Adverse events with usage of human growth hormone: a review

1 Background

Growth hormone (GH) is a critical peptide hormone that regulates growth, cellular reproduction, and regeneration in humans. Its secretion follows a complex regulatory pathway controlled by the hypothalamus through two key hormones: growth hormone-releasing hormone (GHRH) and growth hormone-inhibiting hormone (GHIH or somatostatin) [1]. This delicate balance creates a pulsatile secretion pattern influenced by various physiological factors, including sleep, stress, exercise, nutritional status, and metabolic signals [2].

The physiological effects of GH are wide-ranging but predominantly anabolic. Through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway and janus kinase-signal transducer and activator of transcription protein (JAK-STAT) signaling, GH stimulates the production of insulin-like growth factor 1 (IGF-1) primarily in the liver [3]. This hormone-signaling cascade promotes linear growth through cartilage cell proliferation in bone growth plates (during childhood), enhancement of bone mineralization, growth of muscle mass through sarcomere hypertrophy, and stimulation of lipolysis. Beyond growth promotion, GH significantly influences metabolism by regulating protein synthesis, glucose homeostasis, and lipid utilization [4].

Recombinant human growth hormone (rhGH), manufactured to closely mirror natural GH, has become a crucial therapeutic agent. Its clinical applications primarily include treating growth hormone deficiency (GHD), but its usage has widened to include treating Turner syndrome, Prader-Willi syndrome (PWS), Noonan syndrome, chronic renal insufficiency, and small for gestational age (SGA) conditions; these uses are independent of growth hormone deficiency. While therapeutic benefits are well-documented, rhGH administration requires careful monitoring due to potential adverse effects. Clinical studies have reported various side effects ranging from mild (headaches, injection site reactions) to more serious metabolic alterations and carcinogenic effects. Furthermore, long-term safety surveillance has revealed a complex risk-benefit profile that necessitates individualized dosing strategies and regular monitoring [5].

rhGH can be administered as daily or weekly (long-acting) injections, and it has been recognized as the primary treatment option for pediatric growth hormone deficiency (PGHD) for the last three decades. Although effective and safe, daily rhGH injections can be cumbersome which often leads to poor adherence and lower height gain [6]. To address this noncompliance and to maximize treatment efficacy, weekly formulations that allow fewer injections were developed. The adverse event profile for daily compared to weekly injections is similar, with no clinical significant differences in overall incidence or severeity of events [7]. Although, long-acting GH may be associated with higher frequency of transient injection site reactions compared to daily GH [8].

This scoping review aims to comprehensively examine the adverse events associated with rhGH therapy, focusing on both short-term and long-term safety considerations across different patient populations in both children and in adults and their respective treatment protocols, as well as daily (short-acting) and weekly (long-acting) formulations.

2 Methods

The study selection was conducted using PubMed with the following search terms: “growth hormone” OR “somatropin” OR “growth hormone deficiency”. Results were narrowed down to within the last 15 years with the filters “clinical trial”, “randomized controlled trial”, and/or “multi-center”, generating approximately 300 results. Manuscripts were included if adverse side effects were reported. Importantly, manuscripts involving experimental cell lines or animal models were excluded; our review only included human data. Studies with long-acting growth hormone and short-acting growth hormone were both included. Figure 1 outlines the selection criteria fo rthe manuscripts. Fig. 1

PRISMA flow diagram illustrating the study selection process

3 Reports of adverse events in children

3.1 Cardiovascular

Cardiovascular (CV) adverse effects of growth hormone usage in children primarily include alterations in cardiac structure and function, changes in blood pressure, and metabolic disturbances that may contribute CV risks. These risks and others will be discussed in the section below. While GH treatment is beneficial for individuals with GHD, further investigation is warranted to assess its impact on CV function.

In a two-year prospective multicenter study conducted in 2012, Nygren et al. investigated the effects of GH treatment on two groups of children (n = 127) [9]. One group received a dose of 43 μg/kg/day, while the other received individualized doses ranging from 17 to 100 μg/kg/day. This study included children diagnosed with GHD (n = 89) as well as those with idiopathic short stature (ISS, n = 38). Given the lack of significant differences in outcomes between the GHD and ISS groups, the data were pooled for analysis. Although an increase in left ventricular wall thickness was noted by the third month of the study in both groups, this thickness returned to baseline values by the study’s conclusion. This suggests that there is no association of GH administration with impaired cardiac function [9].

In 2020, Tidblad et al. conducted a population-based cohort study in Sweden that investigated long-term CV risks in 3,408 patients who had previously received rhGH treatment. The median age at treatment initiation was 9.3 years, and the median follow-up duration was 14.9 years [10]. The study demonstrated a similar crude incidence rate of CV events compared to controls (n = 50,036), supporting previous findings. However, it also revealed a significantly increased hazard ratio (HR) for female children compared to male children. In subgroup analyses by treatment condition, the increased HR was more pronounced in patients with ISS than in those with GHD. The highest adjusted HRs were observed among those with the most extended treatment duration (2.08, CI 95% 1.35–3.20) and the highest cumulative dose (2.05, CI 95% 1.18–3.55). While the overall incidence of cardiovascular events in rhGH-treated patients was similar to that of controls, female patients, those with ISS, and individuals receiving prolonged or high-dose therapy exhibited increased CV risk. These findings underscore the importance of assessment and long-term cardiovascular monitoring in patients receiving rhGH therapy, especially in higher risk subgroups such as females or those undergoing extended or high dose treatment [10].

In 2021, Quigley et al. conducted a comprehensive 10-year observational study as an extension of their 2002 randomized clinical trial (RCT) to assess growth, pubertal development, and the safety of long-term GH treatment, aiming to achieve near-adult height in both early treatment and untreated groups [11]. The original study began with a two-year RCT followed by more than a decade of observational follow-up. The RCT was structured as a two-arm, parallel, open-label, multicenter trial involving GH-naive patients between 9 months and 4 years old. The trial included 45 girls in the GH treatment group and 43 girls in the control group, with 19 participants lost to follow-up. Throughout the study, 13 serious adverse events (SAEs) were reported among 11 of the 69 girls. These included three surgeries to correct congenital anomalies, specifically atrial septal defect, anomalous pulmonary venous connection, and ptyergium colli. Additionally, one girl was diagnosed with hypertension. Use of metformin was reported for three subjects with evidence of insulin resistance. Overall, long-term growth hormone treatment was well tolerated, with a small number of SAEs, highlighting the importance of close follow-up for CV and metabolic complications in GH-treated patients, particularly in those with preexisting congenital conditions [11].

Cheng et al. conducted a 2022 Phase 3, single-arm, self-controlled study to evaluate the impact of rhGH therapy on mental development and motor function in infants and young children with PWS [12]. Thirty-five patients received a daily subcutaneous injection of rhGH at 0.5 mg/m2/day for the first four weeks, followed by an increased dose of 1 mg/m2/day for up to 52 weeks. Growth and developmental progress were assessed using the Peabody Developmental Motor Scales-Second Edition and the Griffiths Developmental Scales-Chinese (GDS-C), alongside height standard deviation score (SDS), body weight SDS, and body mass index (BMI) SDS. At the 52-week mark, significant improvements were observed in height, body weight, and BMI SDS. GDS-C scores demonstrated significant enhancements in general quotient (GQ) and its sub-quotients. Linear regression analysis revealed a negative correlation between age and total motor quotient (TMQ), gross motor quotient (GMQ), and fine motor quotient, though rhGH treatment appeared to mitigate TMQ and GMQ decline. Notably, patients under 9 months of age exhibited greater improvements in GQ and locomotor sub-quotient compared to older participants. The treatment was generally well tolerated, with mild to moderate adverse drug reactions reported in six patients and one case of hypertension potentially linked to rhGH therapy. Overall, rhGH was well tolerated in infants and young children with PWS [12]. This study showed treatment with rhGH improved growth and mental development, especially in children with PWS < 9 months old, although it is important to monitor blood pressure in these patients.

Tang et al. conducted a 2024 multicenter, randomized, open-label, negative-controlled Phase 3 study to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) in prepubertal children with chronic kidney disease (CKD)-induced growth retardation [13]. Participants (n = 68, mean age 7.8 ± 3.27 years) were randomized 1:1 to receive either daily subcutaneous injections of rhGH at 0.05 mg/kg/day or no treatment for 52 weeks. At week 52, the height standard deviation score (HT-SDS) in the treatment group increased significantly (0.75 ± 0.58) compared to the control group (0.17 ± 0.47), with a least squares mean difference of 0.58 (95% CI: 0.32–0.84, p < 0.001). Other growth parameters, including height velocity, insulin-like growth factor 1 (IGF-1) SDS, IGF-1/IGFBP-3 (insulin-like growth factor binding protein-3) molar ratio, and height, also demonstrated significant improvements in the treated group (all p < 0.001). Seven patients experienced treatment-related adverse events (TRAEs), which were predominantly mild, and most subjects recovered without intervention. One case of heart failure was reported but was deemed unrelated to rhGH treatment by investigators [10]. In summary, a 52-week regimen of daily rhGH significantly improved growth parameters in Chinese children with CKD-induced growth retardation, with an acceptable safety profile.

Finally, the efficacy of growth hormone therapy has shown promise in patients diagnosed with Noonan syndrome. Noonan syndrome is a multisystem genetic disorder caused by dysregulation of the RAS-nitrogen-activated protein kinase (MAPK) signal pathway, leading to variable cognitive impairment, cardiac defects, face dysmorphism, and short stature [14]. The treatment for short stature in Noonan syndrome patients varies from patients being treated growth hormone deficiency. Both growth hormone deficiency and insensitivity play a role in stature in Noonan syndrome, whereas, insufficient GH secretion is the primary issue in classic GHD [15, 16]. The dose for recombinant human GH in Noonan Syndrome is typically higher (up to 0.066 mg/kg/day) compared to for GH deficieincy (0.024–0.034 mg/kg/day) [17]. In 2023, Sodero et al. analyzed the use of GH therapy in pediatric SD deviation of height among treated subjects, with a range of minimum increase of 0.05 to a maximum of 3.2 SD [18]. The study also reported no side effects in 30 of the 43 studies, while the others (n = 13) had complications mostly from discontinuation of therapy. The most severe side effects seen through the literature review were new onset intracranial or spinal tumors, and recurrence of a previous bone tumor in one case [19].

3.2 Neurology

Neurological adverse effects of GH use in children are generally rare but can be significant when they do occur. GH treatment may increase intracranial and intraocular pressure (IOP) due to fluid retention and increased CSF production, leading to pseudotumor cerebri, or in milder cases: headache, paresthesias or hypoesthesia. GH treatment also causes soft tissue swelling and vasodilation, which may lead to nerve compression, causing various syndromes depending on which nerve is compressed.

In 2011 Stalvey et al. conducted a multicenter, open-label, controlled clinical trial to evaluate the safety and efficacy of GH therapy in children with cystic fibrosis (CF), a condition strongly associated with reduced lean body mass, poor weight gain, and short stature [20]. A total of 68 prepubertal children were randomized into two groups: one receiving daily subcutaneous GH at a dose of 0.043 mg/kg, and a control group that did not receive GH. The study spanned 18 months, with GH treatment discontinued after 12 months. Children in the GH-treated group showed significant improvements in height (p < 0.001), weight (p = 0.0356), and lean body mass (p = 0.0002) compared to controls, who exhibited no comparable increases [11]. The findings suggest that GH therapy may offer beneficial growth outcomes in prepubertal children with CF. Adverse events were reported in all GH-treated patients and 97% of controls, though most were unrelated to GH therapy. In the GH group, seven patients experienced injection site reactions, five reported hyperglycemia, and one discontinued treatment due to papilledema with suspected benign intracranial hypertension [11]. Although papilledema is a potential medical emergency due to the risk of brain herniation, its relationship to GH therapy remains uncertain, as it could be idiopathic or related to the underlying disease. Overall, GH administration demonstrated an acceptable safety profile in children with CF in this study. It also shows the importance of monitoring hypertension in these patients to avoid development of possible intracranial hypertension.

In 2011, López-Siguero et al. conducted a multicenter, open-label, phase 3 clinical study involving 70 children with GHD (44 males, 26 females), who received a daily subcutaneous dose of 0.033 mg/kg of GH for two years [7]. A significant increase in height, height velocity, and IGF-1 and IGFBP-2 concentrations was demonstrated in comparison to their baselines (p < 0.05). The study reported a total of 426 adverse events throughout the duration of the study, and 55 of the 70 patients experienced one or more adverse events. However, 94% of the reported events were not considered to be related to the administration of GH. There were 17 adverse events in 10 patients that were drug-related, but were all considered mild events. Drug-related adverse events related to neurology included myopia, headache, migraine. With an incidence rate of 0.066 for drug-related adverse events over the duration of this study, GH treatment in Spanish GHD children was considered both well-tolerated and effective to treat GHD in this study [12].

