Musculoskeletal complications of Cushing syndrome.

Prolonged exposure to an excess of glucocorticosteroids (GCs), both endogenous and exogenous, leads to a wide range of comorbidities, including cardiovascular, metabolic, psychiatric, and musculoskeletal disorders. The latter comprise osteopenia and osteoporosis leading to skeletal fractures and myopathy. Although endogenous hypercortisolemia is a rare disorder, GCs are among the most frequently prescribed drugs, often administered chronically and despite multiple side effects, impossible to taper off due to therapeutic reasons. The pathophysiology of the effect of GC excess on bone often leads to fractures despite normal or low-normal bone mineral density and it includes direct (mainly disturbance in bone formation processes, through inactivation of the Wnt/ß-catenin signalling pathway) and indirect mechanisms (through suppressing the gonadal and somatotrophic axis, and also through antagonizing vitamin D actions). Glucocorticosteroid-induced fast-twitch, glycolytic muscles atrophy occurs due to increased protein catabolism and impaired synthesis. Protein degradation is a result of activation of the ubiquitin proteasome and the lysosomes stimulated through overexpression of several atrogenes (such as FOXO-1 and atrogin-1). This review will discuss pathophysiology, clinical presentation, prevention, and management of GC-induced osteoporosis (including calcium and vitamin D supplementation, and bisphosphonates) and myopathy associated with GC excess.

Risk of malignancy in adrenal tumors in patients with a history of cancer.

Purpose: Adrenal gland is a common site of metastasis and on the other hand, metastases are the most frequent malignant adrenal tumors. The aim of this study was to estimate the risk of malignancy in suspicious adrenal mass in patients with a history of cancer. Methods: This is a single-center retrospective analysis of patients with adrenal tumors treated previously for different types of cancers. Between 2004 and 2021 a hundred and six such patients were identified. Mean age of patients was 62.6 years (30-78), and mean time from oncologic treatment was 55.8 months (0-274). The most common primary cancer was kidney (RCC): 29 (27.4%), colon/rectum (CRC): 20 (18.9%) and lung (NSCLC): 20 (18.9%). Results: Of 106 patients, 12 had hormonally active (HA) (11,3%) and 94 (88,7%) non active (HNA) tumors In group of patients with HA tumours 4 had hypercortisolaemia and 8 had elevation of urinary metanephrines. In the first group of HA patients pathology confirmed preoperative diagnosis of adrenocortical cancer and no metastasis was found. In all patients from the second group pheochromocytomas were confirmed. Primary (PM) and secondary (SM) malignancies were found in 50 patients (47.2%). In hormone inactive group only SM - 46/94 (48.9%) were diagnosed. The odds that adrenal lesion was a metastasis were higher if primary cancer was RCC (OR 4.29) and NSCLC (OR 12.3). Metastases were also more likely with high native tumor density, and bigger size in CT. The cut-off values for tumor size and native density calculated from receiver operating characteristic (ROC) curves were 37mm and 24, respectively. Conclusion: Risk of malignancy of adrenal mass in a patient with a history of cancer is high (47,2%), regardless of hormonal status. 47,2% risk of malignancy. In preoperative assessment type of primary cancer, adrenal tumour size and native density on CT should be taken into consideration as predictive factors of malignancy. Native density exceeding 24 HU was the strongest risk factor of adrenal malignancy (RR 3.23), followed by history of lung or renal cancer (RR 2.82) and maximum tumor diameter over 37 mm (RR 2.14).

Evaluation of plasma ACTH in the metyrapone test is insufficient for the diagnosis of secondary adrenal insufficiency.

