Somatotropic insufficiency. GH hormone: functions, normal levels in the blood, causes of disorders

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

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

Pseudo-deficiency of growth hormone is also described when its concentration in the blood decreases in the following conditions.

Reversible and obvious conditions:

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

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

Symptoms and signs of pituitary growth hormone deficiency in adults

Reduced GH secretion in adults does not manifest itself with any specific symptoms, although some guidelines identify the so-called growth hormone deficiency syndrome in adults.

System	Complaints	Objective signs (analysis of complaints/examination/tests)
General signs/symptoms	Fast fatiguability	-
	Decreased quality of life	-
	Excessive sweating	-
	Thermogenesis disorder	Low-grade body temperature
	Tendency to obesity	Increased body weight
	Decreased exercise tolerance	-
Leather	Increased formation of wrinkles	Signs of accelerated aging
Subcutaneous fatty tissue	Tendency to abdominal obesity	Centripital obesity
Muscles	Reduced exercise tolerance	Muscle wasting, decreased muscle mass
	Muscle pain	-
Bones	History of fractures (increased risk)	Signs of a fracture
The cardiovascular system	Complaints reflecting illness 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
Gonadal dysfunction	Decline sexual desire	Decreased libido

Blood biochemistry

The following changes are characteristic.

• The content of inflammatory markers, in particular C-reactive protein, is increased.
• Dyslipidemia.
• Hyperinsulinemia.

Instrumental examination

Below are the results of the instrumental examination.

• Increase in fat and decrease in muscle mass of the body.
• Reduction in the size of the left ventricle of the heart, back wall, thickness interventricular septum and left ventricular diameter. Decline contractility heart (ejection fraction).
• When examining the mineral density of the axial skeleton, osteopenia and/or osteoporosis may be detected.
• MRI - depending on the causes of hyposomatotropinemia, changes in the pituitary gland may be detected.

Hormonal examination and diagnostic tests

An examination aimed at diagnosing GH hyposecretion is advisable to carry 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 trauma, severe head injury, previous irradiation of the brain or hypothalamic-pituitary region, with a diagnosis of GH deficiency established in childhood.

In patients with severe organic damage to the pituitary gland, the likelihood of developing a deficiency of 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,
• -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 consequence, the high variability of the level of GH in the serum is not very informative and is not used to diagnose hyposomatotropinemia in adults.
• The IRF-1 study is more reliable for diagnosing GH hyposecretion, since the level of IRF-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, so 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) it is recommended to carry out direct special tests for suppression or stimulation of GH secretion, 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. When a decrease in the secretion of two or more pituitary hormones is combined with IGF-1, the diagnosis of pathological GH hyposecretion can be considered practically proven. However, if the examination is aimed at justifying the need for GH replacement therapy, then even in the case of a combined decrease in the secretion of pituitary hormones, it is advisable to conduct a test stimulating the secretion of GH, especially with an isolated decrease in the level of IRF-1.

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

However, a normal level of IGF-1 does not exclude the diagnosis of hyposomatotropinemia. In this regard, in such cases and with subnormal IGF-1 levels, it is recommended to conduct tests to stimulate GH secretion. However, if a patient has a decrease in the secretion of two or three other tropic hormones of the pituitary gland, then an a priori diagnostic conclusion about GH deficiency can be made without a stimulation test, since when the function of the pituitary gland is impaired, GH secretion is usually the first to disappear. In case of signs organic damage For the pituitary gland, one stimulating test is sufficient, but when the level of growth hormone is low without signs of damage to the pituitary gland or against the background of damage to the pituitary gland, 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 may worsen and even lead to death. Obesity or quick intake large quantity foods can significantly reduce the secretion of growth hormone in the test.

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

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

Combined test with somatotropin-releasing hormone and arginine

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

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

• 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;
• for obesity (body mass index >30) the lower limit of normal is 4.2 ng/ml.

However, in any case, with organic damage to the pituitary gland, the level of growth hormone<4,1 нг/мл однозначно указывает на гипосекрецию СТГ.

