Vol 64, No 5 (2018)

Original Studies
Kisspeptin regulation of male sex development: possibilities of diagnosis and treatment of delayed puberty and hypogonadotropic hypogonadism
Nikitina I.L., Yuchlina Y.N., Vasileva E.Y., Nagornaya I.I.

Background. Kisspeptin system plays an important role in the neuroendocrine control of gonadotropin secretion, sexual differentiation of the brain, puberty, and fertility.

Objective — the study was aimed at assessing blood level of Kisspeptin in healthy boys, depending on puberty stage, as well as in boys with pathological delay of puberty onset.

Material and methods. The study included 43 somatically healthy boys. Group 1 consisted of 12 boys 14—17 years old with delayed puberty, group 2 included 16 boys 14—18 years old with normal puberty, Tanner stage IV — V, group 3 — 15 boys 6—10 years old, Tanner stage I. In group 1, median testosterone level (T) was 0.09 nmol/l, LH — 0.3 IU/l; the peak LH level in the triptorelin test was below 5 IU/l in 50% of this group. Serum level of kisspeptin was assessed by ELISA using a specific kit.

Results. Median serum level of kisspeptin (34.8 pg/ml) was significantly (p>0.05) higher in in the group with delayed puberty than in the groups with age-appropriate sexual development. There were no differences between groups 2 and 3 in this value.

Conclusion. Serum level of kisspeptin, which is low in the case of physiological sexual development (regardless of stage), significantly increases in boys with delayed puberty onset, which can be used as a diagnostic marker of this pathology. The results suggest attenuated effect of kisspeptin due to decrease in its biological activity or decrease in sensitivity of the kisspeptin receptors in the case of delayed puberty and hypogonadism. The possibility of treatment of male hypogonadism with exogenous kisspeptin cannot be ruled out.

Problems of Endocrinology. 2018;64(5):280-285
Variability of glycemia in patients with type 1 diabetes mellitus: the relationship with cognitive dysfunction and the results of magnetic resonance imaging
Samoilova I.G., Rotkank M.A., Zhukova N.G., Matveeva M.V., Tolmachev I.V., Kudlai D.A.

Background. Variability of glycemia is an important problem in the control of diabetes mellitus. It can be assumed that cognitive impairment associated with this disease is due to the fact that variability of glycemia affects not only the structure, but also metabolism of the brain.

Objective — the study was aimed at assessing the values of glycemia variability, as well as their relationship with neuropsychological testing and magnetic resonance imaging data in patients with type 1 diabetes mellitus (DM1).

Material and methods. We carried out a one-stage observational study of sex and age matched patients with DM1 and individuals without diabetes. All participants underwent neuropsychological testing, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (PMRS) of the brain; fasting plasma glucose and glycated hemoglobin (HbA1c) levels were assessed. The results of continuous monitoring of glycemia were analyzed in DM1 patients followed by calculation of glycemic variability coefficients.

Results. DM1 58 patients demonstrated decrease in neuropsychological testing scores (p<0.05), decrease in the gray matter volume (p=0.004), and increase in the white matter volume (p=0.001), as well as impaired metabolism of the brain (p<0.05). Correlations between the total result of the MoCa test and LI (r=–0.34; p=0.008), MODD (r=–0.36; p=0.005), and ADRR (r=–0.28; p=0.032) were found. Negative relationship between the CONGA index and the volume of the left hippocampus (r=–0.27; p=0.044) was found. There were also some correlations between the glycemic variability indexes and the content of the main metabolites in different areas of the brain (p<0.05).

Conclusion. MD1 patients with cognitive dysfunction demonstrated anatomical and metabolic brain disorders associated with glycemic variability.

Problems of Endocrinology. 2018;64(5):286-291
Wound healing mechanisms in rats with streptozotocin-induced diabetes mellitus
Ivanov E.V., Gavrilova S.A., Morozova M.P., Klochihina E.M., Erdyakov A.K., Gorbacheva A.M., Dzhemilova Z.N., Artemova E.V., Galstyan G.R., Koshelev V.B.

Background. Wound healing disorders and formation of diabetic foot, a severe disabling complication of diabetes mellitus, are accompanied by nervous system impairment and/or ischemia.