In an observational 2012 study by Tai et al., 1229 Japanese children with GHD along with 90 Japanese girls with Turner’s Syndrome (TS) received GH [21]. For a three period, the mean administered dose for children with GHD or TS was 0.19 mg/kg/week or 0.33 mg/kg/week, respectively. Within the GHD and TS groups, mean height SDS and height velocity increased each year from − 2.73 (0.63) SD and − 2.71 (0.63) SD at study entry to − 2.22 (0.68) SD and − 2.20 (0.60) SD, although each successive year demonstrated a smaller increase compared to the initial year. Height velocity also increased with GH treatment. The incidence of adverse events was 0.1–3.0%. Adverse events of a serious nature were reported by 20 patients total, and two of which were attributed to GH including craniopharyngioma and neurofibroma [13]. This study showed that GH treatment in Japanese children with TS or GHD increased height and weight, with possible risks of developing intracranial tumors.

In a 2012 observational cohort study by Youngster et al., 58 children born with SGA, ISS, or GHD were recruited to evaluate a potential relationship between long-term GH therapy and increased IOP [22]. This study compared children with GH therapy (0.04 mg/kg/day for 31 months) to 24 children who did not receive any GH. This study not only demonstrated an association between increased IOP and GH therapy, but it also related the increase to the duration of treatment. The mean change of IOP was 3 mmHg (approximately 20%) across all groups, however these values remained normal range for age (mean ± 2 SDs) [14]. Increased IOP may lead to acute or chronic glaucoma, and while Youngster et al. did not directly elicit adverse effects in these 58 children, this study demonstrates the potential and pathophysiology for emergent ocular side effects in children.

Counts et al.’s 2013 open-label, multi-center, randomized study compared the standard dosage of GH’s weight-based treatment to a formula based dosage of GH in children with ISS [23]. The formula based group (n = 202; 144 boys, 58 girls) received GH regiment that was derived for their individual serum concentrations, and doses ranged from 0.18 to 0.7 mg/kg/week. The standard dosage (n = 114; 83 boys, 31 girls) was administered at 0.37 mg/kg/week. By the end of the second year, no significant differences were demonstrated between the two groups. Treatment-related adverse events occurred at a slightly higher rate in the formula-based group (30%) compared to the standard dosage group (24%). Dosages were subsequently reduced in some of the patients in the formula-based group because of minor adverse events, including dizziness, hallucinations, disorientation, and diplopia; the study did not report the specific number of patients that experienced the adverse events. No reductions in dose were necessary in the standard dose group. This study showed that the standard GH dosage and the individualized, formula-based GH dosing regimen had no difference in height gain at the end of two years, and carries risks of neuropsychiatric symptoms at higher doses.

In Jensen et al.’s RCT in 2014, 92 SGA born children were randomized to receive one year of daily administration of subcutaneous GH treatment in the following doses: high dose (67 μg/kg), low dose (35 μg/kg), or IGF-1 titration (tailoring GH dose to upper limit of IGF-1 baseline levels) [24]. The purpose of this was to compare IGF-1 titration alongside with GH administration. After two years, the high-dose group increased in weight (p = 0.002) and height (p < 0.0001) in contrast to the other groups, while IGF-1 and IGFBP-3 were much lower within the titration group (1.16 ± 1.24) in contrast to the GH groups (low: 1.76 ± 1.48; high: 2.97 ± 1.63). The study concluded that IGF-1 titration was not as effective as the GH treatments. Additionally, the high dose GH group reported two adverse events, including one case of torticollis and one case of a child with cerebral palsy who developed epilepsy. In the IGF-1 titration group, there was one case of scoliosis/idiopathic arthritis, another case with viral meningitis, and one case with a requirement for a reoperation of hypospadias. The study’s discussion did not state the relevance of GH therapy to the adverse events [16]. The study showed that IGF-1 titration of GH dosing led to lower growth in SGA children than standard GH administration, but avoids possible risks of musculoskeletal side effects that come with the higher GH dosing.

In a 2015 randomized, multicenter, open-label, parallel-group, active treatment-controlled trial, Backeljauw et al. consented 106 (80% male) pre-pubertal children to be randomly assigned into one of four groups for a three-year study: (A) 45 μg/kg/day GH, (B) 45 μg/kg/day GH + 50 μg/kg/day IGF-1, (C) 45 μg/kg/day GH + 100 μg/kg/day IGF-1, or (D) 45 μg/kg/day GH + 150 μg/kg/day IGF-1 [25]. The study was performed to evaluate the potential benefits of combination therapy of GH and IGF-1 for children of short stature. The change of height was significantly increased between Groups C (p < 0.05) and D (p < 0.001) in comparison to GH alone by the conclusion of the first year. All groups had an increase in BMI after the third year compared to baseline. In all groups, IGF-1 and IGFBP-3 increased, but this was not in a dose-dependent manner. Each patient within Backeljauw’s study reported having at least one treatment adverse event, and the majority experienced minor to moderate effects. The event most reported in all groups was a headache, and this was reported the earliest in the GH and IGF-1 combination groups. Two SAEs were reported, including an 11-year old male in Group D who developed papilledema and intracranial pressure after treatment for 6 weeks. The administration of GH was then suspended for seventy days, and it was restarted with no further complications. The second SAE was a 7-year old female in Group C that presented with intracranial hypertension. She was hospitalized, and treatment was stopped for 14 days until the symptoms subsided; treatment restarted with no further complications [17]. This study showed that coadministration of rhGH and rhIGF-1 together led to a greater linear growth in short children when compared with rhGH alone, with the increased risk of developing intracranial hypertension.

During Quigley et al.’s 2021 10-year observational extension study to assess safety during long-term GH treatment, one girl reported headache. Otherwise, no children reported neurological adverse effects, and overall was well tolerated from a neurological perspective [8]. This study shows that GH treatment, especially when initiated early, can promote growth and enable achievement of adult height with neurological tolerance in children of TS.

Cheng et al.’s 2022 Phase 3, single-arm, self-controlled study studied the value of rhGH treatment in mental development and in motor function in infants and young children with PWS [9]. One subject reported seizures, deemed unrelated to rhGH treatment. Overall, rhGH was well tolerated in infants and young children with PWS [9]. This study showed treatment with rhGH improved growth and mental development, especially in children < 9 months old, but clinicians should maintain vigilance for development of seizures.

Horikawa et al. in 2022 conducted an open-label, randomized, active-controlled Phase 3 study to evaluate the efficacy and safety of once-weekly somatrogon, a glycosylated hybrid protein between GH and human chorionic gonadotropin, compared to once-daily Genotropin (somatropin, rhGH) in prepubertal Japanese children with GHD [26]. A total of 44 children (boys: 3 to < 11 years; girls: 3 to < 10 years) were randomized 1:1 to receive either once-weekly somatrogon (n = 22) with an initial six-week dose escalation (0.25, 0.48, and 0.66 mg/kg/week) followed by 46 weeks at 0.66 mg/kg/week, or once-daily Genotropin (n = 21, 0.025 mg/kg/day) for 12 months. The primary endpoint was annualized height velocity (HV) at 12 months [18]. Baseline characteristics were comparable between groups [18]. At 12 months, the least-squares mean HV was significantly higher in the somatrogon group (9.65 cm/year) compared to the Genotropin group (7.87 cm/year). The mean treatment difference (somatrogon–Genotropin) was + 1.79 cm/year (95% CI, 0.97–2.61), exceeding the preestablished noninferiority margin (− 1.8 cm/year). Safety and tolerability were similar between the two groups, with most adverse events classified as mild to moderate. One patient in the somatrogon group reported hypoparathyroidism. Both groups experienced injection-site pain, though it was more frequently reported with somatrogon [18]. This study showed that in Japanese children with GHD, weekly somatrogon achieved the same effects as daily GH at 12 months, with similar safety profiles.

In 2022 Deal et al. conducted a multicenter, open-label, randomized, active-controlled phase 3 trial to evaluate the efficacy and safety of once-weekly somatrogon compared to once-daily somatropin in prepubertal children with GHD [19]. A total of 224 children (boys aged 3–11 years; girls aged 3–10 years) were randomized 1:1 to receive either somatrogon (0.66 mg/kg/week; n = 109) or somatropin (0.24 mg/kg/week; n = 115) for 12 months. The primary endpoint was annualized HV at 12 months [27]. At 12 months, the least-squares mean HV was 10.10 cm/year in the somatrogon group and 9.78 cm/year in the somatropin group, with a treatment difference of 0.33 cm/year (95% CI: − 0.24, 0.89) [19]. The lower bound of the confidence interval exceeded the prespecified noninferiority margin (− 1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon compared to daily somatropin. Additional growth parameters, including HV at 6 months and change in height standard deviation score (HT-SDS) at 6 and 12 months, were similar between groups [19]. Both treatments were well tolerated, with comparable rates of treatment-emergent adverse events (TEAEs) in the somatrogon (87.2%) and somatropin (84.3%) groups, most of which were mild to moderate [19]. The most common TEAEs included injection-site pain, nasopharyngitis, headache, pyrexia, cough, and vomiting. Severe TEAEs were reported in 8.3% of somatrogon-treated and 5.2% of somatropin-treated subjects. Headaches occurred in 16.5% of the somatrogon group and 21.7% of the somatropin group, with no increased risk of neurological complications associated with somatrogon use. SAEs were rare (somatrogon: 2.8%; somatropin: 1.7%), and none were deemed treatment-related. Somatrogon usage did not correlate with an increased risk of neurologic complications, as compared to somatropin [19]. Overall, this study showed weekly somatrogon was noninferior to daily somatropin in prepubertal children with GHD, with similar side effect profiles.

3.3 Musculoskeletal

GH treatment in children has been associated with adverse musculoskeletal effects in children. Common TRAE include transient arthralgia (joint pain), myalgia (muscle pain), and edema. More serious but less common side effects include slipped capital femoral epiphysis (SCFE) and scoliosis. Carpal tunnel syndrome and other nerve compression syndromes are even rarer. Many of these side effects are considered to be linked to the accelerated growth children administrated GH undergo. A non-randomized prospective study 2011 study by Lin-Su et al. was conducted to assess the effect of GH or GH/LHRHa (luteinizing hormone releasing hormone analog) therapy on growth in children with congenital adrenal hyperplasia (CAH; n = 34) [28]. Patients were initially administered daily subcutaneous injections of the study drugs with a dose of 0.3 mg/kg/week, which was later adjusted based on height velocity to a maximal dose of 0.45 mg/kg/week. Treatment was sustained to the point that adult height was reached; the average time of GH treatment was 5.6 and 4.5 years for males and females, respectively. There was no differences found in patients who were given GH/LHRHa treatment compared with those who were given GH alone. There was one occurrence of the development of bilateral carpal tunnel syndrome due to the GH that was resolved within one week after stopping treatment [20]. Overall, this study showed GH with LHRHa improved final adult height in patients with CAH, with a good side effect profile.

In a 2011 study by Tanaka et al., 96 children with short stature due to being born SGA were randomized into three groups: a control group, a 33 μg/kg/day GH group, and a 67 μg/kg/day GH group [29]. The control group was observed for 52 weeks, while the GH groups were treated for 104 weeks. After 52 weeks, the control group was switched to GH therapy for an additional 156 weeks. At the study’s conclusion, after 208 weeks, the 33 μg/kg/day and 67 μg/kg/day GH groups showed a significant increase in height SDS of 1.01 and 1.99, respectively (p < 0.042, p < 0.0001). Long-term GH therapy effectively improved height, with a dose-dependent response observed, as the 67 μg/kg/day group showed a greater height gain compared to the 33 μg/kg/day group. Most adverse events were mild-to-moderate musculoskeletal or connective tissue issues, such as arthralgia and extremity pain, which were more common in the high-dose group. No data were supplied in the study as to the exact numbers of adverse events or their significance. IGF-1 levels increased significantly in the 67 μg/kg/day group but remained within the normal range (p = 0.0114). No participants developed Type 1 diabetes (T1DM), although there were slight increases in Hemoglobin A1c (HbA1c) and blood glucose levels over time [21]. Overall, long term GH treatment was well tolerated with only asymptomatic hyperglycemia, and improved height in children born with SGA.

In the 2012 study by Tai et al., 1229 Japanese children with GHD were administered 0.19 mg/kg/week of GH for approximately 3 years [13]. Joint pain was reported by 18 participants and was considered a mild and common side effect of GH therapy [13]. This study showed that GH treatment in Japanese children with TS or GHD increased height and weight, with joint pains possibly occurring from the accelerated growth.

In a 2013 open-labeled retrospective study, Meinhardt et al. assessed the efficacy and safety of growth hormone treatment in 41 children with PWS, aged 0–12 years old, who were treated with subcutaneous GH at an average dose of 0.03 mg/kg/day for a mean duration of four years [30]. Height, weight, and body composition measurements were compared using SDS. After 12 months of treatment, children experienced significant improvements in height (0.9 SDS [0.2 SD], p < 0.0001) and lean body mass (9.1%, p = 0.019), while body fat decreased by approximately 9.1%. At the final observation, approximately six years later, height gain was 1.3 SDS (0.3 SD) (p = 0.0001). One hundred and twenty eight adverse events were reported, of which only 33 were considered related to treatment. These treatment-related adverse events included eight diagnosis of scoliosis; of which seven were considered not to be serious [22]. This study showed long-term GH treatment of PWS children improved height and body composition, and was well-tolerated. However, close monitoring for scoliosis may be warranted.

