Growth hormone growth hormone test: find out why you're not growing

Introduction

Children with established growth hormone deficiency receive recombinant growth hormone replacement therapy until adulthood and genetically predicted final height. Despite the fact that somatotropic hormone (GH) has the main range of physiological effects on the body in childhood, and subsequently its production decreases, GH plays an important role in the normal functioning of organs and systems of an adult. Currently, in Russia, a system of providing medical care to children with growth hormone deficiency has been developed [1, 2], but there are no clinical recommendations devoted to the diagnosis and replacement therapy of GH deficiency in adults.

The first studies on the treatment of GH deficiency in adult patients with hypopituitarism were published in 1989 [3, 4]. In the Russian Federation, the first experience of using human growth hormone in adult patients with GH deficiency was published in 2004 [5]. Clinical manifestations of the disease in adult patients are nonspecific and in cases of acquired GH deficiency are often masked by manifestations of deficiencies of other pituitary tropic hormones, which complicates diagnosis.

The purpose of this review is to summarize current data on the diagnosis, treatment and systemic effects of somatropin replacement therapy in adult patients with GH deficiency.

What does a growth hormone test show?

Using a growth hormone test, doctors diagnose a decrease in the function of the thyroid gland and pituitary gland, and identify tumors of the pituitary gland and hypothalamus. The study also makes it possible to distinguish acromegaly (enlargement of specific body parts) from gigantism in adults. Analysis results required

and when monitoring the effectiveness of growth hormone treatment.

• A drop in the concentration of the hormone GH in a person’s blood is most often diagnosed if he develops pituitary dwarfism. Only after performing functional tests does the doctor render a verdict (make a diagnosis). A reduction in the blood concentration of growth hormone may be present with excessive function of the adrenal cortex, pituitary dwarfism, under the influence of radiation, chemotherapy procedures, and with hypopituitarism.
• An increase in the level of growth hormone in the patient's blood can serve as a signal of gigantism or acromegaly. If the case seems unclear or doubtful to the attending physician, the concentration of this hormone is tested several times, the interval between tests is one or two months. An increase in the level of growth hormone in the blood is diagnosed with pituitary gigantism, acromegaly, tumors of the stomach and lungs, and malnutrition of the body. Also, such an indicator may be a signal of anorexia neurogenic, liver cirrhosis, uncontrolled diabetes mellitus, and renal failure. And finally, an excess of this substance can be the result of prolonged fasting and stress.

Attention! Only a professional doctor can correctly interpret the results of a growth hormone test.

Clinical manifestations

GH deficiency in adults is characterized by systemic changes in metabolism with nonspecific clinical manifestations [6].

– Body composition.

An increase in adipose tissue mass, mainly due to visceral fat, a decrease in lean mass [7–9], a decrease in extracellular fluid volume and total sodium concentration [10].

– Physical activity

. Decreased tolerance to physical activity, decreased muscle strength against the background of a decrease in the amount of muscle tissue [11]. Impaired thermoregulation [12].

– Cardiovascular system, lipid metabolism and blood coagulation system

. Increased cardiovascular risk due to dyslipidemia, carbohydrate metabolism disorders and accelerated development of atherosclerosis. Reduced myocardial mass, impaired conductivity, contractility and stroke volume, decreased pumping function and ejection fraction, diastolic dysfunction [13]. Dyslipidemia due to increased concentrations of total cholesterol, LDL cholesterol and triglycerides [14]. Increased activity of fibrinogen and plasminogen activator inhibitor type 1 (PAI-1) [15].

– Carbohydrate metabolism

. Impaired glucose tolerance, insulin resistance [16].

– Skeletal system

. Reduced bone mass and bone mineral density (BMD), increased risk of fractures [17–19].

– Quality of life and cognitive function

. Decreased quality of life: maladjustment, decreased self-esteem, anxiety, apathy, depression, social isolation [20].

How to correctly decipher the analysis results

Blood test for

growth
hormone should normally
provide the following indicators:

• 2-15 ng/ml in women;
• 2-10 ng/ml in men.

Deviations from the norm in the analysis results

may indicate the following problems in the patient.

• An increased concentration of growth hormone in human blood can be detected in cases of malnutrition, tumors of the lungs, stomach, acromegaly, dwarfism, and pituitary gigantism. An increase in this figure can be caused by prolonged refusal of food or excessive physical activity of the patient. This study result is also possible with neurogenic anorexia, liver cirrhosis, uncontrolled diabetes mellitus, and renal failure.
• A reduced concentration of growth hormone in the blood
  , which is detected during the
  analysis
  , may be present as a result of hypopituitarism, excessive function of the adrenal cortex, or pituitary dwarfism. Also, the level of this substance may decrease after exposure to radiation or chemotherapy.

The results of the study can indicate whether the patient has a tumor of the hypothalamus, pituitary gland, and make it possible to detect a reduction in the functioning of the thyroid gland and pituitary gland. It can also be used to distinguish acromegaly from gigantism and monitor the effectiveness of treatment with growth hormone.

Diagnostics

Diagnosis of GH deficiency in adults is difficult for a number of reasons. The clinical manifestations of this disease are nonspecific and therefore have low diagnostic value [21]. Under physiological conditions, GH secretion has a pulsed nature, it is influenced by age, gender and body mass index, and therefore the determination of basal GH concentration has no diagnostic value [22]. Normal serum IGF-1 levels do not exclude the diagnosis of GH deficiency. IGF-1, IGF-binding protein 3 (IGFBP-3) are of approximate value for diagnosis, since the indicators in patients with GH deficiency and healthy people may partially coincide [23].

Currently, the generally accepted method for diagnosing GH deficiency in adults is stimulation tests [22, 24], the protocols of which are presented in Table. 1.

Table 1. Etiology of GH deficiency in adults [24]

Foreign clinical guidelines recommend testing only those patients who are highly likely to have the disease, and hormone replacement therapy with somatotropin will help improve metabolic parameters and quality of life. Provocative tests are not required if one of two conditions is present:

1. The presence of three out of four components:

– significant growth deficit (<-3 SDS);

– at least one additional tropic deficiency;

– low concentration of IGF-1 in the blood;

– congenital defect of the hypothalamic-pituitary region according to MRI: “triad” (hypoplasia of the adenohypophysis, ectopia of the neurohypophysis, aplasia/hypoplasia of the pituitary stalk);

– history of surgical treatment of a tumor of the hypothalamic-pituitary region;

– history of irradiation of the head-neck area.

2. Mutations of genes associated with the development of hypopituitarism: GH1, GHRHR

,
HESX1, LHX3, PROP1, POU1F1
[
PIT1
], etc. [22, 24, 25].

In table 2 presented

Table 2. Stimulation tests for diagnosing GH deficiency in adults; threshold values ​​of diagnostic tests used in the world for diagnosing GH deficiency in adults.

Test with insulin hypoglycemia

Stimulation of GH secretion during hypoglycemia was first described in 1963 [26]. This test is considered the “gold standard” in the diagnosis of GH deficiency in adults [22, 24], however, it has a number of disadvantages. Close medical monitoring is required to monitor for potential adverse events (convulsions or loss of consciousness due to hypoglycemia). In addition, due to the presence of insulin resistance in obese patients, this category may require the use of higher doses of insulin (0.15–0.20 U/kg body weight), which increases the risk of delayed hypoglycemia [27]. The insulin hypoglycemia test is contraindicated in elderly patients, people with high cardiovascular risk and epilepsy. Although the sensitivity of the sample is high, there are limitations in its reproducibility. In addition, variability in the peaks of GH secretion was noted in healthy volunteers depending on the time and in different phases of the menstrual cycle [22].

