Growth hormone (GH) and its effector insulin-like growth factor 1 (IGF-1) are needed to regulate growth in childhood and body composition (1–3). Approved indications for GH replacement include short stature associated with Turner, Noonan and Prader-Willi syndromes (PWS), small size for gestational age, renal failure, idiopathic short stature, short stature homeobox-containing gene (SHOX) deficiency, and GH deficiency (GHD) (1).

The most prominent feature of GHD in children is diminished height velocity, but problems associated with GHD extend beyond decreased linear growth in children (4, 5). For example, individuals who develop GHD in adulthood experience a decrease in lean body mass (LBM), and an increase in visceral fat mass (FM) (6). Patients with childhood-onset GHD that persists into adulthood have more severe clinical manifestations than patients with adult-onset GHD, including lower LBM and higher FM (7).

GH activity shows a regulation of body composition starting in the tissue progenitor cells. Before puberty GH promotes skeletal and LBM growth and differentiation, while later in life GH is involved in the regulation of body composition (8). The effects of GH treatment on body composition in adults with GHD has been explored extensively in the literature, and potential benefits have been reported in terms of an increase in LBM and a decrease in FM (9). The effects of GH on body composition have also been investigated in specific pediatric conditions, such as PWS (10). Relatively few studies have investigated this effect on pediatric patients with GH deficiency that is either idiopathic or a result of hypothalamic-pituitary disease.

In 1973, Collipp and colleagues published the first study investigating body composition changes in pediatric subjects receiving GH (11), but more recently it has begun to be explored more extensively. The techniques used to assess body composition have changed over the years, evolving from the measurement of triceps skinfold thickness (ST) in the first studies to dual energy X-ray absorptiometry (DXA), currently the most reliable and widely used method of determining body composition (12, 13), facilitating the assessment of both FM and LBM (14).

This systematic review summarizes the available evidence relating to the effects of GH treatment on body composition in children with a confirmed diagnosis of GHD treated with GH. Given that both GHD and high FM increase the risk of metabolic disturbances such as dyslipidemia and insulin resistance (8, 15), we also considered the effects of GH treatment on plasma lipid and insulin levels when these were reported in studies included in the review.

The methodology of this systematic review is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (16).

We identified a total of 2,094 records by searching electronic databases ( Figure 1 ). After duplicates were removed, a total of 1,450 records were considered for inclusion. After the first screening, based on title and abstract, 52 full-text articles were selected for assessment of eligibility. After this second screening process, a total of 15 articles were considered eligible for this review (17–31).

Included studies enrolled over 500 pre- or post-pubertal pediatric patients with GHD ( Tables 1 and 2 ).

Our systematic review demonstrated that GH replacement in pediatric populations with GHD is effective in decreasing FM while increasing their LBM. In particular, we found that there is strong evidence for a decrease in FM during chronic rhGH treatment. Furthermore, in four studies, the cessation of treatment almost invariably resulted in increased FM (17, 19, 23, 30), which was mostly evident in subjects with persistent GHD (17). We also found that there is moderate evidence for an increase in LBM during chronic rhGH treatment. In three studies, discontinuation of rhGH treatment resulted in decreases in LBM, which were mostly evident in subjects with persistent GHD (17, 23, 30). In only one study, in which II was used to assess body composition in nine pre-pubertal children, there was no significant increase in LBM or a decrease in FM (21).

Six studies diagnosed GHD using the standard ITT or arginine stimulation test (18, 20, 23, 25, 26, 30). Additional tests used in these studies included the clonidine-betaxolol test (30), and the glucagon stimulation test (18). The heterogeneity of GH makes it impossible for a single assay to capture all GH moieties that may be present in biological fluids. Indeed, results vary widely based on which GH assay is utilized. GH immunoassays such as single-antibody radioimmunoassays (RIAs), immunoradiometric assays (IRMAs), dual antibody sandwich-type immunoassays, enzyme-linked immunosorbent assays (ELISAs), and immune functional assays (IFAs) (36) detect immunological epitopes on GH molecules and are the most sensitive assays available, due to the high binding affinity of antibodies (36, 37). All immunoassays require a tracer or readout, which may be radioactive, colorimetric, fluorescent, or chemiluminescent. Although the most commonly used immunoassay is the solid-phase, dual-antibody, sandwich-type assay (36), our review analyzed studies that utilized IRMAs.

