Vol 63, No 5 (2017)

Original Studies
Mathematical models for predicting final achieved height and its standard deviation rate in children with growth hormone deficiency in the Russian population
Gavrilova A.E., Nagaeva E.V., Rebrova O.Y., Shiryaeva T.Y.

Background. Predicting the efficacy of rGH therapy in patients with GH deficiency, based on the final achieved height (FAH) criterion, is an important tool for the clinician. It enables a personalized approach to the treatment of patients with GH deficiency: to recommend careful adherence to the regimen and dosage of the drug, evaluate the efficacy of therapy in different groups of patients, and clearly demonstrate the factors affecting the FAH indicator.

Aim — to develop mathematical models for predicting FAH and its standard deviation score (SDS) in patients with GH deficiency in the Russian population.

Material and methods. For simulation, we used the data of 121 patients diagnosed with GH deficiency who received rGH since the time of diagnosis to the time of final height and were followed-up at the Institute of Pediatric Endocrinology of the Endocrinology Research Centre in the period between 1978 and 2016. As model predictors, we used 11 indicators: the gender, chronological age at the time of GH deficiency diagnosis, puberty status, disease form, regularity of rGH therapy, height SDS at birth, height SDS at the time of GH deficiency diagnosis, bone age at the time of GH deficiency diagnosis, bone age/chronological index, SDS of a genetically predicted height, and maximum stimulated GH level in a clonidine test. To generate models, we used multiple linear regression, artificial neural networks (ANNs), and the Statistica 13 software.

Results. The developed ANNs demonstrated a high accuracy of predicting FAH (the root-mean-square error was 4.4 cm, and the explained variance fraction was 76%) and a lower accuracy of predicting the FAH SDS (the root-mean-square error was 0.601 SDS, and the explained variance fraction was 42%). Linear regression models that were based on quantitative predictors only had a substantially worse quality. Free software implementation was developed for the best produced ANN.

Conclusion. An ANN-based software-implemented model for predicting FAH uses indicators available for any clinician as predictors and can be used for individual prediction of FAH. In the future, the use of larger databases for simulation will improve the quality of predicting the efficacy of rGH therapy.

Problems of Endocrinology. 2017;63(5):282-290
Tamoxifen in patients with dopamine agonist-resistant prolactinomas
Fedorova N.S., Dzeranova L.K., Pigarova E.A., Vorotnikova S.U., Melnichenko G.A.

Aim — to assess the efficacy and safety of tamoxifen in patients with prolactin-secreting pituitary tumors resistant to treatment with dopamine agonists.

Material and methods. The study included 6 females aged 23—38 years. All patients received cabergoline for a prolonged time without normalization of prolactin levels and reversal of secondary hypogonadism. The cabergoline dose was 1—7 mg/week. Cabergoline administration was combined with tamoxifen at a dose of 20 mg per day, with a subsequent increase to 40 mg per day after 4 weeks of treatment. Patients received this combination therapy for 3 months.

Results. Combined cabergoline and tamoxifen therapy resulted in a significant reduction in prolactin levels in all treated patients, which amounted to 22—66% of the baseline value. However, none of the patients achieved complete normalization of prolactin levels. Despite this fact, 2 patients developed normalization of the menstrual cycle. One of these got pregnant 1.5 months after discontinuation of tamoxifen and gave birth to a child. The second patient had amenorrhea recurrence after tamoxifen discontinuation. After tamoxifen discontinuation, two patients with amenorrhea were treated with dydrogesterone to prevent endometrial hyperplasia. One patient who had a normal menstrual function before tamoxifen developed endometrial hyperplasia, which was the cause for separate diagnostic curettage and a reduction in the tamoxifen dose to 20 mg per day. One month after tamoxifen discontinuation, the patient naturally conceived and subsequently gave birth to twins. One patient underwent placement of an intrauterine system containing levonorgestrel 2 months before the start of tamoxifen.

Conclusion. Tamoxifen in combination with cabergoline provides an additional decrease in prolactin levels in patients with initial resistance to dopamine agonists. In patients with dopamine agonist-resistant prolactinomas and hypoestrogenemia, tamoxifen leads to normalization of the menstrual cycle.

Problems of Endocrinology. 2017;63(5):291-298
Glucagon-like peptide-2 and glucagon in patients with acromegaly and Cushing’s disease: secretion features and influence on glucose metabolism
Machekhina L.V., Shestakova E.А., Belaya Z.Е., Nikankina L.V., Astafieva L.I., Shestakova M.V.