Currently, the range of 3.0–5.0 ng/ml is used as a diagnostic value for stimulated GH secretion during hypoglycemia [22, 24].

According to foreign recommendations, if there are contraindications to a test with insulin hypoglycemia, it is possible to conduct a combined test with stimulation with somatoliberin and arginine, however, the use of arginine for diagnosing GH deficiency has not been registered in the Russian Federation.

Test with somatoliberin and arginine

A test with somatoliberin and arginine, like a test with insulin hypoglycemia, is considered quite sensitive and specific for diagnosing GH deficiency [28, 29], but currently there is no somatoliberin drug on the pharmaceutical market.

The accuracy of this test is determined by the combined use of two stimulating substances: somatoliberin stimulates the synthesis and release of GH by the pituitary gland [30], and arginine enhances this effect by suppressing the release of somatostatin [31]. The concentration of GH during stimulation does not depend on gender and age, however, the result depends on BMI, and therefore three threshold values ​​are used (Table 3).

Table 3. Cut-off points for diagnostic tests according to published clinical guidelines Due to the fact that during this test both the pituitary gland and the hypothalamus are stimulated, false-positive results are possible with the hypothalamic genesis of the disease (for example, after radiation therapy) [32].

Glucagon test

Due to the fact that the main alternative test for diagnosis is not available, the possibility of using a test with glucagon in case of contraindications to a test with insulin hypoglycemia is being actively studied.

Glucagon is a strong stimulator of GH secretion, however, the mechanism of stimulation remains unclear. The stimulating effect is more pronounced when administered intramuscularly or subcutaneously compared to intravenous [33].

The advantages of the glucagon test are reproducibility and safety; its results are not affected by gender and the hypothalamic origin of GH deficiency. Disadvantages are the duration of the test (3–4 hours) and the need for intramuscular administration of glucagon. Side effects of the test are more pronounced in elderly patients: hypotension, hypoglycemia and epileptic seizures [34]. In addition, there is a risk of delayed hypoglycemia, and therefore this test is not included in routine clinical practice.

Two studies compared the diagnostic performance of the glucagon test and the insulin hypoglycemia test, and the patient and control groups were matched by sex and age [35, 36]. In a study by J. Gómez et al. The patient groups were also compared by BMI; this study revealed an inverse correlation of age and BMI with peak GH concentrations in healthy volunteers.

Initially, the threshold value of GH concentration was taken to be 3.0 ng/ml. Further studies revealed that the use of this value leads to overdiagnosis of GH deficiency [37]. Taking this into account, the American Endocrine Association guidelines suggest using a threshold of 1.0 ng/mL for patients with a BMI greater than 25 kg/m2. The authors also note that to clarify the diagnostic accuracy of the reduced threshold value, it is necessary to conduct large prospective studies among patients with different BMI and disorders of carbohydrate metabolism [22].

Growth hormone secretagogues

This class includes molecules that exhibit a strong dose-dependent and specific stimulation effect on somatotrophs [38]. They bind to the growth hormone secretagogue receptor 1a (GHS-R1a) in the hypothalamus and pituitary gland. The natural ligand of this receptor is ghrelin [39]. Other agonists of its receptor are analogues of ghrelin: GHRP-2 (GH-releasing peptide-2, GH-releasing peptide-2), GHRP-6, hexarelin, all of these substances are administered parenterally. Oral ghrelin analogues are also available.

The advantage of GH secretagogues is the possibility of oral administration [40]. They are resistant to proteolysis, since many representatives are non-protein molecules or contain D-isomers of amino acids [41]. The disadvantage is the possibility of obtaining false-positive results in the hypothalamic genesis of GH deficiency [42].

Studies have been conducted to evaluate the diagnostic value of tests with GHRP-6, GHRP-2 and combinations of somatoliberin with hexarelin, pyridostigmine, acipimox, GHRP-6 in comparison with a test with insulin hypoglycemia [43–48].

In studies of the test with somatoliberin and GHRP-6 for the diagnosis of GH deficiency in adults, the test was well tolerated (the only side effect was “hot flashes”), high sensitivity and reproducibility. GHRP-6 is administered intravenously, the peak GH response develops at 15-30 minutes - much earlier than with other pharmacological stimulants. The threshold value for a normal response is 20 ng/ml, for GH deficiency 10 ng/ml [49, 50]. The results of this test are not affected by age, gender or excess body weight, except when BMI exceeds 35 kg/m2, the threshold value is reduced to 5 ng/ml [51].

The GHRP-2 test has been used in Japan since 2006 because it is safe and convenient, using a GH concentration of 9 ng/ml as a threshold value. The peak concentration of GH after stimulation is reached at 60 minutes [52].

In a study where acetylated ghrelin was used as a stimulating agent, the most diagnostically significant GH concentrations for diagnosis were 7.3 ng/ml for normal body weight, 2.9 ng/ml for overweight and 0.6 ng/ml for obesity , diagnostic accuracy was 89.3, 94.1 and 62.5%, respectively. The authors conclude that obesity significantly reduces the GH response to ghrelin stimulation, but this test is a reliable diagnostic tool in patients with normal and overweight [53].

Currently, the use of the above methods in the Russian Federation is impossible, since somatoliberin and GH secretagogue preparations are not available on the market.

Oral secretagogue of GH

In 2022, the Food and Drug Administration (FDA) approved the use of macimorelin for the diagnosis of GH deficiency in adults [54].

Macimorelin is a GHS-R1a agonist with high stability, which allows it to be administered orally. In a phase I study in 36 healthy volunteers, oral administration of macimorelin showed a rapid, dose-dependent increase in plasma concentrations of the drug, with peak concentrations reaching 50–75 minutes after dosing. Dose-dependent stimulation of GH secretion was correlated in time with the maximum concentration of the drug in plasma; the increase in GH concentration lasted about 120 minutes after oral administration or intraduodenal administration. The drug was well tolerated, and no adverse events were identified [55].

A multicenter, open-label study compared the diagnostic value and safety of macimorelin versus somatoliberin + arginine test among adult patients with GH deficiency and healthy volunteers. According to ROC analysis, the optimal threshold concentration of GH was 2.7 ng/ml: sensitivity 82%, specificity 92%, error rate in recognition 13%. Among patients who were prescribed both diagnostic tests, the diagnostic yield of the methods was comparable. Peak GH concentrations were inversely correlated with BMI in the control group. With a single blood draw 45 minutes after taking macimorelin, using threshold values ​​according to BMI (6.8 ng/ml for BMI <30 kg/m2, 2.7 ng/ml for BMI ≥30 kg/m2), the sensitivity of the sample was 90%, specificity – 85%, error rate in recognition – 12.2% [56].

In 2022, the results of a multicenter, open-label, randomized, double crossover study were published, the purpose of which was to establish the effectiveness and safety of a single dose of macimorelin at a dose of 0.5 mg/kg for the diagnosis of GH deficiency in adults, compared with a test with insulin hypoglycemia. Patients were divided into three groups according to the likelihood of having the disease: high ( n

=38), medium (
n
=37) and low (
n
=39), a group of healthy volunteers was also selected (
n
=25).
Using GH concentrations of 2.8 ng/mL for macimorelin and 5.1 ng/mL for the insulin hypoglycemia test as a cutoff point, negative agreement was 95.38% (95% CI 87–99%), positive agreement – ​​74.32% (95% CI 63–84%), sensitivity 87%, specificity 96%. The reproducibility of the macimorelin test was 97% ( n
= 33). A secondary analysis found that using a cut-off point of 5.1 ng/mL resulted in a negative agreement of 94% (95% CI 85–98%), a positive agreement of 82% (95% CI 72–90%), a sensitivity of 92% and specificity 96% [57].