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

Arginine test

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

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

Interpretation of the arginine test. In adults, with a 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 receive normal stimulation in the test, although premenopausal women have more definitive results than men. As in other tests, GH secretion is reduced in obesity and hypothyroidism.

Glucagon test

The glucagon test is described in the section “Hypopituitarism” and is used to study the secretion of GH.

Interpretation. A peak GH value of 3 ng/ml or higher has a high degree of sensitivity and specificity for excluding GH deficiency in adults.

Pathogenesis of symptoms and signs

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

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

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

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

In patients with GH deficiency, atheromas of the abdominal aorta, femoral artery and carotid developed more often than in the population. It has been shown that GH affects the formation of nitric oxide in endothelial cells. Moreover, 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 regarding cardiovascular diseases is more likely to be conjectural than strictly proven. And this is not surprising in 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 animal reaches maximum growth, and the secretion of GH that continues after this is harmful to the body and shortens life expectancy.

In a number of patients with fibromyalgia, a reduced level of IGF-1 and a decrease in the peak of stimulated GH secretion were found. Prescribing GH to such patients reduced the severity of symptoms, although this treatment method is not yet used in clinical practice, and additional research is needed.

With replacement therapy for GH deficiency, physical strength is restored.

In patients with GH deficiency, decreased bone mineral density was detected. Moreover, the severity of osteopenia depends proportionally on both the patient’s age and the degree of GH deficiency. Osteopenia develops due to decreased mineralization of bone tissue. The incidence of fractures increases 2-5 times compared to the population. Prescription of replacement therapy restores bone mineral density, although GH is known to stimulate both bone synthesis and bone resorption. In this regard, it is recommended to continue GH replacement therapy in adolescents in order to prevent their loss of bone tissue, which normally increases until the age of 20-25.

Treatment of pituitary growth hormone deficiency in adults

Not all studies have shown the benefit of GH replacement therapy in adults. Let us consider the arguments “for” and “against” compensation for GH deficiency in adults.

Arguments against treatment of somatotropic deficiency in adults

Safety. At present, no convincing data have yet been obtained regarding the dangers of GH treatment. However, with long-term continuous treatment with GH, there is a potential danger of provoking the development of diabetes mellitus, relapse of a tumor of the hypothalamic-pituitary region and cancer. Although it is recognized that GH replacement therapy reduces the development of risk factors for cardiovascular diseases, there has not yet been data on a reduction in cardiovascular mortality with such treatment.

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 large doses of GH.

However, adverse reactions decrease after reducing the dose of GH.

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

Transition of subclinical variants of hypothyroidism or hypocorticism into manifest forms. GH replacement therapy may reduce free T4 (FT4) levels, probably because it increases the conversion of T4 to T3 in peripheral tissues. A decrease in T4 concentration during GH replacement therapy reflects the transition of latent central hypothyroidism to overt one. It has also been established that GH replacement therapy causes a decrease in the level of cortisol in the blood serum, which reflects the transition of latent central hypocortisolism to a manifest form. Hypocortisolism did not manifest itself in conditions of GH deficiency, since in this case the conversion of cortisone to cortisol is increased. It follows that during GH replacement therapy it is necessary to regularly examine the levels of GH4 and cortisol.

Aging and growth hormone. In recent years, a number of studies have shown that low levels of GH significantly contribute to an increase in life expectancy in experimental animals (rats), even though such animals were obese. Although this kind of data has not been obtained in humans, it is possible that a low level of GH can contribute to human longevity, since studies on experimental longevity have suggested that the biological effect of GH is fully realized with the achievement of maximum growth in animals, and further, even low secretion has only a negative effect on the animal's body.

Arguments for the treatment of somatotropic insufficiency in adults

The following arguments can be made in support of the appointment of STH.

