[Corticotropin-producing pheochromocytoma in multiple endocrine neoplasia type 1].

A clinical case of a man 66 y.o. who was diagnosed with hormone-inactive pituitary macroadenoma complicated by corneal erosion and partial atrophy of the optic nerve of the left eye due to exophthalmos. The increase in prolactin level was regarded due to a «stalk-effect¼. The patient underwent a transnasal pituitary adenomectomy with subsequent regression of symptoms. After 4 years, against the background of a new coronavirus infection, increasing general weakness, headaches, a crisis increase in blood pressure and tachycardia attacks appeared. Computed tomography (CT) accidentally revealed an adrenal incidentaloma, in laboratory tests - hypercortisolism, elevated ACTH levels, hypokalemia, hyperglycemia, increased levels of metanephrine and normetanephrine. The patient developed acute steroid psychosis, after which an adrenalectomy with a tumor was performed, a pheochromocytoma was histologically confirmed. After surgery, there was a regression of symptoms, the development of adrenal insufficiency with reduced levels of ACTH and cortisol. Upon further examination, a polynodose euthyroid goiter was established, the biopsy of the nodes - Hashimoto's thyroiditis (Bethesda II). Meanwhile, primary hyperparathyroidism was detected. According to ultrasound, scintigraphy with Ts99m-Technetril and CT revealed an increase of left parathyroid gland. A bilateral revision of the neck, removal of the right upper and left upper parathyroid adenomas were performed. In the postoperative period, the levels of calcium and parathyroid hormone were normalized. Given the presence of a combination of multiple tumors of the endocrine system (primary hyperparathyroidism, corticotropin-producing pheochromocytoma, hormone-inactive pituitary macroadenoma, polynodose euthyroid goiter), the MEN1 syndrome was clinically established. The study of 2 and 10 exons of the MEN1 gene revealed no mutations, which does not exclude the presence of a hereditary syndrome. The patient continues observation. In the available literature in Russian and English languages the case of ACTH pheochromocytoma as part of the MEN type 1 syndrome have not been found. Therefore, we consider the presented case to be the first one.

[Metastatic risk factors in pheochromocytoma/paraganglioma].

Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic¼ and «non-metastatic¼. Metastatic PPGLs can be with synchronous metastasis (metastases appear simultaneously with the identified primary tumor) or metachronous (metastases develop after removal of the primary tumor). The term metastatic PPGLs is not used in the presence of tumor invasion into surrounding organs and tissues, without the presence of distant metastases of lymphogenic or hematogenic origin. It is generally believed that about 10% of pheochromocytomas and about 40% of sympathetic paragangliomas have metastatic potential. On average, the prevalence of PPGLs with the presence of metastases is 15-20%. Risk factors for metastatic PPGLs are widely discussed in the literature, the most significant of which are groups of clinical, morphological and genetic characteristics. The review presents a discussion of such risk factors for metastatic PPGLs as age, localization and type of hormonal secretion of the tumor, the size and growth pattern of the adrenal lesion, the presence of necrosis and invasion into the vessels, the tumor capsule surrounding adipose tissue, high cellular and mitotic activity, Ki-67 index, expression of chromogranin B and S100 protein, the presence of genetic mutations of three main clusters (pseudohypoxia, kinase signaling and Wnt signaling).Over the past two decades, a number of authors have proposed various predictor factors and scales for assessing a probability of metastatic PPGLs. The review contains detailed description and comparison of sensitivity and specificity of such predictor scales as PASS, GAPP, M-GAPP, ASES and COPPS.

[Clinical and laboratory features of hereditary pheochromocytoma and paraganglioma].