Objective: To determine whether a single measurement of ACTH instead of less available in daily practice 11-deoxycortisol assay is sufficient to rule out or confirm secondary adrenal insufficiency (SAI) in the short Metyrapone test. Design: A retrospective analysis of diagnostic tests (Metyrapone and Synacthen tests) performed at our Center between 2016 and 2018 in patients with suspicion of secondary adrenal insufficiency. Material and methods: In 103 patients short metyrapone test was performed with assessment of 11-deoxycortisol and ACTH concentration after Metyrapone administered at midnight. In 89 of them short Synacthen (SST) test was also done (1 or/and 250 mcg 1-24ACTH). ROC curves have been performed to evaluate the diagnostic performance of ACTH level in metyrapone test as the predictor of secondary adrenal insufficiency (SAI) analysing sensitivity and specificity for various possible thresholds proposed in literature. Results: 40 (39%) of examined subjects were diagnosed as SAI, basing on post-Metyrapone 11-deoxycortisol concentration below 70 µg/l. In this group ACTH concentration was 128.1 ng/l (95% CI 96.8-159.4) versus 289.9 ng/l (95% CI 249.1-330.9) in patients with proper adrenal response. There was only a moderate positive correlation between ACTH and 11-deoxycortisol concentrations (r=0.5; p<0.05). The best cut off value of ACTH in relation to 11-deoxycortisol serum concentrations was 147 ng/l - with sensitivity of 73.2% and specificity 83.9%. However, plasma ACTH was>200ng/ml (the highest threshold proposed in literature) in 8 cases (20%) with positive diagnosis of SAI made on the basis of low 11-deoxycortisole and confirmed in short Synacthen test. Conclusion: Our results indicate that for a valuable evaluation of the results of the metyrapone test, the more readily available plasma ACTH assay cannot replace the measurement of 11-deoxycortisol concentrations.

Poor Performance of Angiotensin II Enzyme-Linked Immuno-Sorbent Assays in Mostly Hypertensive Cohort Routinely Screened for Primary Aldosteronism.

Primary aldosteronism (PA) is the most common, but broadly underdiagnosed, form of hormonal hypertension. To improve screening procedures, current biochemical approaches aim to determine newly appreciated angiotensin II (Ang II) and calculate the aldosterone-to-angiotensin II ratio (AA2R). Thus, the aim of this study was to assess the diagnostic performance of these screening tests in comparison to the aldosterone-to-direct renin ratio (ADRR), which is routinely used. Cheap and available ELISA was used for Ang II measurement. To our knowledge, this is the first study of this laboratory method's usage in PA. The study cohort included 20 PA patients and 80 controls. Ang II concentrations were comparable between PA and non-PA patients (773.5 vs. 873.2 pg/mL, p = 0.23, respectively). The AA2R was statistically significantly higher in PA group when compared with non-PA (0.024 vs. 0.012 ng/dL/pg/mL, p < 0.001). However, the diagnostic performance of the AA2R was significantly worse than that of the ADRR (AUROC 0.754 vs. 0.939, p < 0.01). The sensitivity and specificity of the AA2R were 70% and 76.2%, respectively. Thus, the AA2R was not effective as a screening tool for PA. Our data provide important arguments in the discussion on the unsatisfactory accuracy of renin−angiotensin system evaluation by recently repeatedly used ELISA tests.

ProSAAS peptide of the granin protein family in biochemical diagnostics of pheochromocytoma.

INTRODUCTION: Pheochromocytoma is a hormonally active tumour originating from neuroendocrine cells of the adrenal medulla. Chromogranin A (CgA) and peptide proSAAS belong to the family of granins and are present in neuroendocrine cells of adrenal medulla, from where they are released to circulation, along with catecholamines. The aim of this study was to assess the usability of proSAAS peptide assay in patients with adrenal pheochromocytoma. MATERIAL AND METHODS: 23 patients (13 females and 10 males) with adrenal pheochromocytoma (benign in 18 patients and malignant in 5) confirmed by histopathology examination, and 35 blood donors as a control group. Plasma free metanephrines, CgA, and proSAAS peptide levels were measured in all participants. RESULTS: CgA and proSAAS levels in the group of pheochromocytoma patients vs. the control were: 209 ng/mL and 0.8 ng/mL vs. 59 ng/mL and 0.3 ng/mL (p < 0.001), respectively. The following sensitivity and specificity indexes were obtained from ROC curves for CgA: 83% and 92%, respectively, and for the proSAAS peptide: 39% and 88%, respectively. The combination of 2 parameters: normetanephrine and proSAAS (96% and 100%) had a high diagnostic value, and the value of all determined parameters together (metanephrine, normetanephrine, CgA, and proSAAS) was 100%. CONCLUSION: A single determination of the proSAAS peptide level is associated with a rather low diagnostic value. But collective determination of CgA and proSAAS may be an additional, valuable tool in biochemical diagnostics of pheochromocytoma.

Adrenal "nonadenoma" - clinical characteristics and risk of malignancy.