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

Somatotropic hormone replacement therapy regimen

• The starting dose in patients 30-60 years old is 300 mcg/day. The daily dose should be increased monthly by 100-200 mcg until the target values ​​are achieved, but without side effects, and the IGF-1 level is within the normal age range.
• During dose titration, the patient's condition must be monitored every month or at least once every 2 months.
• After achieving the optimal maintenance dose, the patient’s health status is monitored every 3-6 months:
• IRF-1 level;
• T4 and TSH concentration;
• 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, treatment with GH can be stopped.

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

An example of early diagnosis of a growth slowdown. Patient A. At the time of diagnosis (chronological age 2 years 6 months), height SDS was ~ - 1.8. The disease was suspected due to the slowdown in growth rates and the high height 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 parental average height percentile.

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

Causes of short stature
Familial short stature.
Constitutional retardation of growth and puberty (the first two causes account for about 40% of cases of short stature).
Growth 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 restriction (10%).
Osteochondrodysplasia (achondroplasia, hypochondroplasia).
Chromosomal disorders (Shereshevsky-Turner, Noonan, Down, Prader-Willi syndrome).
Endocrine diseases (hypothyroidism, hypoparathyroidism, hypercortisolism, hypocorticism, premature sexual development).
Chronic somatic diseases (congenital heart defects, chronic renal failure, celiac disease).
Malnutrition.

Familial short stature
There is a hereditary predisposition to growth retardation. One or both parents, and often one of the blood relatives, are short. Growth retardation occurs with early age, however, the growth deficit corresponds to the parental growth deficit. The growth curve goes below, but almost parallel to the lower limit of the norm. Bone age, as a rule, corresponds to chronological age. IGF-1 levels and stimulated growth hormone secretion are normal. The diagnosis of “familial short stature” is valid only in cases where other possible causes of short stature have been excluded. “Family” short stature is often diagnosed in patients with hypochondroplasia.

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

The secretion of somatotropic hormones is normal. If bone age> 10 years, a stimulation test should be carried out against the background of the use of exogenous sex hormones (testosterone 100 mg IM - in 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 IM, 1 time per month for 3 months). usually prescribed to boys 14 years of age and older who are seriously concerned about delayed sexual development.

Growth hormone deficiency
Growth hormone deficiency can be caused by: complete or partial disruption of the secretion of growth hormone at the level of the pituitary gland, secretion of pathological growth hormone, or indirectly by a decrease in the levels of growth factors dependent on growth hormone. There are total (severe) 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 common clinical symptoms. The incidence of growth hormone deficiency in children ranges from 1:4000 to 1:10,000 newborns. Growth hormone deficiency can be idiopathic and organic, familial and sporadic, with identified genetic defect or not identified.

Congenital GH deficiency. Hereditary forms. The genetic basis of growth hormone deficiency in the presence of first-degree relatives with the same pathology (with growth
A genetic basis for growth hormone deficiency can be suspected under the following conditions:
Early onset of stunting
Family history of short stature or consanguineous marriage,
Height is below (-)3 SD from the mean,
Extremely low growth hormone response during stimulation tests,
Very low levels of IGF-I and IGFBP-3 (> 2 SD below the age- and sex-matched mean). 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 the growth hormone deficiency may vary.

The most common of all currently known genetic defects underlying congenital hypopituitarism is PROP1 pathology. In contrast to individuals with a POUIF1 (PIT1) defect, patients with a PROPI mutation have concomitant hypogonadism and hypocortisolism. Hypocortisolism develops gradually and manifests itself, as a rule, no 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 hyperplasia of the adenohypophysis on magnetic resonance imaging, followed by its involution during 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 gland. Currently, a similar MRI picture in a child of any age with growth hormone/Prolactin/theriotropic hormone deficiency is an indication for molecular diagnostics, primarily for 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 combined with septooptic dysplasia (de Morsier syndrome). De Morsier syndrome involves a triad congenital anomalies midbrain, visual analyzer and pituitary gland:
hypoplasia optic nerves and chiasmata;
agenesis/hypoplasia of the septum pellucidum and corpus callosum;
pituitary hypoplasia and hypopituitarism.