The widespread introduction of genetic testing in recent years has made it possible to determine that more than a third of cases of pheochromocytomas and paragangliomas (PPPGs) are caused by germline mutations. Despite the variety of catecholamine-producing tumors manifestations, there is a sufficient number of clinical and laboratory landmarks that suggest a hereditary genesis of the disease and even a specific syndrome. These include a family history, age of patient, presence of concomitant conditions, and symptoms of the disease. Considering that each of the mutations is associated with certain diseases that often determine tactics of treatment and examination of a patient, e.g. high risk of various malignancies. Awareness of the practitioner on the peculiarities of the course of family forms of PPPGs will allow improving the tactics of managing these patients.The article provides up-to-date information on the prevalence of hereditary PPPGs. The modern views on the pathogenesis of the disease induced by different mutations are presented. The main hereditary syndromes associated with PPPGs are described, including multiple endocrine neoplasia syndrome type 2A and 2B, type 1 neurofibromatosis, von Hippel-Lindau syndrome, hereditary paraganglioma syndrome, as well as clinical and laboratory features of the tumor in these conditions. The main positions on the necessity of genetic screening in patients with PPPGs are given.

[The combination of classical tests and methods of chromatography for laboratory diagnostics of cushing's syndrome of different genesis.] / Сочетание ÐºÐ»Ð°ÑÑÐ¸Ñ‡ÐµÑÐºÐ¸Ñ Ñ‚ÐµÑÑ‚Ð¾Ð² и методов Ñ Ñ€Ð¾Ð¼Ð°Ñ‚Ð¾Ð³Ñ€Ð°Ñ„Ð¸Ð¸ в лабораторной диагностике синдрома Кушинга различного генеза.

Immunochemical methods of analysis are traditionally used for diagnosis of various forms of Cushing's syndrome (CS). In the presence of boundary values of hormonal parameters, doubtful situations, a combination of changes both in pituitary and in adrenal glands, it is useful to determine additional differential diagnostic criteria for the diagnosis of various forms of CS. Urinary steroid profiles (USP) were analyzed by gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) for 38 females with adrenal Cushing's syndrome (CSA), 42 females with pituitary CS (CSP) and 25 healthy females (control group). An increase of free cortisol/free cortisone ratio in the urine (UFF/UFE) for CSP patients in comparison of CSA was obtained by HPLC method. Decreased urinary excretion of UFF and UFE by more than 60% after the 8 mg dexamethasone suppression test had 100% sensitivity and specificity of more than 90% for the diagnosis of CSP. GC-MS method in patients with CSA and CSG revealed the peculiarities of androgens, progestins and glucocorticoids metabolism which leaded to obtain specific USP for CS of different genesis. Increased urinary excretions of dehydroepiandrosterone and its metabolites, metabolites of androstenedione, the ratio of sum of cortisol and cortisone tetrahydrometabolites to tetrahydro-11-deoxycortisol (more then 36) in CSP patients compared with CSA are additional signs for differential diagnosis of these diseases. The combination of classical tests and USP obtained by HPLC and GC-MS methods increased the sensitivity and specificity of differential diagnosis of CSA and CSP.

Gas Chromatography-Mass Spectrometry Analysis of Urinary Steroid Metabolomics for Detection of Early Signs of Adrenal Neoplasm Malignancy in Patients with Cushing's Syndrome.

The metabolomics of urinary steroids was studied by gas chromatography-mass spectrometry in 25 patients with Cushing's syndrome without malignant potential and in 12 patients with malignant potential of adrenal neoplasms (Weiss score 1-3). Patients with adrenocortical adenoma (N=24) constituted the control group. In patients with Cushing's syndrome and malignant potential, increased urinary excretion of 16-oxo-androstendiol, tetrahydro-11-deoxycortisol, and 16-hydroxypregnendiol, which had 100% specificity and sensitivity >90% for the diagnosis of malignant potential. Additionally, non-classical 5-ene-pregnenes (16-OHpregnenolone, 21-OH-pregnenolone, 3ß,16,20-pregnentriol, and 3ß,17,20-pregnentriol) were identified. The revealed changes in the metabolomics of steroids can be early signs of malignant potential in patients with Cushing's syndrome. In patients with malignant potential, three signs of reduced activity of 11ß-hydroxysteroid dehydrogenase type 2 were detected and in patients without malignant potential, one sign was found. In patients with and without malignant potential, three signs increased activity of 5ß-reductase were found.

[Fibroblast growth factor-21 as a marker of premature aging in young and middled-aged men with type 2 diabetes].