Historically, clinical guidelines have recommended several different stimulation tests for the diagnosis of GHD, e.g., ITT, arginine stimulation test, clonidine stimulation test, clonidine-betaxolol test, levodopa stimulation test, GH-releasing hormone (GHRH)-arginine stimulation test, and the glucagon stimulation test; all of which carry their respective advantages and limitations (38). GH levels are measured at different times following drug administration, depending on drug type. Additionally, as no single test is 100% effective in eliciting GH release (39), two GH provocation tests are typically conducted. GH levels typically peak 30–90 minutes after insulin administration or onset of arginine infusion, 30–120 minutes after levodopa administration, 60–90 minutes after clonidine administration, and 120–180 minutes after glucagon administration (38). The definition of a ‘normal’ GH response is somewhat arbitrary; generally, a stimulated GH level >10 ng/mL (>10 mcg/L) is sufficient to rule out classic GHD (40, 41).

In the analyzed studies, subjects’ body composition was primarily examined through DXA or BIA. In clinical research, DXA is considered the ‘gold standard’ for assessing FM, fat-free mass (FFM), and bone mineral density (13, 42). However, DXA requires specialized radiology equipment and it is costly, making it almost impossible to use in routine clinical practice. BIA is more commonly used in routine clinical practice (and in research studies); it is a simple, noninvasive, low-cost device that uses the body’s resistance to alternating current to estimate total body water content (TBW) (43, 44). Earlier BIA systems used single-frequency-BIA (SF-BIA) currents and equations that accounted for weight, height, age and the body’s resistance to current flow. With the recent development of multiple frequency-BIA (MF-BIA), researchers and clinical practitioners can now predict intracellular and extracellular water content independently. These systems also calculate a phase angle, a value corresponding to the intracellular:extracellular resistance ratio to cell membrane-specific resistance. As an indicator of cell membrane function, the phase angle is clinically significant, particularly in nutritional and disease risk assessments (45). The phase angle typically decreases with age and height, and increases with greater FFM (46). Notably, several factors may limit the accuracy of BIA in patients with severe obesity. Many of the predictive equations that have been developed in normal-weight subjects with normal body water distribution may not be accurate in severe obesity states; BIA generally underestimates FM in patients with obesity. Comparison of body composition assessment by DXA and BIA according to body mass index (BMI) is poorly documented. In a recent retrospective study, 3,655 measurements of body composition, assessed by DXA and BIA, were compared (47). It was reported that BIA and DXA methods had higher concordance with FM than with FFM values. In this study, the slight bias, particularly in patients with a BMI between 16–18 kg/m², suggested that BIA and DXA methods are interchangeable at a normal population level, but that BIA underestimated FFM and overestimated FM in patients with a BMI ≥18 kg/m².

Two of the analyzed studies assessed body composition using near-infrared interactance (NIR) (21) and measurement of ST with a skinfold caliper (29). ST is difficult to measure with precision and accuracy without rigorous training. Therefore, there is likely to be considerable inter- and intraobserver error in its measurements. ST measurements can mistakenly assume that subcutaneous fat, measured at one or more selected sites, measures total body fat stores. However, subcutaneous fat at one site may not reflect fat stores at another site, and may not be positively correlated with the amount of visceral fat. NIR relies on the fact that different tissue types absorb light at different wavelengths. Percent body fat and lean tissue mass are then obtained by prediction equations based on areas under the curve from spectrophotometric measurements (48). However, NIR cannot differentiate between bone and muscle mass; thus, a lean body mass measurement using NIR reflects both tissue types. Further, NIR is limited in its ability to accurately measure body composition in patients who are extremely obese.