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

Craniopharyngioma, developing from the remnants of the epithelium of Rathke's pouch, is a tumor of the hypothalamic-pituitary region, most often found in childhood. It accounts for about 56% of all tumors of the chiasmal-sellar region). In children with craniopharyngioma up to surgical treatment GH deficiency develops in 97% of cases and in 100% after surgery.

Depending on the location of the initial growth of the tumor, three main localizations are distinguished:
Endosuprasellar (located in the cavity of the sella turcica, as they grow, they raise the diaphragm, located in front of the optic chiasm),
Stem (growth from the pituitary stalk, form numerous cysts on base of the brain),
Intra-extraventricular (histogenetically related to the infundibulum of the third ventricle and often destroys it) and two rarer ones:
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, optic nerve glioma, astrocytoma), anatomically not related to the pituitary gland, but localized in close proximity to the hypothalamic-pituitary region, can also be complicated by growth 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 higher almost 100% causes the development of somatotropic insufficiency. The development of somatotropic insufficiency in children in some cases is observed after general exposure during bone marrow transplantation, in patients receiving chemotherapy for cancer.

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

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

Proportional physique (arm span is equal to height, head circumference corresponds to height, the “upper segment/lower segment” ratio does not exceed normal values). If there is a significant delay in bone maturation, when assessing the proportionality of the physique, it is necessary to take into account the child’s bone age:
Small facial features (“doll face”, “cherub” face) in combination with a large overhanging forehead, due to underdevelopment of the bones of the facial skeleton with satisfactory bone growth brain skull. Sunken bridge of the nose, 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 the large fontanel
Late teething, delayed 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 growth 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 approximately 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, anxiety, 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 adrinocorticotron hormone deficiency.

Hyposomatotropism (somatotropic insufficiency) is an absolute or relative deficiency 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. caused by various genetic disorders;
2. idiopathic disorder of somatoliberin secretion;
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 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 trauma during neurosurgical interventions;
3. neuroinfections (meningitis, encephalitis, etc.);
4. infiltrative diseases (histiocytosis, sarcoidosis, syphilis);
5. vascular pathology (aneurysm of the pituitary vessels, pituitary apoplexy);
6. radiation exposure (irradiation of the head, less often the neck);
7. toxic effects (chemotherapy).

Congenital and acquired growth hormone deficiency, which develops due to the reasons listed above, is absolute. Relative growth hormone deficiency is a consequence of peripheral resistance to growth hormone. It develops for a reason genetic disorders(pathology of the growth hormone receptor gene - Laron 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 - retarded linear growth and physical development of children, however, it has now been proven that in adults, GH deficiency has clinical manifestations that have a noticeable 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 and constant fatigue. At the same time, bone tissue mineralization decreases due to increased 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 aggravates poor tolerance physical activity, depression of emotional reactions is noted, an anxious or depressive state appears, and memory is impaired. In men it is noted sexual weakness, in women there may be impaired fertility. The above factors lead to significant reduction quality of life and may be accompanied by social isolation of the patient.

Metabolic disorders characteristic of GH 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 medical history and results laboratory research. Additional diagnostic tests are performed to verify the cause of the disease.

Laboratory confirmation of the diagnosis is:

