somatotropic insufficiency. STG hormone: functions, norm in the blood, causes of disorders

There are two groups of causes of deficiency of GH secretion in adults:

• deficiency of GH secretion since childhood;
• post-traumatic secretion deficiency that developed in adulthood.

A pseudo-deficiency of growth hormone is also described, when its concentration in the blood decreases under the following conditions.

Reversible and apparent states:

• physical activity in a cold room;
• condition after childbirth;
• obesity;
• thyrotoxicosis;
• hypercortisolism;
• Addison's disease;
• heart failure;
• critical clinical conditions.

The reduced level of IGF-1 against the background of increased secretion of growth hormone, revealed in stimulating tests, is due to peripheral resistance to growth hormone.

Symptoms and signs of pituitary growth hormone deficiency in adults

Reduced secretion of GH in adults does not show any specific symptoms, although some guidelines distinguish the so-called adult growth hormone deficiency syndrome.

System	Complaints	Objective signs (analysis of complaints/examination/tests)
General signs/symptoms	Fast fatiguability	-
	Decreased quality of life	-
	excessive sweating	-
	Impaired thermogenesis	Subfebrile body temperature
	prone to obesity	Increased body weight
	Decreased exercise tolerance	-
Leather	Increased wrinkle formation	Signs of accelerated aging
Subcutaneous adipose tissue	Tendency to abdominal obesity	centripetal obesity
muscles	Decreased exercise tolerance	Muscle hypotrophy, decreased muscle mass
	Muscle pain	-
Bones	History of fractures (increased risk)	Signs of a fracture
The cardiovascular system	Complaints reflecting diseases of cardio-vascular system(increased risk)	Arterial hypertension
		Signs of coronary heart disease
		Signs of violation cerebral circulation
		Signs of atherosclerosis
Nervous system	Symptoms of depression	Objective signs of depression
	Feeling helpless
Gonad dysfunction	decline sexual attraction	Decreased libido

Biochemistry of blood

The following changes are typical.

• Increased content of inflammatory markers, in particular C-reactive protein.
• Dyslipidemia.
• Hyperinsulinemia.

Instrumental examination

The results of the instrumental examination are presented below.

• Increase in fat and decrease in lean body mass.
• Decrease in the size of the left ventricle of the heart, rear wall, thickness interventricular septum and left ventricular diameter. decline contractility heart (ejection fraction).
• In the study of mineral density of the axial skeleton, osteopenia and / or osteoporosis can be detected.
• MRI - depending on the causes of hyposomatotropinemia, changes in the pituitary gland can be detected.

Hormonal examination and diagnostic tests

An examination aimed at diagnosing GH hyposecretion is advisable to be carried out in patients with established lesions of the hypothalamic-pituitary region, especially against the background of identified organic pathology, in particular large pituitary tumors, pituitary injury, severe head trauma, previous irradiation of the brain or hypothalamic-pituitary region, with a diagnosis of GH insufficiency established in childhood.

In patients with severe organic damage to the pituitary gland, the likelihood of developing a deficiency in GH secretion increases with the identification of a concomitant decrease in the secretion of other pituitary hormones:

• in -40% of cases in the absence of concomitant hyposecretion,
• in -60% - with hyposecretion of another hormone,
• in -80% of cases with hyposecretion of two hormones
• in -100% of cases with hyposecretion of three or more pituitary hormones.

Characteristics of basic tests

• The study of the serum basal level of GH due to the pulse secretion of GH and, as a result, the high variability of the level of GH in serum is of little information and is not used to diagnose hyposomatotropinemia in adults.
• The study of IGF-1 is more reliable for diagnosing GH hyposecretion, since the level of IGF-1 in the blood is significantly more stable than GH, and correlates well with GH secretion. At the same time, the level of IGF-1 indirectly reflects the level of growth hormone, therefore, normal values ​​of IGF-1 do not necessarily indicate a normal level of growth hormone, and vice versa. It is for this reason that in some cases (see below) direct special tests of suppression or stimulation of GH secretion are recommended, which clearly indicate a violation of GH secretion.

In patients with organic damage to the pituitary gland, the level of IGF-1 in the blood serum is usually lower age norm which confirms the diagnosis of GH deficiency. With a decrease in the secretion of two or more pituitary hormones combined with IGF-1, the diagnosis of pathological hyposecretion of growth hormone can be considered practically proven. However, if the examination is aimed at substantiating the need for GH replacement therapy, then even in the case of a combined decrease in the secretion of pituitary hormones, it is desirable to conduct a test stimulating the secretion of GH, especially with an isolated decrease in the level of I RF-1.

If an isolated decrease in the concentration of IGF-1 is detected, attention should be paid to the possibility of its non-specific decrease in conditions such as exhaustion, liver disease, decompensated diabetes mellitus or I hypothyroidism.

At the same time, a normal level of IGF-1 does not exclude the diagnosis of hyposomatotropinemia. In this regard, in such cases and with a subnormal content of IGF-1, it is recommended to conduct tests to stimulate the secretion of growth hormone. However, if a patient has a decrease in the secretion of two or three other tropic pituitary hormones, then an a priori diagnostic conclusion about GH deficiency can be made even without a stimulation test, since if the pituitary gland function is impaired, GH secretion usually falls out first. In case of signs organic damage the pituitary gland, one stimulating test is sufficient, but when the level of growth hormone is lowered without signs of damage to the pituitary gland or against the background of its defeat, the content of growth hormone is normal, two stimulating tests are recommended.

Stimulus Tests

Insulin tolerance test

Serves as the gold standard, It is very risky in adults, especially against the background cardiovascular disorders and in elderly patients. Against the background of hypoglycemia, manifestations of vascular complications can worsen and even death is possible. Obesity or fast intake a large number food can significantly reduce the secretion of growth hormone in the test.

Interpretation. Should Special attention pay attention to the research method of STG. The latest immunoradiometric and immunofluorometric methods are more sensitive and specific and give a result 30-40% lower than the traditional radioimmunological method. To stimulate the secretion of growth hormone, the blood glucose level must decrease by more than 50% compared to the initial level. Moderate symptoms of hypoglycemia (sweating, nervousness or tachycardia) are expected signs that do not require elimination and termination of the test.

