The Relationship between the Burden of Acromegaly, Associated Comorbidities, Complications and Disease Status.

Uncontrolled acromegaly causes increased morbidity and mortality. The analysis of acromegaly comorbidities and complications is important when establishing a standard of care for the entire population of acromegaly patients. The aim of this study was to determine the frequency of comorbidities and complications of acromegaly and their dependence on the activity of the disease. A retrospective analysis of medical records from 124 patients with acromegaly was carried out, including 39 who were cured, 73 treated with somatostatin analogs and 12 newly diagnosed patients. The incidence of comorbidities and complications was very high, and those most frequently observed were arterial hypertension, multinodular goiter, lipid disorders, hypopituitarism and degenerative changes. At least one complication of acromegaly was observed in 92% of patients undergoing successful neurosurgery and in all pharmacologically treated patients. By contrast, two or more complications were observed in 77% of cured patients and in pharmacologically controlled and uncontrolled patients, 82% and 91%, respectively. Conclusions: Acromegaly is associated with a high prevalence of complications. Active acromegaly is associated with a higher incidence of complications than in treated groups. Untreated patients have more complications than treated patients. Successfully cured patients have significantly fewer complications than pharmacologically controlled patients and patients with active acromegaly.

FTO Gene Polymorphisms and Their Roles in Acromegaly.

The major causes of both morbidity and mortality in patients with acromegaly are cardiovascular diseases (CVDs). The polymorphisms of the fat mass and obesity-associated gene (FTO) are associated with obesity, as well as with an increased risk of CVDs. The aim of the study was to determine the relationship of risk alleles of four FTO gene polymorphisms with selected parameters of lipid and glucose metabolism as well as with IGF-1 and GH levels in the group of patients with acromegaly compared to the control group. The study group consisted of 104 patients with acromegaly and 64 healthy subjects constituting the control group. In the whole acromegaly group, the data reveal that the homozygous for risk allele carriers (rs1421085, rs9930506, rs9939609) as well as carriers of only one risk allele have lower IGF-1 concentrations. In the well-controlled acromegaly group, the homozygous for three risk allele carriers of FTO gene polymorphisms have lower HDL cholesterol concentration (rs1121980, rs1421085, rs993609). In the cured acromegaly group, homozygous risk allele carriers rs9930506 tend to have higher levels of total cholesterol and LDL cholesterol. These associations are not observed in the control group. Conclusion: there is an association between FTO gene polymorphisms and the metabolism of lipids, suggesting that the FTO gene may be associated with higher CVD risk in patients with acromegaly. In addition, there is an association between FTO gene polymorphisms and IGF-1, implying that FTO gene may influence/modify IGF-1 synthesis. Further investigation on a larger scale is required to provide more precise evidence.

Ghrelin and Leptin Concentrations in Patients after SARS-CoV2 Infection.

SARS-CoV2 infection can lead to severe cytokine storm especially in obese patients. Ghrelin acts not only as an appetite regulator but can also play a key role in the immune reaction. Leptin, secreted mainly by the white adipose tissue, can act as a pro-inflammatory cytokine. The crucial question is whether or not the cytokine storm in COVID-19 patients with obesity is linked to adipokine dysregulation. The aim of this study was to assess ghrelin and leptin concentrations in patients 6 months after SARS-CoV2 infection in comparison to a control group considering the influence of sex. The study group included 53 patients with a history of COVID-19 and 87 healthy subjects in the control group. Leptin and ghrelin concentrations as well as hormonal and biochemical parameters were measured. A significantly higher ghrelin concentration was observed in the COVID-19 group in comparison to the control group, with a statistically significant impact of sex on the relationship between COVID-19 and ghrelin concentration, which was lower in the males. No statistically significant differences in leptin concentration were observed between the groups. A significant negative correlation was observed between ghrelin and testosterone and morning cortisol levels in the COVID-19 group. The current study showed that ghrelin levels were significantly higher in patients 6 months after a mild course of SARS-CoV2 infection. To confirm the hypothetical protective role of ghrelin in the inflammatory process, it would be necessary to compare serum ghrelin levels between patients after mild and severe courses of COVID-19. Due to the small sample size and the lack of patients with a severe course of COVID-19, these observations need further investigation. There were no differences in leptin concentrations between the COVID-19 patients and the control group.

