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I.V. Shlimkevich Mechanisms of Development of Hypothalamic Pubertal Syndrome in Children Ivano-Frankivsk National Medical Unіversity, Ivano-Frankivsk, Ukraine Аbstract. The analysis of Ukrainian and foreign literature with the aim to study the causes, mechanisms of development, the main approaches to classification, and clinical manifestations of hypothalamic pubertal syndrome in children and adolescents was made. An overview of the literature showed the importance of in-depth analysis of hypothalamic pubertal syndrome in children and adolescents and a number of options to solve the problem was identified. Medical and social importance of hypothalamic syndrome is determined by young age of patients, rapidly progressive disease course, severe neuroendocrine disorders which are often accompanied by reduced or total disability. The objective of the research was to consider hypothalamic pubertal syndrome in children and adolescents as neuroendocrine syndrome occurring during puberty and post puberty as a result of functional disorders of the endocrine system. In most cases it was difficult to find out its main cause as manifestations often occurred some years after the action of the causal factor leading to serious reproductive-health consequences among girls (infertility, polycystic ovary syndrome, subsequent obstetric and perinatal complications). Set of symptoms associated with pathological changes in the hypothalamic region characterized by autonomic, endocrine, metabolic and trophic disorders and dependent to some extent on the localization of lesions in the hypothalamus and features of violation of neurohormonal regulation of hypothalamicpituitary relationships was studied. It could also be argued that the main pathogenetic and clinical aspect of hypothalamic pubertal syndrome is hypertension. The mechanisms contributing to the relationship between hypertension and obesity are complex and multifactorial. Keywords: epidemiology; children; hypothalamic syndrome The analysis of Ukrainian and foreign literature with the aim to study the causes, mechanisms of development, the main approaches to classification, and clinical manifestations of hypothalamic pubertal syndrome (HPS) in children and adolescents was made. An overview of the literature showed the importance of in-depth analysis of hypothalamic pubertal syndrome in children and adolescents and a number of options to solve the problem was identified. Recently in Ukraine prevalence of HPS has increased to twice. 18,000 to 20,000 new cases of obesity among children under 14 years of age are registered annually. In industrial cities the rate is even greater– 99.3 per 1,000 adolescents [1, 4, 9]. Medical and social importance of hypothalamic syndrome (HS) is determined by young age of patients, rapidly progressive disease course, severe neuroendocrine disorders which are often accompanied by reduced or total disability. HS causes serious reproductive-health consequences among girls (infertility, polycystic ovary syndrome, subsequent obstetric and perinatal complications). The hypothalamo-hypophyseal neurosecretory system (HHNS) is higher neuroendocrine transmitter which coordinates the endocrine regulation of metabolism with the autonomic nervous system activity and integrated emotional and behavioral reactions of the limbic system. Violation of the relationship between individual parts of HHNS leads to the development of HS in children and adolescents [7, 20, 24], and HHNS dysregulation along with activation of glucocorticoid function of the adrenal cortex is accompanied by carbohydrate and lipid metabolism disorders [7, 22, 11]. The hypothalamo-hypophyseal complex includes: - hypothalamus – the diencephalon region and central limbic system-related circuit; - neurohypophysis which consists of two parts: the median eminence and posterior pituitary lobe; - adenohypophysis - anterior pituitary lobe. Set of symptoms associated with pathological changes in the hypothalamic region is characterized by autonomic, endocrine, metabolic and trophic disorders and depends to some extent on the localization of lesions in the hypothalamus (anterior or posterior pituitary lobes) and features of violation of neurohormonal regulation of hypothalamic-pituitary relationships. Hypothalamic area (hypothalamus) is the part of the brain where integration of the neural and humoral control of endocrine functions takes place providing constancy of the internal environment homeostasis (the stability of the human body’s internal environment). The hypothalamus acts as a higher vegetative center which regulates metabolism, thermoregulation, activity in blood vessels and other internal organs, food and sexual behavior, and psychological functions. In addition, the hypothalamus controls the physiological reactions, so in