In adults, a peak secretion of growth hormone, not exceeding 3 ng / ml, is considered a reliable sign of insufficient secretion of growth hormone. Recently, peak GH values ​​in the range of 3-7 ng/ml have been proposed to be considered partial GH deficiency.

Combined test with somatotropin-releasing hormone and arginine

The combined test with somatotropin-releasing hormone (GH-RG) and arginine is safe compared to the insulin tolerance test and causes a distinct stimulation of GH secretion.

Interpretation. As with other GH stimulation tests, the stimulated secretion peak in to a large extent depends on body weight, but it is especially significant for this test. In this regard, the boundary values ​​of the STG peak depending on body weight are proposed:

• if body mass index<25, то нижняя граница нормы составляет 11,5 нг/мл;
• if 25< индекс массы тела <30, то нижняя граница нормы составляет 8,0 нг/мл;
• with obesity (body mass index> 30), the lower limit of the norm is 4.2 ng / ml.

However, in any case, with an organic lesion of the pituitary gland, the level of STH<4,1 нг/мл однозначно указывает на гипосекрецию СТГ.

Other proposed stimulation tests with arginine (without STH-RH), clonidine, levodopa, or the combination of arginine + levodopa are not sufficiently reliable in terms of both specificity and sensitivity.

Arginine test

Since STH-RH directly stimulates the secretion of STH by the pituitary gland, false-normal results can be obtained in the combined test when the cause of STH-deficiency in a patient is the hyposecretion of STH-RH. If this syndrome is suspected, an arginine test without STH-RH is recommended, with lower normal values ​​than in the combined test. The arginine test is described in the Hypopituitarism section.

The arginine test should be performed with caution in liver and kidney disease.

Interpretation of the arginine test. In adults, with an GH peak of less than 3 ng / ml, severe GH deficiency is diagnosed, and with a GH peak of 3 to 5 ng / ml, the test result is considered doubtful. Only 65-75% of healthy people in the test receive normal stimulation, although the results are more definite in premenopausal women than in men. As in other tests, GH secretion is reduced in obesity and hypothyroidism.

Glucagon test

The glucagon test is described in the Hypopituitarism section and is used to investigate GH secretion.

Interpretation. A peak GH value of 3 ng/mL or greater has a high degree of sensitivity and specificity for ruling out GH deficiency in adults.

Pathogenesis of symptoms and signs

STH causes lipolysis of adipose tissue, and when it is deficient, fat accumulates, especially abdominal fat.

It has been experimentally shown that IGF-1 increases the survival of myocytes after ischemia, in part due to the stimulation of glucose transport. IGF-1 also has a neuroprotective effect. Against the background of a low content of IGF-1, the risk of developing cardiovascular diseases increases, the carotid wall thickens and endothelial dysfunction develops. A low content of IGF-1 also increases the risk of developing insulin resistance.

In a number of studies of the cardiovascular profile in patients with growth hormone deficiency, the following changes were identified:

• accelerated formation of atherosclerotic plaques;
• thickening of the median membrane of the vessels;
• reduced formation of nitric oxide;
• pathological lipid profile;
• increased levels of inflammatory markers;
• insulin resistance.

In patients with growth hormone deficiency, atheroma of the abdominal aorta, femoral artery and carotid developed more often than in the population. It has been shown that growth hormone affects the formation of nitric oxide in endothelial cells. At the same time, nitric oxide is not only a powerful vasodilator, but also an inhibitor of low-density lipoprotein oxidation.

At the same time, a number of scientific works emphasize that the protective effect of GH on cardiovascular diseases is rather hypothetical than strictly proven. And this is not surprising in the light of recent studies on life expectancy - in dwarf mice with genetically disabled GH secretion, life expectancy was significantly higher than in mice with normal GH secretion. In this regard, it was hypothesized that the need for GH is exhausted when the animals reach maximum growth, and the secretion of GH that continues after this is harmful to the body and reduces life expectancy.

In a number of patients with fibromyalgia, a reduced content of IGF-1 and a decrease in the peak of stimulated secretion of growth hormone were found. The appointment of GH in such patients reduced the severity of symptoms, although this method of treatment is not yet used in clinical practice, and additional studies are needed.

Against the background of replacement therapy for growth hormone deficiency, physical strength is restored.

In patients with STH-deficiency, a reduced mineral density of bone tissue was revealed. Moreover, the severity of osteopenia proportionally depends on both the age of the patient and the degree of growth hormone deficiency. Osteopenia in this case develops due to a decrease in bone mineralization. The frequency of fractures increases by 2-5 times compared with the population. The appointment of replacement therapy restores bone mineral density, although GH is known to stimulate both synthesis and bone resorption. In this regard, it is recommended to continue GH replacement therapy in adolescents in order to prevent the loss of bone tissue in them, which normally grows up to 20-25 years.

Treatment of pituitary growth hormone deficiency in adults

Not all studies have shown the benefit of GH replacement therapy in adults. Consider the arguments "for" and "against" the compensation of growth hormone deficiency in adults.

Arguments against the treatment of somatotropic insufficiency in adults

Safety. Currently, there is no convincing evidence regarding the dangers of STG treatment. Nevertheless, with long-term constant treatment of GH, there is a potential danger of provoking the development of diabetes mellitus, recurrence of the tumor of the hypothalamic-pituitary region and cancer. Although it is recognized that GH replacement therapy reduces the development of risk factors for cardiovascular disease, however, data have not yet been obtained on the reduction of cardiovascular mortality with such treatment.

The most common side effects:

• fluid retention;
• paresthesia;
• joint stiffness;
• peripheral edema;
• arthralgia;
• myalgia;
• carpal tunnel syndrome (develops in 2% of cases);
• benign intracranial hypertension (develops very rarely in adults);
• gynecomastia during treatment with high doses of growth hormone.

However, adverse reactions decrease after a decrease in the dose of growth hormone.

Growth hormone and tumor formation. Potentially, GH treatment can cause tumor recurrence or the formation of a new one, although this has not yet been confirmed.