Acromegaly Caused by Ectopic Growth Hormone Releasing Hormone Secretion: A Review.

Introduction: Ectopic acromegaly is a rare condition caused most frequently by growth hormone releasing hormone (GHRH) secretion from neuroendocrine tumors. The diagnosis is often difficult to establish as its main symptoms do not differ from those of acromegaly of pituitary origin. Objectives: To determine most common clinical features and diagnostic challenges in ectopic acromegaly. Patients and Methods: A search for ectopic acromegaly cases available in literature was performed using PubMed, Cochrane, and MEDline database. In this article, 127 cases of ectopic acromegaly described after GHRH isolation in 1982 are comprehensively reviewed, along with a summary of current state of knowledge on its clinical features, diagnostic methods, and treatment modalities. The most important data were compiled and compared in the tables. Results: Neuroendocrine tumors were confirmed in 119 out of 121 patients with histopathological evaluation, mostly of lung and pancreatic origin. Clinical manifestation comprise symptoms associated with pituitary hyperplasia, such as headache or visual field disturbances, as well as typical signs of acromegaly. Other endocrinopathies may also be present depending on the tumor type. Definitive diagnosis of ectopic acromegaly requires confirmation of GHRH secretion from a tumor using either histopathological methods or GHRH plasma concentration assessment. Hormonal evaluation was available for 84 patients (66%) and histopathological confirmation for 99 cases (78%). Complete tumor resection was the main treatment method for most patients as it is a treatment of choice due to its highest effectiveness. When not feasible, somatostatin receptor ligands (SRL) therapy is the preferred treatment option. Prognosis is relatively favorable for neuroendocrine GHRH-secreting tumors with high survival rate. Conclusion: Although ectopic acromegaly remains a rare disease, one should be aware of it as a possible differential diagnosis in patients presenting with additional symptoms or those not responding to classic treatment of acromegaly.

Pasireotide-a novel somatostatin receptor ligand after 20 years of use.

Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike first-generation SRLs. Because of the broader binding profile, pasireotide has been suggested to have a greater clinical efficacy in acromegaly than first-generation SRLs and to be efficacious in Cushing's disease. The consequence of this binding profile is the increased blood glucose level in some patients. This results from the inhibition of both insulin secretion and the incretin effect and only a modest suppression of glucagon. A monthly intramuscular formulation of long-acting release pasireotide has been approved for both acromegaly and Cushing's disease treatment. This review presents data on the efficacy and safety of pasireotide treatment mostly in patients with acromegaly and Cushing's disease. Moreover, other possible therapeutic applications of pasireotide are mentioned.

Complications and Comorbidities of Acromegaly-Retrospective Study in Polish Center.

Introduction: In acromegaly, chronic exposure to impaired GH and IGF-I levels leads to the development of typical acromegaly symptoms, and multiple systemic complications as cardiovascular, metabolic, respiratory, endocrine, and bone disorders. Acromegaly comorbidities contribute to decreased life quality and premature mortality. The aim of our study was to assess the frequency of acromegaly complications and to evaluate diagnostic methods performed toward recognition of them. Materials and Methods: It was a retrospective study and we analyzed data of 179 patients hospitalized in the Department of Endocrinology, Diabetes and Isotope Therapy in Wroclaw Medical University (Poland) in 1976 to 2018 to create a database for statistical analysis. Results: The study group comprised of 119 women (66%) and 60 men (34%). The median age of acromegaly diagnosis was 50.5 years old for women (age range 20-78) and 46 for men (range 24-76). Metabolic disorders (hyperlipidemia, diabetes, and prediabetes) were the most frequently diagnosed complications in our study, followed by cardiovascular diseases and endocrine disorders (goiter, pituitary insufficiency, osteoporosis). BP measurement, ECG, lipid profile, fasting glucose or OGTT were performed the most often, while colonoscopy and echocardiogram were the least frequent. Conclusions: In our population we observed female predominance. We revealed a decrease in the number of patients with active acromegaly and an increase in the number of well-controlled patients. More than 50% of patients demonstrated a coexistence of cardiac, metabolic and endocrine disturbances and only 5% of patients did not suffer from any disease from those main groups.