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case of any pathological changes in the hypothalamic region functional disruption leading to paroxysms (crisis) of vegetative character may occur. Hypothalamic pubertal syndrome (HPS) in adolescents is neuroendocrine syndrome of age-related changes in the body along with hypothalamic dysfunction, pituitary disorders and disorders of other endocrine glands. Synonyms include obesity with pink striae, pubertal basophilism, pubertal-juvenile basophilism, juvenile hypercorticoidism, pubertal hypercortisolism, Cushing syndrome, pubertal-juvenile dyspituitarism, diencephalic syndrome, hypothalamic pubertal syndrome, diencephalic hyperandrogenism (code according to ICD-10 E.33.0) [16, 17, 23]. It is the most common endocrine and metabolic pathology among adolescents the incidence of which has increased in recent years. HPS in adolescents develops mainly during prepuberty or early puberty at the age of 10-18 years (the average age is 16-17 years). It is generally accepted that boys suffer from this disease more often than girls. HPS is a neuroendocrine syndrome that occurs during puberty and post-puberty as a result of functional disorders of the endocrine system. In most cases it is difficult to find out its main cause as manifestations often occurred some years after the action of the causal factor. HPS is a disease which is usually followed by secondary one that is not associated with leptin deficiency and obesity. However, HPS can develop as primary (in adolescents with normal body weight) and secondary disease (in adolescents with leptin-dependent childhood obesity). Risk factors for primary HPS include: pathological pregnancy (fetoplacental insufficiency, toxemia or gestosis occurring in the second half of pregnancy); complicated course of pregnancy (acute diseases, exacerbation of chronic illnesses during pregnancy, poisonings, intoxication, etc.); pathologic or difficult labour (premature labour, weak labour activity, umbilical cord entanglement, etc.); birth traumas (asphyxia, head injuries); perinatal encephalopathy; brain tumors compressing the hypothalamic area; neurotoxicity in newborns; head injuries in early childhood (hypothalamic lesions); neuroinfections (meningoencephalitis, vasculitis and arachnoiditis) in children; neurointoxication (drug addiction, alcoholism, industrial hazards, environmental distress); non-endocrine autoimmune diseases; relapsing bronchitis, acute respiratory viral infections, chronic foci of infection of the nasopharynx and paranasal sinuses, repeated episodes of tonsillitis; acute viral diseases (measles, mumps, influenza, hepatitis); chronic disease that have an autonomic nervous system component (asthma, hypertension, gastric and duodenal ulcers, obesity); chronic stress, endogenous depression, mental overload; autoallergic diseases of the central nervous system; abuse of anabolic steroids; use of hormonal methods of birth control among sexually active adolescent girls; pregnancy and abortion in adolescence [2, 3, 6, 26]. Secondary hypothalamic pubertal syndrome develops on the background of leptin (alimentary-constitutional, hypodynamic) obesity. The disease is characterized by hypothalamic dysfunction along with changes in production of hormones by the adenohypophysis: corticoliberin, somatoliberin and as a result adenohypophysis dysfunction – dispituitarism along with abnormal secretion of tropic hormones: corticotropin, somatotropin and lutropin. Hyperfunction of the anterior pituitary gland along with increased somatoliberin production is typical and as a result increased growth and disruption of gonadotropin-releasing hormone and gonadotropin production: early or late puberty. Hyperfunction of basophil cells of the anterior pituitary without their hyperplasia and functional hypercorticoidism is also common. Synthesis of dopamine, serotonin and endorphins is disturbed; hyperprolactinemia develops with coexistent gynecomastia (more often it is false gynecomastia due to gynoid obesity). Hyperfunction of the hypothalamicpituitary-thyroid-adrenal system along with hyperproduction of corticoliberin, corticotropin, glucocorticoids and adrenal androgens can be seen; production of thyroliberine, thyroid stimulating hormone (TSH) and thyroid hormones is