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

Treatment

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 treatments - 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 (growth hormone deficiency) occurs when large number diseases and syndromes. Based on etiology, there are congenital and acquired, as well as organic and idiopic growth hormone (GH) deficiency.
In its most manifest form, somatotropic deficiency is manifested by dwarfism syndrome (dwarfism, nanosomia, microsomia).
Nanism - clinical syndrome characterized by severe retardation and physical development associated with absolute or relative growth hormone deficiency. Dwarfism is associated with GH deficiency (pituitary dwarfism is not a uniform condition in etiology and pathogenesis). Most patients experience pathology in the regulation and secretion of FSH, LH, TSH, which is accompanied various combinations endocrine and metabolic disorders(panhypopituitary dwarfism).
People of dwarf stature include men with a height below 130 cm, and women with a height below 120 cm.
The smallest described height of a dwarf was 38 cm. Pituitary dwarfism occurs with a frequency of 1:15,000 inhabitants. There are no differences in the incidence of men and women. Most frequent form GH deficiency is idiopathic (65-75%).
Most forms of somatotropic insufficiency are genetic, and more often there is a primary pathology of a hypothalamic nature; insufficiency of 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 in utero, birth or postnatal period. GH deficiency is caused by tumors of the adenohypophysis, hypothalamus, intrasellar cysts and craniopharyngiomas.
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 Central nervous system (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 that includes Silver dwarfism with body hemiasymmetry and high level gonadotropins, Russell's congenital dwarfism. 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; liver cirrhosis, etc.
Changes in internal organs during dwarfism are reduced to thinning of bones, delayed differentiation and ossification of the skeleton.
Internal organs hypoplastic, muscles and subcutaneous fat are poorly developed. In isolated GH deficiency, morphological changes in the pituitary gland are rarely detected.
During long period At the time, absolute or relative deficiency of growth hormone was regarded as a problem exclusively in pediatric endocrinology, and the main purpose of prescribing replacement therapy was to achieve socially acceptable growth. Relatively recently, it was established that the presence of somatotropic insufficiency in adults is the cause of a whole complex of serious metabolic disorders, which requires both timely diagnosis and establishment of the genesis of the disease, and subsequent constant monitoring specialists against the backdrop of ongoing therapeutic measures.
Growth hormone deficiency, first occurring in adulthood, occurs with a frequency of 1:10,000. The most common reasons it is pituitary adenomas or other tumors of the sellar region, the consequences of therapeutic measures for these tumors (surgeries, radiation therapy).

Clinic. The main signs of dwarfism are a sharp lag in growth and physical development. Prenatal growth retardation is typical for children with intrauterine retention height, s genetic syndromes, chromosomal pathology, hereditary GH deficiency due to deletion of the GH gene. Children with classical somatotropic insufficiency are 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 give children an effect similar to GH. A number of studies refutes these ideas, indicating that some growth retardation is noted after birth. Children with organic genesis of GH deficiency (after craniopharyngiomas, traumatic brain injuries, etc.) are more likely to late dates manifestations of growth deficiency after 5-6 years of age. In idiopathic GH deficiency, a high incidence of perinatal pathology: asphyxia, respiratory distress syndrome, hypoglycemic conditions.
With idiopathic pituitary dwarfism, normal proportions of the child’s body are noted against the background of growth retardation. Untreated adults have child-like body proportions. The facial features are small (“doll face”), the bridge of the nose is sunken. The skin is pale, with a yellowish tint, dry, sometimes cyanosis and marbling of the skin are observed. In untreated patients, old age, thinning and wrinkling of the skin (heroderm) early appear, which is associated with insufficient anabolic action of GH and a slow change in cell generations. The distribution of subcutaneous fat varies from emaciation to obesity 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 typically have a micropenis. Sexual development is delayed and occurs when the child’s bone age reaches puberty. A significant proportion of children with GH deficiency have associated 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, is close to that of pituitary dwarfism. Features are a high degree of growth retardation from birth, bone maturation, lag behind the passport, outstripping growth; the onset of puberty is relatively normal timing in half of the patients; possible pubertal growth spurts; frequent attacks hypoglycemic conditions in early childhood; high percentage of congenital malformations (shortened phalanges, cataracts, nystagmus, aortic stenosis, cleft upper lip, dislocation of the hip joint, blue sclera).