A 2013 randomized, multicenter, parallel group study by Jensen et al. followed 111 SGA children who received 67 μg/kg/day GH for a one year duration [31]. The study examined the effect of GH on insulin and glucose metabolism. By the end of this study, an elevation in fasting levels of insulin (p = 0.015) and c-peptide (p = 0.009) in most patients was observed, signifying a general reduction in insulin sensitivity (p = 0.006). These increases were accompanied by elevations in fasting blood glucose (FBG, p < 0.0001) and HbA1C levels (p = 0.008). Treatment-related adverse effects included painful extremities, limping, scoliosis (n = 5), hypertrophy of adenoid tissue or tonsils (n = 4), and periorbital puffiness (n = 3). These effects resolved without treatment [23]. This study shows baseline IGF-1 levels were associated with insulin sensitivity and the response to IGF-1 was associated with insulin secretion, but were accompanied by tissue swelling and joint/extremity pains.

In an 8-month long non-blinded, randomized 2013 study by Bacchetta et al., 36 end-stage renal disease patients were followed to assess the skeletal consequences of GH in children undergoing dialysis [32]. This study evaluated the effects of GH therapy (0.05 μg/kg/day) on bone turnover and growth in pediatric dialysis patients with end-stage renal disease (ESRD). It found that GH therapy increased height and bone formation rates, irrespective of underlying bone histologic features, while disrupting the relationship between parathyroid hormone levels and bone turnover. During the study, eight hypercalcemic and eight hyperphosphatemic adverse events were reported in patients undergoing GH therapy [24]. This study demonstrates that the addition of GH therapy to pediatric renal osteodystrophy may discourage adynamic bone formation but may also contribute to the development of hyperparathyroidism.

Blum et al.’s 2013 prospective, multinational, open-label, randomized study examined GH administration (0.05 mg/kg daily) in children with a short-stature homeobox containing gene deficiency (SHOXd, n = 49) and in children with TS (n = 24) for two years [33]. Three groups were established with a two-phase control period and an extension period: SHOXd patients who did not receive GH in control period, SHOXd patients who received GH, and TS patients who received GH in the control period. Two serious adverse musculoskeletal events attributed to GH treatment occurred–enlargement of bones in hands/feet and scoliosis [25]. Several children also reported arthralgias, which were considered related to GH treatment. This study shows that GH treatment in SHOX deficient children was as effective as that in children with TS, with a favorable side effect profile.

The 2013 study by Counts et al. was completed to compare the standard weight-based dose of GH to formula-based GH regimen in children with ISS [15]. Treatment-related adverse events included 2 cases of skeletal dysplasia that were found in the formula-based group due to GH. Dosages were reduced in some of the patients in the formula-based group due to other adverse events including one case of carpal tunnel that was deemed due to treatment with GH [15]. This study showed that the standard GH dosage and the individualized, formula-based GH dosing regimen had no difference in height gain at the end of two years.

A 3-year open label interventional study by Pinto et al. in 2014 was performed with the intention of evaluating the efficacy and safety of GH therapy (0.053 mg/kg/day) in 19 children with hypochondroplasia (HCH) in comparison to a cohort study of children with HCH [34]. All 19 participants had a starting height of ≤ 2 SDS. By the conclusion of the study, the final mean height among the 19 participants was + 1.78 SDS in comparison to the untreated cohort (p < 0.05). The SDS of IGF-1 were initially amongst the low normal range and increased to the high normal range by the end of the study. Amongst the patients receiving therapy, 3 developed scoliosis and 4 developed genu varum. Genu varum, or bow-legs, is a condition characterized by an outward curvature of the legs, causing the knees to remain apart while the feet and ankles touch when standing. It is often physiologic in infants and young children, resolving naturally by age 3–4, but can result in conditions like rickets, Blount’s disease, or growth plate abnormalities [26]. Orthopedic events could be linked to GH treatment; however, these events are also reported to have happened in the HCH population in general. This study shows that rhGH treatment is effective in HCH patients in improving growth, but the effects must be carefully titrated to each patient to avoid musculoskeletal adverse effects that result from accelerated growth such as scoliosis or genu varum.

In Jensen et al.’s 2014 study, 92 children (61 male; 31 female) who born SGA were selected and randomized into high-dose, low-dose, or IGF-1 titrated groups for one year [16]. The titrated group included one patient who developed scoliosis/idiopathic arthritis. The discussion in the research did not claim any relevance of GH therapy to the adverse events [16]. The study showed that IGF-1 titration of GH dosing led to a lower growth in SGA children than those with standard GH administration, with possible scoliosis risk.

During Quigley et al.’s 2021 10-year observational extension study to assess safety during long-term GH treatment, 21 girls out of 69 in total (30.4%) reported scoliosis [8]. Two of those were SAEs, where the girls required surgery to correct the scoliosis. The study authors did not remark on whether they considered this to be related to GH treatment [8]. While scoliosis has been noted as a potential adverse effect of growth hormone treatment, patients with TS already have an elevated risk of developing scoliosis. This study shows that GH treatment, especially when initiated early, can promote growth and enable achievement of adult height in girls with TS, however clinicians should screen for scoliosis, as GH treatment may be linked to developing scoliosis on top of TS patients’ already elevated baseline risk of scoliosis.

In a 2022 multicenter, randomized, controlled, open-label Phase 3 study, Yuan et al. randomized 3:1 to daily somatropin 0.05 mg/kg/day or no treatment for 52 weeks [35]. The study investigated the efficacy and safety of daily rhGH (somatropin) in prepubertal children with ISS (n = 481) over 52 weeks. It demonstrated significant improvements in height standard deviation scores, height velocity, and IGF-1 levels in the treatment group compared to controls (p < 0.001), with a favorable safety profile and most adverse events being mild to moderate. A total of 481 subjects with a mean baseline age of 5.8 years were enrolled in the study. Drug-related adverse events were reported in 23 subjects (6.4%), with scoliosis (n = 3), elevated thyroid-simulating hormone (TSH, n = 4), elevated blood glucose (n = 2), rash (n = 2), hypersensitivity (n = 1), and hypothyroidism (n = 1) among the observed events. All of the subjects but the three reporting the hypothyroidism, scoliosis and extremity pain recovered from the treatment-related adverse events. The authors did not specify why these adverse events may have happened [27]. Possible etiologies include accelerated growth from GH causing pain and scoliosis, and increased conversion of T4 to T3 or GH-induced suppression of TSH secretion causing hypothyroidism. This study shows that daily somatropin improved growth outcomes in Chinese children with ISS, but were associated with mild musculoskeletal effects.

In 2022, Saem Choi et al. conducted a single-center, open label, RCT to assess whether 12 months of long-acting GH (LAGH) treatment affects nocturnal endogeneous GH secretion, metabolic consequences, and treatment efficacy in patients with idiopathic short stature (ISS) [36]. The study included 9 GH-naïve prepubertal children, randomized 1:1 to receive either daily GH (0.37 mg/kg/weeks) or once-weekly LAGH (0.7 mg/kg/week) for 12 months. Nocturnal endogenous GH secretory profiles, including mean serum GH concentrations, frequency, amplitude, and mass of GH released per burst, remained unchanged in both groups. One child in the LAGH group reported a left humerus fracture and one child in the daily GH group reported abdominal pain, but both considered not related to treatment [28]. This study showed that LAGH does not suppress endogenous GH secretion, and that GH treatment can be used for non-GH deficient short stature, with a favorable safety effect profile.

In a 2022 study, Horikawa et al. randomized 44 prepubertal Japanese children with GHD (boys: 3 to < 11 years; girls: 3 to < 10 years) 1:1 to receive once-weekly somatrogon (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each; n = 22) or once-daily Genotropin (0.025 mg/kg/day; 12 months; n = 21) [18]. 72.7% of children in the somatrogon group reported injection site pain, and 13.6% of the Genotropin group reported injection-site pain [18]. This study showed that in Japanese children with GHD, weekly somatrogon achieved the same effects as daily GH at 12 months, with similar safety profiles.

The 2022 study by Deal et al., participants were randomized 1:1 to receive either once-weekly somatrogon (0.66 mg/kg/week; n = 109) or once-daily somatropin (0.24 mg/kg/week; n = 115) for 12 months [19]. 39% of the weekly group and 25% of the daily group developed injection site pain, and 4.6% of the weekly group and 7% of the daily group developed arthralgias [19]. Overall, this study showed weekly somatrogon was noninferior to daily somatropin in prepubertal children with GHD, although with a higher incidence of injection site pain in the weekly injection group.

A 2023 Phase 2, open-label, randomized, dose-finding, safety study, Zadik et al. compared three different once-weekly somatrogon doses (0.25, 0.48, or 0.66 mg/kg/week) in initially prepubertal children with GHD [37]. The study consisted of five periods. Periods I and II lasted 6 months each, while Periods III, IV, and V lasted 12 months each. In Periods I and II, 53 prepubertal children with GHD were randomized to receive either once-weekly somatrogon (0.25, 0.48, or 0.66 mg/kg/week) or once-daily Genotropin (0.034 mg/kg/day); 48 children continued into the open-label extension (OLE), which is a type of clinical trial designed to collect long-term safety and efficacy data after the initial randomized controlled trial, consisting of Period III (original somatrogon dose or Genotropin recipients randomized to somatrogon doses), Period IV (somatrogon 0.66 mg/kg/week), and Period V (prefilled somatrogon pen at the same dose). Two patients developed scoliosis, resulting in one patient being pulled from the study. One instance occurred in Period IV in year 4 and was considered to be related to study treatment. Another child developed osteochondrosis in Period V in year 1; however the study investigators considered this not related to study treatment. Another child developed injection-site bruising [29]. This study showed that five years of weekly somatrogon caused sustained improvement in height in children with GHD, and underscore the importance of monitoring patients for musculoskeletal complaints.

3.4 Neoplastic

A lengthy observation period is typically required to detect occurrences of cancer. Moreover, childhood tumors are often driven by genetic or chromosomal predispositions, making relatively short-term studies during the childhood unrevealing. It remains inconclusive whether GH administration has an impact on tumor growth, or if specific demographic variables influence the results of these studies. Future research with extensive long-term follow up periods are warranted to determine whether GH treatment causes neoplastic effects.

Blum et al.’s 2013 prospective, multinational, open-label, randomized study examined GH administration (0.05 mg/kg daily) in children with a short-stature homeobox containing gene deficiency (SHOXd, n = 49) and in children with TS (n = 24) for two years [25]. During the extended period, all groups received GH. 13 patients out of 73 experienced benign neoplasia’s (16 events of melanocytic nevi, papilloma, or epithelioma). There were no statistical differences between the adverse events recorded between SHOXd and TS patients [25]. This study suggests that there is no difference in risk for developing neoplasm between SHOX deficient children and TS deficient children when treated with GH.

Quigley et al.’s 2021 10-year observational extension study assessed safety during long-term GH treatment [8]. Four neoplastic events occurred: two SAEs, and two AEs. In the first case, an 11-year old girl with medulloblastoma after 11 months of GH treatment from 1 to 2 years old was initially treated with surgery, chemotherapy, and cranial irradiation. The second case occurred in the same child roughly 2.5 years later where she developed acute myeloblastic leukemia (AML); it was subsequently treated with chemotherapy. The patient died at age 13. The third neoplastic event was a primary mediastinal stage 1 ganglioneuroblastoma in a 7-year old girl who received GH from ages 1.5–2.2 years old. The fourth neoplasia was a tubulovillous adenoma of the colon in a 12-year old girl later found to have polyposis colis [8]. This study shows that GH treatment can coincide with development of tumors in patients who have already received chemotherapy/radiation. Thus, it is uncertain whether the GH treatment was a contributing factor in the children developing cancer.

In a 2022 study, Horikawa et al. randomized 44 prepubertal Japanese children with GHD (boys: 3 to < 11 years; girls: 3 to < 10 years) 1:1 to receive once-weekly somatrogon (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each; n = 22) or once-daily Genotropin (0.025 mg/kg/day; n = 21) for 12 months [18]. One child in the Genotropin group developed craniopharyngioma. This adverse event was considered by the investigators to be related to GH treatment, and the child was withdrawn from the study [18]. This study suggests that weekly somatrogon may contribute to developing craniopharyngioma in children with GHD.

3.5 Infection

The majority of adverse events related to infection reported in the literature were nasopharyngitis, influenza, and gastroenteritis, which are expected childhood diseases in the general population. While the frequencies and severity of these diseases may differ across the various study populations, it is important to note that they were not considered to be related to the treatments but rather to underlying medical conditions.