The Effect of 6 Months' Treatment With Pasireotide LAR on Glucose Metabolism in Patients With Resistant Acromegaly in Real-World Clinical Settings.

Objective: The aim of the study was to evaluate glucose metabolism, as measured by glycated hemoglobin (HbA1c) levels and the need for antidiabetic medical treatment, in patients with acromegaly resistant to first-generation somatostatin receptors ligands (SRLs) treated with pasireotide long-acting release (LAR) in real-world clinical practice. Biochemical control of acromegaly, as measured by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, was also assessed. Study Design: Two-center retrospective cohort of consecutive patients with acromegaly treated with first-generation SRLs at maximum doses, who had not achieved biochemical disease control. After SRLs were discontinued, patients were given pasireotide LAR 40 mg i.m. every 28 days. The dose was increased to 60 mg i.m. in patients for whom adequate control was not achieved after 3 months. Patients were given dietary and lifestyle advice, and antihyperglycemic treatment was modified as needed. Main Outcome Measures: Biochemical disease control parameters (GH and IGF-1 concentration), as well as HbA1c level at baseline and after 6 months. Results: In total, 39 patients with acromegaly were enrolled. GH concentration decreased (Δme =-1.56 µg/L, range -21.38-3.62, p <0.001) during 6 months of pasireotide LAR treatment. A worsening of metabolic status was observed, with an increase of median HbA1c (Δme =0.40%, range -0.20%-2.30%, p <0.001), and antihyperglycemic treatment intensification in 23 (59.0%) patients. The median decline in IGF-1 concentration was: -283.0 µg/L, range -682.7-171.6, p <0.001. IGF-1 reached the age- and gender-specific upper level of normal in 23 (59%) patients. Conclusions: Pasireotide LAR is an effective therapeutic option in patients with acromegaly refractory to first-generation SRLs. However, this therapy may result in pasireotide LAR-associated hyperglycemia, which requires early and aggressive antidiabetic medical therapy to prevent glucose homeostasis alterations.

Etiology, baseline clinical profile and comorbidities of patients with Cushing's syndrome at a single endocrinological center.

PURPOSE: The aim of this study was to compare phenotype of patients with pituitary, adrenal and ectopic CS and identify the differences regarding biochemical parameters, clinical presentations, and comorbidities in CS patients who were diagnosed at the single endocrinological center in Wroclaw. METHODS: The study population involved 64 patients with CS (53 women and 11 men) diagnosed in Department of Endocrinology, Diabetes and Isotope Therapy in 2000-2018. Patients were divided into three etiologic groups: pituitary dependent-CS (P-CS) (64%), adrenal dependent CS (A-CS) (25%), and CS from an ectopic source (E-CS) (11%). RESULTS: Percentage of men in the A-CS group was significantly higher than in the other etiologic groups. ACTH, UFC, and cortisol in DST were significantly higher in E-CS group compare to P-CS and A-CS (p < 0.05). Mean potassium level in E-CS group was significantly lower than in P-CS and A-CS (p < 0.05). Median of time elapsed to diagnosis was significantly lower in the E-CS group compared with either the P-CS and the A-CS group (p < 0.01). The most frequently symptoms in CS patients were skin alterations (82.8%), weight gain (81.2%), and hypertension (81.2%). CONCLUSIONS: The epidemiology of CS is changing toward a growing proportion of A-CS. All patients with E-CS presented a profound hypokalemia. Salient hypokalemia could be a biochemical marker more suggestive for E-CS rather than P-CS. The incidence of diabetes is more frequent in E-CS group than in P-CS and A-CS groups.

The imbalance of cathepsin B-like activity in acromegalic patients--preliminary report.

