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Vol 65, No 4 (2019)

Original Studies
The effectiveness of risk stratification systems in diagnosis of nodular thyroid disorders
Aleksandrov Y.K., Yanovskaya E.A., Shubin L.B., Dyakiv A.D.


BACKGROUND: Risk stratification systems, one of the optimal solutions for differential diagnosis of nodular pituitary disorders, are currently under development. The high prevalence of pituitary diseases makes it necessary to evaluate the effectiveness of risk stratification systems and to widely implement them into routine clinical practice.

AIM: To evaluate the effectiveness of modern risk stratification systems used to diagnose nodular pituitary disorders.

MATERIAL AND METHODS: A total of 1,606 medical records of patients operated on for nodular pituitary disorders in 2006–2014 were analyzed. The preoperative ultrasonography results and cytological findings were evaluated. The ultrasonography results were classified using the TI-RADS system, while the biopsy data were classified using the TBSRTC system. The surgery protocol and the pathomorphological data were the truth criterion. The effectiveness of the TI-RADS and TBSRTC systems, as well as their contribution to the performance of endocrinologists in outpatient clinics, was analyzed.

RESULTS: Cluster analysis revealed a significant volatility of ultrasonography signs in the TI-RADS category, while there was no dominant sign that could be considered the diagnostic standard. Factor analysis proved the consistency of the imaging TI-RADS system based on individual signs. The signs being evaluated are characterized by high significance level but different priorities depending on the type of putative pathology. Discriminant analysis revealed that TI-RADS was a robust and versatile system to be used for various types of nodular pituitary disorders. The overall effectiveness of the TI-RADS system in diagnosis of pituitary tumors was low: it was characterized by 75.4% sensitivity, 84.7% specificity, and 80.1% accuracy. However, this system concretized the indications for fine-needle aspiration biopsy and drew the cytologists’ attention to the likelihood of pituitary tumor. The implementation of the TBSRTC system reduced the percentage of non-informative (by 9.8%) and controversial results (by 1.7%). Cytological examination was more effective in detection of pituitary cancer compared to ultrasonography (91.0% accuracy, 94.9% specificity, and 76.5% sensitivity). The impressions of ultrasound technicians and cytologists were concordant in 873 (54.4%) cases. A survey conducted among endocrinologists in outpatient clinics showed that implementation of the TI-RADS and TBSRTC risk stratification systems reduced the decision time (p<0.001) and errors both in diagnostics (p<0.001) and treatment approach selection (p<0.001).

CONCLUSION: The combined use of the TI-RADS and TBSRTC systems allows one to personalize the treatment approaches for patients with nodular pituitary disorders. The implementation of these systems has a positive effect on endocrinologists’ performance as it reduces the decision time and the likelihood of making errors in diagnosis and treatment strategy selection.

Problems of Endocrinology. 2019;65(4):216-226
The glucagon test in diagnosis of secondary adrenal insufficiency after craniospinal irradiation: the feasibility of application, the features of performing the test, and its diagnostic informativity
Yudina A.E., Pavlova M.G., Sotnikov V.M., Tselovalnikova T.Y., Mazerkina N.A., Zheludkova O.G., Gerasimov A.N., Teryaeva N.B., Martynova E., Kim E.I.


BACKGROUND: The glucagon test (GT) is a promising alternative to the insulin hypoglycemia test (IHT) in diagnosis of secondary adrenal insufficiency (SAI).

AIM: To study the feasibility of using the GT in patients after craniospinal irradiation and to determine the cut-off value to rule out SAI.

METHODS: A total of 28 patients (14 males and 14 females) with the median age of 19 years (17; 23) who had undergone combination treatment (surgery, craniospinal irradiation (35 Gy) with boost to the tumor bed, and polychemotherapy) of extrapituitary brain tumors no later than 2 years before study initiation and 10 healthy volunteers of matching sex and age were examined. All the subjects underwent the GT and IHT with an interval of at least 5–7 days. The cortisol, ACTH, and glucose levels were measured.

