Editorial
The biomedical consequences of the Chernobyl accident are a complex of issues caused by the unprecedented nature of the accident, its enormous scale, the peculiarities of radiation exposure at different time periods, as well as the extremely uneven distribution of radioactive contamination zones even within small settlements. Along with the detection of cancer, genetic disorders, congenital malformations, one of the important areas for studying the medical consequences is screening, diagnosis and treatment of endocrine diseases. The increase in their frequency is demonstrated by epidemiological studies conducted in controlled areas of Ukraine, Belarus and Russia.
Clinical endocrinology
Besides the known factors contributing to the pathogenesis of diabetic nephropathy, the role of immune mechanisms in types I and II diabetes is discussed of late; the contribution of autoimmune mechanisms to pathogenesis of noninsulin-dependent diabetes is virtually unknown. Seventy-six patients with DM2 and 48 with insulin-dependent condition were examined. Under study were levels of antibodies to FxIA and renal glomerular basal membrane antigens in the blood sera of donors and patients with tyres I and II diabetes, as well as concentrations, size, and pathogenicity of immune complexes. Antibodies to FxIA antigen were detected in patients with both types of diabetes with diabetic nephropathy. Detection of circulating antibodies to FxIA aqtigen in more than 70 % of diabetics in the absence of protein in the urine may be used as a test system for the laboratory diagnosis of diabetic nephropathy prestage and as a criterion for prescription as early as at the initial stages of nephroprotective agents.
Cellular nonspecific immunity was found reduced in residents of the lowlands and highlands suffering from alimentary obesity and noninsulin-dependent diabetes mellitus (NIDM), this depression augmenting with the increment of obesity degree and age of NIDM patients (p<0.01-0.001). Activities of antihypoxic enzymes in these patients are drastically depressed under conditions of the highlands and do not depend on the patient’s age. Lymphocyte killer activity in both patient populations is increased, more so in the highlands; this activity functionally or organically impairs insulin in the body forming with it immune complexes.
Phospholipids are the main structural components of cell and subcellular membranes and determine the level of activity of membrane enzymes, tissue sensitivity to insulin. In the literature, the problem of phospholipid metabolism in diabetes mellitus (DM), including diabetic angiopathy, is not adequately addressed.
The aim of the study was to study the indicators of phospholipid metabolism in blood serum and erythrocyte membranes in patients with diabetes, as well as their dynamics under the influence of complex treatment with the inclusion of unitiol and tocopherol.
We examined 92 patients with type 1 diabetes (60 men and 32 women aged 17 to 45 years). The average severity of the disease was in 36 patients, the severe form of the disease was in 56. Diabetic angiopathies of various localization were noted in 63 patients. All patients upon admission to the hospital were in a state of decompensation of metabolic processes. The control group consisted of 24 healthy individuals of a similar age.
The works of recent years have summed up certain results of the study of the processes of free radical lipid oxidation (FRLO) in patients with diabetes mellitus (DM). In these studies, the intensification of the FRLO processes is unequivocally stated. It has been established that chronic insulin deficiency, which acts as a stress factor, activation of lipolysis, and the entry into the vascular bed of a large amount of free fatty acids are a prerequisite for the activation of FRLO. It is known that free radicals have a damaging effect at the level of tissues and cells, participate in the mechanism of destruction of the vascular endothelium, inhibit the synthesis of prostacyclin, a physiological inhibitor of platelet aggregation.
The above suggests a very significant role of the FRLO processes in the pathogenesis of purulent-inflammatory complications of diabetes, important factors in the occurrence of which are neuropathy and regional ischemia, which develops as a result of diabetic angiopathies, and gross structural disorders of the microvasculature.
The mentioned studies mainly concerned the study of the indicators of FRLO and antioxidant protection in the blood in the experiment and in the clinic. The study of these processes in the tissues of a purulent wound in patients with diabetes to date, according to the literature, has not been carried out, which was the basis for this study.
Glutamic acid decarboxylase (GAD) is considered as target antigen in pancreatic beta cell autoimmunity. Two isoforms of GAD (islet and brain GAD) were detected recently. In circulation of approximately 80 % of recently detected patients with insulin-dependent diabetes mellitus (IDDM) autoantibodies to brain GAD (bGAD) have been demonstrated. To detect autoantibodies to bGAD blood sera of 48 children aged 1 to 14, 36 of these with newly diagnosed IDDM, 2 with impaired glucose tolerance (IGT), 10 healthy controls, were tested. Indirect immunofluorescent staining of rat cerebellum cryoslices was carried out. The results were assessed using fluorescent microscopy and processed by statistical methods. Autoantibodies to bGAD were found in 30 out of 36 patients with IDDM: 83,3±12,4 % (p=95%), in 1 with IGT, and in none of controls. The fact that all controls were anti- body-negative proves a high specificity of this immunological marker of IDDM. Family history or a younger age by the moment of diabetes onset were conducive to a higher prevalence of autoantibodies to GAD, each of these factors being unrelated to the other.