The transition of subclinical variants of hypothyroidism or hypocorticism into manifest forms. GH replacement therapy can reduce free T4 (FT4), probably due to the fact that it increases the transformation in peripheral tissues of T4 to T3. The decrease in the concentration of T4 against the background of STH replacement therapy reflects the transition of latent central hypothyroidism to explicit. It was also found that GH-replacement therapy causes a decrease in the level of cortisol in the blood serum, which reflects the transition of latent central hypocorticism into a manifest form. Hypocorticism did not manifest itself in conditions of GH deficiency, since in this case the conversion of cortisone to cortisol is increased. It follows that against the background of GH replacement therapy, it is necessary to regularly examine the content of CT4 and cortisol.

Aging and GH. In recent years, a number of studies have shown that a low level of growth hormone significantly contributes to an increase in life expectancy in experimental animals (rats), even though such animals were obese. Although no such data have been obtained in humans, it is possible that a low level of GH can contribute to human longevity, since experimental longevity studies have hypothesized that the biological effect of GH is fully realized with the achievement of maximum animal growth, and further, even low secretion has only negative effect on the animal organism.

Arguments for the treatment of somatotropic insufficiency in adults

In support of the appointment of STG, the following arguments can be made.

• GH replacement therapy is accompanied by clear improvements in body composition (lean mass increases and fat mass decreases, in particular visceral fat mass), tolerance increases physical activity improves the quality of the skeleton, as well as the quality of life.
• The functional indicators of the heart improve due to an increase in the mass of the myocardium.
• Decreasing levels total cholesterol, low-density lipoprotein cholesterol, apolipoprotein-B100, and C-reactive protein, the activity of pro-inflammatory cytokines is reduced.
• The elasticity of the vessels increases, the thickness of the median membrane of the vessels decreases, and cholesterol plaques regress.
• Peripheral vessels expand and the synthesis of a powerful vasodilating factor, nitric oxide (II), increases.
• Systolic and diastolic blood pressure decreases moderately, but more pronounced in patients with elevated blood pressure.

Scheme of replacement therapy with somatotropic hormone

• The starting dose in patients aged 30-60 years is 300 mcg / day. The daily dose should be increased monthly by 100-200 micrograms until the target values ​​are achieved, but without side effects, and the level of IGF-1 is not in the age range.
• During dose titration, the patient's condition must be monitored every month or at least 1 time in 2 months.
• After reaching the optimal maintenance dose, the patient's state of health is monitored every 3-6 months:
• IGF-1 level;
• concentration of T 4 and TSH;
• cortisol content;
• bone mineral density (according to indications);

The optimal duration of treatment is still unclear. At least if there are no clear signs of improvement within a year, GH treatment can be stopped.

Growth deficit (stunting) - growth below the 3rd percentile or below 2 standard deviations (
Growth disturbances may be present long before growth falls below this level and may be detected much earlier by assessing a child's growth rate and analyzing their individual growth curve.

An example of early detection of growth slowdown. Patient A. At the time of diagnosis (chronological age 2 years 6 months) growth SDS ~ - 1.8. It was possible to suspect the disease due to the slowdown in growth rates and the high growth of the parents (mother - 178 cm, father - 194 cm). The growth curve of a healthy child in most cases does not differ much from the percentile of the average height of the parents.

Deviation from the constitutionally determined growth curve indicates the presence of a pathological factor affecting growth.

Causes of short stature
Family shortness.
Constitutional growth retardation and puberty, (the first two causes account for about 40% of cases of short stature).
Somatotropic hormone deficiency (8%):
- "idiopathic";
- congenital (congenital anomalies of the hypothalamic-pituitary region, pathology of the development of the central nervous system);
- acquired (tumors of the hypothalamic-pituitary region, brain tumors not associated with the hypothalamic-pituitary region, treatment for tumors (surgical treatment, radiation therapy).

Resistance to growth hormone (rare genetic mutations).
Intrauterine growth retardation (10%).
Osteochondrodysplasia (achondroplasia, hypochondroplasia).
Chromosomal disorders (Shereshevsky-Turner syndrome, Noonan, Down, Prader-Willi syndrome).
Endocrine diseases (hypothyroidism, hypoparathyroidism, hypercorticism, hypocorticism, premature sexual development).
Chronic somatic diseases (congenital heart defects, chronic renal failure, celiac disease).
Malnutrition.

family short stature
There is a hereditary predisposition to growth retardation. One or both parents, often some other blood relative, is short in stature. Growth retardation has been early age, however, the growth deficit corresponds to the parental growth deficit. The growth curve is lower, but almost parallel to the lower limit of the norm. Bone age, as a rule, corresponds to chronological age. IGF-1 levels and stimulated secretion of growth hormone are normal. The diagnosis of familial stunting is valid only when other possible causes of stunting have been excluded. "Family" short stature is often diagnosed in patients with hypochondroplasia.

Constitutional stunting and puberty
Most common in adolescence, but can also occur at an earlier age. More common in boys. An individual growth chart is usually in the 3rd percentile or slightly below the lower limit of normal. The growth rate is within the normal range. The lag of bone age from chronological age is 2-4 years, and this difference remains unchanged with age. Due to this, the predicted final growth is within the limits of acceptable values ​​for this family. The onset of sexual development, and with it the pubertal acceleration of growth, is delayed (the timing depends on the degree of retardation of bone age). As a rule, this variant of development has a family history.

The secretion of somatotropic hormones is normal. If bone age> 10 years, the stimulation test should be carried out against the background of the use of exogenous sex hormones (testosterone 100 mg / m for boys or ethinyl esgradiol 0.2-0.5 mg orally 2 times a day for girls, for 3 days for both sexes ).

Treatment
Testosterone therapy (50-100 mg/m, once a month for 3 months). usually given to boys aged 14 and over who are seriously concerned about their delayed sexual development.

