[Show abstract][Hide abstract] ABSTRACT: Context: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. Objective: To study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: University hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL. Outcome: Genetic screening and clinical characteristics. Results: Eleven germline mutations (5 SDHB, 1 SDHC, 1 SDHD, 2 VHL and 2 MEN1) and four variants of unknown significance (2 SDHA, a SDHB, and a SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in 3 pituitary adenomas and LOH at the MEN1 locus in 2 pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, while mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.
Full-text · Article · Dec 2014 · Journal of Clinical Endocrinology & Metabolism
[Show abstract][Hide abstract] ABSTRACT: The current article provides a brief overview of the criteria for defining disease control in acromegaly.
This was a retrospective, narrative review of previously published evidence chosen at the author's discretion along with an illustrative case study from Latin America.
In the strictest sense, "cure" in acromegaly is defined as complete restoration of normal pulsatile growth hormone secretion, although this is rarely achieved. Rather than "cure", as such, it is more appropriate to refer to disease control and remission, which is defined mainly in terms of specific biochemical targets (for growth hormone and insulin-like growth factor-1) that predict or correlate with symptoms, comorbidities and mortality. However, optimal management of acromegaly goes beyond biochemical control to include control of tumour growth (which may be independent of biochemical control) and comprehensive management of the symptoms and comorbidities typically associated with the disease, as these may not be adequately managed with acromegaly-specific therapy alone.
[Show abstract][Hide abstract] ABSTRACT: adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor, and it has recently been suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating the AMPK system. This study aimed to evaluate the effects of candesartan, an angiotensin II receptor blocker, on cardiac and hepatic AMPK activity basally as well as after surgical stress under general anesthesia.
Male Wistar rats were treated with 5 mg/kg/day candesartan in their drinking water for two weeks. Levels of cardiac and hepatic AMPK activity were determined, using a kinase activity assay, basally and after surgical stress under general anesthesia.
Chronic administration of candesartan increased hepatic AMPK activity approximately 4 times (p<0.05) while no significant change was demonstrated in cardiac AMPK. Cardiac and hepatic AMPK activities were not significantly increased by surgical stress alone performed under anesthesia. However, chronic treatment with candesartan decreased AMPK activity in both liver and heart after surgical stress under anesthesia (p<0.01 for both comparisons).
While chronic candesartan treatment may stimulate AMPK activity in certain organs such as the liver, when combined with surgical stress under anesthesia it inhibits pathways regulating AMPK activity.
Full-text · Article · Aug 2013 · Journal of Renin-Angiotensin-Aldosterone System
[Show abstract][Hide abstract] ABSTRACT: Context:Traditionally, acromegaly is viewed as a disease resulting from GH hypersecretion from an autonomous pituitary somatotropinoma.Objective:To test the hypothesis that GH secretion in acromegaly is still subjected to normal hypothalamic control, we studied the daily rhythmicity of GH secretion in normal controls and patients with newly diagnosed, untreated acromegaly.Design and Setting:This was an observational inpatient study in the General Clinical Research Center at the University of Michigan.Patients or Other Participants:One hundred four normal controls and 67 acromegalic patients were included in the study.Intervention:The intervention consisted of frequent blood sampling over 24 hours.Main Outcome Measure(s):We hypothesized that acromegalic patients would show rhythmicity, sexual dimorphism, and age-related decline of GH secretion similar to normal controls.Results:Both normal controls and the patients exhibited 3 major GH waves with the highest values at 12:00 pm, 5:00 pm, and 1:00 am (P < .001 for all). Both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). The amplitude of the maximal (nocturnal) GH secretory wave (1:00 am) as compared with the nadir GH secretion (9:00 am) was clearly different between the 2 groups, with a significantly smaller magnitude in acromegaly (P < .001). A subsequent subanalysis of both groups was performed separately for both genders. Similar to the entire groups, both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). Patients with clearly elevated GH values have shown an age-related decline of GH secretion (r = -0.35, P < .001), similar to controls.Conclusions:The analysis of GH profiles in multiple patients with untreated acromegaly discloses the persistence of the hallmarks of the central control of GH regulation, ie, nictohemeral rhythmicity, sexual dimorphism, and an age-related decline of GH output.
No preview · Article · May 2013 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence suggesting involvement of the renin-angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P < 0.05 compared with baseline). The area under the glucose curve was markedly increased in the ER and VR groups compared with that in the ES group (P < 0.05 for both). Importantly, restraint induced a marked increase in insulin secretion in the ER group compared with only a mild elevation in the VR group; insulin secretion in both groups peaked at 20 min (P < 0.05 compared with baseline). Analysis of the area under the insulin curve confirmed an increase in insulin secretion in the ER compared with the VR and ES groups (P < 0.05 for both). The results of the present study reinforce that the RAS is involved in modulating responses to stress and suggest that RAS inhibition with enalapril may increase glucose-induced insulin secretion in response to acute restraint.