In Linglart et al.’s 2011 open-label, multicentre Phase 3 study, 61 girls below the age of 4 with TS were enrolled to examine the effects of GH (0.035 or 0.05 mg/kg/day for a four year period) [38]. Fifty-one cohort age-matched girls were used as a control group. Forty-seven girls out of 61 reported a total of 236 adverse events. The majority of adverse events (213 or 90%) were due to infectious diseases that are common for that age and sex. Ten adverse events were due to gastrointestinal (GI) disturbances. The study noted infections that were SAEs in the low dosage group: measles (n = 1), serous otitis (n = 1), IgG4 deficiency (n = 1). One patient in the standard dose group reported an SAE needing surgery: tonsillectomy/adenoidectomy (n = 1). This study concluded GH treatment is generally well tolerated, and infections accounted for the majority of adverse events [30]. However, the study authors discussed that it is difficult to determine the cause of infections and whether they are linked to GH administration, given many of these illnesses are common childhood illnesses.

In Kim et al.’s 2014 open-label, multicenter, interventional study, 36 prepubertal children (ages 5–12) with ISS were given GH (0.37 mg/kg/week, 6 days/week) [39]. The study was intended to evaluate the effectiveness of treatment as well as evaluation of adverse events for six months. Of the 36 subjects in the study, 23 of them reported having a total of 65 adverse events. The most commonly encountered adverse event was nasopharyngitis (23/65 events). Less frequent events reported were as following: hordeolum (n = 2), otitis media (n = 4), upper respiratory infection (n = 6), and urticaria (n = 2). None of these was considered to be related to GH treatment. There were not any SAEs reported, or significant changes in laboratory values of concern. Only pruritus at the injection site, which was reported twice by the same person, was deemed to be directly caused by GH administration and was subsequently resolved [31]. This study suggests GH treatment for 12 weeks increased IGF-1 level and improved quality of life (QOL) in patients with GHD, which has a favorable side effect profile.

In Quigley et al.’s 2021 10-year observational extension study to assess safety during long-term GH treatment, several adverse events involving infection were noted: one cellulitis, one gastroenteritis, and two pneumonia. These were deemed to be unrelated to GH treatment [8]. This study shows that GH treatment, especially when initiated early, can promote growth and enable achievement of adult height in girls with TS, and is well tolerated with a good safety profile.

In Cheng et al.’s 2022 Phase 3, single-arm, self-controlled study to evaluate the impact of rhGH therapy on mental development and motor function in infants and young children with PWS, several patients reported infectious pneumonia, all cases of which resolved, and sepsis, from which one child died. None of these events were deemed related to treatment [9]. This study showed treatment with rhGH improved growth and mental development, especially in children < 9 months old, and has a good safety effect profile in regards to infection.

In the 2022 Phase 3 study by Yuan et al., the most common treatment-emergent adverse events in the treatment group related to infection were upper respiratory tract infection (66.0%), fever (19.6%), cough (10.8%), bronchitis (5.5%), respiratory tract infection (7.2%), rhinitis (2.8%), and indigestion (2.5%) [27]. None of these were considered as being related to treatment. One subject withdrew from the study due to neutropenia, which was deemed unrelated to treatment [27]. This study shows that daily somatropin improved growth outcomes in Chinese children with ISS, with the vast majority of infectious adverse events being unrelated to treatment.

In the 2022 Saem Choi et al. conducted a single-center, open label RCT that aimed to determine whether 12-month treatment with LAGH in patients with idiopathic short stature has an effect on the nocturnal endogenous GH secretion, metabolic consequences, and efficacy [28]. In LAGH group, one child experienced fever, and two children reported hordeolum. In the daily GH group, two patients reported the common cold, one reported diarrhea, and one reported Influenza type B infection. All were considered unrelated to GH treatment [28]. This study showed that LAGH does not suppress endogenous GH secretion, and that GH treatment can be used for non-GH deficient short stature with a good safety event profile.

In a 2022 study, Horikawa et al. randomized prepubertal Japanese children with GHD to receive once-weekly somatrogon (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each; n = 22) or once-daily 21 kids Genotropin (0.025 mg/kg/day; n = 21) for 12 months [18]. One child in the somatrogon group reported influenza and febrile convulsion, but was not considered to be treatment related and did not cause the subject to be discontinued from the study [18]. This study showed that in Japanese children with GHD, weekly somatrogon achieved the same effects as daily GH at 12 months, with similar safety profiles.

In the 2023 Phase 2 study, Zadik et al. compared three different once-weekly somatrogon doses (0.25, 0.48, or 0.66 mg/kg/week) in initially prepubertal children with GHD [29]. 27.1% of patients reported upper respiratory tract infections, and 22.9% reported bronchitis, but both disease states were not considered to be related to study treatment [29].This study showed that five years of weekly somatrogon caused sustained improvement in height in children with GHD and was well tolerated.

3.6 Metabolic

Incidence of negative metabolic effects attributed to GH treatment have included pathologies such as hyperglycemia, hyperthyroidism, and Cushing’s syndrome. Other adverse reactions have been reported that might pertain to metabolic disorders caused by treatment such as nephropathy. The following studies discuss such associated adverse events amongst others.

In the 2011 Phase 3 clinical trial, López-Siguero et al. followed 70 children (n = 44 boys, n = 26 girls) with GHD enrolled in a 2-year clinical trial receiving a 0.033 mg/kg of GH daily [12]. Height, height velocity, IGF-1 levels, and IGFBP-2 levels demonstrated a significant increase at a four-year follow-up. In total, 426 adverse events were reported throughout the study’s duration, and 94% of the events were not considered to be related to the administration of GH. There were 17 adverse events in 10 patients which were drug-related, and all of them considered to be mild. Metabolic-related adverse events attributed to rhGH treatment included vomiting (n = 2), gastroenteritis (n = 1), hyperglycemia (n = 1) [12]. GH treatment in Spanish GHD children was considered effective and well-tolerated in this study, with only mild GI and metabolic disturbance.

The 2011 study by Stalvey et al. was designed to assess the efficacy and safety of GH therapy in children with cystic fibrosis [11]. Among the GH group, 10 patients reported events were related to GH, of which five patients had hyperglycemia, while seven patients experienced adverse reactions to injection site such as bruising. One patient discontinued the study after experiencing papilledema [11]. This study highlights that GH therapy may cause papilledema, a side effect that providers should monitor their population to prevent potential vision damage.

In the 2012 study by Tai et al., 1,229 Japanese children with GHD and 90 Japanese girls with TS were administered GH to investigate the efficiency and safety of the therapy [13]. The mean administered dose to children with GHD and TS was 0.19 mg/kg/week for 3 years and 0.33 mg/kg/week for 3 years, respectively. There were 54 treatment-related adverse events reported by 45 GHD patients, six of which developing hyperthyroidism. There was also one report of diabetes mellitus attributed to treatment [13]. This study showed that GH treatment in Japanese children with TS or GHD increased height and weight was associated with higher risk of metabolic side effects, such as hyperthyroidism or diabetes.

In a 2013 randomized controlled study by Simon et al., 30 patients on long-term glucocorticoid therapy were followed to assess the effects of rhGH (0.065 mg/kg/day, adjusted to maintain of serum IGF-1 levels at a SDS of + 2 on body composition [40]. The study included two groups: 15 patients began rhGH treatment at baseline, while the remaining 15 patients received delayed treatment starting 6 months later. After one year, patients in the treatment group showed a significant increases in height SDS (+ 0.2 vs. − 0.2, p = 0.003), lean mass (LM) (+ 7.3% vs. 0%, p = 0.002), and thigh muscle area (MA) (+ 8.8% vs. − 0.6%, p = 0.01). However, no significant improvements in the primary outcome, composite index of muscle strength, were observed (p = 0.07). One patient with nephrotic syndrome reported a headache, thought to be due to water retention. However, following a 2-week interruption of rhGH treatment, treatment was restarted without complication. Fasting and two-hour post load glycemia were increased after one year of treatment. Additionally, five patients developed impairment in glucose tolerance, but without progression to diabetes. GH treatment was overall considered to be well-tolerated in patients receiving long term steroids; rhGH increased height, lean mass, and thigh muscle area; however, muscle strength did not improve [32].

A 2013 prospective, dose-response study by Rogol et al. was conducted to observe the effects of GH therapy in GHD children over a period of 2 years [41]. Subjects (n = 111) were randomly placed into one of three groups: 25, 50, or 100 μg/kg of GH, and patients were studied up to two years post-administration. A significant increase in growth velocity and height in all three groups was demonstrated (p < 0.001). From this study, it was advised that children with GHD should not receive greater than 50 μg/kg of GH due to the statistical insignificance of efficacy. One incidence of hyperglycemia and one incidence of glycosuria were identified throughout the period of GH; however, the incidences were minimal and not related to the therapy at any of the doses [33]. This study found that rhGH promoted growth without altering the onset of puberty.

The 2013 study by Counts et al. compared the standard weight-based dose of GH to formula-based GH regimen in children with ISS [15]. Treatment-related events included impaired glucose tolerance in one individual of the standard treatment group. This AE was not confirmed to be directly due to the GH [15]. This study shows that rhGH treatment is effective in HCH patients in improving growth, but the effects must be titrated to each patient.

A 2013 randomized, controlled, open-labeled study by Hyldstrup et al. was conducted with the purpose of examining the effect of 24 months of GH therapy in bone mass and composition of young adults with childhood-onset GHD [42]. The study followed 160 patients who were randomized into two groups: GH (0.2 and 0.4 mg/day for males and females, respectively, n = 109), and control (n = 51). The dose was gradually elevated to 1.0 and 1.4 mg/day. Bone cortical thickness (p = 0.0001) and endosteal diameter (p < 0.001) demonstrated a significant increase for the GH group in comparison to matched controls. There were 254 adverse events reported by 53% of the study population. Approximately 14% of these events were likely associated with GH treatment. Two SAEs associated with the GH treatment were reported, one of which being recurrence of Cushing’s syndrome and the other being hypertensive hydrocephalus [34]. In summary, GH treatment promotes cortical bone thickening through endosteal bone growth.

A 2014 multinational RCT by Tinggaard et al. aimed to evaluate the effects of GH therapy with regards to female reproductive morphology and function [43]. The study followed 18 girls born with SGA who received one year of GH at a dose of 67 μg/kg/day, followed by a two-year period where subjects received 67–35 μg/kg/day or an IGF-I titrated dose. The parameters of height, weight, along with bone age were significantly increased for all groups who underwent 3 years of GH treatment for 3 years (p = 0.007). Uterine and ovarian volumes demonstrated an increase after one year and a significant increase after 3 years (p < 0.05). Follicles were detectable in 28% of females at baseline, 58% by year 1, 73% by year 2, and 69% by year 3. The baselines of detectable follicles, uterine size, and ovarian size, were all smaller than average. Two abnormalities in pubertal development occurred, warranting the need to monitor the pubertal development in SGA girls undergoing GH treatment. One female subject reported a multicystic ovary 2 years following GH treatment with no signs of pubertal onset. Another female subject developed precocious puberty who required an administration of a GnRH agonist. Onset of puberty was only found in 2/18 girls during the study [35]. Thus, pubertal development or long-term effects with GH therapy could not be evaluated. GH administration may reflect normalization of internal reproductive tracts. GH treatment promoted the growth of internal genitalia, although the size at the conclusion of the study was within normal limits.

In a 2014 randomized, double-blind, parallel-group trial by Kappelgaard et al., 65 Japanese children born SGA who ranged from 3 to 8 years old participated in a 104-week trial received injections of 33–67 μg/kg/day (n = 34 per group) [44]. An additional 156-week extension at the subjects’ assigned dose of GH was offered to the participants after the initial 104-week period concluded (n = 50). The study was meant was to evaluate the effect of GH on height over a 5-year period. After the 5-year period, the height SDS compared with baseline were significantly increased for both GH groups (p < 0.0001), which a larger increase in the patients who received 67 μg/kg/day. Positive impacts were also seen on IGF-1 and on lipid profiles. One male patient withdrew following 151 weeks undergoing 33 μg/kg/day on account of IgA nephropathy [36]. This was the only SAE deemed to be related to GH treatment; however, no mechanisms by which GH provokes IgA nephropathy have been demonstrated. Thus, it remains unclear if the serious event had direct causation from the GH therapy. Overall, GH treatment in children born SGA is effective with possible serious side effects, and has benefits on several metabolic parameters.

In Quigley et al.’s 2021 10-year observational extension study to assess safety during long-term GH treatment, thirteen SAEs were reported for 11 out of 69 subjects, who reported hypothyroidism [8]. FBG values were elevated (> 5.6 mmol/L) for eight of 67 subjects at extension baseline and for 9–21% subjects at various post-baseline visits. Insulin sensitivity was normal (values ≥ 0.30 on quantitative insulin sensitivity check index [QUICKI]) at baseline and year 1 of the extension for all but one subject. One female became hyperglycemic at the extension study’s baseline, with an abnormal oral glucose tolerance test (OGTT) and HbA1c of 6.1% and was later diagnosed with T1DM. Three girls with evidence of mildly impaired glucose tolerance were treated with metformin [8]. This study shows that GH treatment, especially when initiated early, can promote growth and enable achievement of adult height in girls with TS.

