Key endocrine system

The growth hormone (GH)–insulin like growth factor I (IGF-1) axis is the principal endocrine system regulating linear growth during childhood [1,2]. Physiologically, the axis coordinates tissue growth and maintenance by promoting protein synthesis, cell proliferation and cell survival in target tissues, while also regulating protein, lipid, and glucose metabolism [1]. In adults, its predominant role shifts from driving growth to maintaining body composition and metabolic function [2].

Hormone circuit

GH is produced and secreted by the anterior pituitary gland [1]. Its release is stimulated by GH releasing hormone (GHRH) and inhibited by somatostatin, both of which are secreted by the hypothalamus [1]. GH, in turn, stimulates synthesis and secretion of IGF-1 and IGF binding protein 3 (IGFBP‑3) from the liver [1]. Increasing circulating IGF-1 concentrations suppress further GH secretion through a negative feedback loop [1]. In the circulation, IGF-1 is mainly bound to IGFBP-3 within a ternary complex which prolongs the half-life of both proteins while limiting their biological activity [1].

The GH–IGF-1 axis is further modulated by several hormones, including insulin, thyroid hormone, ghrelin, androgens and estrogens [1,2]. Nutritional disorders, such as coeliac disease and anorexia, as well as chronic inflammatory conditions, including Crohn’s disease, can disrupt normal axis function and should be taken into consideration when assessing growth disorders [1].

Role of laboratory biomarkers

Laboratory measurements of GH–IGF-1 axis biomarkers are fundamental to evaluation of disorders associated with GH deficiency or GH excess. Because GH secretion is episodic and pulsatile, with marked fluctuations through the day and very low concentrations between secretory pulses, random GH measurements have limited diagnostic value [2,3]. GH is usually measured after stimulation or suppression [2–4].

In contrast, IGF-1 and IGFBP-3 exhibit relatively stable circulating concentrations with minimal circadian variation [1]. IGF-1 is continuously produced, has a longer half-life than GH and reflects integrated GH secretion over approximately 24 hours [2]. Consequently, serum IGF-1 is widely used as a biochemical marker of GH secretory status [2].

GH deficiency: growth and metabolic disorders

GH deficiency is the most common pituitary hormone deficiency in children and may occur in isolation or together with deficiencies of other pituitary hormones [3].

In pediatric patients, GH deficiency typically presents as growth failure, sometimes accompanied by delayed tooth development [3]. Affected children generally have a height below the third percentile and reduced growth velocity [3]. Depending on the underlying cause, additional features may include delayed or absent puberty, increased adiposity or other endocrine abnormalities [3].

In adults, GH deficiency is associated with adverse metabolic consequences, including altered body composition, reduced bone mineral density and an increased risk of osteopenia, osteoporosis and cardiovascular disease [5].

Laboratory diagnosis of GH deficiency

When GH deficiency is suspected in children, evaluation of the GH–IGF-1 axis begins with measurement of serum IGF-1 and IGFBP 3 [1,3]. These biomarkers can help distinguish GH deficiency from other causes of short stature when interpreted alongside clinical factors [1]. Because IGF-1 levels are physiologically very low during infancy and early childhood, IGF-1 alone may not reliably discriminate normal from deficient GH secretion in younger children [1,3]. In these patients, IGFBP 3 may provide a better indicator of GH deficiency [1,3].

GH levels after stimulation are measured for diagnostic confirmation [1,3]. However, these tests should not be used alone for diagnosis of GH deficiency due to ill-defined thresholds [3,6]. Stimulation testing (also called provocation testing] is performed using agents such as insulin, arginine, clonidine, levodopa or glucagon, with serial GH measurements obtained following administration [3]. Two stimulation tests are typically performed on the same day to improve diagnostic accuracy [3,6]. In adults, serum IGF-1 measurements and confirmatory GH stimulation tests are also employed to support diagnosis of GH deficiency [5,7].

Treatment and monitoring of GH deficiency

Administration of recombinant human GH is the standard treatment for children with short stature and confirmed GH deficiency [3,6]. Measuring baseline IGF-1 and IGFBP-3 concentrations may help predict treatment responsiveness, whereby patients with the lowest levels will generally have a better response to treatment [1]. During GH therapy, IGF-1 and IGFBP-3 measurements are used to assess treatment adherence and guide dose adjustment [1]. The therapeutic dosage is typically titrated to maintain serum IGF-1 within the age-specific normal range [1,6]. IGF-1 measurements during long-term treatment also provide a safety reference to avoid overdosing [1].

Similarly, in adults receiving GH replacement therapy, doses are titrated to normalize serum IGF-1 within the age-adjusted reference interval [5,7]. Once a stable maintenance dose has been established, IGF-1 should generally be monitored every six to twelve months [5,7].