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.

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.

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.

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.

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.

Bone mineral density and bone turnover in hyperprolactinaemia of various origins.

INTRODUCTION: Osteopenia and osteoporosis because of hyperprolactinaemia caused by prolactinoma may be followed by an increased risk of fracture. There are no data on the bone effects of functional hyperprolactinaemia. The aim was to assess the influence of hyperprolactinaemia of various origins on bone turnover and density in different skeletal sites. MATERIAL AND METHODS: The study was carried out in 75 women (aged 30.53 +/- 7.8): Group I--32 women with prolactinoma and Group II--43 women with functional hyperprolactinaemia. Both groups of patients were subdivided into those with hypogonadism and those with normal gonadal function. The control group consisted of 29 healthy women aged (33.59 +/- 4.7). In all subjects PRL and bone turnover markers (BAP, OC, ICTP) were studied. BMD measurements (lumbar spine, forearm, proximal femur and total body) were carried out using DXA. RESULTS: Higher PRL concentrations were observed in patients than in controls. The values of bone turnover markers (BAP, ICTP) were shown to be higher in patient groups and subgroups than in controls. In patients with prolactinoma lumbar spine BMD was lower than in patients with functional hyperprolactinaemia and controls. Total body BMD was also lower, albeit to a lesser extent. CONCLUSIONS: Hyperprolactinaemia caused by prolactinoma in women influences bone metabolism unfavourably, more by the impact on the activity of bone turnover markers than on BMD. This provides an opportunity for earlier assessment of bone metabolism disturbances before the BMD changes can be observed. Functional hyperprolactinaemia does not determine such a harmful effect on bone metabolism as hyperprolactinemia due to prolactinoma.

A follow-up of 130 patients with acromegaly in a single centre.

OBJECTIVES: Acromegaly is a rare disease with increased mortality rate. The aim was to present our centre experience in the diagnosis and treatment of a series of patients suffering from acromegaly. METHODS: 130 patients (55 men, 75 women) aged 19-84 years presenting with clinical and hormonal features of acromegaly, attending Department of Endocrinology and Out-patient Clinic between 1990 and 2004 were studied. They were analyzed their GH and IGF-1 levels, CT and MRI scans, and they were administered medical therapy, neurosurgery and radiotherapy. RESULTS: We have observed 106 macro-, 16 microadenomas and 1 case of ectopic GHRH. 115 patients were operated, as cured were recognized 74 of them. Pituitary irradiation was applied to 11 patients, in 4 of them it did not cure the disease. Medical therapy was efficacious in 12% patients treated with bromocriptine, 73% with long-acting lanreotide and 58% with long-acting octreotide. In 7 patients other malignant neoplasm were detected. 11 patients died during the follow-up. CONCLUSIONS: There is possible underdiagnosis of acromegaly in our region, especially in males. We have observed better diagnostic opportunities in recent years when MRI was available. It was accompanied by better outcome of surgical and pharmacological treatment and better control of the complications of the disease.

[Hyperprolactinemia: etiology, clinical symptoms, and therapy]. / Hiperprolaktynemia: przyczyny, objawy kliniczne i mozliwosci terapeutyczne.

Hyperprolactinemia is one of the most common endocrinological disorders. The main clinical symptoms are limited to hypogonadism, which manifests as fertility disturbances, oligo- or amenorrhea in women, and libido loss, impotence, and fertility disturbances in men, as well as bone density disturbances (osteopenia, osteoporosis) and alactorrhea. Hyperprolactinemia is caused in most cases by drugs or it has an organic etiology (pituitary tumor:--prolactinoma). Differentiation between these two causes is very important for both therapeutic decisions and prognosis. In the medical treatment of a hyperprolactinemic condition dopamine receptors type D2 agonists are used. Such drugs have well-established high therapeutic efficiency (in the vast majority of patients they cause normalization of PRL serum level, tumor shrinkage, and withdrawal of the hyperprolactinemia-related symptoms and tumor mass). This is why they are the first line treatment for prolactinoma. In cases of a lack of pharmacological effect, drug intolerance or resistance, large tumors with accompanying compression symptoms' (tumor mass effect), dynamic tumor enlargement, or if a macroprolactinoma-affected woman desires pregnancy neurosurgery should be considered. Radiotherapy is used mainly as a supplement to surgical treatment.

[Personal observations of puberty in girls after unilateral ovariectomy]. / Wlasne obserwacje dotyczace przebiegu okresu dojrzewania u dziewczat po jednostronnej owariektomii.

The authors present the course of puberty in three girls after surgery because of hormonally active ovarian tumours diagnosed and operated at the age of 3, 6 and 9 years, respectively. In the youngest patient with folliculoma ovari chemotherapy was also given, and girl No. 3 with luteinic capsule was treated for one year with decapeptyl because idiopathic precocious puberty was diagnosed. At present all three girls are in good physical condition with age-adequate development and puberty.