In a 2022 randomized, open-label study of 44 boys with obesity and nonalcoholic fatty liver disease (NAFLD), Xue et al. explored whether rhGH treatment could improve NAFLD in obese children [45]. Subjects were randomized and divided into the treatment group and the control group for six months. The rhGH group showed a significant decrease in C-reactive protein (CRP; 1.17 ± 0.76 vs. 2.26 ± 1.43 mg/L) and BMI SDS (2.28 ± 0.80 vs. 2.71 ± 0.61) than the control group (p = 0.003, p = 0.049, respectively). GH treatment also reduced low density lipoprotein cholesterol (LDL-C; 2.19 ± 0.42 vs. 2.61 ± 0.66 mmol/L; p = 0.016) and increased high density lipoprotein cholesterol (HDL-C; 1.30 vs. 1.15 mmol/L; p = 0.005); there were no changes in total cholesterol (TC), triglycerides (TG) and uric acid (UA) between the treatment group and the control group. At the end of the follow-ups, there were six participants in the treatment group and the control group with FBG above 6 mmol/L (three in the rhGH group, three in the control group). None of them exceeded 7 mmol/L, and no subject had a glucose level > 11.1 mmol/L at the 6 month’s OGTT. The HbA1c was below 6.5% of all participants in the treatment group and the control group. Two subjects in the rhGH group experienced the temporary hypothyroidism, which was found in the follow-up of 3 months of treatment or 6 months of rhGH treatment, respectively [37]. This study showed six months of rhGH may be beneficial for normalizing liver enzymes and improve cardiovascular profile in boys with obesity and NAFLD.

In the 2022 Phase 3, single-arm, self-controlled study conducted by Cheng et al., the value of rhGH treatment in mental development and motor function in infants and young children with PWS was evaluated [9]. Six subjects reported treatment-related adverse effects: one child with sleep apnea (who withdrew from the study), one child with elevated serum alkaline phosphatase, and four children with sleep apnea, adenoidal hypertrophy, elevated serum TSH, and hypothyroidism [9]. This study showed the treatment with rhGH improved growth and mental development, especially in children < 9 months old.

In the 2022 multicenter, randomized, controlled, open-label Phase 3 study by Yuan et al., 481 subjects were randomized 3:1 to daily somatropin 0.05 mg/kg/day or no treatment for 52 weeks [27]. Four children in the treatment group reported elevated TSH, and one had elevated blood glucose level. These were deemed to be related to GH treatment [27]. This study shows that daily somatropin improved growth outcomes in Chinese children with ISS.

In 2022, Saem Choi et al. conducted a single-center, open label, randomized clinical trial that aimed to determine whether 12-month treatment with LAGH patients with idiopathic short stature has an effect on the nocturnal endogenous GH secretion and metabolic consequences, and efficacy [28]. FBG and HbA1c showed a tendency to increase, although not significantly, after treatment. However, the HbA1c level at 12 months in the LAGH group increased significantly compared with that at baseline (p < 0.05), although it was still within the normal range. Lipid parameters, such as TC, LDL-c, HDL-c, and TG levels after treatment did not differ significantly from those at baseline in both the treatment groups. The results of the thyroid function test, with the exception of TSH, after treatment did not differ significantly from those at baseline in both the study groups. Serum levels of TSH at 6 months in the daily GH group decreased compared with those at baseline but were still within the normal range. Beyond these clinically silent metabolic changes, no other adverse events related to metabolism were noted, however the authors discussed the potential for adverse effects should these changes continue [28]. This study showed that LAGH does not suppress endogenous GH secretion, and that GH treatment can be used for non-GH deficient short stature, with no significant effects on metabolism.

In the 2022 study by Deal et al., participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week; n = 109) or once-daily somatropin (0.24 mg/kg/week; n = 115) for 12 months [19]. There were no cases of drug-induced liver function abnormalities in any subjects [19]. Overall, this study showed weekly somatrogon was noninferior to daily somatropin in prepubertal children with GHD, with no metabolic effects.

In the 2023 multicenter, randomized, open-label negative-controlled Phase 3 study, Tang et al. randomized prepubertal subjects 1:1 to either daily subcutaneous injections of rhGH 0.05 mg/kg/day or no treatment for 52 weeks to explore if GH injections would help pre-pubertal short children with CKD prior to transplantation [10]. Two children report elevated blood insulin, one reported glucosuria, and another reported abnormal hepatic function, all of which were considered related to study treatment. Further analysis on glucose metabolism indicated that there was no difference in terms of blood glucose and HbA1c between the treatment and untreated groups. Although blood insulin at week 52 in the treatment group was significantly higher compared with the untreated group (12.44 ± 6.46 vs. 9.49 ± 19.17; p = 0.006), it was still within the normal reference range [10]. In summary, a 52-week regimen of daily rhGH significantly improved growth parameters in Chinese children with CKD-induced growth retardation, with slight abnormalities in glucose metabolism that had no clinical effects in the short term [10].

In the 2023 Phase 2 clinical trial by Zadik et al., prepubertal children with GHD received one of three different once-weekly somatrogon doses (0.25, 0.48, or 0.66 mg/kg/week) [29]. One patient developed mild hypercholesterolemia, and this was determined to be related to study treatment. Measurements of glucose metabolism, thyroid status, cortisol levels, lipid parameters, and hematology/chemistry were within normal limits, similar to the findings from the main study [29]. This study showed that five years of weekly somatrogon caused sustained improvement in height in children with GHD, and was well tolerated with only slight metabolic abnormalities.

3.7 No adverse reactions reported

Several studies (in addition to our previously described literature) have explored the uses of GH treatment in a variety of conditions, both with and without GH deficiency. These studies have looked at the effects of GH replacement therapy in GHD children, each focusing on a different aspect that may be affected by GH treatment: metabolic parameters, correlation between increasing doses of GH and height, coagulation cascade, the dose-sparing effect and safety profile, sleep architecture, QOL, or the psychological impact of gaining height [46,47,48,49,50,51,52,53]. One study tested a novel weeklong formulation of GH [54]. However, no adverse events were reported for these studies.

Five studies involved the usage of GH in SGA children in regards to height, body composition/blood pressure/lipid profile with a high dose of GH, metabolic impact, or validated weight based dosing of GH treatment [55,56,57,58,59]. Six studies evaluated the usage of GH in novel uses such as weaning off parenteral nutrition in children with short bowel syndrome, X-linked hypophosphatemia, Turner syndrome, TS, Silver-Russell syndrome, and ISS [60,61,62,63,64,65,66]. Finally, six studies explored the benefits of GH in treating different aspects of PWS, such as energy expenditure, caloric intake and body composition, muscle thickness and motor strength when combined with physical training, body fat, vitality and behavioral problems when withdrawn, behavioral issues, intellectual disability; however no adverse events were reported for any of these studies [67,68,69,70,71,72].

All of the studies listed above did not specify adverse effects that occurred in the course of the study. There is no clear indication of how well-tolerated the GH treatments were in these patient populations as the safety profile was difficult to determine in these scenarios. Further areas of research into the value of GH treatment in various pediatric conditions should evaluate and include adverse effects.

4 Reports of adverse events in adults

4.1 Cardiovascular

It has been reported that patients with GH deficiency have an elevated risk of CV adverse events. This may be caused by the lack of anabolic effects of the missing hormone. Physiological levels of GH play a significant role in influencing the CV system by enhancing cardiac muscle mass and contractility and by regulating cholesterol metabolism and insulin sensitivity—these are factors that contribute to CV risk. Consequently, several recent studies have documented CV events and/or metabolic effects from GH administration. Derangement in blood glucose and insulin resistance was among the most notable events and effects, although not consistent throughout studies. Importantly, a low incidence rate of CV morbidity and mortality was observed overall.

A randomized, placebo-controlled crossover trial conducted by Nyström et al. in 2012 examined 60 adults with GHD who had been undergoing GH treatment for three years or more, with an average treatment duration of 10 years [73]. The trial lasted four months, during which participants received either GH or a placebo. The results showed a significant decrease in mean serum IGF-I levels, dropping from 168 ± 52 to 98 ± 47 μg per liter during the placebo phase (p < 0.001) [65]. QOL assessments revealed worsening in two domains—emotional reactions and positive well-being—evaluated through the Nottingham Health Profile and the Psychological General Well-Being questionnaires, with results showing significant declines during the placebo period compared to GH treatment (p < 0.05) [65]. Furthermore, waist circumference, subcutaneous fat, and visceral fat mass all increased during the placebo phase, while extracellular water and muscle area decreased (p < 0.05). CRP levels, along with TC, LDL-c, and HDL-c levels, also rose, although insulin sensitivity improved during the placebo period compared to GH treatment (p < 0.05). During the study, one participant experienced atrial fibrillation while on GH treatment, whereas two in the placebo group faced adverse CV events. Specifically, one control patient had an abdominal aortic aneurysm, and another experienced two episodes of atrial fibrillation [65]. These findings underscore that individuals with GHD are at an increased risk of adverse CV events and worsening psychological state, particularly during even a relatively short-term absence of GH, highlighting the significant lack of anabolic effects associated with growth hormone.

In 2012, Bredella et al. conducted a randomized, double-blind, placebo-controlled study to assess the effects of GH on body composition and CV risk markers in abdominally obese premenopausal women. A total of 79 obese premenopausal women were randomized to receive GH (n = 39) or placebo (n = 40) for six months. The primary endpoints were total abdominal fat (TAT), assessed via computed tomography (CT), and high-sensitivity C-reactive protein (hsCRP), a marker of CV risk. Participants in the GH group received a mean daily GH dose of 1.7 ± 0.1 mg, resulting in an increase in IGF-1 SDS from − 1.7 ± 0.08 at baseline to −0.1 ± 0.3 at six months [66]. GH administration led to significant reductions in TAT (p = 0.002) and hsCRP (p < 0.05) compared to placebo [66]. It also increased thigh muscle mass and lean body mass while reducing subcutaneous abdominal and trunk fat, tissue plasminogen activator (tPA), apolipoprotein B (apoB), and the apoB/LDL-c ratio. Within the GH group, visceral adipose tissue (VAT) decreased, while intramyocellular lipid (IMCL) content increased. Furthermore, the six-month change in IGF-1 levels was inversely correlated with reductions in both TAT and VAT. There were no significant differences between the GH and placebo groups regarding the incidence of mild edema (GH: 53.6% vs. placebo: 45.5%; p = 0.8) [74]. Overall, GH administration in abdominally obese premenopausal women led to beneficial changes in body composition and CV risk with mild side effects.

In 2012, Sacca et al. conducted a randomized, placebo-controlled, double-blind study to evaluate the effects of GH as an adjunct to riluzole in patients with amyotrophic lateral sclerosis (ALS), two-thirds of whom exhibit GHD. This study aimed to determine whether titrated GH supplementation could reduce neuronal loss in the motor cortex, decrease mortality, and improve motor function [75]. Patients aged 40–85 years (n = 40) with definite or probable ALS, disease duration of ≤ 3 years, and ongoing riluzole treatment were enrolled. GH was administered subcutaneously every other day, starting at 2 IU and increasing to a maximum of 8 IU (n = 20) while the other group received placebo (n = 20). The primary endpoint was the N-acetylaspartate/(creatine + choline; NAA/Cre + Cho) ratio in the motor cortex, measured via magnetic resonance spectroscopy at baseline, 6 months, and 12 months. Secondary endpoints included mortality and changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) [67]. The study found that the NAA/(Cre + Cho) ratio declined in all patients over the course of the trial, with no significant differences between the GH-treated and placebo groups [67]. GH treatment had no significant impact on cerebral NAA levels or ALS progression as measured by ALSFRS-R [67]. Three patients reported bilateral lower extremity edema, three patients reported hypertension, two patients reported an increase in FBG and 15 patients reported an increase in liver enzymes [67]. No remarks were given as to whether these adverse events occurred in the treatment or the placebo group, or whether they were related to treatment [67]. Overall, GH treatment had no effect on cerebral NAA or clinical progression of ALS, and may or may not be associated with significant side events.

