Diagnosis and therapeutic approach to bone health in patients with hypopituitarism.

The results of many studies in recent years indicate a significant impact of pituitary function on bone health. The proper function of the pituitary gland has a significant impact on the growth of the skeleton and the appearance of sexual dimorphism. It is also responsible for achieving peak bone mass, which protects against the development of osteoporosis and fractures later in life. It is also liable for the proper remodeling of the skeleton, which is a physiological mechanism managing the proper mechanical resistance of bones and the possibility of its regeneration after injuries. Pituitary diseases causing hypofunction and deficiency of tropic hormones, and thus deficiency of key hormones of effector organs, have a negative impact on the skeleton, resulting in reduced bone mass and susceptibility to pathological fractures. The early appearance of pituitary dysfunction, i.e. in the pre-pubertal period, is responsible for failure to achieve peak bone mass, and thus the risk of developing osteoporosis in later years. This argues for the need for a thorough assessment of patients with hypopituitarism, not only in terms of metabolic disorders, but also in terms of bone disorders. Early and properly performed treatment may prevent patients from developing the bone complications that are so common in this pathology. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary disease.

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.

Is H19 RNA a Useful Marker of Acromegaly and Its Complications? A Preliminary Study.

Acromegaly is a rare endocrine disorder caused by somatotroph pituitary adenoma. Besides its typical symptoms, it contributes to the development of cardiovascular, metabolic, and bone comorbidities. H19 RNA is a long non-coding RNA and it is suspected to be involved in tumorigenesis, cancer progression, and metastasis. H19 RNA is a novel biomarker for the diagnosis and monitoring of neoplasms. Moreover, there might be an association between H19 and cardiovascular and metabolic diseases. We enrolled 32 acromegaly patients and 25 controls. We investigated whether whole blood H19 RNA expression is associated with the diagnosis of acromegaly. Correlations between H19 and tumour dimension, invasiveness, and biochemical and hormonal parameters were evaluated. We analysed the coincidence of acromegaly comorbidities with H19 RNA expression. In the results, we did not observe a statistically significant difference in H19 RNA expression between acromegaly patients and the controls. There were no correlations between H19 and the adenoma size and infiltration and patients' biochemical and hormonal statuses. In the acromegaly group, hypertension, goitre, and cholelithiasis were observed more frequently. The diagnosis of acromegaly was a factor contributing to the occurrence of dyslipidaemia, goitre, and cholelithiasis. We found an association between H19 and cholelithiasis in acromegaly patients. To conclude, H19 RNA expression is not a relevant marker for diagnosis and monitoring of acromegaly patients. There is a higher risk of hypertension, goitre, and cholelithiasis related to acromegaly. Cholelithiasis is associated with a higher H19 RNA expression.

The Influence of SARS-CoV-2 Infection on the Thyroid Gland.

It is important to acknowledge the impact that COVID-19 has on the thyroid gland and how the thyroid gland status before and during infection affects SARS-CoV-2 severity. To this day those dependencies are not fully understood. It is known that the virus uses angiotensin-converting enzyme-2 as the receptor for cellular entry and it can lead to multiple organ failures due to a cytokine storm. Levels of proinflammatory molecules (such as cytokines and chemokines) which are commonly elevated during infection were significantly higher in observed SARS-CoV-2-positive patients. In terms of hypothyroidism, hyperthyroidism, and autoimmune thyroid diseases, there is no proof that those dysfunctions have a direct impact on the more severe courses of COVID-19. Regarding hyper- and hypothyroidism there was no consequential dependency between the frequency of SARS-CoV-2 infection morbidity and more severe post-infectious complications. When it comes to autoimmune thyroid diseases, more evaluation has to be performed due to the unclear relation with the level of antibodies commonly checked in those illnesses and its binding with the mentioned before virus. Nonetheless, based on analyzed works we found that COVID-19 can trigger the immune system and cause its hyperactivity, sometimes leading to the new onset of autoimmune disorders. We also noticed more acute SARS-CoV-2 courses in patients with mainly reduced free triiodothyronine serum levels, which in the future, might be used as a mortality indicating factor regarding SARS-CoV-2-positive patients. Considering subacute thyroiditis (SAT), no statistically important data proving its direct correlation with COVID-19 infection has been found. Nevertheless, taking into account the fact that SAT is triggered by respiratory tract viral infections, it might be that SARS-CoV-2 can cause it too. There are many heterogenous figures in the symptoms, annual morbidity distribution, and frequency of new cases, so this topic requires further evaluation.

The clinical complexity of patients with acromegaly.

