Vol 64, No 1 (2018)

Original Studies
Clinical syndromes of compression and surgical transection of the pituitary stalk
Astafyeva L.I., Kadashev B.A., Kalinin P.L., Kutin M.A., Klochkova I.S., Fomichev D.V., Sharipov O.I., Andreev D.N.

Background. The pituitary stalk (PS) is an anatomical structure consisting of the portal vessel system and axons of the hypothalamic nuclei terminating in the posterior pituitary lobe. Surgical injury or compression (by a tumor or another space-occupying process) of the PS can lead to hypopituitarism, diabetes insipidus, and hyperprolactinemia. However, the literature lacks studies on the extent of these disorders depending on PS injury or compression in clinical practice.

Aim. The study aim was to investigate pre- and postoperative endocrine disorders in patients with chiasmo-sellar region (CSR) tumors and the PS compressed and preserved or involuntarily transected during neurosurgery.

Material and methods. The PS compressed before surgery was preserved in 82 patients (41 patients with non-functioning endosuprasellar adenoma and 41 — with suprasellar meningioma). The PS was transected during transcranial surgery in 57 patients (46 patients with pituitary stalk craniopharyngioma and 11 patients with non-functioning endosupresellar pituitary adenoma). All patients underwent blood tests for prolactin (PRL), TSH, LH, FSH, free T4, cortisol, testosterone, or estradiol levels before and 6 months after surgery.

Results. Hyperprolactinemia was detected in 37.4% of patients with CSR tumors compressing the PS. Elimination of PS compression led to normalization of the PRL level in most patients and was not accompanied by worsening of hypopituitarism symptoms. Transection of the PS resulted in panhypopituitarism in 100% of patients and diabetes insipidus in 93% of cases. There was no evidence of hyperprolactinemia in 58.7% of patients with craniopharyngiomas and 81.9% of patients with non-functioning pituitary adenomas.

Conclusion. Given the difference in symptoms, we distinguished two syndromes: PS compression syndrome and PS transection syndrome. Syndrome of PS compression by a CSR tumor was characterized mainly by hyperprolactinemia (37.4% of cases); elimination of PS compression due to tumor resection led to normalization of the PRL level in most patients and was not accompanied by worsening of hypopituitarism symptoms. Syndrome of surgical PS transection in patients with craniopharyngioma (CP) and non-functioning pituitary adenoma (NFPA) manifested as panhypopituitarism in all patients and as permanent diabetes insipidus in most of them. The causes for the absence of hyperprolactinemia in many patients with the transected PS require further research. We can not exclude both adenohypophysis ischemia (due to its impaired blood supply) with partial or complete atrophy of lactotrophic cells and pituitary revascularization with restoration of dopamine transport.

Problems of Endocrinology. 2018;64(1):4-13
Screening for congenital hypothyroidism in the Russian Federation
Dedov I.I., Bezlepkina O.B., Vadina T.A., Baibarina E.N., Chumakova O.V., Karavaeva L.V., Bezlepkin A.S., Peterkova V.A.

Background. Neonatal screening for congenital hypothyroidism (CH) allows the timely diagnosis of disease and onset of replacement therapy. Analytical research in the field of health care provides the basis for making managerial decisions, in particular by public authorities.

Objective — the study objective was to analyze the results of neonatal screening for congenital hypothyroidism in the Russian Federation.

Material and methods. We analyzed reports of local health authorities (LHAs) on the results of activities of regional medical and genetic services, which were monthly submitted to the Ministry of Health of the Russian Federation. The reports included the number of newborns, examined newborns, and newly diagnosed CH cases.

Results. According to the results of neonatal screening, the rate of CH detection in the Russian Federation was 1 case per 3,617 newborns (maximum, 1 per 2379; minimum, 1 per 4752 in different federal districts). The coverage of neonatal screening for CH in the Russian Federation varies by years and regions, from 67.9% (1997) to 99.8% (2012) and from 81.7% (North Caucasian Federal District) to 99.9% (Central Federal District). With the percentage of newborn screening coverage more than 70%, each additional coverage percent results in detection of 6—7 new CH cases.

Conclusion. The conducted analysis indicates the need for further studying the features of congenital hypothyroidism incidence in different regions of the Russian Federation and improving organizational processes of neonatal screening for CH.

Problems of Endocrinology. 2018;64(1):14-20
The analytical review of monitoring of the basic epidemiological characteristics of iodine deficiency disorders among the population of the Russian Federation for the period 2009—2015
Troshina E.A., Platonova N.M., Panfilova E.A., Panfilov K.O.

Background. In the Russian Federation (RF), the problem of iodine deficiency(ID) remains in. Major ongoing events are regional program. In our opinion it is necessary to evaluate their effectiveness and suggestions for improvements of preventive measures if necessary.