Using indirect colorimetry, the authors demonstrated disordered energy metabolism at rest in patients with insulin-dependent diabetes mellitus (IDDM) with a moderate decompensation of metabolism: carbohydrate oxidation was reduced and fat and protein oxidation increased, this being aimed at maintenance of the basic metabolism within the normal range under conditions of insulin insufficiency. Improvement of common parameters of compensation during optimization of insulin therapy and therapeutic diets was associated with approximation of substrate oxidation structure and energetic structure of a diet, as well as with increased production of useful energy coupled with reduced oxygen consumption. Moreover, a positive correlation between insulin level and carbohydrate oxidation rate was revealed. Analysis of the effects of qialitative composition of protein showed a more rapid improvement of metabolism during metabolic diet, whereas during therapy with diets including soybean protein increase of metabolism efficacy is more manifest. Bioenergetic parameters may be used as criteria of the efficacy of IDDM treatment. Changes in these parameters not always correlate with the time course of routine criteria of compensation and provide supplementary information on a patient’s metabolic status.
Repeated courses of hyperbaric oxygenation (HBO) were administered to 39 patients with insulin-dependent diabetes mellitus (IDDM) aged 28.2±11.3 years on an average and mean diabetes duration 5.7±0.5 years without body mass excess, administered insulin in daily dose 35.5±10.1. Control group consisted of 8 IDDM patients matched for clinical parameters and administered no treatment. Daily glucosuri'a, glycemia, HbAi, blood levels of e-peptide, glucagon, STH, and hydrocortisone were measured in the test group and controls before and after HBO course and every 2 months of a years’s follow-up. Repeated courses of HBO administered to IDDM patients during a year are much more effective than a single course as regards diabetes compensation, reduction of insulin consumption, recovery of residual insulin secretion, and suppression of secretion of contrinsular hormones glucagon, STH, and hydrocortisone. Three courses of HBO therapy administered to IDDM patients at 4 months intervals are more effective than two courses with a 6 month interval; at the same time, in a three course modality the maximal positive effect of HBO on the hormonal metabolic status is attained during the second course, and the third course just fortifies the attained effect.
Repeated courses of hyperbaric oxygenation (HBO) in patients with noninsulin-dependent diabetes mellitus (NIDM) are much more effective than a single course as regards their favorable influence on carbohydrate metabolism and hormonal and metabolic parameters (recovery of residual insulin secretion and suppression of secretion of contrinsulin hormones). Three courses of HBO administered to NIDM patients at 4 months intervals are more effective than two courses at 6 months interval; at the same time during a three-course modality the maximal favorable HBO effect on the hormonal and metabolic status is attained after the second course, and the third one only fortifies the attained favorable effect.
Analysis of the mortality of children with insulin-dependent diabetes in Moscow in the eighties revealed a very high specific incidence of diabetic ketoacidosis, the principal cause of lethal outcomes occurring in the period of the disease manifestation in more than a half of the analyzed cases. Mortality index among children with diabetes was found higher than in countries with well-developed economy. The overwhelming majority of untimely lethal outcomes of diabetes mellitus in childhood may be prevented.
Multinodular euthyroid goiter is a disease characterized by the presence of two or more nodes that can be located in one or both lobes of the thyroid gland, and, as a rule, not accompanied by a dysfunction of the latter. Currently, the most common treatment for patients with this pathology is the surgical removal of nodes. However, the volume of surgical intervention for multinodular euthyroid goiter refers to the unresolved problems of surgical endocrinology. On the one hand, after radical operations, a significant number of patients have postoperative hypothyroidism, on the other hand, with less radical operations, a relapse occurs. At the same time, there is a point of view that negates the dependence of disease recurrence on the volume of surgery.
Our observations indicate that with multinodular euthyroid goiter, focal goiter changes are observed in the surrounding thyroid tissue nodes, often with a tendency to nodule formation. In this regard, we set ourselves the goal of studying the morphological features of the structure of resected thyroid tissue in patients with multinodular euthyroid goiter, paying particular attention to the structure of the nodes and to the state of the thyroid tissue outside them. In addition, an attempt was made to establish the dependence of the development of postoperative hypothyroidism and / or relapse of the disease on the amount of left thyroid tissue.