Aim. To analyze secretion of GLP-2 and glucagon in patients with Cushing’s disease (CD) and acromegaly in response to glucose load.

Material and methods. The study included 42 patients with Cushing’s disease and acromegaly; the mean patient age was 37.5 years. All patients were newly diagnosed with Cushing’s disease and acromegaly: none of them had a history of previous drug therapy, radiotherapy, or pituitary surgery. All patients underwent the oral glucose tolerance test with measurements of glucose, glucagon, and GLP-2 levels at 0, 30, and 120 min, respectively.

Results. A significantly higher glucagon level was observed in CD patients at all cut-off points (р=0.001); in acromegaly patients, the glucagon level did not significantly differ from that in controls (р=0.12). The GLP-2 concentration in CD patients was also significantly higher compared to that in controls (р<0.001). There were no significant differences between acromegaly patients and controls. We also found a strong correlation between GLP-2 and glucagon levels at 0 and 30 min in CD patients. In acromegaly patients, a correlation between GLP-2 and glucagon levels was observed only at 0 min. Different GLP-2 and glucagon secretion patterns in patients with CD and acromegaly suggest a direct influence of glucocorticoids on glucagon secretion and no influence in the case of IGF-1.

Conclusion. The found correlation between GLP-2 and glucagon levels might help specify the role of GLP-2 in carbohydrate metabolism regulation. Interactions of cortisol, IGF-1, and GLP-2 look promising for a better understanding of secondary hyperglycemia pathogenesis.

Problems of Endocrinology. 2017;63(5):299-306
Comparative pharmacoeconomic evaluation of the treatment of type 2 diabetes mellitus with insulin degludec and insulin glargine in basal-bolus insulin therapy
Kolbin A.S., Shestakova M.V., Galstyan G.R., Zhao W., Mosikyan A.A., Kurylev A.A., Balykina Y.E., Proskurin M.A., Alekseeva Y.G., Startseva E.Y.

Background. Type 2 diabetes mellitus (T2DM) and its complications are the major causes of long-term disability, significant performance loss, and premature mortality. Poor glycemic control, diabetes-related complications, and insulin therapy are associated with a significant increase in diabetes costs. The high cost of insulin analogues restricts reimbursement of their costs in some countries. Comprehensive clinical and economic assessments of different insulin analogues are the useful tool that may help policy-makers to set priorities in medicine provision within the existing system of healthcare funding.

Aim — to compare the clinical and economic effectiveness of insulin degludec (100 U/mL) and insulin glargine (100 U/mL) in basal-bolus therapy for T2DM.

Material and methods. Economic evaluation was based on cost effectiveness analysis (CEA), incremental cost-effectiveness ratio (ICER), cost effectiveness modelling (using 5-year time horizon), sensitivity analysis, and economic feasibility assessment. The clinical effectiveness was evaluated based on changes in the HbA1c level, frequency of severe hypoglycemia, and number of patient-years without complications. Only direct medical costs (costs for insulin therapy and treatment of severe hypoglycemia and diabetes-related complications) were analyzed.

Results. The mean total direct medical costs amounted to 783,789 RUR/patient for degludec (of these, the cost of insulin therapy accounted for 68%) and 730,805 RUR/patient for glargine (of these, the costs for treatment of severe hypoglycemia and diabetes complications accounted for 62.58%). Degludec has a higher efficacy (additional HbA1c reduction by 0.52%), lower rate of severe hypoglycemia, and larger number of complication-free patient-years. Incremental costs (ICER) for degludec amounted to 101,236 RUR/patient (based on a decrease in the HbA1c level) and 353,224 RUR/patient (based on an increase in the number of complication-free patient-years); these values were 14.3- and 4.1-fold lower than the threshold of willingness-to-pay, respectively. Additional analysis of costs in patients with severe hypoglycemia rates of 3 and >3 events/patient/year demonstrated that the estimated mean total costs for insulin degludec were lower by 5 and 23%, respectively, than those for insulin glargine.

Conclusion. Our findings demonstrate the clinical and cost benefits of insulin degludec in T2DM patients, which supports its broader use in routine clinical practice for achieving the best glycemic control with minimal adverse effects.

Problems of Endocrinology. 2017;63(5):307-319
Five years follow up of patients with Сushing’s disease with and without visualized pituitary adenoma on MRI, who underwent transsphenoidal adenomectomy
Khandaeva P.M., Belaya Z.E., Rozhinskaya L.Y., Vorontsov A.V., Grigoriev A.Y., Voronkova I.A., Lapshina A.M., Sitkin I.I., Melnichenko G.A.