AIM: To investigate the impact of fibroblast growth factor 21 (FGF-21) on the severity of androgen deficiency in young and middle-aged men with type 2 diabetes mellitus. MATERIALS AND METHODS: The study comprised 100 men with type 2 diabetes mellitus, cardiovascular multi-morbidity, obesity and androgen deficiency (study group) and 20 healthy men aged 35-50 years. The study group was further divided into two subgroups. Patients of the subgroup 1 received the standard treatment for type 2 diabetes and cardiovascular disease. Patients of the subgroup two were treated with conventional therapy concurrently with testosterone undecanoate. The baseline examination included the following parameters: glycated hemoglobin, total testosterone, prolactin, thyroid stimulating hormone and blood FGF-21. At nine months after the treatment, the blood levels of glycated hemoglobin, FGF21 and testosterone were re-examined. The evaluation of the severity of androgen deficiency was carried out using the ICEF-5 questionnaire and the Aging Males Symptoms scale (AMS). RESULTS: In the study group, the mean FGF-21 level was 2.7 times higher, and the total testosterone level was 2-2.5 times lower than in the control group (p<0.05). A negative correlation was found between the blood levels of FGF-21 and total testosterone (r=-0.41, p<0.05). At nine months post treatment, the subgroup with testosterone undecanoate administered as add-on therapy showed a further decrease in FGF-21 levels and improved androgen deficiency symptoms. DISCUSSION: FGF-21 is one of the markers for type 2 diabetes, cardiovascular multi-morbidity, obesity and androgen deficiency. Given the association of FGF-21 with androgen deficiency, it can be assumed that FGF-21 plays a role in premature aging. Treatment of androgen deficiency as add-on therapy to the standard treatment of this category of patients improves their prognosis and the quality of life. CONCLUSION: Young and middle-aged men with type 2 diabetes should undergo regular screening for androgen deficiency with the purpose of its early diagnosis and timely treatment. The detection of elevated levels of FGF-21 in young and middle-aged men with type 2 diabetes mellitus and cardiovascular multi-morbidity may indicate premature aging and requires preventive measures.

Different Types of Urinary Steroid Profiling Obtained by High-Performance Liquid Chromatography and Gas Chromatography-Mass Spectrometry in Patients with Adrenocortical Carcinoma.

Urinary steroid profiling (USP) was studied using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) methods in 108 patients with adrenocortical adenoma (ACA) and in 31 patients with adrenocortical carcinoma (ACC). Thirteen ACC and Cushing's syndrome (ACC-CS) patients had two types of USP as well as 18 ACC patients without hypercortisolism. These four types differed by androgen and glucocorticoid secretion of the adrenal cortex. Fifteen main ACC features were observed by GC-MS. Urinary excretion of dehydroepiandrosterone (DHEA) was increased in 67.7 % of ACC patients and tetrahydro-11-deoxycortisol (THS) in 74.2 %. By combination of the following parameters: THS >900 µg/24 h and/or DHEA >1500 µg/24 h with ratios of 3α,16,20-pregnentriol/3ß,16,20-pregnentriol (3α,16,20dP3/3ß,16,20dP3) less than 6.0 and 3α,17,20dP3/3ß,17,20dP3 less than 9.0 and the detection of "non-classical" 5-en-pregnens, not found in ACA and healthy persons, 100 % sensitivity and specificity of ACC and ACA differential diagnosis were achieved. Features of 21-hydroxylase and 11ß-hydroxylase deficiency were observed by GC-MS in 32.2 and 61.3 % of the ACC patients, respectively. Additional features for ACC-CS diagnostic were increased urinary excretion of 6ß-hydroxycortisol, 18-hydroxycorticosterone, the sum (UFF + UFE) obtained by HPLC, tetrahydrocorticosterone, and the sum (THF + THE + allo-THF) obtained by GC-MS.

[Diagnostic value of high performance liquid chromatography of corticosteroids in diseases of the pituitary system].