Clinicohormonal examinations of 19 patients with juvenile struma revealed in many of them signs of latent hypothyrosis (increased age-specific level of blood serum TTH level and hyperergic reaction to TRH). Incubation of thyro- cytes isolated from perinodular tissue of patients with euthyroid nodular goiter with IgG isolated from the blood serum of patients with juvenile struma resulted in a reliably lower content of cAMP in the cells than after thyrocyte incubation with IgG isolated from the blood serum of 9 healthy donors. This is indicative of the presence of thyroblocking antibodies in the blood serum of patients with juvenile struma. Though no correlation could be traced between the tested immunoglobulin activity, on the one hand, and blood serum TTH level and struma size, on the other, one may propose a contribution of thyroblocking antibodies to the pathogenesis of juvenile struma.
To discover the effects of various concentrations of androgenic preparations on lymphocyte cultures from healthy women (group 1) and of women with hyperandrogenism (group 2), a total of 6792 metaphases were examined after peripheral blood lymphocyte culturing after Hangerford. The data indicated a relatively high incidence of aberrant metaphases, total number of ruptures and paired ruptures in the second group, a higher cytogenetic activity of testosterone propionate in both groups, and a higher cytogenetic activity of androgenic hormones in the second group. Bearing in mind a similar, if not higher, activity of endogenic testosterone in a female organism, we must admit a high probability of genetic system involvement in women suffering from hyperandrogenism.
The authors analyze published data on clinical variants and hormonal parameters in patients with this syndrome and present their own observations of children with this condition. Besides early sexual maturation, they describe the clinical picture of Cushing’s syndrome, thyroid nodular hyperplasia. The said disorders do not depend on the tropic effect of the hypothalamohypophyseal system. A hypothesis is put forward about primary activation of adenylate cyclase system in the origin of the disease.
The authors analyze their observations of 118 patients with hypophyseal microadenomas in 1990-1992. Forty-four patients had prolactinomas, 35 somatotropinomas, 29 corticotropinomas, and 10 mixed tumors of the hypophysis. Operative interventions via a transseptal approach developed by the authors were carried out in all the patients. Complications of such operations are analyzed and methods of their treatment presented. The results lead the authors to a conclusion that selective microsurgery should be a method of choice in the treatment of hypophyseal microadenomas.
Case Reports
Intensive mapping of the Y chromosome in recent years has made it possible to determine the localization of a number of loci responsible for male differentiation. On the Y chromosome, the localization of the test-determining factor in the proximal region of the pseudo-autosomal region of the short arm was determined; distal to this gene, it is believed that the gene responsible for the function of the fertility factor SP-2 is located. Loci are located between euchromatin and heterochromatin of the long arm (AZF, SP-3, below - SP-4), which are responsible for controlling spermatogenesis.
Reports on the results of a multilateral examination of clinical cases with impaired spermatogenesis, fertility and anomalies of the Y chromosome are of some value not only for diagnosis and prognosis, but also for the accumulation of more complete information about the genetic regulation of reproductive processes and the development of approaches to correct their disorders. We present our observation.
Currently, more than 50 causes of hypoglycemia are known. Among its rare varieties is hypoclycemia, due to the presence of a large tumor, complicating the course of various extra-pancreatic neoplasms. The frequency of “tumor” hypoglycemia is not exactly established, but it is much less common with insulin occurring with the same clinical picture.
The mechanism for the development of tumor hypoglycemia remains unknown. It is believed that the tumor intensely absorbs glucose or inhibits gluconeogenesis in the liver. According to another theory, extrapancreatic tumors produce insulin-like growth factors that interact with insulin receptors. Despite the lack of a clear understanding of the pathogenesis of tumor hypoglycemia, timely removal of the tumor leads to normalization of carbohydrate metabolism. We present our observation.