The remission rate of Cushing’s disease in patients after neurosurgery varies from 59 to 94%, while the recurrence rate is 3 to 46%.

Aim — to evaluate the five-year outcome in neurosurgery patients with Cushing’s disease (CD), depending on preoperative MRI-based identification of pituitary adenoma.

Material and methods. The study included 105 neurosurgery patients with histologically confirmed CD. CD remission was confirmed by the development of adrenal insufficiency and/or normalization of serum cortisol and 24-hour urinary free cortisol (24h UFC) levels, as well as by clinical remission.

Results. Pituitary adenoma was not visualized by gadolinium MRI in 35 cases. The size of visualized pituitary adenoma varied from 0.3 to 29 mm. After first neurosurgery, remission was achieved in 87 (82.8%) patients. After second neurosurgery, remission occurred in 12 patients. Radiation therapy was conducted in 24 patients. Six patients had bilateral adrenalectomy. Two patients died during remission: one patient died from stroke two years after neurosurgery, and the other patient died due to surgery complications. During five-year follow-up after neurosurgery, remission continued in 76 (72.8%) patients, including 27 (77%) of 35 patients without MRI-detected adenoma and 49 (70%) of 70 patients with MRI-detected pituitary adenoma, p=0.15. Sixty-six patients developed recurrence, and 14 patients had active hypercortisolism.

Conclusion. There was no correlation between the rate of preoperative MRI-based detection of pituitary adenoma and the rate of remission in neurosurgery patients with Cushing’s disease during the five year follow-up. The size of pituitary adenoma was a risk factor for adenoma recurrence.

Problems of Endocrinology. 2017;63(5):276-281
Case Reports
A clinical case of hereditary papillary thyroid carcinoma associated with a germline DICER1 gene mutation
Babinskaya S.A., Kalinchenko N.Y., Ilyin A.A., Severskaya N.V., Chebotareva I.V., Nizhegorodova K.S., Rumyantsev P.O., Tiulpakov A.N.

Here, we report a clinical case of isolated papillary thyroid cancer associated with a germline DICER1 gene mutation in a boy and his father. The father underwent surgery for a euthyroid multinodular goiter at the age of 7 and 9 years. On examination at the age of 27 years, he was diagnosed with papillary thyroid cancer. At the age of 7 years, the boy was suspected of having a multinodular goiter (based on thyroid ultrasonography findings); he underwent total thyroidectomy. A histological examination of the surgical material revealed encapsulated papillary carcinoma. Neither boy nor his father had been exposed to radiation or chemotherapy before the diagnosis of papillary thyroid cancer. To clarify the etiology of disease, a molecular genetic testing was performed using next-generation sequencing (NGS). The proband and his parent had a heterozygous thymine deletion in the exon 4 at position 380, which led to a shift in the reading frame with the formation of a premature stop codon (c.380delT p.L127QfsX3).

Problems of Endocrinology. 2017;63(5):320-324
Mediastinal teratoma with mature fetal pancreatic tissue, nesidioblastosis and focal hyperplasia of neuroendocrine cells. A case report
Rumyantsev P.O., Abrosimov A.Y., Tertychnyi A.S., Selivanova L.S., Slashchuk K.Y.

We present a clinical case of rare and poorly diagnosable mediastinal teratoma containing elements of mature pancreas tissue, nesidioblastosis, and focal hyperplasia of neuroendocrine cells in a somatically healthy 25-year-old male. The main diagnostic difficulties are associated with the asymptomatic clinical course of mediastinal teratomas that are usually incidentally discovered during X-ray for other conditions. The pathology is characterized by pronounced morphological heterogeneity of the tumor; if the morphologist is not sufficiently qualified, this often results in a false-positive conclusion of neuroendocrine carcinoma, which, in turn, leads to an inadequate amount of treatment and a wrong prognosis in the patient. Therefore, for verification of the diagnosis, histological specimens should be examined by experts of institutions experienced in morphological differential diagnosis. In this case, an immunohistochemical study of the tumor for insulin, cytokeratins, and markers of neuroendocrine differentiation as well as measurement of the proliferation index Ki-67 in several areas are the key tests. This pathology is extremely rare, which leads to numerous misdiagnoses.

Problems of Endocrinology. 2017;63(5):325-328
A case report of concomitant myopathy, adrenal insufficiency, and mental retardation linked with deletion of Xp21
Orlova E.M., Kurkina M.V., Sozaeva L.S., Kareva M.A., Kanivets I.V., Antonets A.A., Zakharova E.Y.

