Neural modelling of growth hormone therapy for the prediction of therapy results

Human growth and GH treatment

Human growth is regulated and influenced by many different factors, among them genetic, hormonal, and environmental ones. The growth of a child is genetically determined and it is possible to calculate the TH of a child, that is, to estimate what should be his/her FH after the completion of linear growth, based on the heights of parents. Different unfavorable factors, such as malnutrition, social deprivation, and chronic diseases, including hormonal disorders and genetic defects, may decrease growth rate and lead to short stature.

The main hormone regulating linear growth during childhood is somatotropin (GH), synthesized in the anterior lobe of pituitary gland and released to the bloodstream in a pulsatile manner. The main regulators of GH secretion are two hypothalamic hormones: somatoliberin (GH-releasing hormone) that stimulates GH secretion and somatostatin that inhibits this process. Under physiological conditions, GH secretion is stimulated by such factors as sleep, exercise, acute stress, fasting, and hypoglycemia but reduced in terms of chronic stress or hyperglycemia. Moreover, numerous pharmacological substances may either stimulate or inhibit GH secretion in healthy subjects.

The main peripheral mediator of GH action is IGF-I. The main pool of IGF-I is produced in the liver and secreted into the bloodstream, but IGF-I is also synthesized locally in many tissues, including growth plates. The effect of GH on growth plates occurs mainly through IGF-I as well as directly by binding with GH receptors on chondrocytes. Other important hormones are thyroxin (hypothyroidism decreases GH secretion and action as well as IGF-I synthesis by several mechanisms) and sex steroids (responsible for the increase of GH secretion during puberty, leading to the pubertal growth spurt).

The Polish criteria of qualification GH-deficient children to rhGH treatment are as follows ([1]):

1. Patient height below the third centile for age and gender according to current reference data (centile charts) for a given population; in Poland, the most commonly used are centile charts of Palczewska and Niedzwiecka ([2]);

2. Decreased growth rate (HV) during at least 6 months of observation;

3. Delayed bone maturation (BA), assessed on the ground of the radiogram of left (nonwriting) hand and wrist, according to Greulich-Pyle standards [3];

4. Decreased GH peak <10.0 ng/mL in two stimulation tests (at present, also decreased GH peak after falling asleep);

5. Excluded other causes of impaired growth (chronic diseases, malignancy, malnutrition, and genetic syndromes, especially Turner syndrome in girls);

6. Other conditions, such as hypoglycemia in neonates and infants, organic abnormalities of the hypothalamic-pituitary region, observed in some patients.

The assessment of IGF-I secretion before rhGH therapy administration is an obligatory procedure, but IGF-I deficiency is not the criterion that must be met for inclusion of treatment. Serum concentrations of both GH and IGF-I may be measured by different methods, of which the most frequently used are the chemiluminescent enzyme immunometric assays.

Although the criteria of qualification to rhGH treatment are strictly defined, it still happens that, in some patients, the efficacy of treatment is not fully satisfactory. Moreover, there are some doubts concerning certain parts of diagnostic process. For example, due to the pulsatile rhythm of GH release and variability of its concentration, the only approved methods of assessment of GH secretion are stimulation tests. Unfortunately, these tests have relatively low sensitivity and specificity, so it is recommended to perform at least two tests in each patient. Besides, it has been reported that at least 34 different provocative tests with 189 combinations are used, whereas the cutoff value was arbitrarily established on the same level (10 ng/mL) for all test variants, with no differentiation made to account for the strength of particular stimuli. The most commonly used pharmacological agents are insulin, glucagon, clonidine, arginine, and L-DOPA. In Poland, a few years ago, an assessment of GH peak during 3 h after falling asleep was introduced as an obligatory screening procedure in diagnosing GHD in children; however, it was previously reported that even overnight assessment of GH release may not identify all patients with GHD [4, 5]. Finally, there are disorders that are potentially treatable with rhGH, in which GH peak in stimulation tests is normal, but IGF-I secretion is decreased. They are as follows:

• Neurosecretory dysfunction, defined as decreased spontaneous GH secretion despite normal response to pharmacological stimulation (diagnosed on the ground of decreased spontaneous GH secretion after falling asleep but normal in stimulation tests) and

• GH bioinactivity, which is the secretion of GH molecule of decreased bioactivity (unable to bind with GH receptor and stimulate IGF-I synthesis) but of normal immunoreactivity (detectable by immunometric assays).

Appendix

1. Romer TE, Walczak M, Wisniewski A, Roszkowska-Blaim M, Korman E, Graliński JS, et al. Children with growth disorders qualified in Poland for growth hormone therapy. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw 2001;9:41–54.

2. Palczewska I, Niedzwiecka Z. Somatic development indices in children and youth of Warsaw. Med Wieku Rozwoj 2001;5:18–118.

3. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist, 2nd ed. Stanford University Press, 1993.

4. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hintz RL, et al. Diagnostic controversy – the diagnosis of childhood growth-hormone deficiency revisited. J Clin Endocrinol Metab 1995;80:1532–40.

5. Webb EA, Dattani MT. Diagnosis of growth hormone deficiency. Endocr Dev 2010;18:55–66.