Diagnostics. Main methods clinical diagnostics growth delays are anthropometry and comparison of its results with percentile tables. Based on dynamic observations, 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 evaluate body proportions. When assessing X-rays of the hands and wrist joints the so-called bone (radiological) age is determined, while pituitary dwarfism is characterized by a significant delay in ossification. In addition, in some patients there is destruction of the most traumatized areas of the skeleton during static loading - the heads of the femurs with the development of aseptic osteochondrosis. When radiography of the skull with pituitary dwarfism, usually reveals the unchanged dimensions of the sella turcica, but often retains the childlike shape of a “standing oval” and has a wide (“juvenile”) back. MRI examination of the brain 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 is not important 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. Determination of GH excretion in urine is acceptable for screening studies.
GH deficiency in adults is accompanied by disorders of all types of metabolism and extensive clinical symptoms. There is an increase in the content of triglycerides, total cholesterol and low-density lipoproteins, and a decrease in lycolysis. Obesity develops predominantly of the visceral type. Impaired protein synthesis leads to a decrease in the mass and strength of skeletal muscles, myocardial dystrophy with a decrease in cardiac ejection fraction is noted. Impaired glucose tolerance and insulin resistance are observed. Hypoglycemic states with severe sweating during night sleep and headaches in the morning are not uncommon.
One of the most striking manifestations is changes in the psyche. There is a tendency towards depression, anxiety states, increased fatigue, tendency to social isolation.

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 mortality rate from cardiovascular diseases among patients with panhypopituitarism receiving replacement therapy that does not include growth hormone. Against the background of somatotropin deficiency, a decrease in bone mass develops due to the acceleration of bone resection, which leads to an increase in the incidence of fractures.
Total somatotropic deficiency is diagnosed in the case of a maximum increase in GH levels against the background of stimulation tests (insulin, clonidine) of less than 7 mg/ml, partial deficiency - with a maximum release of GH from 7 to 10 mg/ml. A necessary condition 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 somatomodin binding protein-3. These studies form the basis for 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 lack of specific clinical symptoms and due to the episodic nature of GH secretion, which reduces the diagnostic significance of determining the basal level of the hormone in the blood. The most informative and simple test is to determine the plasma level of IGF-1 (somatomedin C). When it decreases, stimulation tests are carried out with insulin, clonidine, arginine, and somatoliberin.

Differential diagnosis. Idiomatic pituitary dwarfism is distinguished from other forms of short stature: when congenital hypothyroidism, early puberty, congenital dysfunction adrenal cortex, diabetes mellitus(Mauriac syndrome), against the background of severe somatic diseases, with genetic osteoarthropathy with the so-called familial 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 that appear 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, ensophthalmos is pronounced. Rib cage narrow. The limbs are thin, the muscles are atrophic. Mobility in the joints is severely limited. The skin is thin and dry. Sweat and sebaceous glands are missing. Nails are thin and brittle. Teeth erupt late and are positioned abnormally. Neuropsychic development sharply slowed down.
A low level of IGF-1 is detected in the blood plasma with normal daily secretion of GH. 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 glycosaminoglycans in urine and increases with age to 5-6%. In children with progeria, the excretion of hyaluronic acid is increased to 10-20%, which is not observed in any other genetic disease.
It is characterized by intrauterine growth retardation, asymmetry of the body (shortening of the limbs on one side), shortening and curvature of the fifth finger, triangular face, and mental retardation. In a third of patients, premature, 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 position ears, mental retardation, clinodythymia of the fifth finger. Inherited autosomal recessively.
With Prader-Willi syndrome (loss of the paracentromeric region of chromosome 15), along with growth retardation from birth, there is severe obesity, cryptorkism, hypospadias, impaired carbohydrate tolerance, and mental retardation.
Lawrence-Moon-Bardet-Bill syndrome (inherited autosomal recessively) is a combination of short stature, retinal pigmentary degeneration, optic disc trophism, gynogonadism, and mental retardation.
With chondroplasia (inherited in an autosomal dominant manner), pronounced growth retardation occurs due to disproportionate shortening of the limbs, especially the proximal parts (shoulders, hips). There are thickening and shortening of the fingers, a pronounced lumbar muzzle, a round head, a saddle-shaped nose with wide bridge of the nose. Mental development saved. X-ray reveals degeneration of the metaphyses with goblet-shaped areas of rarefaction of bone tissue.