Contiguous gene syndromes (CGS) are the disorders caused by chromosomal abnormalities: deletions, duplications, or other complex rearrangements that alter gene dosage. Initially, before their chromosomal nature is elucidated, they may be misdiagnosed as monogenic disorders depending on the leading clinical symptom cluster. The altered chromosomal region in individuals with this condition is typically less than 5 Mb in size and sometimes cannot be identified by conventional karyotyping. Patients present with signs of the diseases associated with each individual monogenic disorder. The Xp21-linked genetic syndrome, or glycerol kinase deficiency (GKD) (MIM 300474), is an example of this syndrome [1–3]. The genes coding for glycerol kinase (GK), congenital adrenal hypoplasia (NR0B1), and dystrophin (DMD) follow each other in the Xp21.2—p21.3 region. Deletions of an X-chromosome region may cause several monogenic disorders in one patient, including primary adrenal insufficiency and hypogonadotropic hypogonadism as a result of deletion in the NR0B1 gene, Duchenne muscular dystrophy (or a milder form, Becker muscular dystrophy) resulting from deletion in the dystrophin gene, and mental retardation as a result of deletion in the glycerol kinase gene.

We report a case of concomitant myopathy, adrenal insufficiency, and mental retardation linked with deletion of Xp21.

Problems of Endocrinology. 2017;63(5):329-333
Carbohydrate metabolism disorders in salicylate poisoning: diagnostic problems and physician’s tactics
Petryaykina E.E., Vykhristyuk O.F., Koltunov I.E.

Drug poisoning, in particular poisoning with analgesics, is a topical problem in pediatrics. Poisoning signs are diverse, and interdisciplinary collaboration is important for managing these conditions. In this article, we discuss the diagnostic problems of salicylate poisoning, symptoms of which are similar to those in diabetes. In addition, ways to confirm the diagnosis and treatment modalities are described.

Problems of Endocrinology. 2017;63(5):334-337
Identification and overcoming of resistance to somatostatin analogues in real clinical practice
Ilovayskaya I.A.

Resistance to somatostatin analogues (SSAs) is defined as the lack of biochemical and tumor response to the treatment for 12 months. An adequate biochemical response means achieving the target criteria of acromegaly treatment or at least a decrease in the GH and/or IGF-1 levels by >50%. A decrease in the somatotropinoma size by ≥ 20% (when using SSAs as the first line treatment) is considered as the tumor response to treatment. On the basis of treatment efficacy, patients may be classified as non-resistant (biochemical control of acromegaly and tumor response), partially resistant (some degree of biochemical and/or tumor response), and fully resistant (neither biochemical nor tumor response) to SSA therapy. Most patients (up to 60—70%) are partially resistant to the first generation of SSAs. Clinical and biochemical predictors for resistance to SSAs include young age, male gender, high GH/IGF-1 levels, and large invasive sparsely granulated somatotropinoma with high Ki-67 and a hyperintense T2-weighted MRI signal. In recent years, various molecular and genetic predictors for resistance to SSAs have been found; they should be introduced in clinical practice to enable the personalized approach to drug therapy. Treatment options for patients resistant to first-generation SSAs include dose escalation, combined treatment with SSAs and cabergoline, and switching to pasireotide or pegvisomant (not available in Russia); non-drug options include tumor debulking followed by SSA therapy and radiosurgery/radiotherapy.

Problems of Endocrinology. 2017;63(5):338-345
The hypoglicemic syndrome (insulinoma): topical, pathomorphological, and genetic diagnostics and treatment (review, part 2)
Yukina M.Y., Nuralieva N.F., Troshina E.A., Kuznetsov N.S., Platonova N.M.

Insulinoma is the most common functioning tumor of the pancreas. It consists of β-cells of the Langerhans islets. Insulinoma is malignant in 10% of cases and multifocal in 10% of cases. This review discusses the new capabilities for identification of the exact location of insulinoma, in particular given the latest data on expression of different receptors in the tumor tissue. We discuss the modern concept of molecular and genetic aspects of insulinoma development. In particular, we analyze studies on germinal and somatic mutations and epigenetic abnormalities. We describe new biochemical markers of insulinoma, which may be used for differential diagnosis, timely detection of insulinoma recurrence and progression, individual prognosis, and monitoring of treatment. Also, we discuss application of antitumor medications and optimal drug correction of hypoglycemia in insulinoma patients.

Problems of Endocrinology. 2017;63(5):346-355

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