In a randomized controlled single-blind study conducted by Cittadini et al. in 2013, the effects of GH replacement therapy on the progression of chronic heart failure (CHF) were investigated among a cohort of 56 patients [76]. Participants were randomly assigned in a 1:1 ratio, with one group receiving standard CHF treatment along with 0.012 mg/kg of GH every other day, while the control group received only the standard CHF therapy. After a four-year follow-up, assessments were conducted for 17 patients in the GH group and 14 in the control group [68]. Electrocardiographic evaluations indicated no significant differences between the two groups, and GH therapy did not affect primary biochemical or hormonal parameters, including thyroid hormone, testosterone, and HbA1c levels [68]. Notably, the GH group exhibited a two-fold increase in peak oxygen consumption by the four-year endpoint compared to the control group. Additionally, improvements in left ventricular (LV) systolic volume and ejection fraction (EF) were observed among those receiving GH therapy, with five individuals experiencing a 35% increase in EF, which eliminated the need for defibrillator implantation. Serum IGF-1 levels in the GH group also rose by 84%. Concerning safety, six patients in the GH group and ten in the control group died due to CV events. HbA1c levels increased from 7.3 ± 0.9% at baseline to 7.5 ± 1.2% after four years [68]. In patients with pre-existing cardiovascular disease, there was no observed increase in mortality, suggesting that GH may either potentially benefit in delaying the progression of CHF or have minimal impact on cardiovascular risk parameters over the four-year period.

In the 2013 prospective, single-center, open-label study by Elbornsson et al., the authors assessed the long-term CV risk in adults with GHD who had or had not undergone pituitary irradiation therapy (IRR) while receiving 10 years of GH replacement therapy. Eighteen IRR patients and 18 non-IRR patients received daily subcutaneous GH 0.33–0.5 mg/kg. At baseline, IRR patients exhibited a worse CV profile, with higher serum TG and insulin levels and lower HDL cholesterol (all p < 0.05). GH therapy improved body composition, bone mass, and lipid profiles in both groups. Of the IRR patients, two died (from a cardiac arrhythmia and a myocardial infarction, respectively). Two separate IRR patients suffered non-fatal MIs. One non-IRR patient suffered a cerebral infarction. Also, 2 of the 18 IRR patients had non-fatal MIs, and one non-IRR had a cerebral infarction. After 10 years of GH treatment, the CV risk profile of IRR patients improved, and was comparable to non-IRR patients; however, IRR patients remained at higher risk of vascular events, highlighting the need for close cardiovascular monitoring in this population [77].

In 2020, Otsuka et al. conducted a Phase 3, multicenter, randomized, parallel-group trial to assess the safety and efficacy of once-weekly somapacitan (a human growth hormone analog) compared to daily GH over 52 weeks in Japanese patients with adult growth hormone deficiency (A-GHD) [78]. Previously GH-treated patients were randomized in a 3:1 ratio to receive either somapacitan (n = 46) or daily GH (n = 16), with a 20-week dose titration period followed by 32 weeks of fixed-dose treatment. The mean (SD) prescribed doses after titration were 1.780 (1.058) mg/week for somapacitan and 0.197 (0.083) mg/day for daily GH. Adverse events were reported in 10 patients, with a total of 21 treatment-related effects, mostly nasopharyngitis and arthralgia. One patient in the daily GH arm was diagnosed with diabetes mellitus on day 236, with worsening glycemic parameters by week 52. Despite this, no other cardiovascular side effects were noted [70]. Overall, once-weekly somapacitan demonstrated comparable efficacy to daily GH, with a manageable cardiovascular safety profile, supporting its use as an alternative to daily GH in Japanese patients with A-GHD.

In a 2020 single-center, double-blind, placebo-controlled trial by Karason et al., 37 patients (mean age 66 years; 95% male) with ischemic heart failure (EF < 40%) were randomly assigned to receive either rhGH (1.4 mg every other day) or a placebo for nine months, followed by a three-month treatment-free follow-up period [79]. GH treatment began at 0.35 mg (1.05 IU) and was uptitrated over three weeks to a target dose of 1.4 mg (4.2 IU). Throughout the study no significant differences were observed in body weight, BMI, or FBG levels. SAEs occurred in five GH-treated patients (8 SAEs) and six control patients (27 SAEs). Of these, four in the GH group and 17 in the control group were linked to the pre-existing cardiac conditions and deemed unrelated to GH. One GH patient died from ventricular arrhythmia, and another discontinued treatment due to worsening heart failure. In the control group, one patient died from bile duct cancer, and another withdrew after an acute myocardial infarction. Additional adverse effects in the GH group included three cases of gout and one case of renal failure [71]. Consistent with prior findings by Cittadini et al., the GH group showed fewer SAEs, including mortality, than the control group. However, around 50% of SAEs could not be definitively classified as unrelated to GH, possibly due to differences in study populations, dosing methods, or due to Karason’s study being underpowered.

In a 2020 single-center, open-label, prospective study, Damen et al. investigated the effects of GH on glucose homeostasis and metabolic syndrome in 43 young adults with PWS previously treated with GH [80]. After reaching adult height, the GH dose was reduced from 1 mg/m2/day (~ 0.035 mg/kg/day) to 0.33 mg/m2/day (~ 0.012 mg/kg/day). Over three years, estimated mean FBG levels remained stable, from 4.6 (4.4–4.8) mmol/L at baseline to 4.7 (4.6–4.9) mmol/L (p = 0.07), as did fasting insulin levels, from 59.5 (45.2–75.8) pmol/L to 56.7 (45.2–69.6) pmol/L (p = 0.72). Other carbohydrate parameters remained stable, though FBG significantly increased after two years (4.8 [4.6–4.9] mmol/L vs. 4.6 [4.4–4.8] mmol/L, p = 0.018). At baseline, six patients had impaired glucose tolerance (IGT), increasing to 11 by the end of study. One developed T2DM symptomatic with polyuria and polydipsia, requiring treatment with metformin 500 mg BID, reducing fasting glucose to 6.6 mmol/L. Another patient recorded a 2-hour glucose level of 12.1 mmol/L at study end but had normal fasting glucose (4.4 mmol/L) and remained asymptomatic [72]. The prevalence of IGT or T2DM at three years did not significantly differ from baseline (p = 0.18) [72]. No significant changes were observed in blood pressure, total cholesterol, LDL, HDL, or triglycerides. However, patients with IGT/T2DM had a significantly higher mean fat mass percentage (43.3% vs. 36.6%, p = 0.02) [72]. These findings align with Bredella et al.‘s study on obese patients, suggesting glucose intolerance is exacerbated by underlying obesity and treatment with GH. However, the long-term cardiovascular impact of glucose intolerance in this population remains uncertain, due to a lack of longitudinal studies.

In a 2021 single-center, randomized, open-label clinical trial, van Bunderen et al. systematically compared the effects of different GH doses on body fat distribution and microcirculatory function [81]. The study included 30 participants whose IGF-1 levels had remained between − 1 and 1 SDS for at least a year. They were randomized to either reduce their GH dose or increase it over 24 weeks. In the low-dose (LD) group, median daily GH was significantly reduced from 0.25 mg (IQR 0.35) to 0.10 mg (IQR 0.15) (p < 0.001). In the high-dose (HD) group, it increased from 0.25 mg (IQR 0.30) to 0.50 mg (IQR 0.60) (p < 0.001) [73]. IGF-1 levels declined significantly in the LD group (21.40 ± 4.87 nmol/L to 12.43 ± 2.25 nmol/L, p < 0.001) and rose in the HD group (18.53 ± 2.77 nmol/L to 28.13 ± 5.15 nmol/L, p < 0.001) [73]. Higher IGF-1 levels were significantly associated with increased waist circumference (p = 0.05) and insulin resistance (p = 0.03). In the HD group, insulin resistance rose significantly from 0.79 to 1.12 (p = 0.01), while no significant change was observed in the LD group (0.74 to 0.80, p = 0.24). Between-group comparisons also showed a significant difference in insulin resistance (p = 0.03) and insulin levels (from 43/42 to 40/62 pmol/L, p = 0.01). No significant differences were observed in BMI, fasting glucose, lipid profile (TC, HDL-c, LDL-c, TG, free fatty acids), blood pressure, or cardiac index [73]. This study shows a correlation between high-dose GH and increasing insulin resistance without significant clinical sequelae. Long-term cardiovascular impact remains unclear, however, as this study did not focus on side effects, and had no longer-term followup.

In a 2023 six-month randomized, double-blind, placebo-controlled trial, Dichtel et al. evaluated the effects of low-dose GH on NAFLD [82]. The study involved 53 adults (BMI ≥ 25 kg/m2) with NAFLD but without diabetes mellitus, randomized to receive either daily subcutaneous GH (0.2 mg/day for men, 0.3 mg/day for women) or a placebo, targeting IGF-1 levels in the upper normal quartile. Of the 41 participants who completed the trial (20 GH, 21 placebo), those in the GH group experienced a higher incidence of mild lower extremity edema (21% vs. 0%, p = 0.02) [74]. No significant differences were observed between groups in BMI, lean body mass, lipid levels, glycemic measures, or insulin resistance (assessed via HbA1c, FBG, and HOMA-IR) [74]. This study did not reveal any significant impact in metabolic parameters after GH treatment in patients with NAFLD, with a significant side effect of lower extremity edema. No other immediate cardiovascular risks were identified.

4.2 Neurology

GH administration in adults has also been associated with adverse neurological events in adults. Such events have ranged from mild side effects such as headaches, dizziness, and paresthesia to more serious adverse consequences including cerebral infarction.

In a 2012 multicenter, placebo-controlled study, Cuatrecasas et al. evaluated the efficacy of administering 0.006 mg/kg/day of GH in adults with fibromyalgia and low IGF-1 levels [83]. The study included 120 patients randomized 1:1 into two groups. Group A (n = 60) received GH alongside standard fibromyalgia treatment for six months, while Group B (n = 60) received a placebo. From months 7–12, both groups received GH. No significant differences were observed at six months; however, by month 12, Group A showed a significant reduction in the number of tender points (p < 0.05). After 12 months, 53% of Group A and 33% of Group B had fewer than 11 tender points, with this difference persisting at 18 months. QOL declined in both groups following GH withdrawal. IGF-1 levels were significantly higher in Group A until month 7, after which both groups had comparable levels [75]. Group A showed a greater reduction in mean tender points (40% vs. 28%, p = 0.07) and significantly lower pain intensity (5.2 ± 0.72 vs. 6.21 ± 0.56, p = 0.03) [75]. QOL improvements were also greater in Group A, reflected in the Fibromyalgia Impact Questionnaire (FIQ) score (53 ± 6.5 vs. 65 ± 6.5, p = 0.02), EQ-5D score (9.09 ± 0.64 vs. 9.94 ± 0.56, p = 0.047), and Visual Analog Scale (VAS) score (45 ± 6.9 vs. 60.6 ± 6, p = 0.01) [75]. A total of 432 adverse events were reported, mostly unrelated to treatment and consistent with fibromyalgia symptoms (e.g., pain, insomnia, and impaired work ability) [75]. Drug-related adverse events were more frequent in Group A versus Group B, including carpal tunnel syndrome (3.3% vs. 1.7%), paresthesias (5.8% vs. 1.7%), peripheral edema (8.7% vs. 3.4%), and headache (8.3% vs. 11.6%) [75]. This study suggests that GH therapy may improve pain and QOL in fibromyalgia patients with low IGF-1, with mild drug-related adverse events.

The 2012 double-blind, placebo-controlled RCT by Bredella et al. intended to assess the effects of GH on body composition and CV risk markers in abdominally obese premenopausal women [66]. There were no significant differences between the GH and placebo groups regarding the incidence of headache (GH: 35.7% vs. placebo: 36.4%; p = 1.00), or intermittent mild hand paresthesias (GH: 50.0% vs. placebo: 22.7%; p = 0.08) [66]. Overall, GH administration in abdominally obese premenopausal women led to beneficial changes in body composition and CV risk with an acceptable safety profile.

Sacca et al. conducted a randomized, placebo-controlled, double-blind study in 2012 to evaluate the effects of GH as an adjunct to riluzole in patients with ALS, two-thirds of whom exhibit GHD [67]. Two patients reported limb weakness [67]. Overall, GH treatment had no effect on cerebral NAA or clinical progression of ALS.

In Elbornsson et al.’s study in 2013, subcutaneous GH doses of 0.33-0.05 mg/kg were administered to patients undergoing pituitary irradiation therapy [69]. One seventy-five year old patient died due to a fatal MI after nine years of treatment. Three patients had non-fatal MI after 2, 3, and 5 years. These adverse events were not considered to be due to GH treatment, but rather due to radiation-induced angiopathy, which is a known risk factor for stroke [69]. Patients who underwent IRR had increased impairment of their cardiovascular risk profile in comparison with non-IRR patients.

In 2011 and 2013, Biller et al. conducted a 26-week extension of a previous study on LB03002, a long-acting GH analog administered subcutaneously once per week, in adults with GHD [84, 85]. The original 26-week, double-blind, placebo-controlled trial included 147 adults randomized to receive either GH or placebo. Participants started with an average dose of 2 mg/week (3 mg/week for females on oral estrogen), which increased by week 26 to 4.31 mg/week for males, 4.34 mg/week for females, and 6.45 mg/week for females on oral estrogen [84, 85]. Following the initial trial, 136 patients continued in the extension phase. The placebo group switched to GH treatment (switched group), while the original GH group maintained treatment (throughout group). Over 26 and 52 weeks, GH therapy significantly reduced fat mass (FM) in both groups: −1.11 kg (± 1.95) in the switched group (p = 0.001) and − 1.06 kg (± 3.16) in the throughout group (p = 0.002). GH treatment also sustained increases in lean body mass (LBM), serum IGF-1, and IGFBP-3 levels achieved during the first 26 weeks [76, 77]. GH-related adverse events were mostly mild or self-resolving. Headaches were reported in 3.2% of the throughout group and 21.4% of the switched group [76, 77]. Overall, long-term weekly GH administration was effective in reducing FM, increasing LBM, and maintaining elevated IGF-1 levels, with a favorable safety profile.