There are currently no published results on the safety and diagnostic value of this test in morbidly obese patients. The most common side effects include taste disturbances, dizziness, headache, fatigue, and gastrointestinal disturbances (nausea, hunger, and diarrhea). Prescription with drugs that prolong the QT interval should be avoided, as this may lead to the development of ventricular tachycardia. CYP3A4 is the main enzyme that metabolizes macimorelin, so when used in conjunction with drugs that activate it, false-positive results may be obtained [54].

Standardization of kits for determination of GH

The results of stimulating tests are interpreted according to threshold concentration values, and therefore the accuracy of laboratory determination of GH is extremely important. Circulating GH is represented by various isoforms and isomers: the 22 kDa variant is present in the largest proportion, and molecules of smaller mass are also present. Monoclonal antibodies are able to bind specifically to the 22 kDa isoforms but will miss other isoforms. Molecules of a structure similar to GH (placental GH, prolactin), as well as GH-binding protein (with which about 50% of circulating GH is bound) can cross-react and affect the accuracy of the measurement. There are also differences and inconsistencies in calibrations, which limit the ability to compare thresholds across studies. In addition, laboratories may use different units for measuring the concentration or activity of GH [58].

To combat these limitations, a single calibration standard for STG is currently proposed - 98/574. All kit manufacturers must clarify the isoforms being detected, the specificity of the antibodies used, and the presence of cross-reactions with the GH-binding protein [59].

Proteomic biomarkers of GH deficiency

At the time of submission of the article, there were no publications on proteomic biomarkers of GH deficiency in adults. In 2022, the results of a study were published in which circulating proteins in children with GH deficiency were studied using the new generation SWATH-MS proteomic analysis in comparison with healthy volunteers. Three proteins have been discovered that can be biomarkers for non-invasive diagnosis of GH deficiency in children: apolipoprotein A-IV, CFHR4 (complement factor H-related protein 4) and PBP (platelet basic protein) [60]. The question of studying these proteins in GH deficiency in adults remains open.

Growth hormone receptor polymorphisms

In humans, the growth hormone receptor gene (r-GH) is located on chromosome 5. The gene consists of nine exons encoding the receptor and several additional exons in the 5' untranslated region. Two main isoforms of r-GH are known, differing in the presence (fl-GHR, full-length) or absence of exon 3 (d3-GHR, exon 3-deficient). The absence of exon 3 results in the loss of 22 amino acids in the extracellular domain of the receptor [61]. It is currently believed that the binding capacity of both isoforms is the same. The d3 isoform is dominant over fl; about 50% of Europeans are hetero- or homozygous for d3 [62]. Carriage of d3 is associated with tall height, higher sensitivity to GH and is a factor in longevity in men [63].

Patients with the fl/fl genotype had a more pronounced response to somatropin after treatment for 1 week, compared with patients with the d3 alleles [64]. In another study with a treatment duration of 12 months, the increase in IGF-1 in response to therapy was significantly greater in the d3/d3 group. There were no differences in IGF-1 concentrations between the fl/d3 and fl/fl groups [65]. According to S. Meyer et al., no significant differences in IGF-1 concentrations were detected during therapy between carriers of one or two d3 alleles and the fl/fl genotype [66]. In adult patients with GH deficiency with d3 alleles, the risk of vertebral fractures is reduced, regardless of receiving GH replacement therapy [67].

Studies have also been published in which no differences were found between genotypes in clinical manifestations and adverse events, quality of life, IGF-1 concentrations, body composition and fat mass [68–71].

Two studies were conducted that assessed the effect of r-GH polymorphisms on various parameters during GH replacement therapy after 1 year and after 5 years of treatment. In a study by Van der A. Klaauw et al. after the first year of treatment in the d3 carrier group, a more pronounced increase in IGF-1 was observed at the same average doses of somatotropin in the groups. Among d3 carriers, total cholesterol decreased less markedly, and the concentration of HDL cholesterol reached higher values ​​compared to fl/fl. However, after 5 years, no differences were found between the groups [72]. According to S. Giavoli et al., treatment with somatropin normalizes the concentration of IGF-1 and reduces the percentage of fat mass after 1 year and after 5 years of treatment, regardless of the presence of the d3 allele. After one year of treatment in the d3 carrier groups there was an increase in the concentration of HDL cholesterol, and after five years there was a decrease in the concentration of total cholesterol and LDL cholesterol. While the prevalence of carbohydrate metabolism disorders was initially the same, 5 years after treatment in the fl/fl group it decreased, and in the d3 carrier groups it doubled [73].

Currently, data on the effect of r-GH polymorphism on the clinical picture of GH deficiency in adults is scarce, and available publications on the relationship between carriage of the d3 allele and response to replacement therapy are contradictory.

What does preparation include?

Preparing for a blood test for growth hormone is very simple; the patient only needs to scrupulously follow the following simple rules. So, before the tests

The following requirements must be met.

• If approximately 3-5 days before the blood test the patient underwent an X-ray or ultrasound examination, scanning, or other medical procedures, it is imperative to inform the attending physician about this.
• Before conducting the study, you need to be more careful about your daily menu. In particular, approximately 5 days before testing for growth hormone,
  it is advisable not to eat fried, fatty foods.
• It is also highly desirable to avoid all medications that may distort the results of the analysis
  . Of course, this is not always possible, but then you need to notify the doctor about it. The exception is when the study is being conducted to test the effectiveness of a treatment. In this case, you need to stop taking the medications prescribed by your doctor on the day of the test. An increase in the concentration of a somatotropic substance in the blood may well be the result of taking drugs such as bromocriptine, glucan, clonidine, estrogen, insulin, adrenocorticotropic hormone, oral contraceptives, and so on. Ideally, any drug that cannot be stopped should be discussed with your doctor.
• Three days before the blood test for hormones,
  it is strictly forbidden to drink alcohol. It is advisable to give up cigarettes at least on the day of the study (the sooner the better).
• 12 hours before the blood
  test , you can drink only clean water, since the manipulation must be carried out on an empty stomach. It is also prohibited to consume any other drinks - tea, coffee, mineral water, juice.
• Excessive physical activity can also reduce the quality of test results. About three days before donating blood for research, it is better to start abstaining from physical exercise and playing any sports.

If a blood test for growth hormone is repeated, it is advisable to take it in the same laboratory at approximately the same time. Where do hormone tests come from? The answer to this question is from the patient’s vein. The turnaround time for tests depends on the specific laboratory.

Treatment

Determination of indications for replacement therapy

The feasibility of replacement therapy for GH deficiency in adults is determined by the expected benefit for each individual patient. Patients with severe GH deficiency, confirmed by stimulation tests and low serum concentrations of IGF-1, are most likely to benefit from treatment. Clinical manifestations indicating the need for treatment are osteopenia, increased cardiovascular risk, as well as reduced quality of life, which must be confirmed by validated questionnaires for this disease [74].

An important category are patients who have achieved target height during replacement therapy and are transferred under the supervision of an adult endocrinologist. In such patients, full maturation of the skeletal and muscular systems may continue for the next 10 years [75–77]. When somatropin was discontinued after achieving target growth, there was a deterioration in lipid metabolism, body composition and quality of life [76, 78, 79]. After achieving final growth, it is necessary to re-diagnose GH deficiency, 1–3 months after a break in treatment with somatropin (Table 4).