RESULTS: Twelve out of 28 patients were diagnosed with SAI according to the IHT results. ROC analysis revealed that cortisol release during the GT >499 nmol/L ruled out SAI [100% sensitivity (Se); 62% specificity (Sp)], while the absence of a rise >340 nmol/l verified SAI (Sp 100%; 55% Se). For GT, the area under a curve (AUC) was 93.6%, which corresponds to a very good diagnostic informativity. In 19 patients, the IHT and GT results were concordant (in ten patients, the release of cortisol occurred above the cut-off value in both tests; no release was detected in nine patients). In nine cases, the results were discordant: the maximum cortisol level detected in the GT was ≤500 nmol/l, but the IHT results ruled out SAI (the GT yielded a false positive outcome). Contrariwise, in three (10.7%) patients the release of cortisol detected in the GT was adequate, while being insufficient in the IHT test. Adverse events (nausea) were reported during the GT test in 9 (25%) subjects; one patient had hypoglycemia (1.8 mmol/l).

CONCLUSION: GT is highly informative and can be used as a first-level stimulation test for ruling out SAI in patients exposed to craniospinal irradiation performed to manage brain tumors. The cortisol level of 500 nmol/L is the best cut-off value for ruling out SAI according to the GT results. The insulin hypoglycemia test is used as the second-level supporting test in patients with positive GT results.

Problems of Endocrinology. 2019;65(4):227-235
Diagnosis of congenital sexual maldevelopment in boys with bilateral inguinal cryptorchidism during minipuberty
Raygorodskaya N.Y., Bolotova N.V., Chekhonatskaya M.L., Polyakov V.K., Sedova L.N., Somova V.A.


BACKGROUND: Cryptorchidism is associated with the risk of infertility and can be a symptom of congenital sexual maldevelopment.

AIM: To assess the functional status of the pituitary gland and sexual glands in boys aged 1–6 months with bilateral inguinal cryptorchidism and to reveal the congenital sexual maldevelopment during minipuberty.

METHODS: Twenty-one boys aged 1–6 months (the minipuberty period) with isolated bilateral inguinal cryptorchidism and 40 healthy boys aged 2–3 months (the control group) were examined. The gonadal status was assessed and serum levels of sex hormones were measured. Molecular genetic testing was performed if there were indications for it.

RESULTS: The results of hormone analysis were used to divide the patients into three groups: group 1 – patients with normal serum levels of gonadotropin and sex hormones; group 2 – patients with elevated gonadotropin level and low levels of anti-Müllerian hormone (AMH) and inhibin B, and group 3 – patients with zero gonadotropin and testosterone levels and low levels of AMH and inhibin B. Group 1 patients had no functional disturbances in the pituitary–gonadal system. Failure of Sertoli cells associated with a high risk of infertility was detected in group 2 patients. Group 3 patients were diagnosed with hypogonadotropic hypogonadism verified by molecular genetic tests.

CONCLUSION: Hormonal testing of patients with bilateral inguinal cryptorchidism during minipuberty makes it possible to early detect the congenital sexual maldevelopment.

Problems of Endocrinology. 2019;65(4):236-242
Case Reports
A clinical case of combined differentiated thyroid cancer and primary hyperparathyroidism: the complexity of topical differential diagnosis
Slashchuk K.Y., Degtyarev M.V., Serzhenko S.S., Rumyantsev P.O., Sheremeta M.S., Yasuchenia V.S., Trukhin A.A., Sirota Y.I., Baranova O.D., Nikiforovich P.A.


In recent years, the understanding of the epidemiology, symptoms and strategies for managing patients with hyperparathyroidism has changed significantly. The most common cases in clinical practice are of sporadic primary hyperparathyroidism, which today ranks third in prevalence among endocrine diseases (the frequency of occurrence in the adult population is, on average, 1–2%). In primary hyperparathyroidism, solitary parathyroid adenoma is detected in up to 85% of all cases. The only treatment is radical surgical removal of pathologically altered parathyroid tissue. Early diagnosis and treatment of hyperparathyroidism makes it possible to avoid severe lesions of the skeletal bones and visceral organs. A diagnostically challenging clinical case of a combined onco-endocrine pathology in a 70-year-old patient is presented. The main difficulties in the initial diagnosis were associated with the absence of pathognomonic symptoms of the disease, which was often completely asymptomatic. The most urgent problem appears to be the topical diagnosis of pathologically altered parathyroid glands. Therefore, there is a need to develop an algorithm for the combining and sequential use of existing medical imaging methods.