Objective — the study was aimed at assessing the effect of peripheral innervation disorders on the regulation of tissue repair in the streptozotocin-induced rat model of diabetes mellitus.

Material and methods. The study was carried out in male white outbred rats (n=70). The animals were wounded 42 days after induction of diabetes by injecting streptozotocin (diabetes group; this group received insulin Levemir at a dose of 2 units/kg in saline subcutaneously to reduce mortality), or after injection of citrate buffer (CB group). Skin samples were taken on day 8, 16, and 24 after wound modeling. Pain sensitivity was assessed in all animals. The resulting skin fragments were fixed, dehydrated, and embedded in paraffin according to standard procedures. Sections were stained with hematoxylin and eosin, antibodies specific for Ki-67, α1, β1, and β2-adrenoreceptors were used for immunohistochemical staining. Intact animals were used as an additional control group.

Results. Tail withdrawal time measured on day 56 was higher in DM group rats as compared to the control group (p=0.017). CB group demonstrated a tendency towards more rapid wounds healing than diabetic animals, although the difference was not statistically significant due to wide scatter of data in the DM group (p=0.64). The intensity of staining for Ki67 was lower in the DM group (p=0.045). Reduced density of β2-adrenoreceptors was observed at the areas remote from the wound in CB group rats.

Conclusion The results show no correlation between altered innervation and impaired tissue repair in rats with streptozotocin-induced diabetes.

Problems of Endocrinology. 2018;64(5):292-298
Case Reports
Positron emission tomography in combination with computed tomography with 18F-fluorocholine in the topical diagnosis of parathyroid tumors and secondary changes in bone tissue associated with hyperparathyroid osteodystrophy: two case studies
Mokrysheva N.G., Krupinova J.A., Dolgushin M.B., Odzharova A.A., Voronkova I.A., Voskoboynikov V.V., Kuznecov N.S.

Primary hyperparathyroidism (PHPT) is caused by parathyroid malignant neoplasm in 1% of cases. The risk of the latter is higher in patients with symptomatic PHPT. The prognosis in this group of patients depends on the extent of the process and primary surgical intervention.

In these cases, the differential diagnosis between secondary foci in the bones associated with parathyroid cancer and hyperparathyroid osteodystrophy is a challenging problem.

This article describes two cases of severe PHPT accompanied by hyperparathyroid osteodystrophy suspected for metastatic parathyroid cancer. Positron emission tomography in combination with computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) and/or 18F-fluorocholine was included in the examination algorithm. In both cases, pronounced bone changes similar to parathyroid metastases were observed. Accumulation of 18F-fluorocholine was also observed only in altered parathyroid gland. Histological examination of postoperative material verified benign parathyroid tumors, and characteristic lesions of bone tissue were regarded as areas of osteodystrophy.

Therefore, accumulation of 18F-fluorocholine at the areas of bone destruction does not enable differentiation between hyperparathyroid osteodystrophy and metastatic lesions; further research is required to assess sensitivity and specificity of the method with respect to topical diagnosis of altered parathyroid gland.

Problems of Endocrinology. 2018;64(5):299-305
Differential diagnosis of morphological forms of congenital hyperinsulinism using [18F]-DOPA PET/CT
Gubaeva D.N., Melikyan M.A., Ryzhkova D.V., Mitrofanova L.B., Nikitina I.L.

Congenital hyperinsulinism (CHI) is caused by insulin hyperproduction by β-pancreatic cells. CHI is associated with high risk of complications of chronic hypoglycemia, and therefore timely diagnosis of the disease and immediate initiation of therapy is a top-priority task. The choice of treatment tactics largely depends on the morphological form of the disease. Morphological form cannot be established based on clinical and laboratory presentation of the disease, ultrasound, MRI, computed and positron emission tomography (PET) with [18F]-fluorodeoxyglucose. Calcium stimulation test and percutaneous transhepatic blood sampling from the portal vein were previously used for differential diagnosis, but the results provided by these invasive studies are imprecise. At present, preoperative differential diagnosis of diffuse and focal forms of CHI is based on the data of genetic testing and radionuclide diagnosis ([18F]-DOPA PET). The article presents the first results of the use of [18F]-DOPA PET in CHI patients in the Russian Federation. Radionuclide study was performed in 17 patients with pharmacoresistant CHI followed by comparative analysis of the results of 18F-FDG PET/CT and histological picture of intraoperative pancreatic tissue samples, which is known as the gold standard for the differential diagnosis of HI histological forms.