A 2014 multicenter, open-label, single-group Phase 4 clinical trial by Kim et al. was performed to assess the QOL, efficacy, and safety associated with a weekly injection of GH as compared to daily injections [31]. The study included 131 adult patients over a course of 12 weeks with growth hormone deficiency. After 12 weeks, serum IGF-1 levels (p = 0.0111) and QOL (p < 0.0001) both significantly increased. Drug-related side effects deemed related to treatment were headaches and dizziness in three cases and ocular hyperemia in one case. These side effects were mild, and resolved completely [31]. This study shows weekly GH injections are well tolerated, and provide a higher QOL than a daily injection.

4.3 Musculoskeletal

GH treatment has been associated with adverse musculoskeletal effects in adults. Adverse reactions reported include joint discomfort, myalgia, arthralgia, and fractures. This may be due to excessive bone and cartilage growth leading to inflammation and abnormal joint mechanics.

Sacca et al. conducted a placebo-controlled, double-blind RCT in 2012 to evaluate the effects of GH as an adjunct to riluzole in patients with ALS, two-thirds of whom exhibit GHD [67]. Ten patients reported joint swelling and stiffening, and two patients reported injection-site reactions [67]. Overall, GH treatment had no effect on cerebral NAA or clinical progression of ALS.

The 2012 double-blind, placebo-controlled RCT by Bredella et al. intended to assess the effects of GH on body composition and CV risk markers in abdominally obese premenopausal women [66]. There were no significant differences between the GH and placebo groups regarding the incidence of mild edema (GH: 53.6% vs. placebo: 45.5%; p = 0.8), mild joint discomfort (GH: 53.6% vs. placebo: 31.8%; p = 0.2), muscle aches (GH: 17.9% vs. placebo: 13.6%; p = 1), nasal congestion (GH: 25.0% vs. placebo: 22.7%; p = 1), back pain (GH: 10.7% vs. placebo: 22.7%; p = 0.3), headache (GH: 35.7% vs. placebo: 36.4%; p = 1). Overall, GH administration in abdominally obese premenopausal women led to beneficial changes in body composition and CV risk with an acceptable safety profile.

A 2014 Phase 4 clinical trial by Kim et al. was performed to assess the QOL, efficacy, and safety associated with a weekly injection of GH as compared to daily injections. Seven musculoskeletal drug-related adverse reactions were reported—three cases of myalgia/arthralgia, one case of rash, two cases of urticaria, and one case of abdominal pain. All of these adverse events were mild, and resolved completely [31]. This study shows weekly GH injections are well tolerated, and provide a higher QOL than a daily injection.

A randomized, placebo-controlled crossover trial conducted by Nyström et al. in 2012 examined 60 adults with GHD who had been undergoing GH treatment for three years or more, with an average treatment duration of 10 years [65]. Of the 10 SAEs, tibia fracture, severe hip pain were reported. Of the 105 other adverse events, 12 cases of joint/muscle pain occurred in the GH group, and seven cases occurred in the placebo group. Of note, there was no discussion of which of the 105 side effects or 10 SAEs were related to GH treatment [65]. However, given that musculoskeletal side effects are commonly attributed to GH treatment, clinicians should maintain vigilance of these side effects as described. These findings underscore that individuals with GHD are at an increased risk of adverse CV events and worsening psychological state, particularly during even a relatively short-term absence of GH, highlighting the significant lack of anabolic effects associated with growth hormone.

In a 2012 prospective, single-center, open-label study, Elbornsson et al. evaluated the impact of long term GH treatment on bone mineral content (BMC) and bone mineral density (BMD) in 126 adults with GHD (ages 22–74) [86]. Patients initially received an average GH dose of 0.63 mg/day, which was gradually reduced to 0.41 mg/day. The first 64 patients started with a weight-based regimen (11.9 μg/kg per day or 0.25 IU/kg/week), but this approach was phased out within 2–3 years in favor of individualized dosing aimed at normalizing serum IGF-1 levels and optimizing body composition. The remaining 62 patients received individualized dosing from the outset [78]. Patients were monitored over 15 years to assess the long-term effects of GH therapy [78]. By year 7, lumbar spine BMC had increased by 9%, and BMD by 5% from baseline (p < 0.01). By year 15, total body BMC and BMD had risen by 5% and 2%, respectively (p < 0.01). The femoral neck BMD and BMC peaked at year 7 (p < 0.01) but returned to baseline by year 15. Mean body weight and BMI also increased significantly over the study period (p < 0.001). Notably, men exhibited a greater response to GH treatment than women. Two women experienced fractures (one hip and one vertebral), while no fractures were reported in men [78]. This study suggests that 15 year-long GH treatment likely reduces fracture risk in patients with GH deficiency.

A 2016 randomized, open-label, clinical trial by van Bunderen et al. evaluated the safety and efficacy of titrating GH dose to target low-normal and high-normal IGF-1 levels during GH replacement therapy [87]. Adverse events included myalgia in one participant from the low-dose group and six in the high-dose group, as well as arthralgia in three high-dose participants. None of these musculoskeletal symptoms were persistent or required dose adjustments. This study suggests uptitrating GH doses to target a high-normal IGF-1 level may improve body composition and well-being, with a possible increase in the incidence of myalgia and musculoskeletal side effects. Reducing the GH dose to target a low-normal IGF-1 level may lead to increased fatigue [79].

4.4 Neoplasms

Neoplasms have been reported in some studies pertaining to GH therapy in adults. However, in most studies, the neoplasms — whether benign or malignant — are not directly attributed to the GH therapy itself. In contrast, in studies of acromegaly (which are characterized by uncontrolled excess of GH), the increased risk of colon adenocarcinoma and lymphoma have been documented in animal and human studies [88]. Due to the lengthy observation periods required to identify the occurrence of neoplasms, studies that examine neoplasms in detail are typically multicenter and prospective in nature. Overall, these studies have consistently reported a low incidence of neoplasms in adult population.

In the 2012 double-blind, placebo-controlled RCT by Bredella et al. intended to assess the effects of GH on body composition and CV risk markers in abdominally obese premenopausal women [66]. One SAE—a cancer diagnosis—occurred in a placebo recipient, with no other SAEs reported. This was not considered due to study treatment [66]. Overall, GH administration in abdominally obese premenopausal women led to beneficial changes in body composition and CV risk with an acceptable safety profile.

A 2013 prospective, observational, open-label study by Shimatsu et al. evaluated GH replacement therapy in individuals with adult or childhood-onset GHD over a four year period [89]. Among the 402 total patients, a subgroup of 209 GH-naive patients (n = 149 with adult onset GHD and n = 60 with childhood-onset GHD) were included in the study. The GH dosage varied for each patient, with an average of 0.25 mg/day. While no statistically significant effects were found on BMI, waist circumference or body fat, improvements were noted in these metrics when compared to baseline. However, significant improvements were observed in physical and social functioning, vitality, emotional wellbeing, and general health for both adult and child onset GHD groups after GH therapy (p < 0.05). Additionally, serum IGF-1 levels were significantly elevated. 6–9% of patients had IGF-1 levels greater than + 2 SDS (p < 0.001). SAEs included three recurrent tumors, one new benign tumor, 11 new malignant tumours, and one other new tumor. Those patients who developed the 11 new malignant tumors had been on GH therapy for a short period of time, and had various confounding factors in determining whether these malignancies were related to GH treatment, chief among them being older age, prior radiation treatment, and obesity [81]. This study demonstrates that among Japanese adults with adult onset or childhood onset GHD, GH treatment improves QOL, but may be associated with increased risk of tumor development.

In a 2013 prospective study by Hartman et al., the recurrence rates of extracranial and intracranial tumors were compared between GH-treated patients (n = 1988) and untreated controls (n = 442) [90]. The study found that the overall incidence of TEAEs was significantly higher in the GH-treated group compared to the control group (84.1% vs. 69.2%, p < 0.001). After adjusting for baseline differences, SAEs were more common in the GH-treated group, including arthralgia (20% vs. 7.2%, p < 0.001), peripheral edema (15.4% vs. 5.9%, p < 0.001), back pain (8.8% vs. 4.1%, p < 0.004), and myalgia (5.0% vs. 2.0%, p < 0.006), among others. Unexpected adverse events, such as insomnia (6.4% vs. 2.7%, p < 0.014) and dyspnea (4.2% vs. 2.0%, p < 0.006), were also more frequent in the GH-treated group. In terms of tumor recurrence, the incidence of cancer was higher in the GH-treated group (32 cases) compared to the untreated group (12 cases), though no significant differences were found after adjusting for baseline differences (p = 0.57). Skin cancer was the most common cancer in both groups. Interestingly, the incidence of pituitary adenomas, craniopharyngiomas, and other intracranial tumors was lower in GH-treated patients compared to controls. Additionally, no significant difference in the incidence of benign or malignant neoplasms was observed between the groups (GH-treated, 8.1%; untreated, 10.0%; p = 0.77). Cancer incidence rates did not differ significantly between the two groups after adjusting for baseline factors, and the study found no significant relationship between GH therapy and the development of new tumors [82].

In 2022, Johannsson et al. launched a global observational study within the Pfizer International Metabolic Database (using the Kabi International Metabolic Study dataset, KIMS) to further assess the safety of GH therapy in patients with confirmed GHD [91]. The study analyzed 15,809 patients with a mean follow-up period of 5.3 years, reporting 606 deaths. Of the 606 deaths, 146 of them were due to neoplasms. A total of 3.2% of the patients who did not have a prior history of cancer (n = 14,533) developed de novo cancer, with prostate and skin cancers being the most prevalent. The study team calculated the standardized incidence ratio (SIR), a measure that compares the number of cancer cases observed in a population to the number expected, used to determine if a population’s cancer rate is higher or lower than expected. The SIR was calculated by comparing the incidence of cancer in GH-treated patients to the general population, yielding an SIR of 0.92 (95% CI, 0.83–1.01), indicating no significant difference in cancer risk between the two groups. Further analysis showed that patients under 35 years old without a prior cancer history had an elevated SIR. No increased risk was observed for prostate (SIR = 1.21, 95% CI, 0.97–1.50), colon (SIR = 0.66, 95% CI, 0.41–1.01), or breast cancer (SIR = 0.56, 95% CI, 0.40–0.77) [83]. Overall, the incidence rate of cancer in GH-treated patients is comparable to the general populations’ incidence rate.

4.5 No adverse reactions reported

Several studies have observed the effects of GH replacement therapy in GHD adults, each focusing on a different aspect that may be affected by GH treatment: morphological and/or functional changes in the left ventricle, sleep quality, QOL, risk of osteoporotic fracture, effects of a novel weekly formulation of recombinant GH (LB03002) on height, BMD, bone turnover, and bone marrow fat [92,93,94,95,96,97,98]. None of the studies mentioned address adverse effects, or there is scant discussion of the risks of using GH therapy. Additionally, several other studies have examined the effects of GH therapy in patients without GHD—for example, GH use in traumatic brain injury to improve cognitive functions, to counteract muscle and tendon deterioration during periods of immobilization and rehabilitation, or to improve bone mineral density and lessen the risk of fracture in postmenopausal osteoporosis [99,100,101,102]. These are novel uses of GH therapy, and studies like these would benefit from a thorough assessment of the risks, not only the benefits, of GH therapy by reporting adverse events.

For the above listed studies without adverse effects, it is challenging to truly determine the safety of GH treatment especially when the study used GH in a novel manner. Further areas of research into the value of GH treatment in various adult conditions should include adverse effects.

5 Summary of evidence

Neogenesis: GH exerts significant influence on cellular growth, differentiation and metabolism, both directly and indirectly through the stimulation of IGF-1. Both GH and IGF-1 exhibit mitogenic and anti-apoptotic properties, which might contribute to tumor initiation and progression [103]. GH may promote neoplastic transformation via activation of key intracellular signaling cascades—namely the JAK2/STAT, MAPK/ERK, and PI3K/AKT pathways—all of which are frequently dysregulated in human cancers or involve proto-oncogenes. For example, STAT3 activation promotes cell survival and immune evasion in multiple malignancies, while AKT signaling contributes to iapoptosis resistance and unregulated cellular proliferation [104].