Reviews
Starting from 1925, one of the pioneers of insulin therapy, E. Joslin, taught patients what he considered to be the main thing for the treatment success: daily triple determination of glucosuria and the corresponding change in insulin dose. The need for inpatient treatment while using this approach was rare. In the 1930s, the ideas of E. Joslin were developed by the German pediatrician K. Stolte, who essentially promoted exactly what was called intensified insulin therapy: several injections of simple insulin per day, self-monitoring according to glucosuria indicators, flexible change in insulin dose depending on the results of self-monitoring and carbohydrate intake, “free nutrition” and the pursuit of aglucosuria. Among domestic diabetologists, S. M. Genes stood in similar positions, who also considered it necessary to achieve aglycosuria, repeated administration of insulin, and close to normal nutrition; however, they did not practice self-monitoring and training of patients to independently change the dose of insulin. After the emergence of long-acting insulin preparations, the development of insulin therapy went a different way: patients were forbidden to change the dosage on their own, they administered insulin only 1 time per day, for many years they had to forget about normal nutrition, put up with the increased risk of hypoglycemia (due to constant hyperinsulinemia on a large dose of prolonged-acting insulin) and the need for frequent hospitalizations. It is known that before the appearance of prolonged drugs, patients were better compensated, having fewer vascular complications.
Experimental endocrinology
Experiments with primary cultures demonstrated a stimulating effect of TRF on somatotropic hormone (STH) secretion by hypophyseocytes of neonatal but not adult rats and a reduced reactivity of neonatal somatotrophs to the inhibitory effect of somatostatin during short-term incubation. No noticeable serotonin effect on STH release from hypophyseal cells of animals of various ages was observed. During prolonged (24 h) incubation a weak inhibitory effect of bromocryptine and melatonin on STH secretion by pituitary cells of neonatal but not adult rats was observed. These results permit us propose a similarity of the functional characteristics of neonatal pituitary somatotrophs to somatomammotroph properties.
Specificities of functioning and development of the reproductive system and mechanism of its regulation with hypothalamic structures were studied in the progeny of rats with streptozotocin diabetes. For this purpose pituitary sensitivity was analyzed in mature animals, as was functional capacity of the feedback system mediating the hypothalamic regulation of gonadotropin secretion in rat males and females at the age when this system normally starts functioning in health. The hypothalamohypophyseogonadal system feedback mechanism was found to develop in the progeny of female rats with streptozotocin diabetes later than in health. Pituitary sensitivity to LH-RH was reduced and LH level reduced by 1.5 times in mature progeny of rats with streptozotocin diabetes as compared to that in the progeny of healthy rats. These results permit a conclusion that the progeny of rats with streptozotocin diabetes develop disorders in the mechanism regulating the reproductive system of the body, though not so grave as to make this system functioning impossible.
Current Events
If in the 70s and in the beginning of the 80s the only second-generation sulfonylurea drug (eguglucon, daonil, mannilil) dominated the treatment of type II diabetes patients, in recent decades, the arsenal of doctors has been replenished with a number of effective second-generation drugs with differences in clinical properties.
One of these drugs is gliclazide (diamicron), well known to domestic endocrinologists. The drug was released by Servier in the late 70s. A significant structural difference between gliclazide and other sulfonylurea preparations is the presence of a heterocyclic nitrogen-containing ring (azabicyclo-octyl ring), which plays an important role in the hemorheological properties of the drug. The accumulated experience in the use of diabetes in different countries was the subject of discussion at a special symposium held as part of the 29th annual conference of the European Association for the Study of Diabetes.
Of particular interest were the reports comparing the effectiveness of various sulfonamides, the incidence of secondary resistance and complications in their use.
The symposium, held in Saratov from September 15 to 17, 1993, was devoted to two pressing problems: hormone-active pancreatic tumors and the surgical aspects of the treatment of complicated diabetes mellitus and related diseases. The successful choice of problems determined the great interest shown to the symposium not only by surgeons, but also by representatives of other medical specialties, who sent many applications for reports and took an active part in the symposium. Only nonresident participants of the symposium were about 50. Endocrinologists, surgeons, therapists, oncologists and other specialists of the Saratov and Saratov regions took part in the symposium.
The symposium was held on the initiative and with the direct participation of the head of the surgical endocrinology sections of the Russian Association of Endocrinologists, Honored Scientist of the Russian Federation, prof. A.P. Kalinina. The organizers of the symposium were MONIKI them. M.F. Vladimirsky and the Department of Faculty Surgery (Head - Prof. S. S. Slesarenko), Faculty of Medicine, Saratov Medical Institute. It is no coincidence that the Saratov Medical Institute was chosen as the venue for the symposium: for more than 30 years, various areas of endocrine surgery have been developed at its clinical bases. For many years, the pathogenesis, diagnosis and correction of diabetes mellitus in patients with various surgical pathologies has been studied at the faculty surgery department of the medical faculty of the Saratov Medical Institute. Numerous articles and dissertations on the basis of this department were devoted to these issues.