Table 4. Re-diagnosis of GH deficiency after reaching final height

The negative clinical manifestations of GH deficiency and the positive effect of somatotropin replacement therapy also extend to patients over 65 years of age [80]. Despite the known fact that GH secretion decreases with age, diagnostic tests make it possible to distinguish between a physiological decrease and a pathological decrease caused by GH deficiency [81]. Thus, the same criteria apply to older patients as to other age categories. However, for such patients it is necessary to choose a lower starting dosage, which will be discussed in more detail below.

Initiation of treatment and selection of dosages

Treatment of GH deficiency in adults is recommended to begin with low doses (0.2−0.4 mg/day subcutaneously), this reduces the likelihood of side effects [82]. Dose titration is recommended at 6–8 week intervals, depending on clinical response and IGF-1 concentrations, which are recommended to be maintained in the upper half of the reference range. In patients under 30 years of age, it is recommended to choose a higher starting dose (0.4–0.5 mg/day), and in elderly (over 60 years of age) a lower dose (0.1–0.2 mg/day) to minimize the risk of developing side effects, since with age there is a physiological decrease in the need for somatotropin. Women receiving oral estrogen replacement therapy require a higher dose of somatropin because oral drugs inhibit the synthesis and secretion of IGF-1 by the liver [83]. When using transdermal forms of estrogens, dose adjustment of somatotropin is usually not required.

After selecting a stable dosage, a blood test for IGF-1 and evaluation for side effects is recommended every 6 months, and a lipid profile and fasting plasma glucose analysis every 12 months or immediately after increasing the dose of somatotropin. A physical examination measuring blood pressure, weight, waist circumference, and BMI is recommended annually and at every visit. If, according to the data of the first X-ray densitometry, a decrease in BMD is detected, a repeat study is carried out once every 2 years. It is also recommended to annually fill out appropriate questionnaires to assess quality of life.

The maximum duration of treatment is currently unknown. However, if there is no effect of treatment within 1 year, it is necessary to decide on the abolition of somatotropin [24].

Side effects

The main side effects of replacement therapy are caused by changes in water-electrolyte metabolism disorders that occur with GH deficiency or fluid retention in case of drug overdose: arthralgia, joint stiffness, myalgia, paresthesia and peripheral edema. Such side effects quickly regress when the dose of somatotropin is reduced. Since previously the initial dose was selected based on body weight, side effects were more common than when the dose was titrated from the minimum.

Very rare side effects include benign intracranial hypertension (BIH) and macular edema. The prevalence of ADHD in the population of children receiving growth hormone therapy is approximately 100 times higher than in the healthy population [84]. In the literature, there is only one description of ADHD as a side effect of replacement therapy for GH deficiency in an adult patient [85]. Two cases of macular edema were described in patients without diabetes mellitus: in an 11-year-old girl who received somatotropin therapy for Shereshevsky–Turner syndrome, and in a 31-year-old adult patient with traumatic injury to the hypothalamic-pituitary region. In both cases, the side effect developed due to an increase in the dose of somatotropin [86].

Impact on replacement therapy for other deficiencies

GH inhibits 11-β-hydroxysteroid dehydrogenase type 1 and promotes greater cortisone synthesis and decreased cortisol synthesis. Careful monitoring of patients with adrenal insufficiency (AI) is necessary when initiating treatment with somatotropin, since the clinical picture of adrenal insufficiency may develop and the risk of decompensation may increase even in mild infectious diseases [87]. In addition, in patients with subclinical hypocortisolism, after initiation of somatropin therapy, the manifestation of clinical manifestations of NN is possible.

When somatropin is prescribed to patients without secondary hypothyroidism, a decrease in the concentration of serum thyroxine (T4) is observed, but the concentration of triiodothyronine (T3) remains stable. Patients on T4 replacement therapy often require increased doses. It has been suggested that GH may increase the peripheral conversion of T4 to T3 and at the same time suppress the release of TSH in the pituitary gland, but the exact mechanism is unknown [88, 89].

Sensitivity to GH is reduced in patients receiving oral estrogen-containing drugs. This phenomenon is explained by the phenomenon of first passage through the liver and inhibition of IGF-1 production. With the use of transdermal forms of estrogens, this effect is practically absent [90, 91].

Testosterone stimulates the secretion of growth hormone and enhances its stimulating effect on the production of IGF-1. Dihydroepiandrosterone (DHEA) potentiates the production of IGF-1 - patients on DHEA therapy achieve IGF-1 targets on lower doses of growth hormone. The mechanism of this effect is unknown. Since DHEA is metabolized to testosterone, it has been suggested that the increase in serum testosterone concentrations accounts for this effect [92].

Cancer risk

According to epidemiological studies, there may be a relationship between high-normal concentrations of GH and IGF-1 in the blood and the prevalence of cancer [93]. In acromegaly, the risk of developing certain cancers is higher than in the general population [94].

Currently, there is no data on an increase in the frequency of relapses of extra- and intracranial tumors in adult patients receiving somatotropin for GH deficiency. However, treatment with somatotropin is contraindicated in the presence of active cancer [24]. In 2022, a study by D. Olsson et al. was published, which included 426 patients with hormonally inactive adenomas: 207 received somatotropin (median treatment duration 12.2 g), 219 did not receive somatotropin treatment (median follow-up 8.2 g .). Among patients receiving replacement therapy, a decrease in overall mortality was noted and no increase in the incidence of mortality from cancer was detected [95].

According to a meta-analysis that analyzed data from seven prospective and two retrospective studies ( n

=11,191). Somatotropin replacement therapy is associated with a reduction in cancer risks in adults with GH deficiency (relative risk 0.69; 95% CI 0.59–0.82). The risk reduction was maintained in additional subgroup analyses, excluding retrospective studies with fewer than 100 observations, studies among patients with craniopharyngiomas, and studies with less than 3 years of follow-up [96].

Thus, according to existing data, the benefits of somatotropin replacement therapy in adults exceed the theoretical risk of neoplasms. Screening for neoplasms in patients receiving growth hormone replacement therapy is no different from the general population. At the same time, it is worth closer monitoring of mature patients, patients with an oncological history and family predisposition, as well as a group with a proven increase in oncological risk - patients after radiation therapy [97].

The quality of life

The quality of life of adult patients with GH deficiency is assessed using the appropriate questionnaires: QoL-AGHDA [98] and PGWB [99].

In 2012, a meta-analysis by A. Hazem et al. was published, which included data from randomized placebo-controlled trials - a total of 54 studies ( n

=3400). Of the selected studies, 16 assessed quality of life, but the authors were unable to conduct a meta-analysis due to data heterogeneity and lack of quantitative data. Eleven studies reported significant improvements in quality of life according to at least one assessment method [100].

Mortality

The study, based on data from the Dutch National Registry for Growth Hormone Treatment, compared 2229 patients receiving growth hormone treatment with a first control group of 109 untreated patients with GH deficiency and a second control group of 356 patients after discontinuation of growth hormone. The standardized mortality rate in the treatment group was 1.27 (1.04–1.56) relative to the general population. After excluding patients with acromegaly and Itsenko-Cushing's disease from the analysis, the indicator was 1.29 (1.05–1.59), after excluding high-risk patients (craniopharyngiomas or other formations of the hypothalamic-pituitary region) - 1.00 (0.79 –1.26). There was also a significant increase in the standardized mortality rate among women in the treatment group - 2.52 (1.57-4.06), and this was observed even after excluding high-risk patients. The authors note that this may be due to the long-term course of uncompensated GH deficiency, which negatively affected cardiovascular risk, but this assumption requires further study [101].