Growth Hormone Deficiency
Growth hormone deficiency can be caused by: a complete or partial violation of the secretion of somatotropic hormone at the pituitary level, the secretion of pathological growth hormone, or indirectly - a decrease in the levels of growth factors dependent on somatotropic hormone. There are total (pronounced) and partial (moderate) GH deficiency, congenital and acquired GH deficiency (manifests at any time after birth). Growth hormone deficiency can be isolated (isolated GH deficiency, isolated growth hormone deficiency) or combined with a deficiency of other tropic hormones of the adenohypophysis (multiple deficiency of adenohypophysis hormones, hypopituitarism). Hypopituitarism is defined as the absence or decreased function of two or more pituitary hormones. Currently, GH-deficiency syndrome in children is considered as a complex of pathogenetically different diseases, united by a common clinical symptomatology. The frequency of growth hormone deficiency in children ranges from 1:4,000 to 1:10,000 newborns. Growth hormone deficiency can be idiopathic and organic, familial and sporadic, with identified genetic defect or unidentified.

Congenital STH deficiency. hereditary forms. The genetic basis of growth hormone deficiency in the presence of first-degree relatives with the same pathology (with growth
The genetic basis of growth hormone deficiency can be suspected under the following conditions:
Early onset of stunting
A positive family history of short stature or consanguineous marriage,
Height below (-) 3 SD from the average,
Extremely low response of somatotropic hormone against the background of stimulation tests,
Very low levels of IGF-I and IRFSB-3 (> 2 SD below the mean for age and sex). Hereditary isolated growth hormone deficiency Congenital isolated growth hormone deficiency is associated with 5 different inherited diseases.

Patients with POU1F1 mutations are characterized by severe growth hormone/prolactin deficiency, while the severity of TH deficiency may vary.

The most common of all currently known genetic defects underlying congenital hypopituitarism is PROP1 pathology. Unlike individuals with a POUIF1 (PIT1) defect, patients with a PROPI mutation have concomitant hypogonadism and hypocorticism. Hypocorticism develops gradually and manifests, as a rule, not earlier than adolescence, more often in the third decade of life, although there may be cases with a debut in early childhood.

About 20% of patients with PROP1 mutations have adenohypophysis hyperplasia on magnetic resonance imaging with its subsequent involution in the course of life, up to the development of an "empty sella turcica". Previously, this MRI picture of adenohypophysis hyperplasia was regarded as tumor process(craniopharyngioma, pituitary adenoma), which sometimes led to surgical interventions on the pituitary. Currently, such an MRI picture in a child of any age with growth hormone/prolactin/theriotropic hormone deficiency is an indication for molecular diagnostics, primarily for the analysis of the PROP1 gene.

Pathology of the HESX-1 gene (“homeobox gene expressed in embryonic stem cells”) has been described in children with hypopituitarism associated with septo-optic dysplasia (de Morsier syndrome). de Morsier syndrome implies a triad congenital anomalies midbrain, visual analyzer and pituitary:
hypoplasia optic nerves and chiasma;
agenesia/hypoplasia of the septum pellucidum and corpus callosum;
pituitary hypoplasia and hypopituitarism.

Acquired growth hormone deficiency
Tumors of the central nervous system are the most common cause of acquired growth hormone deficiency. various etiologies, primarily affecting the hypothalamic-pituitary region. After the treatment of such tumors (surgery, radiation therapy, chemotherapy), as a rule, the manifestations of hypopituitarism increase.

Craniopharyngioma, which develops from the remnants of the epithelium of Rathke's pocket, is a tumor of the hypothalamic-pituitary region, the most common in childhood. It accounts for about 56% of all tumors of the chiasmal-sellar region). Children with craniopharyngioma surgical treatment STG deficiency develops in 97% of cases and in 100% after surgery.

Depending on the site of the initial tumor growth, three main localizations are distinguished:
Endosuprasellar (located in the cavity of the Turkish saddle, as they grow, they raise the diaphragm, located in front of the chiasm of the optic nerves),
Stem (growth from the pituitary stalk, form numerous cysts on base of the brain),
Intra-extraventricular (histogenetically associated with the infundibulum of the bottom of the third ventricle and often destroy it) and two more rare:
Subsellar (growth from the main sinus),
Intraventricular (located in the third ventricle, the bottom of the third ventricle remains intact). Rarer tumors are pituitary adenoma, germinoma, and hamartoma.

Progressive growth or ongoing treatment volumetric formations(for example, glioma of the optic nerves, astrocytoma), anatomically not associated with the pituitary gland, but localized in close proximity to the hypothalamic-pituitary region, can also be complicated by somatotropic hormone deficiency.

Somatotrophs are extremely sensitive to radiation, which is used to treat patients with medulloblastoma, retinoblastoma, lymphogranulomatosis, and acute lymphoblastic leukemia. Irradiation of the brain at a dose of 40 Gy and above causes the development of somatotropic insufficiency in almost 100%. The development of somatotropic insufficiency in children in some cases is observed after total exposure in bone marrow transplantation, in patients receiving chemotherapy for cancer.

Acquired somatotropic insufficiency in most cases is combined with a deficiency of other tropic hormones, regardless of the causes of its occurrence. In this case, the “fallout” of pituitary hormones does not occur simultaneously, but has a certain staging. The secretion of somatotropic hormone suffers first of all, and only then can deficiency of thyrotrophs, gonadotrophs, corticotrophs join. Much less likely to develop diabetes insipidus.

Clinical picture
The main clinical features of somatotropic insufficiency are:
postnatal growth retardation;
progressive growth retardation.

Proportional physique (armspan is equal to height, head circumference corresponds to height, the coefficient "upper segment / lower segment" does not exceed normal values). With a significant lag in bone maturation, when assessing the proportionality of the physique, it is necessary to take into account the bone age of the child:
Small facial features (“doll face”, face of a “cherub”) in combination with a large overhanging forehead, due to underdevelopment of the bones of the facial skeleton with satisfactory bone growth cerebral skull. Sunken nose bridge, shallow orbits, micrognathia may occur
Characteristic early postnatal symptoms of congenital GH deficiency: fasting hypoglycemia, often severe prolonged jaundice, neonatal cholestasis.

Delayed bone maturation
Late closure of a large fontanelle
Late teething, belated change of teeth.
Sometimes - underdevelopment of enamel, improper growth of teeth. Often - multiple dental caries.

Thinning skin ___
Increased venous network on the scalp in young children (partly due to thinning of the skin).