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

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

People with dwarf stature include men with a height below 130 cm, and women with a height 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 5000 newborn children. There are no differences 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 deficiency. In addition to disruption of the formation of growth hormone in the pituitary gland, some other causes can lead to pituitary dwarfism. These include: the formation of a hormone with an incorrect chemical structure and a congenital defect in the receptors sensitive to this hormone, as a result of which they do not respond in any way to the production of somatotropin by the pituitary gland.

For the most part, somatotropic deficiency is caused by 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 a 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 internal organs with dwarfism include thinning of the bones, delayed growth and ossification of the skeleton. Internal organs, muscles and subcutaneous fat are poorly developed.

For a long time, growth hormone deficiency was regarded only as a problem in childhood endocrinology. The main goal of treatment was considered to be the child’s achievement normal height. 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, first occurring in adulthood, occurs in 1 case per 10,000 population.

The main signs of dwarfism are a sharp lag in the growth and physical development of the child. Children with classic somatotropic insufficiency are born with normal body weight and length. They begin to lag behind in development starting from 2-4 years of age. This development of the disease is explained by the fact that the hormone prolactin, which enters the child’s body with mother’s milk, in the first years of early childhood can give children an effect similar to growth hormone. In the case of hereditary growth hormone pathology in children with delayed growth 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, childish body proportions are noted.

The facial features are small (“doll face”), the bridge of the nose is sunken. The skin is pale with a yellowish tint, dry, sometimes there is a bluish coloration and marbling of the skin. In untreated patients, it appears early senile look, the skin becomes thinner and wrinkled. The distribution of subcutaneous adipose tissue ranges from wasting to obesity, in which excess adipose tissue is deposited predominantly in upper half torso. Hair can be either normal or 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 extremely small, and sexual development is delayed. Most children with growth hormone deficiency have a concomitant deficiency of hormones that promote the development of reproductive 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. Features in this case are: a high degree of growth retardation from birth, bone age lags behind the passport age, but is ahead of the child’s growth, sexual development begins at a relatively normal time in 50% of children, growth spurts may occur. In addition, with Laron 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, cleft lip, congenital dislocation of the hip joint, blue sclera.

The main methods by which pituitary dwarfism can be identified and confirmed are: anthropometry (measurement of height) and comparison of its results with the proper values ​​for the age of the child being studied; dynamic observation for the child's growth. 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 body proportions. When conducting an X-ray examination of the bones of the hands and wrist joints, the so-called bone (x-ray) age is determined. In the case of pituitary dwarfism, a significant delay in ossification is detected. X-rays of the skull reveal the size and shape of the sella turcica (the bony receptacle of the pituitary gland), characteristic of childhood. Regardless of the fact that all of the above survey methods are highly informative, the most precise method To correctly diagnose pituitary dwarfism, it is necessary to determine the level of somatotropic hormone in the blood serum. A single determination of the level of growth hormone in the blood for diagnosing somatotropic insufficiency is not important due to the fact that the hormone is released episodically during the day, which can lead to the determination low level even in healthy children.

Growth hormone deficiency in adults is accompanied by disorders of all types of metabolism and very diverse manifestations. As a result of impaired fat metabolism, obesity develops. Impaired protein synthesis leads to a decrease in the mass and strength of skeletal muscles, and depletion of the heart muscle is noted. Quite often one can note the appearance of hypoglycemic conditions (occur when there is a deficiency of glucose in the blood), which are accompanied by excessive sweating during night sleep and the appearance of headaches in the morning.

In case of growth hormone deficiency, the most striking manifestation is changes in the human psyche. There is a tendency to frequent depression, anxiety, the person quickly gets tired, suffers general health, emotional reactions are disrupted. Over time, a tendency towards social isolation of people suffering from this disease begins to be clearly visible.

Among people with growth hormone deficiency who receive treatment without growth hormone, there was a twofold increase in the mortality rate from cardiovascular disease. 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 disruption of all types of metabolism, including mineral metabolism. This increases bone fragility, which leads to an increase in the incidence of fractures.

Treatment. The basis of treatment for pituitary dwarfism is 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 subcutaneous injections in the evening (20.00-22.00). The use of growth hormone for Laron syndrome does not bring any effect.