Uterine fibroids in women diagnosed with acromegaly: a systematic review.

The review discusses the relationship between acromegaly and uterine fibroids. It highlights variations in research methodologies and inconsistent findings, emphasizing the complex nature of fibroid development and the role of the somatotropic axis. Additionally, it addresses demographic factors and examines the potential impact of therapies on the risk and prevalence of uterine fibroids in individuals with acromegaly. We conducted an analysis of previously published literature that examined the repercussions of acromegaly on gynecological health in female cohorts, with specific attention directed towards elucidating the prevalence of uterine fibroids. We suggest that larger, more focused studies are needed to understand the specific impact of different treatments on the occurrence of gynecological issues in acromegaly patients. Additionally, our study emphasizes the importance of factors such as disease duration and treatment effectiveness. We hypothesize that a relationship between acromegaly and uterine fibroids may occur. However, it remains an area of ongoing research, with the need for larger, multi-center studies to draw more definitive conclusions.

Pathologic Characteristics of Somatotroph Pituitary Tumors-An Observational Single-Center Study.

The pathologic evaluation of a tumor tissue is an essential part of an acromegaly patient's assessment. This study aimed to analyze the pathologic characteristics of pituitary tumors in patients with acromegaly. The demographic data, in addition to the hormonal, imaging, and pathologic results of 120 patients with acromegaly after pituitary surgery, were extracted from the Polish Acromegaly Registry. We compared sparsely and densely granulated tumors, GH(+), mixed GH(+)/PRL(+) and plurihormonal tumors, α-subunit-positive and α-subunit-negative tumors, and tumors of various Ki-67 indices in terms of the abovementioned features. Sparsely granulated tumors were more frequent in women than in men (p = 0.001) and in younger patients (p = 0.011), and they were larger (p < 0.001) compared to densely granulated tumors. Tumors with positive α-subunit were smaller (p = 0.013), showed extrasellar extension less often (p = 0.039), and were more often densely granulated (p < 0.001) compared to α-subunit-negative tumors. Patients with a higher Ki-67 index were younger (p < 0.001) and more often diagnosed with genetic syndromes (p = 0.02); they had higher GH concentrations (p = 0.007), larger tumors (p = 0.006), and cavernous sinus invasions more frequently (p = 0.022). Conclusions: The pathologic characteristics of somatotroph pituitary tumors are associated with patient's age, sex, hormonal results, tumor size, and the degree of extrasellar expansion.

Skeletal complications in acromegaly.

Hypersecretion of growth hormone (GH) is rare and typically results from a pituitary functional tumor - somatotropinoma. It leads to excessive linear bone growth and manifests as gigantism if occurring in childhood and adolescence, before the closure of epiphyses or as a acromegaly in adulthood. The excess of GH impacts bone metabolism directly as well as indirectly through increased insulin-like growth factor 1 (IGF-1). In acromegaly as a consequence of overproduction of GH and IFG-1 and the influence of these hormones on bone osteoblasts, bone metabolism, growth and density increase. However, bone turnover is accelerated causing impaired bone microstructure and strength, which may lead to increased risk of vertebral fractures irrespective of normal bone mineral density. Apart from the changes in bone architecture, acromegaly also results in a degenerative joint disease of a different nature than primary osteoarthritis. Moreover, acromegaly leads to cardiovascular, metabolic and respiratory complications, and thus significantly impairs the quality of life. In this review, authors summarize the pathophysiology, diagnosis, and treatment of bone and joint disease in acromegaly.

Macro-GH - A clinical entity causing a diagnostic challenge - A case report.