Symptoms of multiple adenohypophysis hormone deficiency:
Typically normal intellectual development - signs characteristic of congenital growth hormone deficiency

Hypoglycemia
Since somatotropic hormone plays an important role in the regulation carbohydrate metabolism, activating the production of glucose by the liver and slowing down its peripheral clearance, in conditions of growth hormone deficiency, hypoglycemia may develop. Hypoglycemia is more common in patients younger age are detected in about 10% of cases. In the first year of life, the risk of developing hypoglycemia is much higher. Clinical manifestations of hypoglycemia: increased appetite, pallor, sweating, restlessness, convulsive syndrome, as a rule, are observed in the early morning hours, but can also occur during sleep. The risk of neonatal hypoglycemia is higher with concomitant ADHD deficiency.

Hyposomatotropism (somatotropic insufficiency) is an absolute or relative insufficiency of somatotropic hormone, which is accompanied in childhood by growth retardation (pituitary dwarfism) and severe metabolic disorders in adults.

Etiology and pathogenesis

Growth hormone deficiency can be congenital or acquired; absolute and relative; organic and idiomatic; isolated and combined with insufficiency of other tropic hormones of the adenohypophysis.

Congenital deficiency of somatotropic hormone ( STG) May be:

1. hereditary, i.e. due to various genetic disorders;
2. idiopathic violation of the secretion of somatoliberin;
3. anatomical defects in the formation of the hypothalamic-pituitary zone (aplasia or hypoplasia of the pituitary gland, cystic degeneration of the pituitary gland).

The development of an acquired GH deficiency is possible due to:

1. tumors of the hypothalamic-pituitary zone (craniopharyngeoma, hamartroma, pituitary adenoma, germinoma, etc.) and other parts of the brain or suprasellar cysts;
2. traumatic brain injury, including surgical in neurosurgical interventions;
3. neuroinfections (meningitis, encephalitis, etc.);
4. infiltrative diseases (histiocytosis, sarcoidosis, syphilis);
5. vascular pathology (aneurysms of the pituitary gland vessels, pituitary apoplexy);
6. radiation exposure (irradiation of the head, less often the neck);
7. toxic effects (chemotherapy).

Congenital and acquired deficiency of growth hormone, which develops due to the above reasons, is absolute. The relative deficiency of growth hormone is a consequence of peripheral resistance to growth hormone. It develops because genetic disorders(pathology of the growth hormone receptor gene - Laron's syndrome); development of biologically inactive growth hormone or resistance to somatomedin (IGF-1).

The pathogenesis of GH deficiency is associated with a deficiency in the action of the hormone at the level of peripheral tissues and the effect of somatomedins (IGF-1 and IGF-2), which determine linear growth, growth of organs and tissues, and other metabolic effects. Until the last decade, growth hormone deficiency was regarded as the prerogative of childhood due to the main and most obvious symptom of the disease - the lag in the linear growth and physical development of children, however, it has now been proven that in adults, the lack of growth hormone has clinical manifestations that have a significant impact on the quality of life.

Symptoms

GH deficiency in adults is characterized by a decrease in muscle mass due to muscle wasting and atrophy, an increase in body weight due to the formation of visceral. A decrease in muscle mass leads to a decrease in muscle strength and endurance, patients complain of weakness, constant fatigue. At the same time, bone mineralization decreases due to an increase in osteoclast activity and a slowdown in bone remodeling processes with the development of osteopenia and osteoporosis and an increased risk of fractures.

In patients with GH deficiency, cardiac output decreases due to myocardial dystrophy, which exacerbates poor tolerance physical activity, inhibition of emotional reactions is noted, an anxious or depressive state appears, memory is disturbed. In men it is noted sexual weakness, in women, fertility may be impaired. These factors lead to significant reduction quality of life and may be accompanied by social isolation of the patient.

Metabolic disorders characteristic of growth hormone deficiency in adults are characterized by insulin resistance, hyperlipidemia and the development of atherosclerosis, inhibition of fibrinolysis.

Diagnostics

The diagnosis of GH deficiency is established by clinical signs based on the history and results laboratory research. Additional diagnostic tests are carried out to verify the cause of the disease.

Laboratory confirmation of the diagnosis are:

• decrease in the basal level of growth hormone, fluctuations in the level of growth hormone during the day. To obtain an evidence base, functional tests with various stimulants (insulin, arginine, clonidine, glucagon, L-dopa, pyridostigmine).
• a decrease in the level of IGF-1 and the IGF-SB-3 protein that recalls it is the most accurate method for diagnosing growth hormone deficiency, while the determination of IGF-SB-3 is optimal.

Treatment

The treatment is carried out with synthetic growth hormone (somatotropin) at a dose of 0.3 mg/day in men and 0.4 mg/day in women intramuscularly. Side effects treatment - arthralgia, peripheral edema, myalgia, parasthesia - in most cases do not lead to the abolition of replacement therapy, accompanied by a significant improvement in the quality of life.

Etiology. Somatotropic insufficiency (lack of growth hormone) occurs when large numbers diseases and syndromes. According to etiology, congenital and acquired, as well as organic and idiooptic growth hormone (GH) deficiency are distinguished.
In the most manifest form, somatotropic insufficiency is manifested by the syndrome of dwarfism (dwarfism, nanosomy, microsomia).
Nanism - clinical syndrome, characterized by a sharp lag in growth and physical development associated with absolute or relative growth hormone deficiency. Nanism is associated with GH deficiency (pituitary dwarfism is not a homogeneous condition in terms of etiology and pathogenesis). In most patients, there is a pathology of regulation and secretion of FSH, LH, TSH, which is accompanied by various combinations endocrine and metabolic disorders(panhypopituitary nanism).
To people of dwarf growth include men with a height below 130 cm, and women - below 120 cm.
The smallest described growth of a dwarf was 38 cm. Pituitary dwarfism occurs with a frequency of 1:15,000 inhabitants. There is no difference in the incidence of men and women. Most frequent form GH deficiency is idiopathic (65-75%).
Most forms of somatotropic insufficiency are genetic, while there is more often a primary pathology of a hypothalamic nature, insufficiency of the hormones of the anterior pituitary gland is a secondary phenomenon.