Aims — to analyze the dynamics of the main epidemiological indicators of iodine deficiency disorders (IDD) in children, adolescents and adults population of the RF, sing the figures in the statistical form № 63 «Information on diseases related to micronutrient deficiency» and the statistical form №12 «Data on number of diseases registered at patients, living in area of medical service of medical institutions» (retrospective study), to evaluate the effectiveness of preventive measures for elimination of ID and formulate possible solutions.

Material and methods. It have been analyzed the main epidemiological indicators of IDD among children (0—14 years), adolescents (15—17 years) and adult (18 and older) population of the RF for the period 2009—2015. For the assessment of the key epidemiological indicators was constructed a linear regression model, calculated the slope of the trend line (k-factor; a quantitative expression of the dynamics of prevalence/incidence), using Student’s t-test assessed the significance of k: were considered reliable (presence of speakers) at the level of p value p<0.05. Data processing was performed using Microsoft Excel 2010, R (version 3.2.3).

Results. Latest analytical data on the prevalence and incidence of IDD has shown that despite preventive actions, the problem IDD is still remaining, as evidenced by the increase in the prevalence and incidence of IDD. The downward trend in the prevalence and incidence of some IDD is likely to be associated with the implementation of regional programs for the prevention of IDD. Also challenges and successes in managing ID in RF highlighted, given some normative-legal acts related to salt iodization.

Conclusions. Formulate practical proposals to improve preventive measures to prevent the development of IDD.

Problems of Endocrinology. 2018;64(1):21-37
Case Reports
Familial case of normosmic hypogonadotropic hypogonadism with polydactyly, associated with defect of FGFR1 gene
Gerasimova M.V., Kalinchenko N.U., Vasiliev E.V., Petrov V.M., Tiulpakov A.N.

Congenital isolated hypogonadotropic hypogonadism refers to a group of predominantly monogenic diseases associated with impaired production, secretion, and/or action of the gonadotropin-releasing hormone (GnRH), which leads to a pronounced delay or absence of puberty. Clinical and genetic heterogeneity is typical of this group of diseases. To date, about 30 candidate genes associated with the development of various forms of secondary hypogonadism are known. Congenital hypogonadotropic hypogonadism can be verified only using molecular genetic diagnostics. The correct diagnosis is necessary for predicting the disease course and choosing the proper approach for managing the patient. We describe a familial case of normosmic hypogonadotropic hypogonadism and late puberty associated with a mutation in the FGFR1 gene. The case is interesting because of pronounced phenotypic manifestations and their high concentration in the proband’s family history. Also of interest is the phenotype untypical of mutations in this gene. The molecular genetic study was performed using new generation sequencing with the authors’ panel of primers and a PGM semiconductor sequencer (Ion Torrent). The Sanger method was used to confirm the identified mutation and examine the proband’s relative. In both patients, a heterozygous mutation in the FGFR1 gene, previously described in Kallmann syndrome, was detected.

Problems of Endocrinology. 2018;64(1):38-41
Neonatal hypoglycemia in the De Morsier syndrome
Kovalenko T.V., Petrova I.N., Tarasova T.Y.

The article discusses the causes and diagnostic criteria of the septo-optic dysplasia or De Morsier syndrome. De Morsier syndrome attracts attention of endocrinologists due to the development secondary hypofunction of the endocrine glands and somatotropic deficiency associated with this disease. Septo-optic dysplasia is a polyetiologic disease. The relationship of the disease with the antenatal influence of alcohol, narcotic substances, neurotropic drugs, significant perinatal infections, maternal endocrine diseases, gene mutations, in particular, mutations in the HESX1 gene, encoding the pituitary transcription factors involved in the embryogenesis of the adenohypophysis. We report a clinical case of the disease accompanied by congenital hypopituitarism symptoms. The disease manifested in the neonatal period. The child had severe hypoglycemia in combination with neurological symptoms in the form muscle hypotonia and oculomotor disturbances. The diagnosis of the De Morsier syndrome was verified by the results of MRI of the brain. Endocrine disorders in this patient were characterized by low levels of ACTH, cortisol, IGF-1, and free T4. The administered therapy corrected endocrine disorders in the child. In summary, septo-optic dysplasia or De Morsier syndrome is the subject to interdisciplinary attention of neonatologists, endocrinologists, neurologists, optometrists, and geneticists.

Problems of Endocrinology. 2018;64(1):42-44
Disorder of sex development 46,XY associated with mutations in the gene MAP3K1. The report of clinical cases
Kopylova I.V., Kuznetsova E.S., Chugunov I.S., Orlova E.M., Danilenko O.S., Brovin D.N., Kareva M.A., Peterkova V.A.