AIM: Presentation of a new case of a patient with macro-GH, that may interfere with different GH assays leading to false-positive results in serum samples. CASE PRESENTATION: A 61-year-old female was referred with a pituitary macroadenoma and elevated growth hormone levels. The laboratory tests showed increased fasting GH level, measured by a sandwich chemiluminescence immunoassay (LIAISON® XL) without suppression on oral glucose tolerance test and normal IGF-1. The patient did not have the typical signs and symptoms of acromegaly. The patient underwent a transsphenoidal resection of a pituitary tumor, showing only α-subunit immunostaining. Postoperative GH levels remained elevated. An interference in the determination of GH level was suspected. GH was analyzed by three different immunoassays, UniCel DxI 600, Cobas e411 and hGH-IRMA. Heterophilic antibodies and rheumatoid factor were not detected in serum sample. GH recovery after precipitation with 25 % polyethylene glycol (PEG) was 12 %. Size-exclusion chromatography confirmed the presence of macro-GH in serum sample. CONCLUSION: If results of laboratory tests are not consistent with the clinical findings, the presence of an interference within immunochemical assays could be suspected. To identify interference caused by the macro-GH, the PEG method and size-exclusion chromatography should be used.

Effects of acromegaly treatment on left ventricular systolic function assessed by speckle tracking echocardiography in relation to sex differences: results from a prospective single center study.

Background: Despite the preserved LVEF, patients with acromegaly are characterized by subclinical systolic dysfunction i.e., abnormal global longitudinal strain (GLS) assessed by speckle tracking echocardiography (STE). The effect of acromegaly treatment on LV systolic function assessed by STE, has not been evaluated so far. Patients and methods: Thirty-two naïve acromegalic patients without detectable heart disease were enrolled in a prospective, single-center study. 2D-Echocardiography and STE were performed at diagnosis, 3&6 months on preoperative somatostatin receptor ligand (SRL) treatment and 3 months after transsphenoidal surgery (TSS). Results: Treatment with SRL resulted in reduction in median (IQR) GH&IGF-1 levels after 3 months, from 9.1(3.2-21.9) to 1.8(0.9-5.2) ng/mL (p<0.001) and from 3.2(2.3-4.3) to 1.5(1.1-2.5) xULN (p<0.001), respectively. Biochemical control on SRL was achieved in 25.8% of patients after 6 months and complete surgical remission was achieved in 41.7% of patients. TSS resulted in decrease in median (IQR) IGF-1 compared to IGF-1 levels on SRL treatment: from 1.5(1.2-2.5) to 1.3(1.0-1.6) xULN (p=0.003). Females had lower IGF-1 levels at baseline, on SRL and after TSS compared to males. The median end diastolic and end systolic left ventricle volumes were normal. Almost half of the patients (46.9%) had increased LVMi, however the median value of LVMi was normal in both sex groups: 99g/m2 in males and 94g/m2 in females. Most patients (78.1%) had increased LAVi and the median value was 41.8mL/m2. At baseline 50% of patients, mostly men (62.5% vs. 37.5%) had GLS values higher than -20%. There was a positive correlation between baseline GLS and BMI r=0.446 (p=0.011) and BSA r=0.411 (p=0.019). The median GLS significantly improved after 3 months of SRL treatment compared to baseline: -20.4% vs. -20.0% (p=0.045). The median GLS was lower in patients with surgical remission compared to patients with elevated GH&IGF-1 levels: -22.5% vs. -19.8% (p=0.029). There was a positive correlation between GLS and IGF-1 levels after TSS r=0.570 (p=0.007). Conclusion: The greatest beneficial effect of acromegaly treatment on LV systolic function is visible already after 3 months of preoperative SRL treatment, especially in women. Patients with surgical remission have better GLS compared to patients with persistent acromegaly.

Severe ectopic Cushing syndrome in a transgender man with a metastatic gastrinoma and an adrenal tumor-A case report and review of the literature.