The causes of pituitary dwarfism can be underdevelopment, or aplasia, of the pituitary gland, its dystopia, cystic degeneration, atrophy or compression by a tumor (craniopharyngioma, chromophobe adenoma, meningioma, glioma), trauma to the central nervous system of intrauterine, birth or postnatal period. Tumors of the adenohypophysis, hypothalamus, intrasellar cysts, and craniopharyngiomas lead to GH deficiency.
In this case, compression of the pituitary tissue occurs with wrinkling, degeneration and involution of glandular cells, including somatotrophs with a decrease in the level of GH secretion.
Infectious and toxic damage CNS (intrauterine viral infections, tuberculosis, syphilis, malaria, toxoplasmosis; neonatal sepsis, meningo- and arachnoencephalitis) in early childhood. Intrauterine lesions of the fetus can lead to dwarfism from birth, the so-called cerebral primordial dwarfism.
This term combines a group of diseases, which includes Silver's nanism with hemiasymmetry of the body and high level gonadotropins, Russell's congenital nanism. Severe chronic somatic diseases are often accompanied by severe short stature, for example, glomerulonephritis, in which azotemia directly affects the liver cells, reducing the synthesis of somatomedins; cirrhosis of the liver, etc.
Changes in the internal organs during dwarfism are reduced to thinning of the bones, delayed differentiation and ossification of the skeleton.
Internal organs hypoplastic, muscles and subcutaneous fatty tissue are poorly developed. In isolated GH deficiency, morphological changes in the pituitary gland are rarely detected.
During long period time, the absolute or relative deficiency of growth hormone was regarded as a problem exclusively in pediatric endocrinology, and the main goal of substitution therapy was to achieve socially acceptable growth. Relatively recently, it has been established that the presence of somatotropic insufficiency in adults is the cause of a whole range of serious metabolic disorders, which requires both timely diagnosis and establishment of the genesis of the disease, and subsequent constant surveillance specialists against the background of ongoing therapeutic measures.
Growth hormone deficiency that first occurs in adulthood occurs at a rate of 1 in 10,000. common causes it is pituitary adenomas or other tumors of the sellar region, the consequences of therapeutic measures for these neoplasms (surgery, radiation therapy).

Clinic. The main signs of nanism are a sharp lag in growth and physical development. Prenatal growth retardation is common in children with intrauterine delay growth, with genetic syndromes, chromosomal pathology, hereditary GH deficiency due to deletion of the GH gene. Children with classical somatotropic insufficiency born with normal weight and body length and begin to lag behind in development from 2-4 years of age. To explain this phenomenon, it is assumed that up to 2-4 years of age, prolactin can have an effect similar to GH in children. A number of works refute these ideas, indicating that some growth retardation is noted already after birth. For children with an organic genesis of GH deficiency (after craniopharyngiomas, craniocerebral injuries, etc.), more late dates manifestations of growth deficiency, after 5-6 years of age. In idiopathic GH deficiency, there is a high frequency perinatal pathology: asphyxia, respiratory distress syndrome, hypoglycemic conditions.
With idiopathic pituitary dwarfism, against the background of growth retardation, normal proportions of the child's body are noted. In untreated adults, childish body proportions are noted. Facial features are small ("doll face"), the bridge of the nose sinks. The skin is pale, with a yellowish tinge, dry, cyanosis, marbling of the skin are sometimes observed. In untreated patients, old appearance, thinning and wrinkling of the skin (geroderm) appear early, which is associated with a lack of anabolic action of GH and a slow change in cell generations. The distribution of subcutaneous fat ranges from emaciated to obese with predominantly upper or "cushingoid" deposits. Hair can be either normal or dry, thin, brittle. Secondary hair growth is often absent. Muscular system poorly developed. Boys usually have a micropenis. Sexual development is delayed and occurs at the time when the bone age of the child reaches the pubertal level. A significant proportion of children with GH deficiency have concomitant deficiency gonadotropins.

The clinical symptoms of Laron syndrome, the pathogenesis of which is based on insensitivity to GH as a result of a defect in the GH receptor gene, are close to those in pituitary dwarfism. Features are a high degree of growth retardation from birth, bone maturation, lagging behind the passport, ahead of growth; the onset of puberty in relatively normal timing in half of the patients; possible pubertal growth spurts; frequent seizures hypoglycemic conditions in early childhood; a high percentage of congenital malformations (shortening of the phalanges of the fingers, cataracts, nystagmus, aortic stenosis, splitting upper lip, dislocation of the hip joint, blue sclera).

Diagnostics. The main methods clinical diagnostics growth retardation are anthropometry and comparison of its results with percentile tables. On the basis of dynamic observation, growth curves are constructed. In children with GH deficiency, the growth rate does not exceed 4 cm per year. To exclude various skeletal dysplasias (achondroplasia, hypochondroplasia), it is advisable to assess the proportions of the body. When evaluating the X-ray of the hands and wrist joints the so-called bone (radiological) age is determined, while the pituitary dwarfism is characterized by a significant delay in ossification. In addition, in some patients, destruction of the most traumatized areas of the skeleton, the heads of the femur, with the development of aseptic osteochondrosis, is noted. When x-raying the skull with pituitary dwarfism, the Rule reveals the unchanged size of the Turkish saddle, but often retains the childlike shape of a “standing oval”, has a wide (“juvenile”) back. An MRI study of the brain is then for any suspicion of intracranial pathology. For the diagnosis of pituitary dwarfism, the leading one is the study of somatotropic function. A single determination of the level of GH in the blood for the diagnosis of somatotropic insufficiency does not matter due to the episodic nature of GH secretion and the possibility of obtaining low, and in some cases, zero basal values GH even in healthy children. Urinary excretion of GH is acceptable for screening.
GH deficiency in adults is accompanied by a violation of all types of metabolism and extensive clinical symptoms. An increase in the content of triglycerides, total cholesterol and low density lipoproteins, a decrease in lycolysis are noted. Obesity develops mainly in the visceral type. Violation of protein synthesis leads to a decrease in the mass and strength of skeletal muscles, myocardial dystrophy with a decrease in cardiac output fraction is noted. Impaired glucose tolerance, insulin resistance are observed. Hypoglycemic conditions are not uncommon with severe sweating during night sleep and headache in the morning.
One of the most striking manifestations are changes in the psyche. There is a tendency to depression, anxiety states, increased fatigue, tendency to social exclusion.