OBJECTIVE: Acromegaly is a rare disease due to growth hormone (GH) excess. Patients must be carefully follow up because of mortality and co-morbidity increased risks. Since routinely used GH and insulin-like growth factor-1(IGF-1) estimations are not always sufficient, patients require assessment of organ- or tissue-specific tests. Cysteine proteases (CP), including cathepsin B, have been tested in a number of pathologies in respect of a role in pathogenesis and potential utility in the disease activity and prognosis assessment. There is lack of data on CP activity in acromegaly. MATERIALS AND METHODS: In present study cathepsin B-like and cysteine peptidase inhibitor (CPI) activities have been tested in 29 acromegaly patients and in 15 healthy controls. Cathepsin B activity was assayed with N-bansoyl-DL-arginine-beta-naphthylamide (BANA) as substrate by the Barrett method. CPI activity was determined by measuring the inhibition of papain. RESULTS: Serum cathepsin B activity (median: 1.38 U/ml) and CPI activity (median: 93.08 U/ml) were higher in acromegaly then in controls (0.93 U/ml and 82.55 U/ml, p=0.000017 and 0.00285, respectively). Neither cathepsin B nor CPI activity was correlated with GH or IGF-1 level. No correlation was recorded between cathepsin B and CPI activity. CONCLUSION: It was shown for the first time that cathepsin B and CPI activities are increased in acromegaly. These findings suggest to study cathepsin system as an adjuvant parameter in the assessment of the overall acromegaly complications. Moreover, CP may be involved in pathomechanism of organ complications in acromegaly and may interfere with IGF-1 action.

The role of fibrinogen and CRP in cardiovascular risk in patients with acromegaly.

INTRODUCTION: Patients with active acromegaly have 2- to 3-fold increased cardiovascular mortality. Alterations of acute phase proteins, observed in acromegaly, could lead to cardiovascular diseases. Aim of the study was to evaluate fibrinogen and C-reactive protein (CRP) secretion in patients with acromegaly. MATERIAL AND METHODS: Seventy-seven patients were divided into groups with active (AA, n = 56) and controlled acromegaly (CA, n = 21). Twenty age- and sex-matched healthy subjects served as controls. Serum fibrinogen, CRP, fasting glucose, insulin, total cholesterol, LDL and HDL cholesterol, and triglycerides were measured, and body mass index (BMI) was calculated. RESULTS: Comparison between the groups revealed: higher fibrinogen, triglycerides, glucose levels, and BMI values in AA than in the controls; higher CRP, fibrinogen, triglyceride levels, and BMI values in CA than in the controls; higher LDL cholesterol and insulin levels and lower CRP levels and BMI values in the AA group than in the CA group. Fibrinogen concentration was highest in the AA group and lowest in the control group. Fibrinogen levels were high in all patients with acromegaly, irrespective of disease status, and they were significantly higher than in healthy subjects. CRP concentration was highest in the CA group and lowest in the control group. CRP levels were significantly and paradoxically lower in patients with AA than in patients with well-controlled disease and did not explain the increased cardiovascular mortality in acromegaly. CONCLUSIONS: Fibrinogen plays an important role as a cardiovascular risk factor in acromegaly, irrespective of the cure of the disease. The role of CRP as a cardiovascular risk factor in patients with uncontrolled acromegaly should be better explained in future studies. (Pol J Endocrinol 2010; 61 (1): 83-88).

Evaluation of temporal bone computed tomography and paranasal sinuses magnetic resonance images in acromegalic patients.

OBJECTIVE: Acromegaly is a rare disease, which symptoms are caused by excess secretion of a growth hormone (GH) from the anterior pituitary benign tumor - adenoma. Authors present an evaluation of computed tomography (CT) and magnetic resonance (MR) images of temporal bone and paranasal sinuses of patients with acromegaly. CONCLUSIONS: 1. In all patients with acromegaly, morphological changes in paranasal sinuses were shown. They were mostly pronounced within the maxillary sinuses including the mucosa thickening up to 6 mm and encysted fluid occurrence. 2. CT of temporal bone did not reveal structural changes of internal and median ear. 3. There is a need for further studies on hearing impairment in patients with acromegaly.

Long-term survival and nearly asymptomatic course of carcinoid tumour with multiple metastases (treated by surgery, chemotherapy, (90)Y-DOTATATE, and LAR octreotide analogue): a case report.