A 38-year-old transgender man with advanced metastatic functional pancreatic neuroendocrine neoplasm (PanNEN) gastrinoma was admitted to the Department of Endocrinology due to severe ACTH-dependent hypercortisolemia. An ectopic production of ACTH by PanNEN was suspected. The patient qualified for bilateral adrenalectomy after preoperative treatment with metyrapone. Finally, the patient underwent resection of the left adrenal gland with the tumor only, which surprisingly resulted in a significant decrease in ACTH and cortisol levels, leading to clinical improvement. Pathology report revealed an adenoma of the adrenal cortex with positive ACTH staining. The result of the simultaneous liver lesion biopsy confirmed a metastatic NEN G2 with positive ACTH immunostaining as well. We looked for a correlation between gender-affirming hormone treatment and the onset of the disease and its rapid progression. This may be the first case describing the coexistence of gastrinoma and ectopic Cushing disease in a transsexual patient.

Clinical, hormonal and pathomorphological markers of somatotroph pituitary neuroendocrine tumors predicting the treatment outcome in acromegaly.

Background: Transsphenoidal adenomectomy (TSS) of somatotroph pituitary neuroendocrine tumor (PitNET) is the first-line treatment of acromegaly. Pharmacological treatment is recommended if surgery is contraindicated or did not lead to disease remission. The choice of treatment best fitting each patient should be based on thorough investigation of patients' characteristics. The current analysis attempts to create a tool for personalized treatment planning. Aim: This study aimed to assess whether clinical, biochemical, imaging and pathological characteristics can predict surgical remission and response to first-generation somatostatin receptor ligands (SRLs) and pasireotide-LAR in acromegaly. Patients and methods: A retrospective study of 153 acromegaly patients, treated in the Department of Endocrinology in Bielanski Hospital in Warsaw, Poland was performed. Data on demographics, hormonal and imaging results, pathological evaluation, and treatment outcome was extracted from the Polish Acromegaly Registry collecting information from 11 endocrinology centers in Poland and analyzed. Results: Patients with surgical remission had lower GH and IGF-1 concentrations at diagnosis (median GH 5.5 µg/L [IQR: 3.1-16.0] vs. 19.9 µg/L [IQR: 9.8-42.4], p=<0.001 and mean IGF-1 3.1xULN ± SD=1.2 vs. 3.7xULN ± SD=1.2, p=0.007, respectively) and smaller tumors (median 12.5mm [IQR: 9-19] vs. 23mm [IQR: 18-30], p<0.001). These tumors were more often densely granulated (DG) (73.2% vs. 40.0%, p=0.001) with positive staining for alpha-subunit (α-SU) (58.3% vs. 35.5%, p=0.021) and lower Ki-67 index (p=0.002). Patients responding well to SRLs were more often male (55.6% vs 44.4%, p=0.026), presented lower GH concentration (median GH 17.2 µg/L [IQR: 6.2-29.0] vs. 23.8 µg/L [IQR: 11.2-49.5], p=0.048) and had more often DG tumors (63.0% vs. 14.3%, p<0.001). No significant differences between good and poor-response to pasireotide-LAR groups were found. In multivariate logistic regression analysis fasting GH concentration <8.63 µg/L, maximal tumor diameter <15.5mm, normoprolactinemia and DG tumor turned out to be independent predictors of surgical remission (OR=0.92, p=0.026; OR=0.87, p=0.069, OR=3.86, p=0.096 and OR=3.05, p=0.181, respectively). Fasting GH concentration <36.6 µg/L and DG tumor turned out to be independent predictors of good response to first-generation SRLs (OR=0.96, p=0.06 and OR=10.68, p=0.002, respectively). Conclusions: Younger age at diagnosis, male sex, lower GH, IGF-1 and PRL concentrations, smaller tumor size at diagnosis as well as positive α-SU staining, lower Ki-67 index and DG tumors predicted better treatment outcome in acromegaly patients.

Pituitary MRI Features in Acromegaly Resulting From Ectopic GHRH Secretion From a Neuroendocrine Tumor: Analysis of 30 Cases.