In a study by R. Gaillard et al. among 13,983 patients with GH deficiency receiving somatropin (average follow-up period 4.9 years), an increase in overall mortality was noted by 13% compared with the general population (standardized mortality rate 1.13 (1.04–1.24)), however, mortality rates from cardiovascular diseases and cancer did not differ [102]. According to the results of a meta-analysis by J. Pappachan et al., the standardized mortality rate was 2.40 [95% CI 1.46–3.34] in patients with GH deficiency without treatment and 1.15 [95% CI 1.05–1. 24] in patients receiving somatotropin [103]. K. Stochholm and G. Johansson also demonstrated lower mortality among patients receiving growth hormone compared with patients without treatment: hazard ratio for all-cause mortality 0.34 (95% CI 0.15–0.77) [104].

Metabolic effects of replacement therapy

Since GH is one of the significant regulators of metabolism and energy homeostasis [105], treatment of GH deficiency in adult patients affects body composition, lipid, carbohydrate and bone-mineral metabolism, which is confirmed by meta-analysis data.

Body composition.

In a meta-analysis by A. Hazem et al.
54 RCTs were included ( n
~3400). Somatropin treatment significantly reduced body weight (–2.31 kg, 95% CI –2.66– –1.96) and fat mass (–2.56 kg, 95% CI –2.97– –1.3) and increases lean body mass (1.38 kg, 95% CI 1.10–1.65). However, no significant effect on bone mineral density (BMD) was detected, which may be due to the small number of observations [100].

The meta-analysis by C. Newman et al., which aimed to compare the effectiveness of low and higher doses of somatropin on body composition and lipid metabolism, included the results of 22 RCTs ( n

=1153). Lean body mass significantly increased in treatment groups compared with placebo, while fat mass decreased. Changes in lean body mass and fat mass showed a dose-dependent effect, with treatment at higher doses being more effective [106].

Cardiovascular system and lipid metabolism.

According to a meta-analysis by P. Maison and P. Chanson, which included 16 studies, compensation of GH deficiency promotes an increase in the mass of the left ventricle, the thickness of the interventricular septum and the posterior wall of the left ventricle, an increase in the diameter of the left ventricle in diastole and stroke volume [107]. It is known that the thickness of the intima-media complex of the carotid arteries is a predictor of progression of coronary heart disease [108]. It has been shown that treatment of GH deficiency leads to a decrease in this indicator [109]. Studies have demonstrated a decrease in total serum cholesterol, almost entirely due to a decrease in the concentration of LDL cholesterol. The effect is more pronounced

Indications for a blood test for growth hormone

The content of the article

Blood test for growth hormone

may be prescribed to the patient in the following situations:

• signs of dwarfism;
• symptoms of accelerated growth rates;
• excessive sweating;
• hair growth disorder;
• osteoporosis;
• muscle weakness;
• reduction in blood glucose levels (for example, after drinking alcohol);
• porphyria.

If a patient comes to an initial consultation with a specialist with ready-made test results, he should definitely check the expiration date of hormonal tests.

ADDITIONAL ANALYSIS AND SERVICES

Human pituitary growth hormone (GH) as a therapeutic agent was first obtained in 1958, and was used only in children who had the most severe forms of GH deficiency. In 1985, rGH, synthesized by recombinant DNA, appeared on the pharmaceutical market. This circumstance has greatly expanded the use of rGH throughout the world, given a powerful impetus to intensive study of the effectiveness of rGH therapy, improvement of dosage and methods of its administration and, as a result, improvement of the final growth and quality of life of patients, expansion of indications for the use of rGH.

GH deficiency

GH deficiency in children.

GH deficiency in children is the first and absolute indication for rGH replacement therapy. The frequency of GH deficiency in children ranges from 1:4000 to 1:10,000 newborns. According to the National Register, which has been maintained at the Federal State Institution ERC since 1990, there are currently 1932 young patients with this disease, boys account for 75%, and 54 patients with acquired GH deficiency. Without rGH replacement therapy, such patients are doomed to dwarfism: the final height of untreated women is 129.8 cm, for men - 139.2 cm [1]. Before the era of rGH, among patients with pituitary dwarfism there was an extremely high percentage of people (74.3%) who completed only 8–10 grades of secondary school. 60.8% of patients were professionally engaged in the circus genre, creating groups of little people [1]. In conditions of GH deficiency in the body, starting from childhood and gradually worsening with age, various metabolic disorders develop, which significantly worsen the health status and cause premature mortality of patients.

With adequate and early initiation of rGH therapy, it is possible to achieve completely normal final height, corresponding to values ​​for a healthy population. Currently, based on the results of numerous studies, an optimal dosage and administration regimen of rGH has been developed, which is accepted throughout the world. The standard dose of rGH currently used in children with GH deficiency is 0.025–0.050 mg/kg per day subcutaneously. Based on domestic and foreign experience (“Consensus of 1999 on the diagnosis and treatment of growth hormone deficiency in children and adolescents”, “Conclusion of the scientific society for the study of growth hormone 2000”, “Recommendations of the American Association of Clinical Endocrinologists on the use of growth hormone in adults and children, 2003”) in 2005, Russia adopted the “National Consensus on the diagnosis and treatment of somatotropic deficiency in children” [2]. In accordance with the Consensus in the Russian Federation, the recommended dose of rGH is 0.033 mg/kg per day, rGH is administered subcutaneously daily before bedtime.

The goals of treatment for rGH in GH deficiency are:

— normalization of growth and achievement of final height within or above genetically predicted;

— normalization of body composition;

- increasing bone mineral density and reducing the risk of fractures;

— normalization of metabolic processes;

— reduction of risk factors for the development of cardiovascular complications;

— normalization of reproductive function;

- normalization of psychological state and vitality.

Over 20 years of use around the world, significant experience has been accumulated in the treatment of rGH in children with GH deficiency, on the basis of which its safety has been established. Side effects in children during rGH therapy are extremely rare. They include: benign intracranial hypertension, prepubertal gynecomastia, arthralgia, edema. As a rule, relief of these conditions occurs with a temporary dose reduction or temporary cessation of treatment. The relationship of such conditions as slipped femoral head, ischemic necrosis of the femoral head and scoliosis with rGH therapy has not been clearly established.

Since 2000, the Ministry of Health of the Russian Federation and the Academy of Medical Sciences have carried out large purchases of rGH for the treatment of children with GH deficiency, and since 2008, the state has taken care of the continuous provision of this category of young patients within the framework of a special order of the Government of the Russian Federation.

In 2006, the first domestic rGR Rastan was registered, which is not inferior in effectiveness and safety to foreign analogues. Since 2011, it has become possible to administer Rastan using a convenient dispenser - a syringe pen.

The efforts jointly undertaken by the Government, the Ministry of Health and Social Development, the Federal State Institution Endocrinological Center and regional endocrinological services allow us to hope that in Russia such a phenomenon as “pituitary dwarfism” will be completely eliminated.

GH deficiency in adults.

GH deficiency in adults is characterized by changes in body composition, carbohydrate and lipid metabolism, decreased bone mineral density [3], increased risk of fractures and cardiovascular diseases, and reduced quality of life.

The goal of rGH replacement therapy in adults is to achieve normalization of the metabolic, functional and psychological consequences of hypopituitarism or GH deficiency.

