drugs in the medical treatment of pituitary tumors. The differences between the effectiveness and the resistance to different dopaminergic agents, the new challenging results from clinical and experimental studies, as well as the future of dopamine agonists in the therapy of pituitary tumors are discussed. [ABSTRACT FROM AUTHOR]

Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells and pituitary adenomas. Indeed, initially several dopaminergic drugs, and lately somatostatin analogs, have been developed for the treatment of pituitary adenomas. Recently, it has been demonstrated that subtypes of somatostatin and dopamine receptors may form homo- and hetero-dimers at the membrane level, as part of their normal trafficking and function. Interestingly, a specific ligand for a given receptor may influence the activity of an apparently unrelated receptor, and the association between the two different receptors could be induced by addition of either dopamine or somatostatin. The new properties of these families of G-protein coupled receptors (GPCRs) offer a potential explanation for the apparent conflicting results observed both in vivo and in vitro in human cell systems treated with the presently available analogs. Moreover, this observation not only increases the possibilities of modulating the activities of these receptors, but also raises new questions on the role of associations of specific receptors in the control of cell functions. In fact, results from preclinical studies have shown that receptor activation may not only trigger different intracellular signaling pathways, but also induce a distinct response depending upon the specific cell type. Recently, a number of new interesting compounds (subtype selective analogs and antagonists, as well as bi-specific and hybrid somatostatin/dopamine compounds) have been developed. The effects of these new molecules have been explored in few animal and human cell lines and primary cultures from human tumors, revealing a heterogeneous, but broader, profile of activities. Further studies are certainly needed to fully elucidate the complex interplay between the GPCRs and consequent biological effects, to identify suitable therapies for controlling hormonal secretion of pituitary tumors. However, these recent observations form the basis for the application of new interesting strategies for the treatment of not only pituitary tumors but also other human malignancies. [ABSTRACT FROM AUTHOR]