In several adult cancers, including breast, prostate, colorectal, and lung cancer, overexpression of IGF-1 and IGF-1R enhances tumor proliferation, invasion, survival, and metastasis. In breast cancer, IGF-1R interacts with estrogen receptor signaling to drive tumor growth. In prostate cancer, IGF-1 enhances androgen-independent cell survival. In colorectal and lung cancer, the GH-IGF-1 axis stimulates angiogenesis and tumour progression via MAPK and AKT activation [105]. Congenital IGF-1 deficiency and low levels of IGF-1 are associated with reduced cancer risk [106, 107].

Experimental and preclinical studies further substantiate GH’s role in neogenesis. In vitro studies with cell lines and animal models have demonstrated that GH and IGF-1 support tumor initiation, growth and dissemination [108,109,110].

Clinical data is mixed. The French cohort of the SAGHE study (Safety and Appropriateness of Growth Hormone Treatments in Europe) reported increased all-cause mortality primarily due to cerebrovascular events and bone tumours, in individuals treated with recombinant human GH during childhood [111]. However, no increase in cancer-related mortality was observed in the Dutch, Belgian and Swedish cohorts [112]. A subsequent 2017 analysis stratified patients into low-, intermediate-, and high-risk groups; low-risk patients had isolated growth failure (IGHD, ISS, SGA), intermediate risk had non-isolated growth failure, Turner syndrome, Noonan syndrome, etc.; and high risk had prior malignancies. Increased cancer mortality and incidence were observed only in the high-risk group, primarily consisting of patients with prior malignancy and were significantly associated with higher daily rhGH doses risk [113]. Incidence of bone cancer was elevated in the intermediate-risk group, while no increase in cancer mortality or incidence was found in the low-risk group.

A recent international observational study found that while the absolute risk of malignancy following pediatric GH treatment is low, the relative risk may be elevated for second primary neoplasms in childhood cancer survivors [114]. These data suggest that GH is not a direct carcinogen but may enhance tumor progression in predisposed individuals. Most observational studies, excluding the French SAGHE cohort, have not found elevated cancer risk in otherwise healthy GH-deficient children up to 15–16 years post-therapy [115]. Nonetheless, all existing studies are subject to substantial confounding, limited controls, and methodological variability. The absolute number of malignancies is low, and ethical considerations preclude untreated control groups. Familial cancer predisposition and environmental exposures are often unaccounted for.

In summary, current evidence suggests that GH therapy may accelerate tumor growth in patients with existing or latent oncogenic predispositions. Clinicians should exercise heightened caution when prescribing rhGH in individuals with prior neoplasia or known cancer-predisposing conditions, including RASopathies (e.g., Noonan syndrome), chromosomal instability syndromes, and DNA repair disorders (e.g., Fanconi anemia, Bloom syndrome, Down syndrome).

Cardiovascular: GH plays a significant role in cardiovascular physiology, influencing vascular and cardiac remodeling, and altering lipid and glucose metabolism. In patients with GH excess, such as those with acromegaly, CVD is a major contributor to morbidity and mortality. While comorbidities such as hypertension, diabetes, and dyslipidemia are common in these patients, GH/IGF-1 excess itself appears to independently contribute to CVD risk.

Mechanistically, GH/IGF-1 may impair endothelial function via several pathways: promoting endothelial cell proliferation, disrupting endothelial progenitor cells, increasing oxidative stress, and reducing antioxidant defenses [116, 117]. GH also stimulates lipolysis, elevating free fatty acid levels, which disrupt insulin signaling in muscle and adipose tissue. GH antagonizes insulin at the hepatic level, promoting gluconeogenesis and inhibiting glycogen synthesis. Additionally, GH and IGF-1 directly act on vascular smooth muscle and endothelium to enhance nitric oxide production, causing vasodilation and improved vascular tone. Chronic GH exposure may, however, lead to vascular hypertrophy and endothelial dysfunction—features observed in acromegaly [118].

GH also exerts anabolic effects on the myocardium, increasing myocardial contractility and left ventricular mass. Supraphysiologic GH exposure may lead to maladaptive hypertrophic remodeling [119].

Epidemiologic data is mixed. The French cohort of SAGHE reported significantly increased cardiovascular mortality (standard mortality ratio SMR 3.07, 95% CI 1.40–5.83) in young adults treated with rhGH for IGHD, ISS, or SGA [111]. In contrast, data from Belgium, the Netherlands, and Sweden showed no increased CVD mortality. The full eight-country SAGHE analysis (n > 24,000; 25 years follow-up) found no overall increase in mortality among low-risk patients (IGHD, ISS), though mortality was elevated in those born SGA. Mortality was not associated with daily or cumulative rhGH dose [120].

Conversely, in GH-deficient patients, replacement therapy improves cardiovascular health by restoring lean mass, reducing visceral adiposity, and improving myocardial performance. GH also directly lowers plasma cholesterol through hepatic LDL receptor upregulation [121]. Children with congenital GH insensitivity (Laron syndrome) exhibit low LDL-C levels despite obesity. However, GH may transiently increase LDL and triglycerides early in therapy before metabolic adaptation occurs, suggesting that the net lipid effect depends on individual metabolic context.

Neurological: Growth hormone influences the central nervous system through both direct receptor-mediated signaling and indirect effects via IGF-1. GH-responsive neurons are distributed across multiple brain regions, including the hypothalamus, hippocampus, and cerebral cortex, indicating its role in neuromodulation [122]. GH signaling is essential for adaptive responses to metabolic stress, neuroendocrine regulation, and cognitive function. Disruption of GH receptor signaling in neurons impairs feeding behavior during glucoprivation, alters neuroendocrine responses during caloric restriction, and affects gestational metabolism.

In both children and adults with GH deficiency, clinical symptoms frequently include fatigue, impaired memory, mood disturbances, and sleep irregularities. These symptoms may result from reduced IGF-1 levels, decreased insulin sensitivity, or direct central effects of GH deficiency. In experimental models, brain-specific deletion of STAT5—a key transcription factor downstream of the GH receptor—impairs spatial learning and memory, without altering circulating IGF-1 levels, underscoring the role of direct GH signaling in brain function [123, 124].

GH also interacts with other neuroendocrine systems. For instance, chronic stress in rats reduces hippocampal GH levels, leading to cognitive impairment and memory deficits [125]. Elevated ghrelin levels have been shown to increase GH in the amygdala, enhancing fear memory formation and potentially contributing to PTSD-like behavior [126]. These data support a role for GH in modulating affective and cognitive processing.

A possible mechanism linking GH therapy to adverse neurological symptoms such as headaches is vasodilation [127]. GH and IGF-1 increase nitric oxide production and may influence cerebral blood flow. Since migraines are associated with intracranial vasodilation, GH-induced vascular changes could plausibly contribute to headache pathogenesis in susceptible individuals [128, 129].

Musculoskeletal: GH plays a central role in musculoskeletal development through direct action and via IGF-1. It stimulates chondrocyte proliferation and differentiation at the epiphyseal growth plate, promoting endochondral ossification and longitudinal bone growth. GH also increases osteoblast activity and local IGF-1 production in bone, supporting bone formation and remodeling [130]. In skeletal muscle, GH promotes amino acid uptake, nitrogen retention, and protein synthesis, resulting in increased muscle mass and strength [131].

In GH-deficient children, these anabolic actions are impaired, leading to short stature, low bone mineral density, and reduced muscle strength [132]. GH therapy reverses these deficits, but the rapid acceleration in growth velocity can place biomechanical stress on the developing skeleton.

Clinical complications include growing pains and, more seriously, orthopedic disorders such as slipped capital femoral epiphysis (SCFE) and progression of scoliosis. SCFE is particularly associated with increased growth rate and body mass relative to physis strength, making the growth plate susceptible to shear stress [133, 134]. GH-induced increases in bone turnover and muscular force may also contribute to transient musculoskeletal discomfort or overuse injuries. Bone pain may reflect increased periosteal bone formation and transient resorption [135].

Immunological/Infectious: GH exerts modulatory effects on the immune system through both direct receptor-mediated mechanisms and indirect effects via IGF-1. GH receptors are expressed on numerous immune cells, including T and B lymphocytes, monocytes, and neutrophils. Activation of these receptors can enhance chemotaxis, cytokine production, and phagocytic activity [136, 137]. IGF-1 further supports lymphocyte development and function [138].

In theory, GH therapy in children with GHD could enhance immune competence and reduce infection risk, particularly in those with immune dysfunction secondary to hormonal deficiency. Some observational studies report reduced frequency of respiratory tract infections after initiation of GH therapy, possibly due to improved thymic function and normalized lymphocyte profiles [139, 140].

However, the clinical evidence remains limited. Few large-scale or randomized studies have directly assessed infection outcomes in GH-treated children, and infection rates are often not systematically recorded in long-term registries like SAGHE. Moreover, childhood infections are common and multifactorial, complicating attribution to GH therapy alone. While GH may play a role in immune enhancement, definitive conclusions require more robust and targeted data.

Metabolism: GH regulates metabolism through a complex network of direct actions and IGF-1–mediated effects. One of GH’s primary metabolic functions is lipolysis: it stimulates triglyceride breakdown in adipocytes, leading to increased free fatty acid release and fat oxidation. This results in reduced fat mass, especially visceral adiposity [141].

GH also exerts anti-insulin effects by impairing insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. This occurs through interference with post-receptor signaling at the level of insulin receptor substrate phosphorylation and downstream PI3K/Akt pathways [142, 143]. As a result, both endogenous GH excess and rhGH therapy can lead to insulin resistance.

Importantly, this insulin antagonism appears to be dose-independent. Even within clinically recommended dosing ranges, insulin sensitivity may be impaired [144]. GH also enhances protein synthesis and reduces protein catabolism, primarily through IGF-1, contributing to increased lean body mass. In GH-deficient individuals, rhGH therapy normalizes body composition by reducing fat mass, increasing muscle mass, and improving energy expenditure and physical performance [145].

6 Conclusions

Recombinant GH administration is a commonly used treatment for a wide variety of populations seeking its anabolic and therapeutic effects, from its usage in treating GHD to addressing other metabolic dysfunctions. GH’s role in regulating metabolism and overall homeostasis across various organ systems have been well established. Numerous studies have highlighted GH’s role in increasing height, body mass index, and muscle tone in children and adults, while other studies focused on the detrimental effects of GH use such increased insulin resistance, neurologic dysfunction, and increased risk of conditions such as acromegaly [11, 13, 69, 77]. Our review outlines the cardiovascular, neoplastic, infectious, neurological, metabolic, and musculoskeletal adverse effects reported in adults and children pertaining to GH, which have been summarized in Table 1. The side effects of excess GH, seen in acromegaly, can lead to CV disease, diabetes, joint issues and visible deformity [31]. Several studies have also shown the effects of excess GH, including atrial fibrillation, malignancy, headache and arthralgia [65, 69, 74, 76]. This underscores the importance of maintaining GH levels within the therapeutic range to avoid the detrimental effects of excess GH. GH is usually administered as a daily injection to match the physiologic daily spike of GH. However, recently the usage of GH has expanded from GHD to PWS to new usages in fibromyalgia, ischemic and non-ischemic heart failure, and CKD [22, 71]. As new weekly formulations of GH dawn on the market, it will be especially necessary to titrate the dosage properly to avoid excess GH levels in the blood in these patient populations. Table 1 Summary of Treatment-Related adverse effects of GH therapy in children and adults

Full size table

In contrast, standard GH therapy and weekly PEGylated GH therapy (when monitored and titrated well) have generally proven to be safe and effective [15]. However, certain conditions, such as CKD, PWS, intrauterine growth restriction, and ISS, often require higher doses of GH [22]. For these populations, the therapeutic dosages producing circulating GH and IGF-1 levels exceed the normal physiological range. These elevated levels may introduce the risk of adverse effects, which include insulin resistance, joint complications, and an increased predisposition to various malignancies [13, 78]. The potential side effects of GH therapy, especially when used off-label or in excess, include injection site reactions, joint swelling, and carpal tunnel syndrome [11, 20]. Additionally, GH has been associated with an increased risk of diabetes and insulin resistance, which can complicate the management of underlying conditions. More severe adverse effects include the development of certain cancers and a range of neurological symptoms, including frequent headaches [11, 17, 74]. While the safety profile of GH in clinical use is relatively favorable at standard doses, the higher doses required for certain medical conditions and off-label uses increase the potential for these detrimental outcomes.

In conclusion, GH therapy can provide significant benefits, particularly for GHD and related conditions. As the usage of GH expands into both legitimate and illegitimate uses, the monitoring and titration of this medication is exceedingly important, particularly with the recent introduction of long-acting GH and the risk of serious complications, including acromegaly, metabolic derangement, and cancer. Further studies are needed to investigate the long-term efficacy and adverse effects of GH. In particular, the effect of transient increases in GH and IGF-1 levels in the long term should be studied [146]. Lastly, the diverse benefits of GH in relation to its cost effectiveness and accessibility should be explored. Understanding the balance between therapeutic benefits and risks and being able to personalize treatment for the individual patient is crucial in the clinical advancement of GH therapy.

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