INTRODUCTION: There is an increasing number of adrenal tumours discovered incidentally during imaging examinations performed for many different indications. Based on imaging results, it is possible to differentiate benign from malignant adrenal masses, although there is still a number of equivocal imaging findings. Our study presents 77 cases of adrenal tumours in which imaging was inconclusive and the final diagnosis was stated only after surgery and histopathological examination. MATERIAL AND METHODS: Retrospective data analysis: 77 cases of indeterminate adrenal tumours with a presumptive diagnosis of "nonadenoma" in patients operated within a 16-year period (2004-2019). None of the patients had a history of malignancy, and all tumours were hormonally inactive. On contrast-enhanced computed tomography (CT), the native density of all tumours was higher than 10 Hounsfield Units (HU), and the absolute percentage washout (APW) and relative percentage washout (RPW) were lower than 60% and 40%, respectively. RESULTS: The most common findings were adrenal adenoma (25.9%), macronodular adrenal hyperplasia (16.9%), ganglioneuroma (15.6%), and haemorrhage with posthaemorrhagic changes (13%). In total, there were 12 various histopathological diagnoses in this group. There were only 2 (2.6%) malignant (adrenal cancer and leiomyosarcoma) and 3 (3.9%) potentially malignant (pheochromocytoma) lesions in this group. CONCLUSIONS: It is often impossible to make a correct diagnosis in a clinical setting until it is histologically verified. "Nonadenoma" adrenal tumours constitute a heterogeneous group including very rare pathologies. The risk of malignancy in indeterminate adrenal tumours is relatively low.

High prevalence of steroid-induced glucose intolerance with normal fasting glycaemia during low-dose glucocorticoid therapy: an oral glucose tolerance test screening study.

OBJECTIVES: To evaluate the prevalence and risk factors of new-onset glucose metabolism impairment using an oral glucose tolerance test (OGTT) in patients with normal fasting glycaemia on long-term glucocorticoid (GC) treatment. METHODS: An OGTT was performed in 150 patients without a previous history of pre-diabetes or diabetes who were diagnosed with inflammatory rheumatic diseases and treated with GCs >3 months. All participants underwent clinical and biochemical evaluation for risk factors of diabetes: age, sex, current and cumulative dose of steroids, treatment duration, waist circumference, BMI, Homeostatic Model Assessment for Insulin Resistance, fasting insulin concentration, family history of diabetes, CRP, 28-joint DAS with CRP, type of connective tissue disease and trunk fat percentage measured by DXA. Logistic regression analysis was conducted to evaluate the association between the presence of impaired glucose tolerance (IGT) in the OGTT and analysed risk factors. RESULTS: A total of 102 patients (68%) had fully normal glucose tolerance. Diabetes, isolated impaired fasting glucose, isolated IGT and combined impaired fasting glucose + IGT was diagnosed in 3.3, 4.67, 19.33 and 4.67% of patients, respectively; 20% of participants had IGT or diabetes despite normal fasting glucose concentration. The median cumulative dose and current dose (5 mg) of GCs and treatment duration were similar compared with the normal glucose tolerance group. In a multivariate logistic regression model, only older age (particularly ≥50 years of age) and trunk fat percentage remained significant factors predicting IGT or diabetes in the OGTT. CONCLUSION: New-onset GC-induced glucose intolerance, even in patients on long-term low-dose treatment, is prevalent despite normal fasting glucose concentration and patients should be screened with an OGTT despite the absence of classic risk factors of diabetes.

Supplementation of dehydroepiandrosterone (DHEA) in pre- and postmenopausal women - position statement of expert panel of Polish Menopause and Andropause Society.

Dehydroepiandrosterone (DHEA) concentration decreases with age, therefore, DHEA has been considered a hormone that reduces the symptoms associated with aging, so the usefulness of DHEA in premenopausal and postmenopausal women, and the options of hormone therapy have received a large amount of attention. The effectiveness of DHEA in the premenopausal women remains unclear, while in postmenopausal women with coexisting estrogens deficiency is controversial. Despite many years of study, the use of DHEA is still controversial, especially regarding its effectiveness. The aim of present article was to evaluate DHEA specific effects on metabolic parameters, bone mineral density, insulin resistance as well as the therapeutic potential of DHEA in pre- and postmenopausal women using measures of sexual activity, cognition and well-being. The summary of this article is the position statement of expert group of the Polish Menopause and Andropause Society regarding the efficacy and safety of DHEA supplementation in women. We concluded, that currently available clinical trials and meta-analyses indicate that DHEA supplementation is effective in women with adrenal insufficiency and chronically treated with exogenous glucocorticoids, postmenopausal women with low bone mineral density and/or osteoporosis, premenopausal women with sexual disorders and low libido, and in women with vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause. Currently available clinical trials also suggest that DHEA supplementation is probably effective in postmenopausal women with hypoactive sexual disorders, infertile women with diminished ovarian reserve, women suffering from depression and anxiety, and women with obesity and insulin resistance. No serious adverse effects have been reported.