Problems of Endocrinology. 2019;65(4):243-250
Hypoglycemia in neonates: a review of the literature and a case report
Taranushenko T.E., Kiseleva N.G., Lazareva O.V., Kalygnaja I.I.


Hypoglycemia in the neonatal period is one of the urgent problems of pediatric endocrinology. The main factors that lead to disruption of carbohydrate homeostasis are generally known, but the issues of neonatal hypoglycemia continue to be actively studied. In the last few years, the effect of low blood glucose on brain neurons has been studied, the issues of glycemia monitoring in the first days of life have been outlined, and strategies for managing newborns with hypoglycemic syndrome are being discussed.

Problems of Endocrinology. 2019;65(4):251-262
Secondary hyperaldosteronism and medullary nephrocalcinosis caused by self-administered and uncontrolled laxative use in an adolescent patient
Sibileva E.N., Mironova N.Y., Korobitcina G.V., Koshlakova O.T., Ipatova O.E.


Secondary hyperaldosteronism is respondent aldosterone secretion increase, occurring due to some diseases or drug use. It may be accompanied by normal arterial pressure with/without water retention or arterial hypertension without water retention. Secondary hyperaldosteronism without arterial hypertension and without water retention is usually caused by the use of laxative and diuretic drugs. This condition is characterized by the lack of salt wasting symptoms, presence of myalgia and muscle weakness resulting from hypokalemia, calcium oxalate crystalluria and sonographic signs of medullary nephrocalcinosis. Such characteristics of water-salt exchange and presence of nephrocalcinosis in combination with hypercalciuria are defined as Bartter-like syndrome. Peculiarity of the given clinical case is determined not by a diagnostic difficulty of secondary hyperaldosteronism but concealment of long term self-administered use of laxatives > 2 years without medical indications in a female patient, resulting in medullary nephrocalcinosis. A well-informed patient may endanger medical practice, because it is impossible to foresee everything including the uncontrolled self-administered drug use leading to the undesirable consequences.

Problems of Endocrinology. 2019;65(4):263-267
Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome
Kalinchenko N.Y., Kolodkina A.A., Petrov V.M., Vasiliev E.V., Tiulpakov A.N.


Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.

Problems of Endocrinology. 2019;65(4):268-272
Virilizing ovarian tumor: the challenges of differential diagnosis
Kalashnikova M.F., Likhodey N.V., Tiulpakov A.N., Fedorova E.V., Bryunin D.V., Bakhvalova A.A., Glushakova M.A., Smirnova S.A., Fadeyev V.V.


Sertoli–Leydig cell tumor is a rather rare type of ovarian neoplasms belonging to the group of sex cord–stromal tumors. This malignancy is characterized by androgen overproduction, which results in the so-called virilization and can be accompanied by various metabolic disorders such as abdominal obesity, disturbances of carbohydrate and protein metabolism, and high blood pressure.

During differential diagnosis, it is important to identify the source of androgen overproduction. An androgen-secreting ovarian tumor needs to be differentiated from androgen-secreting adrenal tumor, ovarian stromal thecomatosis (hyperthecosis), and endogenous hypercorticism (the Cushing’s syndrome). In most cases, the Sertoli–Leydig cell tumor is associated with DICER1 mutation carriership. If a patient is found to carry the DICER1 mutation, patient’s relatives need to undergo genetic testing as the individuals with mutations in this gene have an elevated risk of developing a broad range of benign and malignant tumors (most of these tumors are relatively rare in the overall population).

The awareness of this rare ovarian neoplasm among medical specialists (obstetricians–gynecologists, endocrinologists, and oncologists) is supposed to ensure timely diagnosis and adequate treatment of this disease.