Decreased fibrinolytic activity of the blood, disorders lipid spectrum leading to the development of atherosclerosis, as well as changes in the structure and function of the heart muscle are the reasons for a twofold increase in the death rate from cardiovascular disease among patients with panhypopituitarism receiving non-growth hormone replacement therapy. Against the background of somatotropin deficiency, a decrease in bone mass develops due to the acceleration of bone resorption, which leads to an increase in the frequency of fractures.
Total somatotropic insufficiency is diagnosed in the case of a maximum rise in the level of GH against the background of stimulation tests (insulin, clonidine) less than 7 mg / ml, partial deficiency - with a maximum release of GH from 7 to 10 mg / ml. A prerequisite for testing is euthyroidism.
One of the most valuable studies in the diagnosis of somatotropic insufficiency is the determination of the level of IGF-1 and IGF-2, as well as somatomedin-binding protein-3. These studies underlie the diagnosis of Dron's dwarfism and other conditions belonging to the group of peripheral resistance to the action of GH. Diagnosis of GH deficiency in adults is quite difficult both due to the absence of specific clinical symptoms and due to the episodic nature of GH secretion, which reduces the diagnostic significance of determining the basal content of the hormone in the blood. The most informative and simple study is the determination of the plasma level of IGF-1 (somatomedin C). With its decrease, stimulating tests with insulin, clonidine, arginine, somatoliberin are carried out.

Differential diagnosis. Idiomatic pituitary dwarfism is distinguished from other forms of short stature: with congenital hypothyroidism, early puberty, congenital dysfunction adrenal cortex, diabetes(Mauriac's syndrome), against the background of severe somatic diseases, with genetic osteoarthropathy with the so-called family short stature. Pituitary dwarfism must be differentiated from a number of genetic syndromes.
Hutchinson-Gilford syndrome (progeria, senile dwarfism) is a rare genetically determined disease of children with clinical signs premature aging. The first symptoms appearing by the end of the 1st year of life are growth retardation and progressive alopecia.
characteristic appearance patient: big head with prominent frontal tubercles and underdeveloped lower jaw. The face is mask-like, with a thin beak-shaped nose, enzophthalmos is pronounced. Rib cage narrow. The limbs are thin, the muscles are atrophic. Mobility in the joints is severely limited. The skin is thin, dry. sweat and sebaceous glands missing. Nails are thin and brittle. The teeth erupt late, are located abnormally. neuropsychic development sharply slowed down.
In the blood plasma, a low level of IGF-1 is detected with normal daily GH secretion. A marker of aging is the amount of daily excretion hyaluronic acid.
Normally, in children and adolescents, its content is less than 1% of all urinary glycosaminoglycans and increases with age to 5-6%. In children with progeria, hyaluronic acid excretion is increased to 10-20%, which is not observed in any other genetic disease.
It is characterized by intrauterine growth retardation, asymmetry of the trunk (shortening of the limbs on one side), shortening and curvature of the fifth finger, triangular face, mental retardation. In a third of patients, a pre-temporary hearth development is observed. Renal anomalies and hypospadias are characteristic.
Seckel syndrome (bird-headed dwarfs) is characterized by intrauterine growth retardation, microcephaly, hypoplasia facial skull, big nose, low location ears, mental retardation, clinodilethymia of the fifth finger. It is inherited in an autosomal recessive manner.
With Prader-Willi syndrome (loss of the paracentromeric region of chromosome 15), along with growth retardation from birth, there are severe obesity, cryptorchidism, hypospadias, impaired carbohydrate tolerance, and mental retardation.
Lawrence-Moon-Barde-Bill syndrome (inherited in an autosomal recessive manner) is a combination of short stature, pigmentary retinal degeneration, optic disc trophism, gynogonadism, and mental retardation.
With chondroplasia (inherited in an autosomal dominant manner), severe growth retardation occurs due to disproportionate shortening of the limbs, especially the proximal sections (shoulders, hips). There are thickening and shortening of the fingers, a pronounced lumbar muzzle, a round head, a saddle nose with wide bridge of the nose. Mental development saved. X-ray revealed metaphyseal dystrophy with goblet areas of rarefaction of bone tissue.

Treatment. At the core pathogenetic therapy Pshophysial dwarfism is based on replacement therapy with growth hormone preparations. The drug of choice is genetically engineered human GH. The recommended standard dose of GH in the treatment of classical GH deficiency is 0.07-0.1 units/kg of body weight per injection daily subcutaneously at 20.00-22.00 h. Prescription of GH in Laron's syndrome is ineffective. Promising direction therapy for peripheral resistance to GH is treatment with recombinant IGF-1.
If GH deficiency has developed as part of panhypopituitarism, in addition, replacement therapy for hypothyroidism, hypocorticism, hypogonadism, diabetes insipidus is prescribed.
For the treatment of somatotropic insufficiency in adults, the recommended doses of engineered human GH range from 0.125 U/kg (initial dose) to 0.25 U/kg ( maximum dose). The optimal maintenance dose is selected individually based on the study of the dynamics of IGF-1. The question of the total duration of GH therapy currently remains open.

Somatotropic insufficiency (lack of growth hormone) occurs in a large number of diseases and syndromes. In most cases, this disease is manifested by the syndrome of dwarfism (from the Greek nanos - "dwarf"). Nanism is a condition characterized by a sharp lag of the child in growth and physical development from their peers, which is associated with an absolute or relative deficiency in the body of growth hormone. Since growth hormone is produced by the endocrine gland of the brain, which is called the pituitary gland, then nanism is pituitary.