No preview · Article · Dec 2012 · Clinical and Experimental Pharmacology and Physiology
[Show abstract][Hide abstract] ABSTRACT: Prolactinomas are prolactin-secreting neoplasias accounting for 40% of the pituitary adenomas. Much is known about the effects of prolactinomas on the reproductive system, but few data are yet available regarding their induced changes on metabolism. This study was aimed at evaluating patients with prolactinomas for insulin resistance and adiponectinemia. Forty patients with prolactinoma were allocated to 2 different groups according to disease control: 20 with uncontrolled disease (UPRL) and 20 with controlled disease in the last 6 months (CPRL). Forty healthy individuals (CG) matched for age, sex, and body mass index were taken as controls. Patients with prolactinoma were compared both as a one group and according to disease control with CG. All subjects were evaluated for waist/hip ratio (WHR), blood pressure, lipid profile, fasting glucose, homeostasis assessment model of insulin resistance (HOMAIR), and adiponectin. Patients with prolactinomas (UPRL+CPRL) showed higher insulin (p<0.05) and HOMAIR (p<0.05), alongside with lower adiponectin levels (p<0.01) than matched controls. When UPRL was compared to CPRL and CG, UPRL was disclosed as a subgroup of significant altered metabolic profile as related to WHR (p<0.01 for comparisons), high-density lipoprotein cholesterol (p<0.05 for comparisons), triglycerides (p<0.05 for comparisons), HOMAIR (p<0.05 and p<0.01, respectively), and adiponectin (p<0.01 for comparisons). All these metabolic abnormalities, except hypoadiponectinemia (p<0.01), were not observed in CPRL. These data suggest that prolactinomas are associated with hypoadiponectinemia, which is further exacerbated in uncontrolled patients when insulin resistance is also prominent.
No preview · Article · Jul 2012 · Hormone and Metabolic Research
[Show abstract][Hide abstract] ABSTRACT: Acromegaly is a chronic disease characterized by the presence of a pituitary growth hormone (GH)-producing tumour, excessive secretion of growth hormone, raised levels of insulin-like growth factor I (IGF-I) and characteristic clinical presentation of acral enlargement. Over the past two decades, major advances have occurred in the understanding of some aspects of acromegaly-such as the biology of pituitary tumours, the physiology, molecular mechanisms of GH secretion and IGF-I generation, and the pathogenesis of comorbidities. Moreover, new approaches to diagnosis and surveillance (both in terms of screening and follow-up) of acromegaly have led to increases in the number of patients diagnosed with active disease, many of whom would previously have been missed. The development of sensitive assays for detecting plasma GH and IGF-I levels, as well as the widespread use of MRI for visualization of small tumours, have been major contributing factors to these improvements. Treatment advances have resulted in improved cure rates and disease control through novel neurosurgical techniques and pharmacological approaches. This Review summarizes and discusses the changes in our understanding of the epidemiology, diagnosis, treatment, and follow-up of acromegaly and its comorbidities.
No preview · Article · Jun 2012 · Nature Reviews Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Women with previous gestational diabetes mellitus (pGDM) face a higher risk of developing type 2 diabetes and, consequently, a higher cardiovascular risk. This study aimed to compare the carotid intima-media thickness (cIMT) from young women with pGDM to those with metabolic syndrome (MS) and to healthy controls (CG) to verify whether a past history of pGDM could be independently associated with increased cIMT.
This is a cross-sectional study performed in two academic referral centers. Seventy-nine women with pGDM, 30 women with MS, and 60 CG aged between 18 and 47 years were enrolled. They all underwent physical examination and had blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLc), and triglycerides determined. The cIMT was measured by ultrasound in several carotid segments. The primary endpoint was cIMT and clinically relevant parameters included as predictors were: age, systolic blood pressure, waist, BMI, total cholesterol, LDLc, triglycerides, fasting glucose, previous history of GDM as a whole group, previous history of GDM without MS, presence of DM, presence of MS, and parity.
cIMT was significantly higher in pGDM when compared to CG in all sites of measurements (P < 0.05) except for the right common carotid. The pGDM women showed similar cIMT measurements to MS in all sites of measurements, except for the left carotid bifurcation, where it was significantly higher than MS (P < 0.001). In a multivariate analysis which included classical cardiovascular risk factors and was adjusted for confounders, pGDM was shown to be independently associated with increased composite cIMT (P < 0.01). The pGDM without risk factors further showed similar cIMT to MS (P > 0.05) and an increased cIMT when compared to controls (P < 0.05).