The positive effect of rGH replacement therapy on body composition, consisting of a significant increase in muscle mass and a decrease in fat mass, as well as on the lipid profile, was noted in the first small studies [4] and confirmed in subsequent ones. Treatment with rGH for 2–5 years causes normalization of muscle strength [5]. With a long duration of rGH treatment, changes in bone mineral mass (MBM) and bone mineral density (BMD) are observed, both in patients with congenital [6] and acquired GH deficiency [7]. Men respond to rGH treatment with a greater (approximately 9%) increase in BMC than women. Since not only BMC increases, but also bone size (its area), the increase in BMD is less pronounced, but its normalization is noted in most patients [7].

rGH has a complex effect on serum lipids. Its overall effect is to reduce the levels of total cholesterol, LDL and apoprotein B. Some studies [8] revealed an increase in the concentration of HDL. The basal lipid profile is partly a reflection of the patients' overall cardiovascular risk. In this regard, lipoprotein concentrations are usually regularly monitored, especially in patients who had hyper-/dyslipoproteinemia or other cardiovascular risk factors before rGH therapy.

There are currently no data directly demonstrating a reduction in cardiovascular morbidity and mortality in adults with GH deficiency receiving long-term rGH replacement therapy. One of the most used indirect indicators of atherosclerosis is intima media thickness (IMT). In adults with GH deficiency, IMT is increased, and some studies have demonstrated its reduction with rGH replacement therapy [9]. Moreover, there are reports indicating that mortality during long-term rGH replacement therapy in adults with GH deficiency does not exceed mortality in the general population. However, to confirm this, a longer observation period is required.

During long-term rGH replacement therapy in adults with GH deficiency, there were no changes in insulin sensitivity, as well as an increase in the incidence of type 2 diabetes mellitus compared with the incidence observed in the general population.

The mitogenic and growth-stimulating effects of GH and IGF1 and their influence on the development of neoplastic processes laid the theoretical basis for the assumption that rGH therapy can increase the risk of tumor development and influence their continued growth. When assessing the risk of developing cancer, it is necessary to take into account the fact that patients with hypopituitarism due to genetic or tumor causes may have a higher risk of developing neoplasia compared to healthy people. In addition, tumor treatment itself, including radiation therapy, is a risk factor for the development of secondary neoplasia.

It is known that serum IGF1 levels exceeding normal values ​​are predictors of tumor processes. A meta-analysis of hormonal predictors of prostate cancer showed that those men whose testosterone or IGF1 concentrations correspond to the upper limit of reference values ​​have a twofold increased risk of developing prostate cancer [10]. Among premenopausal women, the risk of developing breast cancer was 4.5 times increased in those whose IGF1 concentrations corresponded to the upper limit of reference values ​​compared with those whose IGF1 was at the lower limit of normal [11]. Similar results were found for rectal cancer in men [12]. These studies also demonstrated a negative correlation between cancer risk and IGFBP-3 concentrations (increased risk observed in those with high IGF1 and low IGFBP-3 concentrations. The significance of these findings in patients with hypopituitarism is unclear because rGH treatment causes increased values both IGF1 and IGFBP 3. In the context of rGH replacement therapy, it is nevertheless advisable to maintain IGF1 levels in normal values, promptly titrating the dose, which depends on the age and gender of the patient, as well as on concurrent replacement therapy with other hormones.

Patients with GH deficiency who have been treated with rGH for a history of neoplasm are at risk of developing a secondary tumor, however, there is no data indicating that treatment with rGH increases the risk of its development. There is also no information on the incidence of de novo cancer and leukemia in patients treated with rGH.

Active tumor process is a standard contraindication for rGH in both children and adults. Relative contraindications are proliferative diabetic retinopathy and benign intracranial hypertension. It is currently believed that patients with hypopituitarism and diabetes mellitus can be treated with rGH, but initial doses should be lower and titrated more slowly with frequent and regular glycemic monitoring.

20 years of experience with the use of rGH has shown that rGH replacement therapy in adults with correctly diagnosed GH deficiency, adequate dose titration and monitoring of treatment by monitoring IGF1 and clinical effectiveness is safe. However, it is generally accepted that further observations are necessary to obtain information about the long-term consequences of treatment with rGH.

Growth diseases without GH deficiency

Currently, the range of diseases for which rGH is used has been significantly expanded and is not limited only to somatotropic insufficiency. Already in 1983, the International Conference on the Use of GH declared the need to conduct research in “short children who do not have GH deficiency” [13]. The availability of rGH has made it possible to actively study the effectiveness of rGH therapy for short stature due to various non-pituitary causes. Short children without GH deficiency may have subtle defects in one of many regions of the GH–IGF1 axis. Considering the different genesis of growth problems in these diseases, the primary goal of treatment for short children without GH deficiency is to increase the growth rate and normalize linear growth without affecting the underlying causes. Therefore, for conditions not caused by GH deficiency, rGH is used more as a pharmacological agent than as a physiological substitute. RGH therapy for short children without GH deficiency is characterized by a dose-dependent nature of effectiveness.

Nowadays, rGH is used for syndromic short stature (Shereshevsky-Turner syndrome, Silver-Russell, Prader-Willi, Noonan, Sekkl, etc.), intrauterine growth retardation, idiopathic short stature, chronic renal failure, juvenile idiopathic arthritis, diseases of the hematopoietic system (leukemia , lymphoma, Fanconi anemia), neurofibromatosis, cystic fibrosis, etc. All these diseases have one thing in common: the short stature that accompanies them is not caused by GH deficiency.

It is believed that the action of exogenous rGH is carried out through interaction with GH receptors and, like endogenous GH, it causes the same intracellular signaling response, regardless of the specific defect underlying the disease.

rGH therapy is effective in most cases of short stature associated with elevated serum levels of GH and IGF1 binding proteins. However, in both mice [14] and humans, a number of growth effects of GH appear to be indistinctly dependent on hepatic IGF1 production. In most studies conducted in various types of short stature [15], the correlation between the height response to rGH therapy and the increase in circulating IGF1 (standardized for age and sex) only partly explained the treatment effect.

In addition to changes in the concentration of IGF1, factors influencing the results of rGH therapy are polymorphism of the GH receptor [16], nutritional status, age of initiation of therapy, dose of rGH and duration of rGH treatment.

Shereshevsky-Turner syndrome (STS).

The use of rGH for short stature associated with TTS was approved in France in 1990, in the rest of Europe in 1993, and in the USA in 1996.

Adult women with TTS are on average 20 cm shorter than women in the healthy female population in the respective country [17] and approximately 20 cm shorter than their target height. However, there is a strong correlation between final untreated height and target height, suggesting that, despite X-chromosomal pathology, a significant component of linear growth in STS is modeled by non-X-chromosomal genes.

A large amount of clinical material accumulated over the past 20 years indicates the effectiveness of rGH in increasing the growth rate and final height in patients with STS. Already the first results demonstrating an increase in growth rate in girls with this pathology inspired optimism and were the basis for the fact that this therapy was widely used even before receiving official approval. For more than two decades since the introduction of rGH, treatment results for rGH in STS have been published with various dosages and treatment regimens, rGH alone or in combination with the non-aromatized anabolic steroid oxandrolone, or sex steroids.

Overall, in registered studies, patients treated with rGH for 5 to 7 years before reaching final or near-tip height improved their height by 5 to 8 cm. This result suggests that the effect of long-term rGH therapy on final height is predicted in patients with STS is on average 1 cm per year of treatment.

