Vol 65, No 2 (2019)

Original Studies
The effect of intravitreally administered angiogenesis inhibitor on the concentration of angiotensin-converting enzyme in the blood serum and lacrimal fluid in patients with diabetic macular edema
Neroev V.V., Chesnokova N.B., Okhotsimskaya T.D., Ryabina M.V., Fadeeva V.A., Pavlenko T.А., Beznos O.V.
Abstract

BACKGROUND: Diabetic retinopathy (DR) is one of the more serious complications of diabetes and the main cause of blindness among working-age individuals. In recent years, information has emerged on the possible role of the renin-angiotensin system (RAS) in the pathogenesis of DR, and DR’s possible connection with the system of pro-angiogenic factors.

AIM: To study the impact of anti-angiogenic therapy on systemic and local concentrations of angiotensin-converting enzyme (ACE), a key component of RAS, for patients with diabetic macular edema (DME).

MATERIAL AND METHODS: The concentration of ACE in the lacrimal fluid and blood serum in 10 patients (20 eyes) with DME was determined before and after intravitreal injection (IVI) of ranibizumab. The comparison group consisted of 7 patients (14 eyes) with age-related macular degeneration (AMD). The control group consisted of 10 healthy individuals (20 eyes). All groups were comparable in age and sex. The concentration of ACE was determined by enzyme immunoassay. The main group was examined four times: before IVI of ranibizumab, and then one week, two weeks and one month after IVI of ranibizumab. The comparison group was examined before, and then one week after, IVI of ranibizumab.

RESULTS: In patients with DME, there was an initial 1.8-fold increase in the concentration of ACE in the lacrimal fluid of both eyes. A week after IVI of ranibizumab, the concentration of ACE in the lacrimal fluid began to decrease, reaching the control level after two weeks, and remaining there one month after IVI of ranibizumab. Initially, the concentration of ACE in the blood serum in patients with DME was 2.2 times lower than the control level. After IVI of ranibizumab there was an increase in the concentration of ACE in the blood serum, but by the end of the observation, the indicators continued to remain well below the control level. In patients with AMD, the initial concentration of ACE in the lacrimal fluids was not elevated; the concentration of ACE in the lacrimal fluids decreased 1.4 times one week after IVI of ranibizumab. The concentration of ACE in the blood serum of the patients with AMD was initially 25% lower than the control level, and essentially did not change after IVI of ranibizumab.

СONCLUSIONS: Changes in the concentration of ACE in patients with DME may be a new prognostic criterion for the development of DME for patients with diabetes. These changes in the concentration of ACE, in the context of antiangiogenic therapy, indicate an interaction between the renin-angiotensin and angiogenic systems. Similar changes that were observed after IVI of ranibizumab in patients with AMD confirm the mutual influence of these two systems.

The data presented in this study open up prospects for finding new pathways of pathogenic therapy for diabetic macular edema and diabetes.

Problems of Endocrinology. 2019;65(2):72-78
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The forearm fractures in patients with diabetes and without diabetes in population sample aged over 50 years (Novosibirsk)
Mazurenko E.S., Malyutina S.K., Shcherbakova L.V., Mustafina S.V., Nikitenko T.M., Bobak M., Rymar O.D.
Abstract

BACKGROUND: The attention to the forearm fractures, as to osteoporotic fractures, is important for ensuring early detection of individuals at increased risk of future fractures and taking preventive measures.

AIMS: To determine the frequency of a history of forearm fractures in patients with type 2 diabetes mellitus (DM2) and without diabetes, and their association with risk factors for chronic non-communicable diseases (NCD).

MATERIAL AND METHODS: In 2015–2017, in Novosibirsk, a random urban population sample of males and females, 58–84 years old (n=3878), was surveyed. The study included persons who signed the informed consent to conduct the study, excluded individuals who wrote a waiver of taking blood to determine biochemical parameters. In total, the analysis included n=3393 people, 718 of them with DM2 (21.2%). Work design is cross-sectional research. The collection of information on fractures during for the last 3 years, the registration of socio-demographic data; and risk factors for NCD, a study of biochemical blood parameters. The analysis of the association of DM2 and a complex of risk factors for NCD with a chance of a forearm fracture.

RESULTS: The prevalence of forearm fractures in the last 3 years did not differ in patients with DM2 compared with those examined without diabetes and was 2.4% and 2.8%, respectively (p=0.557). Men with fractures had higher cholesterol and HDL values, women had lower body mass index (BMI), compared with people without fractures. According to the results of a multivariate analysis in women, the chance of a forearm fracture is directly associated with smoking in the past, a total cholesterol level of more than 200 mg/dl and inversely associated with a BMI. In men, associations were found of the chance of a forearm fracture with an increase in the level of cholesterol. There was no evidence of DM2 with forearm fracture.

CONCLUSION: The obtained data on the incidence of fractures and their association with risk factors for chronic low risk infections suggest the need for preventive measures for osteoporotic fractures, both in people with and without DM2.