CONTEXT: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. OBJECTIVE: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. DESIGN: Multicenter, international, retrospective. SETTING: Tertiary referral pituitary centers. PATIENTS: Thirty ectopic acromegaly patients having GHRH hypersecretion. INTERVENTION: None. MAIN OUTCOME MEASURE: MRI characteristics of pituitary gland, particularly T2-weighted signal. RESULTS: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. CONCLUSIONS: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Real-world experience with pasireotide-LAR in resistant acromegaly: a single center 1-year observation.

CONTEXT: Pasireotide-LAR, a second-generation somatostatin receptor ligand (SRL), is recommended for patients with acromegaly as second-line treatment. Its efficacy and safety were assessed in clinical trials; however, the real-world evidence is still scarce. OBJECTIVE: The aim of this study was to evaluate the impact of 1-year treatment with pasireotide-LAR on disease control and glucose metabolism in acromegaly patients resistant to first-generation SRLs. DESIGN: A single-center prospective study. METHODS: Twenty-eight patients with active acromegaly or acrogigantism on first-generation SRLs following ineffective pituitary surgery were switched to treatment with pasireotide-LAR 40 or 60 mg i.m. every 28 days. To assess the efficacy of the treatment GH and IGF-1 levels were measured every 3 months. Safety of treatment was carefully evaluated, especially its impact on glucose metabolism. RESULTS: Complete biochemical control (GH ≤ 1 ng/mL and IGF-1 ≤ 1 × ULN) was achieved in 26.9% of patients and partial + complete response (GH ≤ 2.5 ng/mL and IGF-1 ≤ 1.3 × ULN) in 50.0% of patients. Mean GH level decrease was the largest within first 6 months (P = 0.0001) and mean IGF-1 level decreased rapidly within the first 3 months (P < 0.0001) and they remained reduced during the study. Blood glucose and HbA1c levels increased significantly within 3 months (P = 0.0001) and stayed on stable level thereafter. Otherwise, the treatment was well tolerated and clinical improvement was noticed in majority of patients. CONCLUSIONS: This real-life study confirmed good effectiveness of pasireotide-LAR in patients resistant to first-generation SRLs. Pasireotide-LAR was overall safe and well tolerated, however significant glucose metabolism worsening was noted.

Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review.

Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.

Subclinical left ventricular systolic dysfunction in patients with naive acromegaly - assessment with two-dimensional speckle-tracking echocardiography: retrospective study.

INTRODUCTION: The aim of the study was to evaluate global longitudinal strain (GLS) in patients with naive acromegaly with normal left ventricular (LV) ejection fraction (EF). MATERIAL AND METHODS: Forty-three consecutive patients with naive acromegaly with normal LV systolic function as measured by EF, examined from 2008 to 2016, and 52 patients of a control group matched for age and sex underwent two-dimensional speckle-tracking echocardiography to assess GLS. RESULTS: The median GLS was significantly lower in the acromegaly group than in the control group (in %, -16.6 vs. -20.7; p < 0.01). The majority of acromegalic patients (n = 26; 60.5%) had abnormal GLS. Patients with impairment in GLS had a longer median duration of acromegaly symptoms (in years, 10.0 vs. 5.0; p < 0.05) and greater LV thickness (posterior wall in mm, 12.5 vs. 12.0; p < 0.05) compared to those with normal GLS. Patients with abnormal GLS had higher IGF-1 concentration, but without statistical significance. Diabetes mellitus and arterial hypertension, which are more common in acromegaly, were not significant determinants of abnormal GLS. The mean left ventricular mass index (LVMI) was increased in the acromegaly group compared to controls (in g/m², 136 vs. 97; p < 0.01). There was a significant negative correlation between LVMI and GLS (R = -0.47; p < 0.01). CONCLUSIONS: Naive acromegalic patients presented abnormal GLS, which indicates subclinical systolic dysfunction in these patients. It has not been proven that arterial hypertension and diabetes mellitus are significant determinants of abnormal GLS.

Corticotropinoma as the underlying cause of intermittent Cushing's syndrome in a patient previously diagnosed with primary pigmented nodular adrenocortical disease.