OBJECTIVES: The main aim of the study was to investigate the factors related to the biopsychosocial complexity in the group of patients with acromegaly with different disease activity. METHODS: A cross-sectional observational study was performed. First, a linguistic adaptation of the INTERMED - self-assessment questionnaire (IMSA) and after that the assessment of the biopsychosocial complexity among patients with acromegaly and the factors which relate to the complexity was made. The following tools were used to assess: biopsychosocial complexity: The INTERMED -self-assessment (IMSA); quality of life: The World Health Organization Quality of Life - BREF (WHOQoL) and Acromegaly Quality of Life questionnaire (AcroQol); mental state: The General Health Questionnaire - 28 (GHQ-28). RESULTS: The final analysis included 71 patients. According to the principal component analysis the mental state (GHQ-28) and the quality of life (AcroQol) are the most important factors related to the clinical complexity among patients with acromegaly. In the model created by a stepwise regression analysis for the total IMSA score higher growth hormone (GH) concentration, longer illness duration, and better general quality of life were included as the protective factors of the clinical complexity. By contrast, a high score in the severe depression subscale of GHQ-28 was a factor of higher clinical complexity. CONCLUSION: The mental state and quality of life are the most important determinants of the clinical complexity in the group of patients with acromegaly whereas the biochemical normalization is of lesser importance.

Trabecular Bone Score and Osteoprotegerin as Useful Tools in the Assessment of Bone Deterioration in Acromegaly.

Purpose: This study aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) in 61 patients from the acromegaly group (AG) with regard to the activity of the disease in comparison to 42 patients-control group (CG). We also analyzed selected bone markers and their association with BMD and TBS. Materials and Methods: Lumbar spine and femoral neck BMD measurements were performed. TBS values were obtained. Serum concentrations of selected bone markers, including osteoprotegerin (OPG), were measured. Results: We revealed a difference in TBS values between the AG and CG as well as between the TCA (treatment-controlled acromegaly) vs. CG and TCA+CA (cured acromegaly) vs. CG. We did not observe any statistically significant difference in BMD. OPG had a lower concentration in the CG compared to the AG. TBS correlated negatively with OPG in the AG (r = -0.31, p = 0.01) and in the TCA+ CA group (r = -0.3, p = 0.01). Conclusions: The acromegalic patients have altered bone microstructure as indicated by the decreased TBS regardless of the activity of the disease and BMD. OPG could be a marker of the destruction of the bone microstructure, but further studies are needed.

Osilodrostat - an emerging drug for the medical management of Cushing's disease.

Cushing's disease (CD) is a rare endocrine disorder characterized by the overproduction of adrenocorticotropic hormone (ACTH) by pituitary adenoma followed by hypercortisolaemia with severe complications. Although transsphenoidal resection of the defined pituitary adenoma has been the treatment of choice for the past decades, it does not always result in long-term remission - 10-30% of cases show ineffective surgical treatment or tumour recurrence even after initial success. Pharmacological therapies for cortisol reduction are often required for those who either cannot undergo pituitary surgery or when the surgery has failed, and patients still present with the persistent disease. Osilodrostat is a potent oral steroidogenesis inhibitor that has lately been shown as an effective adjuvant therapy in the management of patients with CD. In this article, we review the recent reports on the efficacy and safety of osilodrostat in clinical settings.

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.

The frequency of TLR2 (rs3804099, rs3804100, and rs5743708) and TLR4 (rs4986790 and rs4986791) polymorphisms in women with polycystic ovary syndrome - preliminary study.

INTRODUCTION: Low-grade chronic inflammation may participate in PCOS etiology. Toll-like receptors (TLRs) may play a pivotal role in the initiation and progression of inflammatory process. We examined TLR2 and TLR4 gene polymorphisms in women with PCOS and their associations with metabolic/hormonal parameters. MATERIAL AND METHODS: Sixty-eight women qualified for the study. PCOS was diagnosed in 40 women. The control group consisted of 28 women. All patients underwent anamnesis, physical examination, anthropometric measurements, and biochemical/hormonal assessments. The TLRs gene polymorphism was tested using PCR and the minisequencing method. RESULTS: The frequency of TLR2 gene polymorphisms genotypes (rs3804099, rs3804100, and rs5743708) did not differ significantly between the groups. The difference in frequency of genotypes of TLR4 gene polymorphisms (rs4986790 and rs4986791) was close to the statistical significance level. No significant correlations between TLR2/TLR4 polymorphisms and anthropometric/metabolic parameters in PCOS group were observed. However, the relationship between HDL concentration and TLR2 S450S (rs3804100) polymorphism was close to the statistical significance level. Positive correlations between the two TLR4 polymorphisms (rs4986790 and rs4986791) were found, as well as between the TLR2 S450S (rs3804100) gene polymorphism and FSH concentration. CONCLUSIONS: The TLR4 gene polymorphism may play a role in the PCOS etiopathogenesis but this observation needs further investigation.

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.

H19 in Endocrine System Tumours.

Long non-coding RNAs (lncRNAs) are over 200 nucleotides long recently discovered RNA molecules that are not involved in the translation process. Accumulating evidence shows that H19 lncRNA is an important regulator of gene expression and its altered expression contributes to carcinogenesis. The aim of this review was to reveal current knowledge about H19 lncRNA and its impact on tumours of the endocrine system. We present findings about H19 altered regulation and its association with tumorigenesis, cancer progression and differentiation, and its potential use in diagnostics, prognostics and therapy. The mechanism and molecular pathways involved in these processes are discussed.