Pitfalls in the diagnostics of aldosterone-producing adrenocortical carcinoma.

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Adrenal metastases - long-term results of surgical treatment, single-centre experience.

INTRODUCTION: The adrenal gland is a frequent site of metastases in different types of cancer. The aim of this study was to assess the results of metastatic adrenalectomy in a single institution and to identify factors for survival. MATERIAL AND METHODS: A retrospective, single-centre analysis of outcomes of 39 patients (22 male, 17 female) with adrenal metastases who underwent surgery within 14 years (2004-2017) was performed. The median age at the time of adrenal surgery was 64.8 years (range 49-79 years). RESULTS: In our study group non-small cell lung cancer (NSCLC) was the most frequent primary tumour type (15 pts), followed by renal cell carcinoma (RCC) (14 pts) and colon cancer (6 pts). Most of the metastases - 36 (92%) - were metachronous (> 6 months). All synchronous metastases were NSCLC. The mean time from primary cancer to adrenalectomy was 42.3 months (range 1-176) and was statistically longer for RCC. In 3 patients (8%) metastases were bilateral and both adrenal glands were removed. In all patients, surgery was limited to the adrenal gland, and no major complications of surgery were observed. The median overall survival after metastasectomy was 18 months (3-81) and was statistically longer for colon cancer - 29.5 months (p = 0.012). In patients who died, tumours were significantly bigger than in survivors, 76.5 mm vs. 52.5 mm (p = 0.026). CONCLUSIONS: Surgery for adrenal metastasis is safe and indications for this procedure should be individualized. In selected patients, surgical removal of adrenal metastasis was associated with longer survival.

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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Low-dose etomidate for the management of severe hypercortisolaemia in different clinical scenarios: a case series and review of the literature.

BACKGROUND: Severe Cushing's syndrome (SCS) is associated with acute cardiovascular, metabolic and infectious complications. It is considered an emergency, requiring an immediate diagnosis, together with a broad spectrum of supportive and hypocortisolaemic treatments. Surgical intervention, aimed at removing the source of cortisol or adrenocorticotropic hormone (ACTH), is the optimal treatment in most cases of Cushing's syndrome. However, in hypercortisolaemic states, surgical intervention has high rates of perioperative mortality and morbidity. Oral adrenal steroidogenesis inhibitors, even if more effective in combination, are not always efficient enough or well tolerated. Despite their common use, a more potent, parental, immediate, and thus life-saving, therapy is necessary. METHODS: The authors present three different clinical scenarios of etomidate treatment in patients hospitalized in the third reference endocrinological centre in Poland between 2016 and 2017. RESULTS: Patients with Cushing's disease, ectopic Cushing's syndrome and adrenocortical carcinoma presented with severe hypercortisolaemia and exacerbated cortisol-dependent comorbidities. In these three cases, etomidate acted as an accurate, well tolerated and effective cortisol-lowering drug for several days or even months. Patients were monitored in a general ward setting, and no side effects of the therapy were observed. CONCLUSIONS: In doses far lower than those used for anaesthesia, etomidate works as a useful cortisol-lowering therapy in patients intolerant to or unable to take oral medications. Additionally, if urgent, the most potent and effective medical intervention is necessary, and clinicians should be aware of such a therapeutic option.

The Relationship Between Health-Related Quality of Life and Anabolic Hormone Levels in Middle-Aged and Elderly Men With Prediabetes: A Cross-Sectional Study.

The aim of this study was to compare health-related quality of life (HRQoL) between men with prediabetes (PD) and a control group as well as to investigate the relationship between HRQoL and anabolic hormones. The analysis was carried out in 176 middle-aged (40-59 years) and elderly (60 80 years) men with PD, and 184 control peers. PD was defined according the American Diabetes Association and HRQoL was assessed by the SF-36 questionnaire. Total testosterone (TT), calculated free testosterone, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF-1) were measured. Analysis of the standardized physical and mental component summary scores (SF-36p and SF-36m) revealed that patients with PD had lower SF-36p and SF-36m than control group ( p < .02 and p < .001). Middle-aged men with PD had lower SF-36p and SF-36m than control peers, whereas elderly men with PD had lower only SF-36p. In men with PD negative correlations between glycated hemoglobin (HbA1c) and SF-35m score ( r = -0.3768; p = .02) and between HbA1c and SF-36p score ( r = -0.3453; p = .01) were reported. In middle-aged prediabetic men, SF-36p was associated with high free testosterone and low HbA1c while SF-36m with high TT and high DHEAS. In elderly patients with PD, SF-36p was associated with high TT, high IGF-1, and low HbA1c, while SF-36m correlated with high free testosterone and high DHEAS. In conclusion, PD in men is associated with decreased HRQoL in comparison with healthy men, and generally better quality of life is associated with higher testosterone, higher free testosterone, higher DHEAS, and lower HbA1c.