Previous GDM was independently associated with increased composite cIMT in this young population, similarly to those with MS and regardless the presence of established cardiovascular risk factors.
Full-text · Article · May 2012 · Cardiovascular Diabetology
[Show abstract][Hide abstract] ABSTRACT: 5' adenosine monophosphate-activated protein kinase (AMPK) plays a prominent role as a metabolic stress sensor. The role of hypothalamic AMPK in response to restraint and surgical stress has not been previously investigated. It has been recently suggested that the renin-angiotensin system, in addition to its role in stress regulation, may play a significant role in regulating metabolic pathways including the regulation of the AMPK system. This study was thus aimed to evaluate the effects of candesartan, an angiotensin II AT1 receptor blocker drug, on hypothalamic AMPK activity under basal conditions and after restraint in conscious rats or after surgical stress under general anesthesia. Male Wistar rats were treated with 5 mg/kg/day candesartan in the drinking water for 2 weeks. The hypothalamic AMPK activity was determined under basal and stress conditions, using a kinase activity assay. Chronic administration of candesartan significantly increased hypothalamic AMPK activity. Hypothalamic AMPK activity was also increased by restraint stress whereas no change was observed during surgical stress under anesthesia. The high levels of hypothalamic AMPK activation observed in candesartan-treated rats were not changed by restraint stress but were reduced to control levels by anesthesia and surgery. In conclusion, chronic candesartan treatment and restraint stress in conscious rats stimulate the hypothalamic AMPK activity, whereas surgical stress under anesthesia inhibits pathways regulating the AMPK activity even in candesartan-treated rats.
Full-text · Article · Jan 2012 · Stress (Amsterdam, Netherlands)
[Show abstract][Hide abstract] ABSTRACT: Neuroglucopenia induced by 2-deoxy-D-glucose (2DG) activates hypothalamic glucoreceptors leading to increased hepatic glucose production and insulin inhibition. This response is similar to what is observed with intravenous injection of angiotensin II (Ang II). However, the involvement of an angiotensin-converting enzyme inhibitor on neuroglucopenia has not been investigated. The aim of this study was to determine the effects of chronic enalapril treatment on plasma glucose, insulin and lipid levels in response to neuroglucopenia. Male Holtzman rats (120-170 g) were chronically treated with enalapril (10 mg/kg per day) in the drinking water for two weeks. On the day of experiment the animals received an i.v. enalapril final dose one hour before the neuroglucopenic stress by 2DG infusion (500 mg/kg), and blood samples were drawn before and 5, 10, 20, 30 and 60 minutes following infusion. The hyperglycaemic response to 2DG was not significantly changed by enalapril treatment. The enalapril-treated group exhibited a peak of plasma insulin higher than controls. Plasma triglyceride showed a significant increase only in the enalapril group after neuroglucopenic stress (p < 0.05).These data show that chronic enalapril treatment changes insulin and triglyceride responses to neuroglucopenia, suggesting an effect on glucose-induced insulin secretion and the storage of triglycerides.
Full-text · Article · Aug 2011 · Journal of Renin-Angiotensin-Aldosterone System
[Show abstract][Hide abstract] ABSTRACT: Classical endocrinology was based on the quantitative features of hormone secretion, i.e., its deficiency or excess. Recent
studies have shown that qualitative features of hormone delivery to the target cells may have an independent effect on tissue
responses. Whether growth hormone (GH) may share a similar mechanism, through its continuous or pulsatile release, is a burgeoning
field of recent endocrine research. This chapter provides an overview of the different regulators of GH signaling and the
impact of these signals upon GH pulsatility, concentrating primarily on human studies, outlining the roles of total GH output,
GH pulses, and interpulse levels in determining generation of IGF-1 (i.e., growth) and metabolic effects (primarily, lipolysis)
in health and disease. These data suggest that it is not only the gross quantity of GH output, but also the pattern of presentation
of GH to the peripheral tissues that plays an important role in determining its biological properties. The understanding of
the kinetic properties of GH secretion and their potential impact on growth and metabolism may alter our understanding of
GH physiology and action, and potentially devise novel and superior strategies to optimize the effects of exogenously administered
GH tailored to a specific therapeutic goal.
KeywordsGHRH-GH pulsatility-Somatostatin-Ghrelin and analogs-GH and IGF-1 feedback regulation
[Show abstract][Hide abstract] ABSTRACT: This study reports on the Brazilian Portuguese adaptation of the QoL-AGHDA (Quality of Life Assessment of Growth Hormone Deficiency in Adults) for use in adult growth hormone deficient (GHD) patients.