Problems of Endocrinology. 2019;65(2):78-87
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Case Reports
Hereditary Cushing’s syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia
Mamedova E.O., Vasilyev E.V., Petrov V.M., Izmailova N.S., Buryakina S.A., Rozhinskaya L.Y., Tiulpakov A.N., Belaya Z.E.
Abstract

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing’s syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25–55% of all PBMAH cases.

This article describes a clinical case of hereditary Cushing’s syndrome caused by PBMAH in a 37-year old patient. The patient’s family history is remarkable for the presence of Cushing’s syndrome and PBMAH in the patient’s mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.

Problems of Endocrinology. 2019;65(2):89-94
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Differential diagnosis between autoimmune thyrotoxicosis and thyroid hormone resistance syndrome: clinical case report
Mazurina N.V., Troshina E.A., Chukhacheva O.S.
Abstract

We report a case of 50-year-old woman with thyroid hormone resistance syndrome. For 20 years this patient have been treated for autoimmune thyrotoxicosis: she underwent thyroid surgery and then was on thyroid-blocking therapy. Repeated laboratory tests demonstrated elevated serum thyroid hormones concentrations and elevated TSH concentration. Inappropriate TSH secretion became the reason for conducting further investigations. In those cases, the diagnostic approach is complicated and cases may be referred as a syndrome of thyroid hormones resistance or as a pituitary mass. Results of magnetic resonance imaging as well as results of octreotide test did not confirm TSH-producing pituitary adenoma. Lack of consistent thyrotoxicosis symptoms and normal level of biochemical markers that reflect peripheral tissue response to excessive thyroid hormones action were regarded as an evidence for thyroid hormones resistance syndrome. In cases of thyroid hormone resistance syndrome, there is no reduction in thyroid hormones after octreotide administration and we could observe it in our patient. Thereby clinical data and laboratory tests supported the diagnosis of thyroid hormone resistance syndrome. To establish definitive diagnosis and to verify genetic cause of the disease we performed direct sequencing of the THRB gene exons 9–10.

Problems of Endocrinology. 2019;65(2):95-100
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Manifestation of Graves’ disease, resulting from radiosurgical treatment of acromegaly, in a patient with panhypopituitarism
Astafyeva L.I., Kalinin P.L., Kienia T.A., Fadeyev V.V.
Abstract

Cases of thyrotoxicosis associated with a previous case of secondary hypothyroidism are extremely rare. This article presents a rare clinical case of Graves’ disease manifestation in a patient with secondary hypothyroidism after radiosurgical treatment of acromegaly. A 38-year old woman presented with acromegaly and endo-supra-laterosellar pituitary adenoma. After non-radical removal of the pituitary adenoma, radiosurgical treatment of the of the residual tissue of the pituitary tumor in the cavernous sinus area was performed. After 14 months of radiation therapy, the acromegaly was in remission; after 24 months of radiation therapy, panhypopituitarism developed (secondary hypothyroidism, adrenal insufficiency, hypogonadism, and growth hormone deficiency). Furthermore, 1.5 years after the panhypopituitarism was diagnosed, the manifestation of Graves’ disease was also noted, requiring thyrostatic and radioactive iodine treatments.

Diagnostic criteria for secondary hypothyroidism are low levels of the thyroid hormones free T4 and free T3, with a reduced, normal or slightly elevated level of thyroid stimulating hormone (TSH). The criterion for the development of thyrotoxicosis in the context of the secondary hypothyroidism was the persistent increase in the level of free T4 despite adequate drug therapy with levothyroxine. In the case report, the patient’s diagnosis of Graves’ disease was confirmed by the presence of a high level of antibodies to the TSH receptor.

Problems of Endocrinology. 2019;65(2):101-106
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Sustained ventricular tachycardia in a patient with a single ventricle of the heart and a pheochromocytoma
Melkozerov K.V., Kuznetsov A.B., Kalashnikov V.Y., Abdulkhabirova F.М., Kuznetsov S.N., Gorbacheva A.M., Dedov I.I.
Abstract

A pheochromocytoma is a rare tumor that develops from adrenomedullary chromaffin cells and produce ones or more catecholamines, including adrenaline, norepinephrine, and dopamine. On rare occasions a pheochromocytoma is hormonally inactive. Cyanotic heart disease is also a relatively rare pathology. One of its least frequently occurring variants is the single ventricle of the heart. Presumably, in patients with cyanotic heart defects, the occurrence of pheochromocytes and paragangliomas will be higher due to the presence of certain germinative and somatic mutations. In cyanotic heart defects, the development of malignant arrythmias is one of the frequent causes of death. A combination of a pheochromocytoma with a single ventricle of the heart is extremely rare: only eight such cases have been described in the literature. This article describes a young patient with a unique case of a single ventricle of the heart, pheochromocytoma and sustained ventricular tachycardia. The cause of the ventricular tachycardia, in all likelihood, was inappropriate medical care – in this case, a prescription for verapamil. The surgical excision of the pheochromocytoma and the referral of the patient for cardiac surgery became possible only after correcting the antihypertensive and antiarrhythmic therapy. Verapamil was replaced with a combination of doxazosin and amiodarone, resulting in relatively satisfactory blood pressure readings and sinus rhythm.