Problems of Endocrinology. 2018;64(5):306-311
The first case of a rare form of isolated glucocorticoid insufficiency associated with to NNT gene mutation reported in the Russian Federation
Chernyak I.Y., Kalinchenko N.Y., Tlif A.I., Kleshenko E.I., Vasiliev E.V., Petrov V.M., Tiulpakov A.N.

Familial glucocorticoid deficiency (FGD, MIM*202200) is a rare form of primary chronic adrenal insufficiency characterized by resistance of the adrenal cortex to ACTH, decrease in secretion of glucocorticoids and adrenal androgens, and increase in plasma ACTH level. Currently, at least 7 genes whose mutations lead to the development of FGD have been described. These are MC2R, MRAP, STAR, CYP11A1, NNT, TXNRD2, and AAAS. E. Meimaridou and J. Kowalczyk were the first who described NNT gene mutation in 2012 in one patient who underwent molecular genetic examination and 9 patients with clinical presentation of familial glucocorticoid deficiency. Understanding of the exact cause of primary chronic adrenal insufficiency enables adjusting the treatment, predicting the development of possible complications and related dysfunctions of other organs, as well as the need for medical and genetic counseling of the family.

Problems of Endocrinology. 2018;64(5):312-314
Sensitivity to androgens: beyond the well-known facts
Khripun I.A., Vorobyev S.V.

Gonadal and extragonadal effects of testosterone in males have been extensively investigated in recent years. To date, there is no doubt that testosterone deficiency in males is associated with increased risk of obesity, type 2 diabetes mellitus, hypertension, and atherosclerosis. Sensitivity to androgens determined by the length of CAG-repeats in the androgen receptor gene is one of the underlying mechanisms of testosterone action. Increase in the number of CAG-repeats reduces activity of androgen receptors, which manifests in the form of low sensitivity to testosterone. On the contrary, decrease in the number of trinucleotide repeats is accompanied by increased sensitivity of the receptors to androgens. This review discusses the effect of androgen receptor gene polymorphism on embryogenesis and sex differentiation, regulation of spermatogenesis, progression of cancer and benign prostatic hyperplasia, symptoms of hypogonadism, control of carbohydrate and lipid metabolism, bone mineral density, vascular endothelium, response to replacement therapy with testosterone, as well as on the psychosocial aspects of personality in males. Implementation of the study of androgen receptor gene polymorphism into clinical practice will enable not only predicting male fertility or the risk of developing prostate cancer, but also selecting an individual therapy for testosterone deficiency.

Problems of Endocrinology. 2018;64(5):315-320
Klinefelter syndrome in children and adolescents
Bespalyuk D.A., Chugunov I.S.

Klinefelter syndrome is a chromosomal pathology, which is the most common anomaly of sex chromosomes and the most common form of primary male hypogonadism. The presence of an extra X-chromosome in the karyotype causes infertility, azoospermia, small size of testicles, high level of gonadotropins and low level of testosterone, tallness and disproportionate physique, learning difficulties, and developmental speech disorders. Despite the high incidence of the syndrome in the population, only 25% of patients are aware of their disease during their lifetime. Late diagnosis and delayed treatment are often due to pronounced clinical polymorphism of the disease, different symptom onset time, as well as high incidence of associated conditions, so that these patients are followed by various specialists, but they are not aware of the main diagnosis.

This review presents data on the history, etiology of the syndrome, clinical and laboratory features characteristic of children, adolescents, and adults. The most common associated diseases are listed and current data on their prevalence and the effect of testosterone replacement therapy on these conditions are provided.

Problems of Endocrinology. 2018;64(5):321-328
Correlation between type 2 diabetes mellitus and air pollution with suspended particles
Kolpakova A.F., Sharipov R.N., Volkova O.A.