The translation process adopted the dual panel methodology. The questionnaire was tested through field-test interviews (16 GHD patients). In the final stage, data from 120 GHD patients (81 included in a test-retest analysis) were analyzed for internal consistency, test-retest reliability, convergent validity and validity among known groups.
The translation panels were successful and the draft version was amended to improve the wording as a result of the field-test interviews. Cronbach's alpha was 0.90 and test-retest reliability 0.88. QoL-AGHDA scores had the expected pattern of association with NHP scale scores and QoL-AGHDA was able to differentiate significantly between patients based on patient-reported general health (p < 0.01) and QoL (p < 0.01).
The adaptation of the QoL-AGHDA for a Brazilian population was successful and the adapted questionnaire was shown to be reliable and valid.
Full-text · Article · Dec 2010 · Arquivos brasileiros de endocrinologia e metabologia
[Show abstract][Hide abstract] ABSTRACT: Measurement of GH after oral glucose tolerance test (OGTT) is used for the diagnosis and surveillance of acromegaly. However, there are major discrepancies between glucose-suppressed GH and plasma IGF1 as indices of biochemical activity of acromegaly in patients with relatively mild GH oversecretion. This study was aimed to assess the performance of OGTT in patients with acromegaly and variable GH outputs.
Forty adults with newly diagnosed, untreated acromegaly (15 with GH >4.3 μg/l and 25 with GH <4.3 μg/l) and elevated IGF1 levels were studied. All underwent Q10 min for 24 h sampling for GH followed by an OGTT.
Postglucose nadir GH (GHn) correlated significantly to 24 h GHn, mean 24 h GH, and baseline GH (P<0.001 for all comparisons). GHn correlated significantly to IGF1 z-scores for the 'low' GH group and for the entire group (P<0.0001 for both comparisons), but not for the 'high' GH group. None of the patients with mean GH >4.3 μg/l had GHn below 1 μg/l. In contrast, 13 out of 25 patients (52%) with GH <4.3 μg/l showed GHn lower than 1 μg/l, and 7 of them (28%) had GHn lower than 0.4 μg/l. These groups did not differ significantly either for average or for maximal GH suppression in OGTT.
Our data show that suppressibility of GH by glucose in acromegaly is a function of the degree of GH hypersecretion and that OGTT has only limited diagnostic value in patients with biochemically active acromegaly but only mildly increased GH output.
No preview · Article · Oct 2010 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Acromegaly is a disease of exaggerated somatic growth and distorted proportion arising from hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Although almost never malignant, somatotropinomas may cause significant morbidity and the uncontrolled excess of GH is related to mortality 2 to 4 times higher than the expected rate. Recently, clinicians treating acromegalic patients have been aware of the importance of trying to normalize IGF-1 while GH values may differ depending on assay. Despite the significant efforts made over the last decade, little is known about the genetic causes of somatotropinomas and even less of this knowledge is applied therapeutically. In this review, we attempt to address the genetic and molecular knowledge regarding somatotropinomas and their therapeutic aspects.
[Show abstract][Hide abstract] ABSTRACT: Pancreas transplantation involves a set of procedures that, in some cases, lead to different complications and outcomes. The aim of this study was to analyze the long-term effects of pancreas transplantation regarding carbohydrate and lipid metabolism parameters to determine differences between simultaneous pancreas-kidney (SPK) transplantation and pancreas transplantation alone (PTA).
Sixty-four patients (46 SPK and 18 PTA), with an immunosuppression protocol based on tacrolimus plus mycophenolate mofetil and prednisone, were evaluated for at least 1 year after transplantation. No patient made use of any hypoglycemic or hypolipidemic drugs. Comparisons were performed between SPK and PTA patients using the chi-square test, Fischer's exact test, and unpaired Student's t test, as appropriate.
Patients were 39.8+/-9.3 years old, predominantly male (60.9%), with a mean follow-up of 25.4+/-10.4 months after transplantation. The PTA group exhibited worse renal function and higher tacrolimus levels than the SPK group. Fasting glucose, 2 hr plasma glucose after overload, C-peptide, and HbA1C were within the normal range, with no statistically significant differences between the PTA and SPK groups. Insulin (INS) and the homeostasis model assessment of INS resistance index were above the normal range in both the groups. Lipids were also similar between groups.
The majority of patients with long-term functioning pancreas transplant achieved good glucose control without use of exogenous INS or oral antidiabetic drugs, although they were hyperinsulinemic. There were no significant differences concerning glucose and lipid parameters between the SPK and PTA groups, even though the PTA patients exhibited higher tacrolimus levels and worse renal function.