The effect of therapy on final height has been shown to correlate with the duration of estrogen-free rGH treatment. Therefore, in order to delay estrogen-mediated bone maturation and thus maximize the duration of rGH treatment, there has been a trend in general clinical practice to deliberately delay the start of estrogen replacement therapy by a significant time interval from the usual age of physiological thelarche. However, more recent work using therapy with ultra-low doses of estradiol, started at physiological times (close to 12 years of age), demonstrated the concomitant effect of rGH and estrogen on increasing final height [19]. Moreover, significant delay in the initiation of sex steroid replacement therapy negatively affects psychosocial development, bone mineral accumulation, uterine development, sexual maturation, self-esteem and possibly the risk of developing cardiovascular diseases [20]. Approaches that avoid the need to delay feminization (such as early initiation of rGH therapy or, for those who have not started rGH therapy so early, combining it with oxandrolone) can be successful in most cases, if the criteria for success are not only height indicators [20].

Treatment with rGH, started at an early age (on average at 9 months), prevents the slowing of growth rates characteristic of girls with TTS in the first years of life and restores linear growth indicators almost to average normal values ​​[21]. These results substantiate the validity of early initiation of rGH therapy in STS. Thus, the modernized principles for the management of girls with TTS are currently as follows: the need for rGH therapy can be considered as soon as growth rates decrease; the initial dose of rGH is 0.05 mg/kg per day, followed by individual dose selection depending on the growth response; up to 9–12 years of age, therapy is carried out with rGH alone, then in combination with sex steroids, with preference for transdermal forms.

With early diagnosis and early initiation of treatment for rGH, final height can be improved in the majority and normalized in a number of patients (83% of girls with STS achieve normal final height, 63% achieve target height) [22]. Currently, a final height of 150 cm is an achievable goal for most girls with TTS.

Patients with STS are at increased risk of carbohydrate metabolism disorders [23], so close attention has always been paid to this aspect of safety. Although most long-term results regarding the worsening of these problems in patients with TTS during treatment with rGH appear to be optimistic [24], such girls should be regularly monitored by an endocrinologist for signs and symptoms of type 2 diabetes.

Patients with STS have an increased risk of developing scoliosis and kyphosis compared to girls in the general population. These diseases occur in approximately 10–20% of girls and women with STS [25]. Both problems may be exacerbated by the accelerated linear growth rates associated with rGH treatment. Other problems seen with increased frequency in STS include slipping of the femoral head [26] and an increased number of pigmented nevi [27]. Although it is hypothesized that rGH therapy increases the size and number of such nevi, there is no evidence to support this.

In general, adverse events of rGH therapy in STS are rare. However, with this syndrome, fatal cases of aortic aneurysm, dissection or rupture are not uncommon in young patients, usually associated with risk factors such as bicuspid aortic valve, coarctation or dilatation of the aorta, and arterial hypertension [28]. At the same time, there is no data on the side effects of rGH therapy on aortic diameter (according to MRI results) [20].

Intrauterine growth retardation.

The use of rGH in short children with a history of intrauterine growth retardation (IUGR) has received approval in both Europe and the United States. Postnatal growth disorders in short children with IUGR are likely multifactorial. Factors causing IUGR may include cellular hypoplasia [30], damage to the IGF1–GH axis, and the influence of polymorphism of the GH receptor gene (the presence or absence of the d3GHR allele, which is believed to affect sensitivity to GH).

The rGH era has seen numerous studies attempting to optimize treatment outcomes using different dosing routes and administration strategies for rGH [30–32]. The dose of rGH currently used for IUGR ranges from 0.033 to 0.067 mg/kg per day. The experience of using rGH in this category of children, accumulated at the Federal State Research Center, indicates the effectiveness and safety of this treatment. In the first 2-3 years of therapy, accelerated (catch-up) growth rates are observed, allowing the child to return to his genetically determined growth curve [30]. During this period, the dose-dependent effect of rGH is especially evident. Subsequent treatment with rGH provides the patient with a growth rate that is normal for the appropriate age and sex; cessation of rGH therapy leads to a significant decrease in growth rate. These data indicate the need for long-term therapy with rGH, despite the normalization of growth parameters, at least until puberty.

Although treatment results vary across studies and between patients, on average, 1 year of rGH therapy can increase final height by 1 cm. Factors that improve treatment effectiveness include significant growth deficits in the child relative to his target height; a large dose of rGH (less important in the maintenance phase of treatment), young age at the start of therapy, significant duration and continuity of therapy, and possibly the presence of the d3GHR allele [32], although this point of view remains controversial.

With long-term therapy with rGH, 85% of patients with IUGR achieve normal final height and 98% achieve target height [31]. Due to the inherent tendency of children with IUGR to develop insulin resistance, there is some concern about the effect of exogenous rGH in these patients on glucose metabolism. During rGH therapy, children with IUGR experience a slight increase in insulin resistance, which usually disappears after cessation of treatment [33]. In this regard, the instructions for the use of rGH in children with IUGR stipulate that treatment of these patients should be carried out under regular close monitoring of carbohydrate metabolism indicators [32].

In addition to insulin resistance, patients born with IUGR syndrome have an increased risk of developing metabolic disorders such as dyslipidemia, hypertension and metabolic syndrome in adulthood. However, there is currently no information on whether rGH therapy in childhood increases this risk in adulthood, and further long-term follow-up is required.

Idiopathic short stature.

Conditions accompanied by short stature not caused by GH deficiency, in which all known causes of short stature are excluded, are usually united under the general term “idiopathic short stature” (ID). The currently available data on the effectiveness of the use of rGH in children with ID are somewhat contradictory.

Within 20 years after the introduction of rGR, more than 40 studies were conducted involving children with ID. It has been demonstrated that the average increase in final height with rGH in IN is about 1 cm/1 year of rGH treatment, similar to that observed in STS and IUGR. However, all studies noted that the response to rGH therapy among patients with IN is extremely variable [34]. Accurate prediction of treatment outcome based on pretreatment parameters is currently not possible. The concentration of IGF1 at the time of initiation of rGH treatment does not have an independent correlation with height gain and, as evidenced by regression analysis, plays a relatively small role in predicting the results of long-term treatment [35]. More significant factors influencing long-term growth outcomes are age at treatment initiation, rGH dose, duration of rGH therapy, and target height [35].

Since patients with IN are practically healthy, they have a relatively low risk of developing adverse events during rGH therapy. Data from large, long-term post-marketing studies do show that the incidence of adverse events in these patients is lower than in other groups of children with growing pains. Thus, the frequency of otitis media, scoliosis, slipped femoral head, hypothyroidism, carbohydrate metabolism disorders and arterial hypertension in patients with IN is identical and even lower than the frequency of these conditions in GH deficiency and STS [36]. There were no cases of intracranial hypertension, edema, or prepubertal gynecomastia in children with ID. Treatment with rGH did not cause skeletal changes or accelerated pubertal development [35, 37], and similar results were published in a large post-marketing database [38]. The incidence of malignancy, as well as diabetes mellitus, in children with ID treated with rGH is identical to the frequency in the general population [39].

Chronic renal failure (CRF).

Short stature in children with chronic renal failure is one of the first conditions not caused by GH deficiency approved for the treatment of rGH. It has been shown that 36% of children with chronic renal failure have a height below 3‰ (–1.88 SDS) [40]. Subnormal rates of linear growth in children with chronic renal failure are a consequence of many factors, including the specific etiology of renal disease, hypocaloric low-protein diet, disturbances in the body’s acid-base balance, hyperparathyroidism, and changes in the GH-IGF1 system [40]. Obvious disturbances in sensitivity to endogenous growth hormone, the concentrations of which are increased, develop as a result of decreased renal clearance of growth hormone [41]. In addition, the detected decrease in the concentration of circulating GH-binding protein [42], which is the extracellular domain of the GH receptor, indicates a decrease in the expression of the GH receptor in the liver. In addition, dysfunction of the post-receptor signaling mechanism (Janus kinase, a signaling transducer and activator of the transcription system) was revealed [43]. The state of insensitivity to GH is biochemically expressed by a decrease in the IGF1/IFBP ratio, leading to a decrease in the concentration of free IGF1. The multiple (7–10 times) increase in concentrations of IGFBP-1, -2, -3 and -6 observed in chronic renal failure, as well as the concentration of growth hormone, occurs as a result of a decrease in renal clearance [44].