disrupted. Signs of HPS in adolescents mainly include hyperproduction of cortisol and dehydroepiandrosterone [6, 8, 12, 21]. The mechanism of obesity in HPS is associated with lipogenic effect of corticotropin and glucocorticoids and insulinotropic effect of corticotropin on beta cells in the islets of Langerhans [7, 19]. There are also hereditary risk factors for HS with autosomal dominant inheritance patterns. They include hypertension, obesity, and diabetes mellitus type 2, autoimmune endocrine diseases and disorders. The risk of HS increases significantly if three or more risk factors are present simultaneously [1, 5, 13]. Hypothalamic syndrome is a combination of autonomic, endocrine, metabolic and trophic disorders caused by hypothalamic lesions. An essential component of HS is neuroendocrine disorders. Manifestation of HPS during early puberty is caused by activation of the anterior pituitary function, primarily adrenocorticotropic, gonadotropic, somatotropic, and thyrotropic functions of the hypophysis causing “jump-starting” puberty and leading to changes in function of the adrenal glands, gonads and thyroid gland. In most cases of HPS physiological feedback and secretion of hormones, especially the adrenal glands are disturbed. During this period the
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load on the hypothalamic-pituitary system increases significantly which leads to dysfunction of the hypothalamicpituitary system if there are some pathogenic factors. Violation of the synthesis and metabolism of monoamines (especially neuropeptides, serotonin, and norepinephrine) plays the main role in pathogenesis leading to hyperactivation of the anterior pituitary functions, primarily corticotropic and gonadotropic functions, and to a lesser extent somatotropic and thyrotropic functions of the hypophysis. Dysfunctional feedback is formed between central and peripheral endocrine glands and hormonal and metabolic disorders develop [1, 7, 10, 14]. Increased secretion of gonadotropins leads to stimulation of the gonads and significant increase in total and free testosterone levels (hyperestrogenemia) in boys at the age of 10-14 years and significantly elevated serum levels of progesterone (hyperprogesteronemia) in girls of similar age. In HPS an activation of the pituitary-thyroid system is observed. It is accompanied by a moderate increase of thyroid-stimulating hormone (TSH) levels which further leads to stimulation of the thyroid gland which increases in volume while increasing the secretion of thyroid hormones, mainly triiodothyronine (T3). Prolactin secretion remains normal [7]. Manifestation of HS is observed against a background of activation of the sympathoadrenal system (SAS), increased serotonin production and low melatonin levels. During the progression of pathology reserves of SAS decrease, however, serotonin production remains increased. Indicators of melatonin level are closely associated with clinical manifestations of HS and in case of unfavorable course of pathology remain low. The leptin - hormone of adipose tissue - which is responsible for feeling of fullness plays an important role in the pathogenesis of HPS. The serum levels of leptin are elevated in patients with HS, especially in case of abdominal obesity. Then leptin resistance develops. On the background of the above mentioned hormonal imbalances insulin resistance occurs which leads to increased secretion of immunoreactive insulin and C-peptide. The degree of hyperinsulinemia and insulin resistance depends directly on the degree of obesity and increases significantly in case of abdominal obesity. Dysregulation of lipid (when leptin levels increase excessive hunger appears indicating a violation of eating through bodily feedback) and carbohydrate metabolism (hyperinsulinemia leads to a rapid increase in body fat and protein mass and the development of hypertension) plays a leading role in the pathogenesis. Hyperinsulinemia is considered to cause sodium and water retention, it affects the distal portions of the nephron, dose-dependently stimulates the sympathetic nervous system, increases catecholamine levels in the blood. HPS development is accompanied by increased activity of proteolytic enzymes - collagenase and elastase, and violation of metabolism of connective tissue proteins [1, 7, 18, 25]. Violation of lipid metabolism is one of the main metabolic disorders in case of HPS. Dyslipoproteinemias (DLP) type IV is most common among patients with HPS (according to the Fredrickson classification): high triglyceride (TG) levels, high levels