[Adrenal gangliuoneuroma - features of 10 cases in own material]. / Adrenal gangliuoneuroma ­ features of 10 cases in own material.

Adrenal ganglioneuroma is a rare benign neuroblastic tumor. Most of adrenal ganglioneuromas are asymptomatic and discovered incidentally during imaging examinations performed for many different indications. Proper preoperative diagnosis is challenging and most of this masses are described as being poor lipid adenomas or pheochromocytomas. AIM: The aim of the study was to present experience of referral center with this rare adrenal pathologies. MATERIALS AND METHODS: Analysis of our data - 374 adrenalectomies performed over last 13 years (2004-2016) in patients referred to our department from different endocrinological centers. Date of all patients were reviewed retrospectively in order to focus on adrenal ganlioneuroma. RESULTS: Among this patients histopathological report confirmed 10 adrenal ganglioneuromas (2,67% of cases, median age 51 years, range 39-74), diagnosed in 4 men and 6 women. Preoperative CT tumors were described as homogenous masses with mean attenuation on unenhanced images 28 (19-39 HU). In 5 patients (50%), progressive enhancement on delayed-phase postcontrast imaging was observed. 7 right and 3 left adrenalectomies was performed (laparoscopic approach in 50% of cases) Mean size of the resected tumors in histopatogical report was 47mm ( 5-85 ). CONCLUSIONS: Proper preoperative diagnosis of adrenal ganglioneuroma is challenging. In our series all diagnosis was made by histopathological examination. Surgery is indicated because it's difficult to distinguish adrenal gangioneuroma from other adrenal malignances. Radical excision is a definitive cure and may be done safely by laparoscopy.

Prognostic factors in adrenocortical carcinoma: data from a large Polish series.

Introduction Adrenocortical carcinoma (ACC) is a rare malignancy, associated with poor outcome and few therapeutic options. Despite increasing attention, the knowledge about the clinical course and treatment of these tumors is limited. Objectives Survival rates in ACC are still low and the percentage of relapse is high. Thus, it is crucial to identify the prognostic factors of overall survival (OS) and recurrence­free survival (RFS). Patients and methods This was a retrospective analysis of 66 patients diagnosed with ACC between 2002 and 2015. Results The median OS was 43.5 months, 78.19 months for stage I + II, 22.95 months for stage III, and 19.54 months for stage IV ACC. Older age, stage IV ACC, margin status R2, and no mitotane treatment were associated with poor OS. Low Ki67 and mitotic indices were related to improved OS in a univariate analysis. The median RFS was 101.1 months. Disease recurrence after potentially curative surgery was reported in 1 patient (25%) with stage I, 12 patients (46%) with stage II, and 9 patients (45%) with stage III ACC. Male sex and no mitotane treatment were associated with a reduced RFS in a multivariate analysis and higher Ki67 and mitotic indices in the univariate analysis. Conclusions Ki67 and mitotic indices should be considered as prognostic factors when planning the adjuvant treatment of ACC. Mitotane treatment may be independently associated with better outcomes regardless of the tumor stage.

Adrenopause - does it really exist?

In ageing human adrenal glands there occur some morphological changes which result in alterations of their cortex endocrine function. Glucocorticoid-excreting cells in the zona glomerulosa live longer than androgen-producing cells in the zona reticularis, which undergo significant apoptosis. Therefore, in elderly humans cortisol levels are normal (significantly higher than at young age), while adrenal androgen concentrations decline with ageing. Function of the zona glomerulosa is affected by the adrenal status, circulatory system condition, efficiency of the kidneys and liver and medication. An important problem of ageing is the rising incidence of non-secreting, incidentally detected, benign adrenal tumors, called incidentalomas. They necessitate clear-sighted radiological and hormonal diagnosis.