Carcinoids are the most common neuroendocrine tumours. They are usually slowly growing, located in the small intestine, secrete serotonin, and are characterized by long survival of patients, so prognosis is generally good. The most frequently encountered clinical presentations of carcinoids are intermittent abdominal pain and carcinoid syndrome (diarrhoea and flushing). Metastases worsen the prognosis and limit the survival of the patients. We report a case of carcinoid tumour with primary focus in the ileum, with an appendix infiltration, in a thirty-two-year-old woman with acute appendicitis symptoms only. Carcinoid was diagnosed postoperatively by histopathological examination. Nowadays, twenty-five years after the surgery, there is evidence of nearly asymptomatic numerous metastases. Only intermittent abdominal pain for about 1-2 years was reported. Partial metastases resection was performed, followed by chemotherapy, (90)Y-DOTATATE and then long-acting release octreotide analogue therapy. In the meantime, severe chronic heart failure (NYHA IV) due to tricuspid combined valvular heart disease and pulmonary hypertension was diagnosed. Combined therapy, typical for chronic heart failure, together with long-acting octreotide analogue highly improved the patient's heart sufficiency and reduced carcinoid syndrome symptoms. The only adverse events of octreotide therapy were hyperbilirubinaemia and itching. Long-term survival is typical for carcinoids, but 30-years survival has not been described in the literature yet.

[Pheochromocytoma in 8-year observation at a single endocrinological center in Wroclaw]. / Guz choromochlonny w 8-letniej obserwacji akademickiego osrodka endokynologicznego we Wroclawiu

INTRODUCTION: Pheochromocytoma is rare tumor with a highly variable clinical presentation. This report provides clinical picture, efficiency of diagnostics and treatment of pheochromocytoma in 8-years in the endocrinological center in Wroclaw. MATERIAL AND METHODS: The records of 37 patients with pheochromocytoma were identified, who were treated in 2000-2007 in the Department of Endocrinology, Diabetology and Isotope Treatment in Wroclaw. There were 23 women (age 23-75 year) and 14 men (age 17-74). We studied frequency of clinical signs, usefulness of diagnostic methods and efficacy of treatment. RESULTS: The duration of the clinical history ranged from 2 months to 16 years. The most frequent symptoms were: hypertension paroxysmal and constant, palpitations, headache, sweating and anxiety. The most sensitive diagnostic method was increased concentration of urinary metanephrine in 24-hour urine. Computed tomography was the most widely used method for tumor localization. Adrenal pheochromocytoma was detecting by CT in all patients, predominated in right adrenal, in 1 case in urinary bladder. Surgery caused remission of hypertension in 59%, improvement in 26.8%, and no changes in 13.9% of patients. Malignancy was reported in 2 cases, 1 woman died after surgery. MEN 2A occur in 21.6%. CONCLUSIONS: The diagnosis of pheochromocytma is usually made after long duration of the disease. The study confirms that clinical presentation of pheochromocytoma is variable and nonspecific, this finding makes the diagnosis very difficult. The most typical symptom is paroxysmal hypertension, which is present only in 40%, other symptoms are nonspecific. The measurement of 24-hour urinary metanephrines was the best indicator. CT was almost always successful in localizing the tumor. Patients with pheochromocytoma should be consider for other endocrine diseases especially medullary carcinoma, primary hyperparathyroidism and other component of MEN 2A.

Additional metabolic effects of adding GH receptor antagonist to long-acting somatostatin analog in patients with active acromegaly.

OBJECTIVE: Somatostatin analogs, dopamine agonists and GH-receptor antagonist--pegvisomant are used in medical therapy of acromegaly. Since pegvisomant has not antitumor effect, the combination of pegvisomant and somatostatin analog could be an attractive option. Aim of study was to assess the effects of pegvisomant and octreotide LAR treatment on GH and IGF-1 levels, and glucose tolerance in acromegaly, and to assess efficacy and tolerability of rapid (after 7 days) pegvisomant dose titration. MATERIAL AND METHODS: Six patients (4 men, 2 women) aged 47.5 years (median) with active acromegaly, after neurosurgery failed, resistant to maximal doses of octreotide, received daily 10-20 mg pegvisomant throughout 2 weeks. They were given octreotide LAR 30 mg monthly for at least 6 months before pegvisomant therapy. Clinical symptoms, GH, IGF-1, fasting glucose and insulin levels were measured on the 0, 8th and 15th day of pegvisomant therapy. On the 8th day pegvisomant dose was titrated based on serum IGF-1 level. RESULTS: IGF-1 levels reduced from 739 at the beginning to 418 ng/ml (medians) on the 15th day of treatment and normalized in one patient. These changes were associated with improvement of glucose metabolism. One diabetic patient could even stop insulin therapy. CONCLUSIONS: Pegvisomant is an attractive adjuvant therapy for controlling acromegaly. Pegvisomant improves insulin sensitivity as well as glucose tolerance. The GH receptor antagonist is good option for patients with active acromegaly coexistent with disturbances of glucose metabolism, especially with diabetes mellitus. Rapid pegvisomant dose increasing to efficient or maximal is well tolerated and effective.

