If a child grows significantly slower or is much smaller than their peers, parents generally get worried. While this may just be a temporary delay that balances out in later growth phases, a lack of growth can also have endocrine causes and may persist: Such growth disorders require treatment and stem from a lack of human growth hormone (GH, also called somatotropin).
The function of GH in the body
The peptide hormone GH is secreted by the anterior pituitary gland and has two main functions: It stimulates the growth of bones, muscles and viscera, and also plays a crucial role in the metabolism, especially in the processing of carbohydrates, proteins, fats and minerals. Human height growth ends once the growth plates in the bones have closed. After that, GH mainly contributes to maintaining a normal body structure.
The effects of GH are mainly mediated indirectly through stimulation of the production of the hormone IGF-I (insulin-like growth factor 1) in the liver. IGF-I takes effect in the respective target tissues and inhibits the release of GH via negative feedback. In the blood, IGF-I is primarily bound to the transport protein IGFBP-3, which is also regulated by GH and produced in the liver.
Endocrine growth disorders due to GH deficiency or excess
In hypopituitarism, an insufficient amount of GH is secreted. This may be caused by genetic defects, tumours or injuries to the pituitary gland. In children, GH deficiency leads to short stature, which is often recognised between the age of 2 and 10. It is estimated that one in every 4000 to 10,000 children is affected. Once parents seek out medical advice, a suspected hormone deficiency can be clarified quickly and a suitable therapy, such as the administration of recombinant GH, can be initiated to optimally support the child’s growth and development. However, if the symptoms of low GH secretion are only mild or the disorder first occurs in puberty or adulthood, diagnosis may be made very late or not at all. Without timely treatment, the limitations due to GH deficiency may be significant: In addition to short stature, which can affect mental health, it may manifest as poor general health, bone weakness, reduced muscle mass and fat maldistribution. Obesity and cardiovascular disease may result.
In the opposite case of GH overproduction, IGF-I oversecretion due to disorders of the anterior pituitary gland causes either gigantism – when the growth plates are not yet closed – or acromegaly, when the excess occurs at a later stage. While the body proportions in gigantism are mostly normal, excessive growth in acromegaly only affects the acra (nose, chin, fingers, toes), causing them to become enlarged in proportion to the rest of the body and leading to the typical physiognomy. The viscera may also be affected. If the cause of the GH excess is not addressed (e.g. by administering medication inhibiting GH production), it may lead to a wide range of health problems and risks. These include joint pain, impaired vision, headaches, breathing difficulties, excessive sweating, enlarged internal organs, cardiovascular disorders, diabetes, sensory disorders and symptoms of paralysis. The insidious course of this hormone disorder and the lack of typical symptoms in the early stage make diagnosis very difficult. Patients therefore depend on accurate diagnostics to enable a quick start of therapy and its subsequent monitoring.
Markers for the GH status
Growth disorders are generally determined by measurement of the hormone levels for GH, IGF-I and IGFBP-3. However, a single measurement of circulating GH has limited value due to its pulsatile secretion based on the circadian rhythm, causing significant fluctuation. It also has a short half-life of approximately 20 minutes. As a result, GH serum levels are generally low in persons who are healthy and awake. To diagnose GH deficiency and excess, it is therefore recommended measure GH concentration after stimulation or suppression tests 1–6. Serum concentrations of IGF-I and/or IGFBP-3 do not fluctuate throughout the day, meaning they can be used as a diagnostic aid in suspected GH deficiency. These markers’ primary use, however, is the indirect assessment of the GH status as part of therapy monitoring under GH substitution 7, 8.
In acromegaly, a single measurement of GH is also not sufficient for diagnostics: In the case of increased GH serum levels, suspected acromegaly is generally confirmed or disproved by means of functional tests (e.g. glucose tolerance test to check GH suppression). The determination of the IGF-I serum level is also useful in diagnosing the disorder, as it allows conclusions to be drawn on GH secretion. After the start of therapy, it also provides information on the therapy success: An increased IGF-I level is considered indication of the disease persisting.
Assays for growth disorders in children, adolescents and adults
Endocrine growth disorders such as GH deficiency and acromegaly can, in summary, not only be detected using suitable markers, but these markers are also a key part in the monitoring of therapeutic measures. EUROIMMUN and IDS offer a comprehensive portfolio of high-quality chemiluminescence assays for automated, standardised and accurate measurement of the relevant parameters:
• IDS Human Growth Hormone (hGH)
• IDS Insulin-like Growth Factor-I (IGF-I)
• IDS Insulin-like Growth Factor Binding Protein-3 (IGFBP-3)
The assays are calibrated using international WHO standards and require only small sample volumes. They can be processed conveniently using walk-away automation and on the same platform. The IDS Human Growth Hormone (hGH) also allows to determine GH during pegvisomant therapy (recombinant GH antagonist for treatment of acromegaly) and pregnancy as there are no cross reactions with pegvisomant and placental GH. Extensive study data on the parameters IGF-I and IGFBP-3 were collected using the IDS assays in order to determine reliable reference ranges for both adults and children 9–11.
Did we spark your interest? Discover our endocrinology panels and parameters and learn more about diagnostics in this area! If you would like to know more about endocrine disorders, take a look at the other blog articles in this series, e.g. on endocrine hypertension and bone disorders!
References:
1. Schilbach K, et al. Determinants of the growth hormone nadir during oral glucose tolerance test in adults. Eur J Endocrinol 181(1):55-67 (2019).
2. Klose M, et al. Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism. J Clin Endocrinol Metab 99(1):101-10 (2014).
3. Wagner IV, et al. Clinical evidence-based cutoff limits for GH stimulation tests in children with a backup of results with reference to mass spectrometry. Eur J Endocrinol 171(3):389-97 (2014).
4. Deutschbein T, et al. Anthropometric factors have significant influence on the outcome of the GHRH-arginine test: establishment of normative data for an automated immunoassay specifically measuring 22 kDa human growth hormone. Eur J Endocrinol 176(3):273-281 (2017).
5. Garcia JM, et al. Sensitivity and specificity of the macimorelin test for diagnosis of AGHD. Endocr Connect 10(1):76-83 (2021).
6. Manolopoulou J, et al. Automated 22-kD growth hormone-specific assay without interference from Pegvisomant. Clin Chem 58(10):1446-56 (2012).
7. Blum WF, Ranke MB. Use of insulin-like growth factor-binding protein 3 for the evaluation of growth disorders. Horm Res 33 Suppl 4:31 – 7 (1990).
8. Ranke MB, et al. Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children. Horm Res 54(2):60 – 8 (2000).
9. Bidlingmaier M, et al. Reference intervals for insulin-like growth factor-1 (igf-i) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations. J Clin Endocrinol Metab 99(5):1712 – 21 (2014).
10. Friedrich N, et al. Age- and sex-specific reference intervals across life span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 ratio measured by new automated chemiluminescence assays. J Clin Endocrinol Metab 99(5): 1675 – 86 (2014).
11. Bidlingmaier M, et al. Differences in the Distribution of IGF-I Concentrations Between European and US Populations.J Endocr Soc 6(7):bvac081 (2022).