The disorders of sex development (DSD) 46,XY may be caused by mutations in a number of genes involved in the gonadal differentiation. The XY sex inversion can be also due to disturbances at the level of mitogen-activated protein kinase (MAPK) kinase kinase 1 gene (MAP3K1) and MAPK-signaling pathway. During the last decade, the involvement of the MAPK pathway in the SRY gene up-regulation during the formation of male gonadal sex in mammals has been demonstrated. The role of MAPK-signaling pathway in the human sex determination is not fully understood. Probably, MAP3K1 and the MAPK-signaling pathway are one of the genetic pathways controlling normal development of human testis. So far, several families and sporadic cases of 46,XY DSD due to mutations in MAP3K1 gene have been reported in the literature. Clinical presentation of DSD in these patients varies from female phenotype with normal externalia to male phenotype with hypospadias. We describe rare cases of the DSD 46,XY (a family case of DSD in uterine sisters and a sporadic case) with mutations in the MAP3K1 gene that haven’t been previously described. The article also presents brief literature review on this pathology.

Problems of Endocrinology. 2018;64(1):45-49
Familial case of late diagnosis of Persistence of Müllerian derivatives syndrome type 1
Kalinchenko N.Y., Brovin D.N., Kostrova I.B., Petrov V.M., Vasiliev E.V., Tiulpakov A.N.

Persistent müllerian duct syndrome (PMDS) is a rare variant of the disorder of sex development (DSD) 46,XY characterized by the presence of Müllerian duct derivatives in 46,XY males. Since cryptorchidism is the only external manifestation of PMDS, until recently, PMDS was not diagnosed in patients and detection of Müllerian duct derivatives during the surgical treatment of cryptorchidism in patients with 46,XY karyotype was regarded as a variant of gonadal dysgenesis, leading to an erroneous choice of treatment strategy in these patients. Only the development of the molecular diagnostics methods, in particular, new generation sequencing, which enable simultaneous investigation of several candidate genes, provided accurate differential diagnosis of the PMDS. This article reports a clinical case of late diagnosis of the familial form of PMDS caused by mutation in the AMH gene. Detected persistent Müllerian derivatives in combination with agenesis of the testicle in the proband at an early age led to the diagnosis gonadal dysgenesis. Given the proven high risk of malignization of the gonads located outside the scrotum in patients with gonadal dysgenesis, the patient underwent removal of the only gonad located in the inguinal canal. The correct diagnosis was established after a comprehensive molecular genetic study using a new generation sequencing with the «disorders of sex development» panel. This study detected a homozygous mutation in the AMH gene.

Problems of Endocrinology. 2018;64(1):50-53
Gestagens in the treatment of endometriosis
Fedotcheva T.A., Shimanovskiy N.L.

Endometriosis occurs in 10% of females of reproductive age and ranks third among gynecological diseases, being one of the causes of infertility. The success of endometriosis treatment depends on individually selected therapy based on molecular-genetic characterization of the patient endometrial tissue. The review addresses the mechanisms of endometriosis development and the role of gestagens in the pathogenesis of this disease. We describe the genetic and epigenetic mechanisms of endometriosis development, which lead to resistance to endogenous progesterone, a key link in the pathogenesis of endometriosis. Because gestagen monotherapy is considered as first-line treatment, we analyze the gestagen properties that underlie the indications for their use in endometriosis. In particular, gestagen should have high gestagenic activity and an antiproliferative effect on target cells. An original domestic drug, an oral gestagen Gestobutanoil based on 17a-acetoxy-3b-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (AMP-17), is promising for clinical use. The gestagenic activity of AMP-17 in the Clauberg-McPhail test is 102-fold higher than that of progesterone. AMP-17 has a pronounced antiproliferative effect on estrogen-dependent targets, such as breast cancer cells, cervical cancer cells, etc.

Problems of Endocrinology. 2018;64(1):54-61
Leptin resistance: unsolved diagnostic issues
Borodkina D.A., Gruzdeva O.V., Akbasheva O.E., Belik E.V., Palicheva E.I., Barbarash O.L.

Leptin and its receptors are key regulators of body weight and energy homeostasis. A decrease in tissue sensitivity to leptin leads to the development of obesity, insulin resistance, dyslipidemia, etc. Currently, the phenomenon of leptin resistance is explained by a number of mechanisms, including impairment of gene structure, leptin transport through the blood-brain barrier, and leptin receptor signaling. However, it is not known, a decrease in the number of receptors of which area leads to the development of leptin resistance. No relationship has been found between the basal leptin level in obesity and expression of leptin receptors in the skeletal muscles. It is also important to investigate the contribution of fatty tissue of different localization to leptin secretion regulation and activity of its receptors. The term «leptin resistence» reflects a complex pathophysiological phenomenon with broad perspectives for study. In this review, we analyze methods of diagnosing leptin resistance.

Problems of Endocrinology. 2018;64(1):62-66

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