Problems of Endocrinology. 2019;65(4):273-277
An ovarian hyperstimulation syndrome caused by gonadotropinoma in a young woman
Gorbacheva A.M., Przhiyalkovskaya E.G., Azizyan V.N., Stanoevich I.V., Grigoriev A.Y., Sazonova A.I., Lapshina A.M., Belaya Z.E.


From 14 to 54% of all pituitary adenomas are nonfunctioning pituitary adenomas (NPAs), their prevalence is estimated as 7.0–41.3 cases per 100 000 population. The most common type of NPAs (73% of cases) are gonadotropinomas. In most cases, gonadotropinoma is characterized by secretion of biologically inactive hormones, so the release of gonadotropins does not lead to the development of any clinical symptoms. For this reason the diagnosis of gonadotropinomas is most often performed on the basis of immunohistochemical analysis. However, in rare cases, gonadotropinomas secrete biologically active hormones, most often follicle-stimulating (FSH). Ovarian hyperstimulation syndrome due to gonadotropin-secreting pituitary tumors occurs in about 3% of women with hormonally inactive pituitary adenomas at reproductive age and in 8% of patients with verified gonadotropinomas. This clinical case describes a young patient with a rare pathology: FSH/LH-secreting macroadenoma of the pituitary, which led to the development of ovary hyperstymulation symdrome. The diagnosis of pituitary adenoma was performed due to the identified hyperprolactinemia one month before the development of visual impairment, which can be considered a late diagnosis. Surgical treatment of gonadotropinomy was carried out successfully and without complications, remission of the disease was achieved, visual function was restored, the patient successfully became pregnant.

Problems of Endocrinology. 2019;65(4):278-288
Pathogenetic features of immunological disorders in women with thyroid peroxidase antibodies presence and their effect on infertility treatment by in vitro fertilization (IVF)
Druzhinina A.S., Vitiazeva I.I.


Autoimmune thyroiditis (AIT) is the most common thyroid disease among women of fertile age. An increase of thyropercosidase antibodies (TPO-Ab) occupies one of the leading positions among other autoantibodies in patients with idiopathic infertility. Stimulation of superovulation in assisted reproductive technology (ART) programs leads to thyroid overstimulation, relative hypothyroxinemia and an increase of thyroid stimulating hormone (TSH) level in women with positive TPO-Ab carrier state, leading to a decrease in the reserve capacity of the thyroid affected by the autoimmune process. There is a large number of studies concerning the effect of autoimmune thyroid diseases on the infertility treatment outcomes in ART programs, but the results are contradictory. One of the hypotheses is that TPO-Ab affect the embryo implantation process in the uterus, based on an imbalance of cytokine production by T-helper type 1, 2, and 17, which are not easy to correct by classical hormone replacement therapy with levothyroxine. Nowadays, the immunological mechanisms of these disorders are not well investigated.

Problems of Endocrinology. 2019;65(4):289-294
Erratum: The forearm fractures in patients with diabetes and without diabetes in population sample aged over 50 years (Novosibirsk) (Problems of Endocrinology (2019) 65(2) DOI: 10.14341/probl9799)
Mazurenko E.S., Malyutina S.K., Shcherbakova L.V., Mustafina S.V., Nikitenko T.M., Bobak M., Rymar O.D.


A corrigendum on the article «The forearm fractures in patients with diabetes and without diabetes in population sample aged over 50 years (Novosibirsk)» by E.S. Mazurenko, S.K. Malyutina, L.V. Shcherbakova, S.V. Mustafina, T.M. Nikitenko, M. Bobak, O.D. Rymar (2018). Problems of Endocrinology 65(2). doi: 10.14341/probl9799

There was an error on the page 84 in the Table 4: symbol “greater than or equal to” was confuse with “lower than” in the table raw for menopause; symbol “lower than or equal to” was confuse with “greater than” in the table raw for total cholesterol level.

The authors and editors apologize for this error. The original article has been updated.

Problems of Endocrinology. 2019;65(4):e1-e2

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