The ‘gold standards’ for quantifying visceral adipose tissue in normal and obese populations are magnetic resonance imaging and computerized tomography. These imaging techniques quantify visceral adipose tissue more precisely than DXA in normal subjects, with coefficients of variation within 1–3% (49–52). This may be explained by DXA’s limited ability to distinguish visceral fat from peripheral fat in the abdominal region. In contrast, DXA measurements are more precise in obese individuals, as altering the reference lines in DXA analysis software can increase or decrease individuals’ fat compartments more slowly than in a lean individual, resulting in less analyst-initiated variation. The precision of DXA visceral adipose tissue assessments should continue to increase as software becomes more accurate at distinguishing visceral fat from peripheral fat. Currently, there are no other validated methods to differentiate between visceral and peripheral fat in this population.

GH treatment seemed to temporarily alter glucose metabolism. In summary, HbA1c, which is known as a specific marker of impaired glucose metabolism (53), was evaluated in two studies, one in which there was an increase in HbA1c during the first 3 months of rhGH treatment to a level at the upper end of the normal range (21), and the other in which there was no change in HbA1c after cessation of GH treatment (30). Moreover, insulin levels increased significantly during rhGH treatment in three studies (20, 27, 28), and decreased significantly after discontinuation of rhGH in two studies (18, 23). In one of these studies, significant increases in insulin levels and HOMA were also reported during rhGH therapy (20). These changes in glucose metabolism could be a consequence of the antagonistic effect of GH therapy with regard to insulin’s action on peripheral tissues, such as the skeletal muscle, liver, and adipose tissue. GH thereby increases glucose production by the skeletal muscle and liver and decreases glucose uptake by adipose tissue (54). Insulin production is increased to compensate for the increased circulating glucose after GH administration (54). We also noted transient changes in lipid metabolism, although results were conflicting (21, 24, 27–29, 31). Indeed, GH has a crucial role in carbohydrate metabolism by acting actively on gluconeogenesis, hyperinsulinemia, and insulin resistance, because it interferes with insulin intracellular signaling, as well as the GH-induced increase of free fatty acids. GH also reduces both abdominal fat and FM in adult subjects with obesity characterized by lower GH secretion, with fewer GH secretory pulses and shorter half-life duration (8).

In general, our findings indicate that GH influences body composition, and therefore periodic changes in FM and LBM should be assessed in children with GHD receiving rhGH therapy to ensure that a satisfactory body composition is maintained over time. Lipid and glucose profiles should also be monitored during treatment.

If during or after GH treatment, no changes are observed in a patient’s body composition, physicians should assess how well the patient complies with the therapy and the appropriateness of their lifestyle/dietary choices; recommendations for additional interventions or lifestyle modifications should be introduced accordingly.

Our review clearly shows that rhGH therapy in children with GHD increases LBM and reduces FM. The main implication of this finding is to emphasize the fundamental importance of performing specific and precise periodic assessments of body composition before, during and after treatment. We strongly recommend avoiding the routine measurement of weight or BMI as a substitute for assessing body composition because these parameters may not be reliable indicators of FM or LBM (60). By adopting the suggestions summarized in Table 4 physicians could reduce errors in the GHD diagnosis pathway and further improve the body of knowledge pertaining to body composition as an indicator of disease status and the most effective timetable for therapy.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

AF, MV, AP, and FA contributed to the study conception, writing of first draft, and critical revision and editing of subsequent drafts. AF and MV contributed to the data analysis. PC, NZ, AG, C-EF, and GP contributed to critical revision and editing of subsequent drafts. All authors approved the final version for submission and agree to be accountable for the content of the work. All authors contributed to the article and approved the submitted version.