The review presents the modern concept of the relationship between air pollution with fine particulate matter (PM) and the prevalence of diabetes mellitus (DM). The role of PM in the pathogenesis of DM, in particular, DM2, depending on their size, origin, chemical composition, and concentration in the air is discussed. For this purpose, we used materials from the articles indexed in the PubMed and RSCI databases. Road transport-related PM, containing intermediate valence metals are believed to be the most dangerous ones. Long-term exposure to high concentrations of fine and ultrafine PM is associated with the risk of type 2 diabetes and mortality. Short-term exposure to PM causes vascular insulin resistance and inflammation triggered by oxidative stress in the lungs. Oxidative stress caused by exposure to PM is the central stage of inflammatory reactions, leading to release of pro-inflammatory cytokines from cells and systemic inflammation. Exposure to PM sized 2.5 microns or less results in significant increase in expression of proinflammatory genes and activation of corresponding signaling pathways. Involvement of PM into impairment of glucose homeostasis and increase in inflammation in adipose tissue, liver, and central nervous system has been confirmed in models and experimental studies. The role of air pollution with PM in the pathogenesis of type 2 diabetes is still not fully understood, especially at the molecular and cellular level. The development of formalized descriptions of the processes mediating the effect of PM on the human body will provide better understanding of the role of air pollution with suspended particles in the pathogenesis of various diseases and, in particular, DM2, which can contribute to improvement of treatments and preventive measures.

Problems of Endocrinology. 2018;64(5):329-335
Vildagliptin: ten years in the service for type 2 diabetes mellitus patients. The journey of discovery, innovation and success in clinical practice
Demidova T.Y.

Type 2 diabetes mellitus is a multifactorial multiorgan disease. Over the last decade, the implementation of brand-new therapeutic opportunities led to tremendous rise of research studies in the field of diabetes as well as to shift in priorities of the management of patients with type 2 diabetes from a glucocentric approach and towards holistic control of the key underlying pathophysiological processes of the disease development and progression. The use of dipeptidyl peptidase-4 inhibitors shows good glycemic control because of physiological glucose — dependent mechanism of action mediated with the improvement of incretin hormones effects. Moreover, dipeptidyl peptidase-4 inhibitors have a wide range of pleiotropic effects owning to additional properties of incretins and inhibition of dipeptidyl peptidase enzymatic activity, which leads to beneficial impact on metabolic and pathogenetic processes of type 2 diabetes mellitus. Dipeptidyl peptidase-4 inhibitors are effective drugs with good safety profile as for risks related to type 2 diabetes and have no limitative disadvantages such as hypoglycemia and weight gain. This publication reviews vildagliptin, the first developed dipeptidyl peptidase-4 inhibitor, with an emphasis on its use in different clinical settings of diabetes management.

Problems of Endocrinology. 2018;64(5):336-347
On the Occasion of the Anniversary of Adolf I. Bukhman

Adolf I. Bukhman, one of the founding fathers of Russian roentgenology, was celebrating his 90th anniversary on September 30, 2018.

A.I. Bukhman has developed, modified, and launched into clinical practice 27 diagnostic and radiation therapy procedures (lymphography of the thyroid and parathyroid glands, electroroentgenography and thermography in patients with endocrine disorders, bone age assessment tables taking into account developmental acceleration, etc.). He was first to address the issue skeletal mineralization with respect to age, characterize the condition of soft tissues in patients with diabetes mellitus and acromegaly, and develop radiation therapy to manage angiopathies, arthropathies, and trophic ulcers. A.I. Bukhman has significantly contributed to the development of mammography. He was first to publish the first studies on using mammography in patients with endocrine disorders in the USSR. Adolf Isaakovich has also been the first roentgenologist worldwide who has described fluoromammography.

Adolf Isaakovich has earned love and respect from his colleagues. On his anniversary, the staff of the National Medical Research Center for Endocrinology are wishing Adolf Isaakovich sound health, many fruitful years for the benefit of Russian roentgenology and endocrinology, success in future endeavors, wellbeing, vivacity and fortitude.

Problems of Endocrinology. 2018;64(5):348-349

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