People of dwarf growth include men with a height below 130 cm, and women - below 120 cm. The smallest height of a dwarf described in the literature was 38 cm. Pituitary dwarfism occurs with a frequency of 1 case per 5,000 newborns. There is no difference in the incidence of men and women. The most common form of growth hormone deficiency is idiopathic (65-75%). It should be noted that with the introduction of MRI studies into practice and the improvement of genetic research methods, the proportion of patients with idiopathic growth hormone deficiency is gradually decreasing, since it is increasingly possible to identify specific causes of somatotropic insufficiency. In addition to a violation of the formation of growth hormone in the pituitary gland, some other reasons can lead to pituitary dwarfism. These include: the formation of a hormone with an incorrect chemical structure and a congenital defect of receptors sensitive to this hormone, as a result of which they do not respond to the production of somatotropin by the pituitary gland.

For the most part, somatotropic insufficiency is due to a genetic defect. However, other reasons for the development of this disease may be: underdevelopment of the pituitary gland, its incorrect location in the brain, the formation of cysts, compression by the tumor, trauma to the central nervous system. In addition, infectious and toxic damage to the central nervous system in early childhood is of particular importance: intrauterine viral infections, tuberculosis, syphilis, malaria, toxoplasmosis, neonatal sepsis, inflammation of the brain and its membranes. Changes in the internal organs with dwarfism are thinning of the bones, growth retardation and ossification of the skeleton. Internal organs, muscles and subcutaneous adipose tissue are poorly developed.

For a long time, growth hormone deficiency was regarded only as a problem of childhood endocrinology. The main goal of treatment was the achievement by the child of normal growth. Only relatively recently it was found out that the presence of somatotropic insufficiency in adults is the cause of a whole complex serious violations metabolism. This condition requires constant monitoring by specialists and the necessary drug treatment. Growth hormone deficiency, which first occurs in adulthood, occurs at a frequency of 1 case per 10,000 population.

The main signs of nanism are a sharp lag in the growth and physical development of the child. Children with classical somatotropic insufficiency are born with normal weight and body length. They begin to lag behind in development from 2-4 years of age. This development of the disease is explained by the fact that the hormone prolactin, which enters the body of a child with mother's milk, in the early years in early childhood can give children an effect similar to growth hormone. In the case of a hereditary pathology of growth hormone in children with growth retardation and sexual development, in most cases, upon questioning, it is possible to identify similar cases of short stature in the family of one of the parents. In adults who have not received necessary treatment in childhood, children's body proportions are noted.

Facial features are small ("doll face"), the bridge of the nose sinks. The skin is pale with a yellowish tint, dry, sometimes there is a cyanotic color, marbling of the skin. In untreated patients, early onset senile appearance, the skin becomes thinner, becomes wrinkled. The distribution of subcutaneous adipose tissue ranges from malnutrition to obesity, in which excess adipose tissue is deposited mainly in upper half torso. Hair can be both normal and dry, thin, brittle. Secondary hair growth, which should appear during puberty, is absent in most cases. The muscular system is poorly developed. In boys, as a rule, the penis is excessively small, sexual development is delayed. Most children with growth hormone deficiency have a concomitant deficiency of hormones that promote the development of the genital organs (gonadotropins).

Laron Syndrome - endocrine disease, which is based on the loss of sensitivity of body cells to growth hormone as a result of a genetic mutation. The manifestations of this deviation are approximately the same as in the case of pituitary dwarfism. The features in this case are: a high degree of growth retardation from birth, bone age lags behind the passport age, but outstrips the growth of the child, sexual development begins at a relatively normal time in 50% of children, growth spurts may occur. In addition, with Laron's syndrome, there is high risk the appearance of various congenital malformations, the most common of which are: shortening of the phalanges of the fingers, cataracts, involuntary movements eyeballs(nystagmus), narrowing of the aortic lumen, splitting of the upper lip, congenital dislocation of the hip joint, blue sclera.

The main methods by which pituitary dwarfism can be identified and confirmed are: anthropometry (height measurement) and comparison of its results with the proper values ​​for the age of the child under study; dynamic surveillance for the growth of the child. In children with growth hormone deficiency, the growth rate does not exceed 4 cm per year. To exclude various congenital diseases skeletal dysplasia it is necessary to evaluate the proportions of the body. When conducting an x-ray examination of the bones of the hands and wrist joints, the so-called bone (radiological) age is determined. In the case of pituitary dwarfism, a significant delay in ossification is revealed. An X-ray of the skull reveals the size and shape of the Turkish saddle (bone receptacle of the pituitary gland), characteristic of childhood. Regardless of the fact that all the above survey methods are highly informative, the most exact method for the correct diagnosis of pituitary dwarfism is the determination of the level of somatotropic hormone in the blood serum. A single determination of the level of growth hormone in the blood for the diagnosis of somatotropic insufficiency does not matter due to the fact that the hormone is secreted sporadically during the day, which can lead to the determination low level even in healthy children.

Growth hormone deficiency in adults is accompanied by a violation of all types of metabolism and very diverse manifestations. Obesity develops as a result of impaired fat metabolism. Violation of protein synthesis leads to a decrease in the mass and strength of skeletal muscles, there is a depletion of the heart muscle. Quite often, one can note the appearance of hypoglycemic conditions (occur with a deficiency of glucose in the blood), which are accompanied by excessive sweating during a night's sleep and the appearance of a headache in the morning.

In case of insufficiency of somatotropic hormone, the most striking manifestation is changes in the human psyche. There is a tendency to frequent depression, anxiety, a person quickly gets tired, suffers general well-being, emotional reactions are disturbed. Over time, there is a clear trend towards social isolation of people suffering from this disease.

Among people with somatotropic insufficiency who receive treatment without growth hormone, there was a two-fold increase in the rate of death from cardiovascular diseases. The reason for this is a change in the composition of their blood, an increase in the amount of fat in it, which begins to settle on the inner surface of the walls. blood vessels leading to the development of atherosclerosis.

With a lack of somatotropin, a decrease in bone mass occurs as a result of a violation of all types of metabolism, including mineral. This increases the fragility of the bones, which leads to an increase in the frequency of fractures.

Treatment. The basis of therapy for pituitary dwarfism is the replacement therapy with growth hormone preparations. The drug of choice in this case is human growth hormone, obtained by genetic engineering. Somatotropin in the treatment of classical growth hormone deficiency is administered daily in the form of subcutaneous injection in the evening (20.00-22.00). The use of growth hormone in Laron's syndrome does not bring any effect.