[Acromegaly--from myths to facts]. / Akromegalia--od mitów do faktów.

The authors present numerous historical descriptions of persons who might suffered from gigantism or acromegaly. The oldest medical data of patients, initial attempts of causal neurosurgical treatment, history of growth hormone, insulin-like growth factor-1, growth hormone releasing hormone and somatostatin discovery is reported. The highest contemporary living persons are also listed.

Assessment of brainstem auditory evoked potentials (BAEPs) in patients with acromegaly.

OBJECTIVES: Acromegaly is associated by various systemic complications, involving also the nervous system. Other studies revealed peripheral but not central nervous system impairment with somatosensory evoked potentials examinations in acromegaly. Aim of the present study was to assess whether brainstem transmission in acromegaly is disturbed. MATERIAL AND METHODS: The study was carried out in 37 patients. The control group consisted of 47 healthy persons. In all of the subjects, peripheral transmission, reflected by peak I latency, and brainstem transmission, tested by interpeak latency I-V (IPL I-V), were examined. RESULTS: Peak I latency was delayed in 6 out of 37 patients (1 - bilaterally, 2 - right side, 3 - left side). The group-mean latency of peak I was 1.53 msec and 1.56 msec, for the right and left side, respectively. There were found no statistically significant differences between the right and left side, likewise in comparison with control group. In turn, as compared with the controls, IPL I-V was disturbed in 25 out of 37 patients: in most of the cases IPL I-V prolongation was observed (8 - bilateral prolongation, 11 - right side, 6 - left side). Moreover, the statistically significant difference between the brainstem sides (4.27 vs. 4.11 msec; p<0.05) was observed. CONCLUSION: In the examined patients with acromegaly, there was no peripheral disturbance in transmission, as examined by BAEPs registrations. Conversely, in nearly half of the patients with acromegaly, brainstem transmission was found to be delayed, and significant difference between responses from the both sides of the brainstem were noted.

The role of cyclase activating (CAP) and cyclase inhibiting (CIP) parathormone fractions in the assessment of bone metabolism disturbances in women with hyperprolactinemia of various origin.

OBJECTIVES: Hyperprolactinemia could be one of possible causes of bone loss. The reason is thought to be connected with hypogonadism due to PRL excess and the role of other hormones like PTH and PTH-rP. There is no data on the influence of PTH fractions (CAP and CIP) on bone turnover and density in hyperprolactinemia. The aim of the study was to assess the influence of PTH and its fractions on bone metabolism in hyperprolactinemia of various origin. MATERIAL AND METHODS: The study was carried out in 75 women. Group I consisted of 32 women with prolactinoma, group II consisted of 43 women with functional hyperprolactinemia. Both groups were subdivided in patients with hypogonadism and normal gonadal function. The control group consisted of 29 healthy women. In all subjects PRL, PTH and its fractions (CAP, CIP), and bone turnover markers (BAP, ICTP) were studied. BMD measurement was carried out using DXA. RESULTS: In patients with functional hyperprolactinemia i-PTH and CAP levels were lower than in controls. CIP concentrations were lower in patients than in controls. CAP/CIP ratio was higher in patients with prolactinoma than in patients with functional hyperprolactinemia and controls. Higher values of bone turnover markers (BAP, ICTP) in patients groups and subgroups were shown as compared to controls. Some correlations between PTH and its fractions, and BMD and bone turnover were observed. CONCLUSIONS: There is no direct benefit from the assessment of parathormone fractions and CAP/CIP ratio in the prognosis of bone metabolism changes in hyperprolactinemia of various origin.