Problems of Endocrinology. 2019;65(2):107-112
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Reviews
Aldosterone- and cortisol-co-secreting adrenal tumors: an uneasy sum of well-known parts (review)
Shifman B.M., Platonova N.M., Molashenko N.V., Troshina E.A., Romanova N.Y., Kolesnikova G.S.
Abstract

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension. In patients with PA, more so than in the general population, there is a prevalence of insulin resistance, diabetes mellitus, metabolic syndrome, osteoporosis, and symptoms of depression; these conditions are more likely to manifest a gluco- rather than mineralocorticoid excess. This fact is of particular importance in light of recent studies that have shown that PA is often associated with glucocorticoid excess. Since the first reports of cases of combined secretion of aldosterone and cortisol in 1979, the number of cases of so-called Connshing syndrome has increased. An analysis of data from recent studies suggests that hypercortisolism in PA is closely associated with an increased risk of cardiovascular complications, metabolic disorders and post-surgical adrenal insufficiency. The most important diagnostic problem in adenomas with combined secretion is the risk of false interpretation of the results of adrenal venous sampling (AVS). The indications that suggest aldosterone-and-cortisol-co-producing adenoma are the lack of suppression of cortisol levels following a night test with 1mg of dexamethasone, and an adrenal tumo of over 2.5cm. As an alternative test capable of differentiating this type of tumor, a number of researchers have proposed measuring the level of so-called hybrid steroids in the peripheral plasma and urine. Taking into account the high prevalence and potential risks, ruling out of excess corisol secretion is obligatory in all cases of PA before AVS and when planning surgery.

Problems of Endocrinology. 2019;65(2):113-123
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Prevalence of anabolic androgenic steroid use, its effect on the male pituitary-gonadal axis, and the possibility of reproductive rehabilitation
Lykhonosov M.P., Babenko A.Y.
Abstract

The purpose of this review is to assess the prevalence of AA steroid use, to identify the steroids that are used, and to present the negative effects of AA steroids on the human body while describing the mechanisms of their actions on the male reproductive system. The review highlights the diagnostic features of steroid-induced hypogonadism, and assesses the effectiveness of various drugs in the reproductive rehabilitation of patients who cease taking AA steroids. Emphasis is placed on the feasibility and effectiveness of various drug treatments in the context of post cycle therapy (PCT), which seeks to stabilize and restore normal hormonal function. All this data is necessary for the development of modern treatment algorithms for steroid-induced hypogonadism in men.

Problems of Endocrinology. 2019;65(2):124-133
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Pretibial myxedema: pathogenetic features and clinical aspects
Sabanova E.A., Fadeyev V.V., Potekaev N.N., Lvov A.N.
Abstract

Pretibial myxedema (PTM) or thyroid dermopathy is a rare extrathyroidal manifestation of Graves’ disease. The condition is accompanied by mucinous skin changes, mainly in the anterior tibial surface.

Severe forms may lead to lymphatic congestion and disability. Prolonged and intense autoimmune aggression is supposed to be necessary for PTM manifestation. However, data on the role of TSHR antibodies in the development of thyroid dermopathy are very ambiguous; evidence of IGF-1 receptor involvement in the pathogenesis was reported recently.

Typically, PTM is localized on the anterior and lateral surfaces of both tibias and can be represented by diffuse, tumorous, plaque-like, or elephantiasic forms. Currently, early diagnostics involves regular preventive examination of the pretibial area. A diagnostic biopsy is indicated only in complex cases.

Maintaining euthyroidism, smoking cessation, preventing injuries, and avoiding tight shoes that disturb lymphatic drainage are measures reducing the risk of PTM in GD patients.

Currently, there are no accepted clinical guidelines for the diagnosis and treatment of thyroid dermopathy. This review provides the recent scientific data on etiopathogenesis and management of patients with PTM.

Problems of Endocrinology. 2019;65(2):134-138
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Endometrial cell apoptosis impairment associated with hormonal imbalance as a key factor in the development of endometriosis
Ukrainets R.V., Korneva Y.S.
Abstract

The review describes the effect of certain hormones and their imbalance on apoptosis of retrogradely refluxed endometrial cells in the abdominal cavity and the effects of estrogen, progesterone, anti-Mullerian hormone, and gonadotropin-releasing hormone on the internal and external apoptotic pathways of various cell populations in endometriotic foci. The nuclear estrogen receptor β (ER-β) is shown to inhibit TNF receptors that trigger the external apoptotic pathway, but the effects of estrogens do not play a key role in the pathogenesis of endometriosis. The role of progesterone and changes in the receptor status towards prevalence of PR-A with a decreased response of endometrial tissue to progesterone and inhibition of apoptosis are described. We discuss the role of the anti-Müllerian hormone and gonadotropin-releasing hormone II (GnRH II) as activators of apoptosis in normal endometrial tissue and in endometriosis. Investigation of endocrine effects on apoptosis of parenchymal and stromal cells of endometriotic foci may provide a theoretical basis for searching for new therapeutic targets in this hormone-dependent pathology.

Problems of Endocrinology. 2019;65(2):140-144
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