Bone densitometry by radiofrequency echographic multi-spectrometry (REMS) in acromegaly patients.

INTRODUCTION: Radiofrequency echographic multi-spectrometry (REMS) is a recently introduced non-ionising technology employed in the evaluation of osteoporosis. The aim of our study was to compare bone mineral density (BMD) in acromegaly patients and healthy controls by performing novel REMS densitometry. The second objective was to analyse the correlation between results of REMS and classical dual-energy X-ray absorptiometry (DXA) in acromegaly patients. MATERIAL AND METHODS: We enrolled 33 patients with acromegaly (AG) and 24 controls (CG). The acromegaly patients were divided into two subgroups: well-controlled acromegaly (WCA) and surgery-cured acromegaly (SCA). REMS was performed in all participants, while DXA was performed only in the acromegaly group. IGF-I and GH levels were measured in acromegaly patients. RESULTS: Bone mineral density of the lumbar spine (LS) and the femoral neck (FN) obtained from REMS did not reveal significant differences between AG, CG, WCA, and SCA. Similarly, there were no significant differences in BMD measured by DXA at the LS and at the FN between WCA and SCA. Significant positive correlations between IGF-I concentrations and BMD obtained from both REMS and DXA were detected in the AG and WCA. In the AG and WCA, there were positive correlations between T-scores and LS BMD obtained from both methods. CONCLUSIONS: Radiofrequency echographic multi-spectrometry is a potential method in assessment of bone status in acromegaly. Further studies with participation of active disease patients are needed.

Therapeutic effect of presurgical treatment with longacting octreotide (Sandostatin® LAR®) in patients with acromegaly.

INTRODUCTION: The aim of this study was to assess the therapeutic effect and the safety of pre-surgical treatment with long-acting octreotide in patients with acromegaly. MATERIAL AND METHODS: This project was conducted in 25 centres across Poland as a non-interventional, multicentre, observational study in patients with acromegaly, in which long-acting octreotide Sandostatin® LAR®) was administered before surgery. They were 148 patients included into the study: 88 females and 60 males aged 18-86 years (51.3 ± 13.4). RESULTS: Eighty patients completed the study (underwent tumour surgery). The CRF included: baseline visit, four follow-up visits every three months before surgery, and two follow-up visits every three months after surgery. Sandostatin® LAR® was administered every four weeks. The efficacy measures were as follows: change of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, number of patients fulfilling criteria of cure, and change of adenoma (micro- and macroadenomas) size during the treatment. Normalisation of GH and IGF-1 concentrations were obtained in 42.4 and 49.1% of patients at the end of medical therapy, respectively. Normalisation of GH and IGF-1 concentrations were obtained in 77.9 and 83.8% of patients after surgery, respectively. Reduction of microadenoma size was documented in 58.8% of patients, and in 70% of patients with macroadenomas at the end of medical therapy. In 74.0% of patients no pituitary tumour was shown on MRI after surgery. CONCLUSION: We have shown good surgical outcome in patients with acromegaly after pre-treatment with somatostatin analogue, and good tolerance and safety of the therapy, supporting the national recommendation for pre-surgical treatment with long-acting somatostatin analogues in acromegaly patients.

Association of Vitamin D Receptor Polymorphisms With Activity of Acromegaly, Vitamin D Status and Risk of Osteoporotic Fractures in Acromegaly Patients.

Introduction: The vitamin D receptor (VDR) gene is one of the most widely studied tumorigenesis-related genes. The primary objective of this study was assessment of possible roles of VDR gene polymorphisms in acromegaly, with regard to the activity of the disease and compared them with a control group. Furthermore, we have assessed the associations between these polymorphisms with vitamin D status as well as with TBS (trabecular bone score) and risk for osteoporotic fracture in acromegaly patients. Materials and Methods: We studied 69 patients with acromegaly and 51 healthy controls (CG). Acromegaly patients were divided into three subgroups on the basis of disease activity (AA, active acromegaly; CD, controlled disease; CA, cured acromegaly). In all patients, blood samples were obtained to assess the hormonal and metabolic status as well as genetic analysis. VDR polymorphisms were determined by means of two methods, Polymerase Chain Reactions (PCR) and minisequencing (SNaPshot). Results: Genotype frequencies for VDR ApaI, TaqI, BsmI, and FokI polymorphisms did not deviate significantly from Hardy-Weinberg equilibrium (HWE) in the acromegaly group as well as in the control group. There was no statistically significant difference in distributions of these four VDR genotypes between acromegaly patients and the control group. This study revealed statistically significant negative correlation between risk of major osteoporotic fractures and genotypes tt (TaqI), aa (ApaI) and bb (BsmI) in acromegaly groups. Furthermore, the negative correlations were observed between TBS and risk for major osteoporotic fractures and hip fractures. Conclusions: Our study suggests that tt (TaqI), aa (ApaI) and bb (BsmI) of VDR gene may be associated with better bone quality and microarchitecture (higher TBS), which lead to a lower risk of osteoporotic fractures in acromegaly patients. TBS may be a useful tool for predicting risk of fractures in acromegaly patients.