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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.