of very-low-density lipoprotein (VLDL) cholesterol (CH), normal total cholesterol levels (Total), high levels of VLDL cholesterol and increased low-density lipoprotein (LDL) cholesterol levels. Type IIa dyslipoproteinemia is more rare. This condition should be suspected if levels of LDL are elevated with moderate increase in total cholesterol levels and blood triglyceride levels are normal. On the background of insulin resistance and hyperinsulinemia in HS disorders of carbohydrate metabolism arise. Patients with HPS develop violation of metabolism of connective tissue proteins. “Flat” (hyperinsulinemic) glycemic curve is observed almost in one third of patients. Carbohydrate intolerance is often diagnosed, particularly in typical clinical variant of HS. Insulin sensitivity indices HOMA-IR (homeostasis model assessment) reach their maximum values in these patients, although in case of other variants of the disease they exceed the threshold value. The acute phase of the disease is characterized by increased functional activity of the central parts of the SAS and accompanied by increased catecholamine and serotonin secretion, which stimulates the hypothalamic nuclei responsible for reproductive function. Excessive activation of the hypothalamic-pituitary-adrenal system occurs as a result of high levels of hypothalamic tropic hormones. Hormonal imbalance leads to endocrine and metabolic disorders: lipid, carbohydrate, and water and electrolyte metabolism along with co-existent secondary disorders of endocrine function [20, 24]. The exhaustion of structures producing catecholamine and serotonin is observed 2-3 years after the onset of the disease. Activity of the hypothalamus, hypophysis and their dependent endocrine glands is reduced leading to a decrease in appropriate hormones secretion. Hyperinsulinism is still present. The disease becomes chronic, lasting at least four years - neurovegetative symptoms are put in the forefront. The main pathogenetic and clinical aspect of HPS is arterial hypertension (AH). The mechanisms contributing to the relationship between hypertension and obesity are complex and multifactorial.Thus, obesity in HPS is associated
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with ED, dyslipidemia, excessive C-reactive protein production, increased blood viscosity, impaired glucose tolerance, microalbuminuria, increased levels of inflammatory markers, vascular remodeling, left ventricular hypertrophy and premature atherosclerosis – almost all of the risk factors for cardiovascular diseases and target organ damage in arterial hypertension. All these factors play an important role in raising blood pressure (BP) and the development of hypertension in children and adolescents with HPS [2, 5, 17]. At the same time, hyperinsulinemia and insulin resistance, which contribute to the activation of oxidative stress, tissue hypoxia, overproduction of insulin-like growth factor on the background of disturbances of carbohydrate, lipid, and protein metabolism, hemodynamic and other properties of blood play leading roles in the pathogenesis [7, 23] . Hyperinsulinemia activates receptors termed AT1 and AT2, contributes to the development of arterial hypertension and atherosclerosis, activates the SAS, and increases ET-1 levels. Arterial hypertension is closely linked with high plasma renin levels, increased levels of plasminogen, and high levels of insulin-like growth factor, which play an important role in the development of HPS [20, 22, 24]. The development of arterial hypertension in HPS is largely associated with an increased demand for oxygen which occurs when a person is overweight. Obesity is accompanied by a compensatory increase in cardiac output due to the increase in stroke volume and blood volume. The total peripheral vascular resistance decreases slightly and inadequately, resulting in increased BP. Hypervolemic and hypokinetic types of blood circulation lead to an increased pressure load on the heart forming a “vicious circle” [2, 15]. Hyperactivity of the SAS is crucial in the development of co-existent metabolic disorders such as insulin resistance (IR) and hyperlipidemia [12, 8]. Activation of the sympathetic nervous system (SNS) in HPS is one of the pathogenic mechanisms of chain of overeating - hyperinsulinemia - IP - increase in metabolic products of fatty acids. The SNS promotes the development of peripheral IP, whereas hyperinsulinemia provides re-stimulating effect on the SNS, thereby closing the “pathological circle” [13, 18].
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