Dwarfism and its Therapy with Growth Hormone
Classical methods in experimental endocrinology include the removal of endocrine organs in animals, after which they are replaced with presumably active elements in order to demonstrate specific effects. Such experimentation is not considered ethical when examining a person; instead, in order to broaden our understanding of growth and developmental abnormalities, detailed studies of rare genetic disorders that cause an increase in specific defects in hormonal action or secretion can be used. This knowledge can be used in finding the right treatment for disorders that can be much more frequent than the rare conditions discussed below. Some “nature experiments” that can provide similar information about the effect of sex hormones on growth in the puberty period will be described.
An all-American collaborative study of the effectiveness of treatment with growth hormone (GH) for Turner syndrome was launched in 1983. 70 girls with Turner syndrome were divided into groups: without treatment, treatment with only GH, treatment with oxandrolone only, combined therapy with GH and oxandrolone. The duration of treatment was 12-24 months. After completion of this stage, patients who received treatment only with GH remained on the previous therapy, while all other patients were transferred to the treatment of GH in combination with oxandrolone. Currently, there are data on 62 girls who have been on therapy for at least 3-6 years. When compared with the growth rate usually observed in untreated patients with Turner syndrome, it turned out that during the treatment of both GH and the combination of GH and oxandrolone, there was an increase in the growth rate, which was maximally expressed during the first 2 years of the study and lasted for 6 years. Although the treatment of GH is currently not yet completed in half of the patients, in 14 (82%) of 17 girls receiving only GH and in 42 (93%) of 45 patients receiving combined therapy, the growth already exceeded their predicted adult rates age. In 30 patients who completed treatment, the average growth is currently equal to 151.9 cm, while their predicted final growth was initially 143.8 cm. These results suggest that GR therapy can lead to short-term (3-6 years ) accelerating growth, as well as improving the final growth indicators.
The etiology of Growth Hormone Insensitivity Syndromes (GH) is represented by various factors, one of which is Growth Hormone Receptor Insufficiency (HGHR). Currently, it is customary not to use the previously used terms - “dwarf” and “dwarfism”, therefore, to denote the insufficiency of receptors for GR, it is recommended to use the eponymous name “Laron syndrome”.
According to reports, patients with a number exceeding 150 with growth hormone receptor deficiency (HSCI) are mainly living in the Mediterranean region, with the exception of 7 patients from the Indian subcontinent. In Israel and Ecuador, the highest population concentrations of patients with HSCG are noted. For both of these places of population concentrations, incest is typical; there are also reports of a similar phenomenon in sporadic cases from other places. As with any hereditary disorders, apparently, in this condition there is both wide genetic heterogeneity and variable phenotypic expression.
Twenty-seven patients (14 - female, 13 - male; 3 - having achieved puberty) with growth hormone receptor deficiency (Laron syndrome) received treatment with recombinant insulin-like growth factor 1 (IGF-1) at a dose of 40-120 mcg per 1 kg body weight 2 times a day for 12 months. SDS for growth at the beginning of treatment ranged from -9.1 to -3.2 (age 3.7-22.9 years). Before treatment, most patients had an increased basal concentration in the serum of growth hormone (2.4–208 mU/L) and a low serum concentration of IGF-1 (<20–69 μg/L), IGF-2 (69–295 μg/L) and IRF-binding protein-3 (0.16-1.59 mg/l). In all but the two oldest patients, the growth rate increased by more than 2 cm / year compared with those before treatment. Asymptomatic hypoglycemia (blood glucose level <3.0 mmol / L) was recorded in 10 patients in 0.7% of measurements. In 4 patients symptomatic hypoglycemia was noted. Most patients after injections showed a transient decrease in serum potassium levels.
By January 15, 1992, the KIGS database included 258 children (the ratio of boys to girls 1.5: 1) with growth hormone deficiency, which developed against the background of craniopharyngioma. The duration of growth hormone (GH) treatment ranged from 0.2 to 15.4 years (average 3.9 years). Over 1338 years of GH treatment (total for all patients), 17 children had a relapse of CF after 0.25-4.8 years (on average 2.3 years) from the start of GH treatment. The age at the time the tumor was detected, the age and SDS for growth at the beginning of GH treatment, the dose of GH, as well as the growth rate before and during the first year of GH treatment did not differ in patients with and without relapse. The recurrence rate was also the same in patients who underwent one surgical treatment, and in those in whom the operation was combined with radiotherapy.
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