What is growth hormone deficiency

Growth hormone (GH) is produced in somatotrophs – cells of the glandular part of the pituitary gland – in the amount of about 0.5 mg/day. In healthy subjects, it is secreted into the blood in pulses, according to a characteristic diurnal rhythm – the highest frequency and amplitude of pulses falls on the night hours. The secretion of GH into the blood is under the control of the hypothalamic neurohormones somatoliberin (GH-RH) and somatostatin (STS), and also depends on the feedback inhibitory effect of IGF-I. GH circulates in the blood in complexes with a binding protein, which is a proteolytically cleaved extracellular fragment of the hepatic growth hormone receptor. The main role of GH is to stimulate growth in the body. Its anabolic, insulin-like effects on muscle and fat tissue are also important. The growth-promoting action of GH is mediated by insulin-like growth factor-I (IGF-I). GH may also have a direct mitogenic effect on thymocytes, arterial wall cells, and the erythrocyte lineage of bone marrow cells. It also affects glucose metabolism – both insulin-like and diabetogenic depending on the site and time of action.

Growth hormone deficiency (GHD) in isolated form or combined with multihormonal pituitary insufficiency, as well as its consequences in the form of growth inhibition and bone maturation have been known for a long time in children. For a long time it was believed that the deficiency of this hormone, which appears only in adulthood, does not play an important role in the regulation of metabolic processes.

In recent years, however, much more evidence has been obtained that adults with GH deficiency have poorer health. Retrospective studies have shown in both men and women with GH deficiency a shorter survival period relative to the rest of the population because of the higher prevalence of cardiovascular disease.

The diagnosis of GHD in adults is based on the finding of most of the characteristic clinical signs and symptoms. It must also be confirmed by a decreased GH secretion (less than 3 ug/l) in a post-insulin hypoglycemia test or other diagnostic tests (including with Arginine, GHRH, L – dopa, Hexarelin, GHRH + Arginine, GHRH + Pyridostigmine) after compensation for possible deficiencies of cortisol, thyroxine and gonadal hormones. In patients with multihormonal pituitary hypopituitarism, one test should be performed; in the case of isolated GH deficiency, two tests are recommended. GH deficiency diagnosed in childhood requires confirmation upon entering adulthood.

Additional confirmation is provided by the finding of decreased plasma IGF-I levels (after exclusion of malnutrition, liver disease, uncompensated diabetes mellitus, and hypothyroidism) and the presence of hypothalamic-pituitary lesions on nuclear magnetic resonance imaging (MRI). Specific IRMA methods calibrated to IRPs of pituitary origin 80/505 are recommended for GH determinations.

Patients with GHD with GH deficiency in adulthood can be divided into several groups:

– Patients with known pituitary disease, pituitary tumor, or peri-pituitary region; more than 90% of patients with GHD in adulthood come from groups of patients with pituitary tumor, after surgical treatment of pituitary tumor, after traumatic brain injury, or after radiation therapy to the peri-pituitary region. Other causes include postpartum pituitary stroke, tuberculosis, sarcoidosis, histiocytosis X, and autoimmune causes.

– Patients with abnormal levels of various pituitary hormones. Researchers found isolated GH deficiency in only about 33% of the patients they studied, whereas the remainder were deficient in at least two or more pituitary hormones.

– Patients with GHD were diagnosed and treated as early as childhood; a diagnosis made in early life is not sufficient to diagnose GHD in adulthood, but the likelihood of the deficiency persisting beyond adulthood is very high.

Symptoms of GH deficiency in adults

Decreased sense of psychological well-being by:

• decreased energy and vitality;
• decreased sense of health;
• impaired self-control;
• disturbed emotional reactions;
• states of mental depression;
• feelings of anxiety;
• self isolation from other people.

Increased abdominal obesity.

Decreased ability to physical activity and mental toughness.

Decreased skin thickness and skin dryness.

While the most significant physical symptoms include:

• visceral obesity (increase in waist-to-hip dimension);
• thinning and drying out of the skin (superficial vascular congestion);
• abnormal body composition (increase in the amount of adipose tissue with a simultaneous decrease in the weight lean body mass and extracellular water);
• increased presence of coronary heart disease risk factors (hyperlipidemia, fibrinolysis disorders);
• decreased bone mineral density;
• impaired renal function;
• increased insulin resistance;
• decreased exercise capacity;
• psychological disorders.

GH deficiency and body composition

GH significantly influences the structure, proportions and composition of body tissues. In adults with GH deficiency, increased body fat mass (mainly visceral fat) and decreased fat-free mass (FFM) are observed. Thus, changes in body composition may lead to a decrease in exercise capacity, deterioration of well-being, and are an important risk factor for cardiovascular disease.

The current view is that GH replacement therapy leads to beneficial changes in body composition. The most commonly described results include a decrease in body fat mass, especially visceral fat, an increase in lean body mass and total body water (TBW), a more proportional distribution of body fat (abdominal fat loss). Long-term analysis of the sequelae of GH administration shows that changes in body fat and FFM occur during the first 6 months of replacement therapy and persist during continued treatment. In general, during GH replacement therapy, mean body weight did not differ significantly from pretreatment body weight because the increase in lean body mass was accompanied by a decrease in fat mass. The increase in FFM during GH replacement therapy appears to be due to an increase in extracellular water (ECW) volume and an increase in total cellular mass, including muscle mass. A study showed normalization of extracellular water volume after only one month of therapy.

GH influences body composition mainly by enhancing lipolysis and protein synthesis. Growth hormone has both direct and indirect lipolytic effects by increasing its sensitivity to other hormones such as adrenaline or testosterone. Most data indicate that this activity plays a critical role in fat reduction during GH replacement therapy. Another important effect of GH is to increase protein synthesis. Available data indicate that a significant increase in total body nitrogen is already observed during the first 2 to 6 months of GH administration.

GH deficiency, muscle function and exercise capacity

In patients with GHD, a marked decrease in exercise capacity, reduced maximal oxygen uptake by skeletal muscles as well as concomitant impaired cardiovascular function are observed. One theory is that the reduced ability to lose heat characteristic of GHD patients (they show impaired ability to sweat) also contributes to their reduced exercise capacity.

Most reports indicate that GH replacement therapy leads to increased exercise capacity. On the other hand, increased skeletal muscle mass and strength have undoubtedly been reported following the use of GH. The therapy also resulted in greater oxygen utilization by skeletal muscles. In a study spanning more than 3 years, it was found that the exercise capacity of the quadriceps thigh muscle normalized after approximately 16 months of therapy and remained normal for a further 22 months.

GH deficiency and cardiovascular system

Long-term studies have established the important role of GH in maintaining normal cardiovascular function. Adults with GHD have been shown to have a higher prevalence and greater severity of coronary heart disease risk factors – mainly abnormal blood lipid and lipoprotein concentrations and decreased plasma fibrinolytic activity. The studies indicate a significant increase in blood concentrations of total cholesterol, LDL cholesterol fraction, triglycerides and apolipoprotein B and a concomitant decrease in HDL cholesterol fraction in subjects with GHD.

There are also reports indicating significantly higher plasminogen activator inhibitor (PAI) activity and higher fibrinogen levels in the blood of patients with GHD compared to healthy subjects. The results of these studies indicate a decrease in plasma fibrinolytic activity and an increased risk of intravascular thrombus formation, with no difference between the isolated GH group and patients with multihormonal hypopituitarism.