The current indication for rGH therapy in chronic renal failure is not stunting (height below a certain value), but rather decreased growth velocity (subnormal growth velocity). The recommended dose of rGH for chronic renal failure is 0.035-0.040 mg/kg per day.

A meta-analysis of randomized controlled trials of rGH therapy in children with chronic renal failure showed that accelerated growth rates are observed in the 1st year of treatment; subsequently, growth rates decrease and further accelerated growth rates are not observed [45]. Continuing rGH therapy helps maintain normal growth rate and prevents the progressive decline that occurs when rGH treatment is stopped. Limited domestic and foreign data indicate that final height can be improved by 1–1.5 SDS (7–11 cm) [46, 47]. A longitudinal Dutch study [48] demonstrated progressive improvement in height SDS in a small group of children, where after 6 years of treatment the mean height SDS approached the target height SDS (i.e. genetically determined).

It is believed that the beneficial effect of rGH therapy against the background of increased concentrations of endogenous GH develops, at least in part, as a result of the achievement of a significant increase in IGF1 during treatment, an increase in the IGF1/IGFBP ratio and, consequently, an increase in the concentration of free IGF1.

Concern regarding the safety of rGH therapy in children with chronic renal failure concerns two aspects: renal dysfunction and carbohydrate metabolism. 20 years of research into rGH therapy have proven that, subject to regular monitoring of the patient’s condition and hormonal-biochemical parameters, it is safe in this category of patients. There was no increase in the frequency of adverse events in children treated with rGH compared to untreated children [48]. Although rGH therapy is approved for use in chronic renal failure only before kidney transplantation, there are increasing reports of treatment in children and after transplantation, indicating similar rates of graft rejection in rGH-treated and untreated patients [49]. However, the effectiveness of treatment for rGH after transplantation is lower, which is explained by the need to use cytostatics and glucocorticoids. Despite the general impression that rGH therapy is safe in children with chronic renal failure, careful monitoring of renal function during treatment is mandatory.

Since children with chronic renal failure may have partially impaired glucose tolerance even in the absence of exogenous GH, carbohydrate metabolism in children treated with rGH is especially studied. Although early clinical trials and reviews did not report an increased incidence of diabetes mellitus in rGH-treated children compared with untreated children, analysis of a large multicenter post-marketing study showed that diabetes mellitus or impaired glucose tolerance occurs in rGH-treated children with chronic renal failure at approximately the same rate. frequency as in a healthy population.

Since rGH therapy in children with chronic renal failure can increase fasting insulin concentrations, in terms of safety, monitoring of carbohydrate metabolism is mandatory, especially in children with a history of diabetes mellitus and in those receiving glucocorticoid therapy.

Rheumatoid arthritis.

In children with active juvenile idiopathic arthritis (JIA), IGF1 synthesis and secretion are impaired. This is due both to the disease itself and to the need to use large doses of glucocorticoids. rGH therapy has a positive growth-stimulating effect in children with severe forms of JIA. Treatment with rGH can restore IGF1 deficiency, but the severity of the effect largely depends on the activity of the pathological process, the number and severity of exacerbations.

In children with severe short stature and JIA, long-term (4 years) rGH therapy at a dose of 0.028–0.045 mg/kg per day provides a 1 SD increase in height, while patients without rGH treatment lose 0.7 SD [50]. Markers of disease activity negatively correlate with SDS growth rate, as a result of which treatment with rGH is effective only with the abolition of glucocorticoids or with a dose of prednisolone not exceeding 10 mg/day.

During treatment with rGH for JIA, no adverse effects are observed; rGH does not have a clinically significant effect on the course of arthritis and the activity of the inflammatory process. Considering the lipolytic effect of GH, its administration may reduce excess fat mass, which is a consequence of both the underlying disease and the use of glucocorticoids.

Use of rGH for diseases not accompanied by short stature

Osteoporosis.

Since decreased secretion of GH is considered to be a pathogenetic mechanism of osteoporosis, attempts are being made to administer rGH to healthy people with osteoporosis to reduce bone loss. It has been shown that in men, after just 6 months of treatment with rGH, rates of bone formation and resorption increase; a slight increase in bone mineral density (BMD) was observed only in the spine. In women, an increase in BMD in the spine is observed with the combined use of rGH and calcitonin [51]. With longer-term (2-year) treatment with rGH and calcitonin, women with osteoporosis experience, although less pronounced than with the use of estrogens or bisphosphonates, an increase in BMD in the spine and femur.

Myocardial infarction and heart failure.

rGH is currently being considered as a potential new therapeutic agent for the treatment of myocardial infarction (MI) and congestive heart failure (CHF). rGH prolongs the survival of rats with post-infarction CHF; this effect is accompanied by a significant suppression of cardiomyocyte apoptosis [52]. In addition, rGH reduces pathological interstitial remodeling in the myocardium and improves left ventricular relaxation. Clinical studies in patients with CHF show that rGH increases left ventricular mass, improves cardiac function, hemodynamic parameters, and reduces pulmonary vascular resistance [53]. At the same time, given the significant variability of responses, an increase in the volume of extracellular fluid, and the possibility of developing edema during this therapy, large randomized studies are necessary in the future.

Catabolic states.

The anabolic effects of rGH have encouraged attempts to use it in catabolic conditions such as surgery and burn injuries. Negative nitrogen balance in critical conditions is partly explained by resistance to growth hormone and decreased production of IGF1. Recovery after surgery is accompanied by excessive catabolic processes. rGH administered to patients after surgery results in a positive nitrogen balance. The positive effect of rGH in patients with extensive burns is observed in both children and adults.

Sport.

Ethical issues regarding the use of rGH in athletes are currently very relevant. Isolated or in combination with anabolic steroids, rGH is used by many athletes today to increase muscle mass. However, long-term use of rGH in supraphysiological doses in athletes can lead to side effects observed in acromegaly, which in turn reduce physical endurance [54].

Thus, over the past 20 years, a large amount of data has been collected regarding the effectiveness of rGH therapy for various diseases in both children and adults, and there are impressive results in the treatment of rGH in children with some diseases accompanied by growth disorders. However, many treatment questions remain open, and therefore further collection of long-term treatment results is necessary.

Epidemiological studies suggest possible associations between IGF1 concentrations at the upper limit of normal (especially in the setting of reduced IGFBP-3 concentrations) and breast, prostate, colorectal and lung cancer. The difficulty of the assessment lies in the fact that IGF1 and IGFBP-3, which increase during rGH therapy, have a direct opposite effect on growing cells: IGF1 is anti-apoptotic, IGFBP-3 is pro-apoptotic. IGF1 and IGFBP-3 have been shown to have opposite effects on the risk of colorectal cancer. The interpretation of the complex relationships between IGF1, its binding proteins and neoplasia is subject to extensive study. Despite the optimistic data on many thousands of treated patients, the presence of a potential GH–IGF1 link, neoplasia requires careful monitoring of the treatment against the background of mandatory monitoring of IGF1 and IGFBP-3 and subsequent long-term observation of patients receiving rGH.