A hundred and ninety-one patients with different adrenal cortical tumors were studied to assess the diagnostic value of HPLC of corticosteroids in the biological fluids. HPLC of corticosteroids in the biological fluids revealed the signs of the hormonal activity of incidentalomas, organic endogenous hypercorticism, and mass malignancy. Some patients with adrenal cortical incidentalomas (15.5%) were found to have impaired steroid formation that is typical of 11ß-OH- or 17-OH-hydroxylase deficiencies. The findings allow one to diagnose adrenal disorders at the early stages of disease and to define indications for surgical treatment.

[The specific features of adrenal steroidogenesis in patients with congenital adrenal cortical dysfunction due to 21-hydroxylase deficiency].

Forty-two patients with classical forms of congenital adrenal cortical dysfunction (CACD) (22 patients with salt-loosing form and 20 patients with simple virile form) caused by 21-hydroxylase deficiency and 29 female with an obscure form of the disease were examined. The patients with classical CACD received therapy with gluco- and mineralocorticoids. Radioimmunoassay and enzyme immunoassay were employed to estimate the levels of 17-OH-progesterone and the activities of plasma renin and serum corticotropin, aldosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. High performance liquid chromatography (HPLC) was used to measure the blood levels ofcortisol, cortisone, corticosterone (B), 11-deoxycorticosterone (DOC), and 11-deoxycortisol (S). There were increases in the levels of В and DOC in patients with the simple form at the decompensation stage and in those of DOC in patients with the simple form at the compensation stage, which is indicative of activation of the renin-angiotensin system. There were also rises in В and DOC in 35.8 and 33.0% of the patients with obscure CACD, respectively, as well as a significant elevation of the content of S. A study of the profiles of corticosteroids by HPLC in patients with 21-hydroxylase deficiency-related CACD is an additional method for assessing the compensation of the disease in patients with classical CACD and for diagnosing the obscure form of the disease.

[The pathogenesis of sexual disorders in men with diabetes mellitus]. / K patogenezu narushenii polovoi funktsii u muzhchin pri sakharnom diabete.

The examination of 217 males suffering from diabetes mellitus revealed copulative dysfunction in 111 (51.1%) of them. The investigation of sex, gonadotropic hormones, testicular reserves, sexual constitution and sexual formula was carried out in 22-55-year-old males with sexual dysfunction and healthy controls. It was an erectile phase of the sexual cycle that suffered most frequently. Reduced libido was observed in 19% of the patients. All the diabetes examined showed constitutional predisposition to impaired potency. The patients had high serum concentrations of prolactin, lutropin and dihydroepiandrosterone in low testosterone and insignificantly elevated follitropin and estradiol. There was also low gonadal resistance to choriogonin stimulation. These findings and literature data lead to the conclusion that insulin insufficiency entailing hyperglycemia brings about a rise in prolactin and dihydroepiandrosterone levels which may reduce the sensitivity of the receptors and lutropin in the testes and inhibit testosterone secretion. This is confirmed by inactive gonadal response to stimulation of chorionic gonadotropin. Spermatogenic disorders observed in 25% of the patients were associated with sexual affections and local structural changes (hypotrophy) of the testes.

[The function of the hypophysis-gonadal system in men with diabetes and in men with thyroid diseases]. / Funktsional'noe sostoianie sistemy gipofiz--gonady u muzhchin s sakharnym diabetom i u muzhchin s zabolevaniiami shchitovidnoi zhelezy.

A study was made of indices of the hypophyseogonadal system in men with diabetes mellitus, in men with autoimmune thyroiditis and hypothyroidism, and in men with Basedow's disease. Sexual dysfunction was detected in 51% of patients with diabetes mellitus and in 78.5% patients with hypothyroidism. A high level of serum prolactin in these patients resulted in a decrease in the sensitivity of testicles to LH, causing a decrease in testicular androgenic function. It was confirmed by a low blood level of T and a decreased response of the gonads to CG administration. Patients with hypothyroidism demonstrated a decrease in the blood level of LH and TSH causing testicular dysfunction. An increased level of LH and T was found in patients with Basedow's disease. The absence of an adequate rise of the blood concentration of T in response to CG administration in this group of patients can be attributed to the fact that in Basedow's disease the hypophyseogonadal system functions under great strain.