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Immunotherapy of solid tumors: safety of treatment.

Immunotherapy with immune checkpoint inhibitors (ICIs) was shown to improve survival of patients with solid tumors such as: melanoma, renal carcinoma, non-small cell lung cancer, cutaneous carcinomas, or head and neck carcinoma. However, a special type of ICIs toxicity is observed, namely noninfectious inflammation of different organs associated with autoimmunity known as immune­related adverse events (irAEs). This noninfectious inflammation may affect the endocrine system, gastrointestinal tract, heart, skin, and nervous system. The lungs are also often involved and this condition is referred to as checkpoint inhibitor pneumonitis. The toxicity of ICIs is graded from 1 to 5 depending on the clinical course, 5 being a fatal complication. Corticosteroids are the treatment of choice, generally with good efficacy. In some difficult cases, escalation of immunosuppression is required. Knowledge of irAEs should be promoted among clinicians of all specialties, nurses, patients and their families. The aim of this review is to present the wide spectrum of irAEs: clinical signs and symptoms, differential diagnosis, diagnostic procedures, and treatment. Data are supported by our own clinical observations.

Heart in Acromegaly: The Echocardiographic Characteristics of Patients Diagnosed with Acromegaly in Various Stages of the Disease.

To determine whether the echocardiographic presentation allows for diagnosis of acromegalic cardiomyopathy. 140 patients with acromegaly underwent echocardiography as part of routine diagnostics. The results were compared with the control group comprising of 52 age- and sex-matched healthy volunteers. Patients with acromegaly presented with higher BMI, prevalence of arterial hypertension, and glucose metabolism disorders (i.e., diabetes and/or prediabetes). In patients with acromegaly, the following findings were detected: increased left atrial volume index, increased interventricular septum thickness, increased posterior wall thickness, and increased left ventricular mass index, accompanied by reduced diastolic function measured by the following parameters: E'med., E/E', and E/A. Additionally, they presented with abnormal right ventricular systolic pressure. All patients had normal systolic function measured by ejection fraction. However, the values of global longitudinal strain were slightly lower in patients than in the control group; the difference was statistically significant. There were no statistically significant differences in the size of the right and left ventricle, thickness of the right ventricular free wall, and indexed diameter of the ascending aorta between patients with acromegaly and healthy volunteers. None of 140 patients presented systolic dysfunction, which is the last phase of the so-called acromegalic cardiomyopathy. Some abnormal echocardiographic parameters found in acromegalic patients may be caused by concomitant diseases and not elevated levels of GH or IGF-1 alone. The potential role of demographic parameters like age, sex, and/or BMI requires further research.

Fatal Carney Complex in Siblings Due to De Novo Large Gene Deletion.

Context: Carney complex (CNC) is a rare multiple neoplasia syndrome involving cardiac, endocrine, neural, and cutaneous tumors and a variety of pigmented skin lesions. CNC can be inherited as an autosomal dominant trait, but in about one-third of patients, the disease is caused by de novo mutation in the PRKAR1A gene localized on chromosome 17q22-24. Most of the mutations include single base substitutions and small deletions/insertions not exceeding 15 base pairs. Recently, large germline PRKAR1A deletions have been described and may cause a more severe phenotype. Case Description: Herein, we report the cases of two siblings with CNC with a de novo large deletion of 107 kb at 17q24.2 associated with acromegaly in both and primary pigmented nodular adrenocortical disease, cardiac myxoma, and lethal metastatic melanotic schwannian tumor at the age of 27 years in one of them, supporting the hypothesis that large deletions of PRKAR1A lead to severe disease. Conclusions: To our knowledge, this is the first description of familial CNC in siblings in which neither parent carried the deletion in blood-derived DNA, suggesting that one of them had germ cell mosaicism for this deletion. Testing for large gene deletions should be obtained in all patients who meet the diagnostic criteria for CNC but do not have a PRKAR1A mutation by Sanger sequencing.