Safety surveillance of recombinant human growth hormone : An observational, pharmacovigilance study leveraging FAERS database

Safety surveillance of recombinant human growth hormone : An observational, pharmacovigilance study leveraging FAERS database | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 6 February 2025 V1 Latest version Share on Safety surveillance of recombinant human growth hormone : An observational, pharmacovigilance study leveraging FAERS database Authors : Shiyu Feng 0009-0000-5480-4336 , Qingxin Yang [email protected] , Huarong Deng , and Yuwei Zeng Authors Info & Affiliations https://doi.org/10.22541/au.173882792.24431559/v1 502 views 228 downloads Contents Abstract Introduction Materials and methods Results Discussion conclusion Abbreviations Conflict of Interest Authors’ contributions Funding Acknowledgments Data Availability Statement References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Objective: To analyze adverse event signals of growth hormone based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and provide a reference for safe clinical drug use. Methods: The FAERS database was retrospectively queried to extract reports related to recombinant human growth hormone(rhGH) from 2014 to 2024. Various disproportionality analyses, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were used to identify and assess potential adverse events in patients receiving recombinant human growth hormone. Results: We detected 327 valid signals involving 22 SOCs. These included ADEs commonly associated with rhGH such as headache, dizziness, and arthralgia. Unexpected serious ADEs were also identified, including seizures, thrombosis, and gout. The median time to onset of ADEs associated with rhGH was 37.5 days (IQR 0–395 days), with the majority of cases occurring within the first month after administration (n = 3148). However, some ADEs may still occur after 1 year of rhGH treatment (n = 1740). Conclusion: Our investigation revealed several possible safety issues associated with rhGH in real-world clinical practice, which may provide necessary evidence for clinicians and pharmacist managers to be vigilant about the safety of rhGH. Shiyu Feng 1 , Qingxin Yang 1* ,Huarong Deng 1 , Yuwei Zeng 1 1 Department of Pharmacy,Mianyang Orthopedic Hospital, Mianyang, Sichuan, China * Correspondence: Qingxin Yang [email protected] Keywords: FAERS 1 , Disproportionality analysis 2 , recombinant human growth hormone 3 , data mining 4 , adverse drug reaction 5 . Abstract Objective: To analyze adverse event signals of growth hormone based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and provide a reference for safe clinical drug use. Methods: The FAERS database was retrospectively queried to extract reports related to recombinant human growth hormone(rhGH) from 2014 to 2024. Various disproportionality analyses, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were used to identify and assess potential adverse events in patients receiving recombinant human growth hormone. Results: We detected 327 valid signals involving 22 SOCs. These included ADEs commonly associated with rhGH such as headache, dizziness, and arthralgia. Unexpected serious ADEs were also identified, including seizures, thrombosis, and gout. The median time to onset of ADEs associated with rhGH was 37.5 days (IQR 0–395 days), with the majority of cases occurring within the first month after administration (n = 3148). However, some ADEs may still occur after 1 year of rhGH treatment (n = 1740). Conclusion: Our investigation revealed several possible safety issues associated with rhGH in real-world clinical practice, which may provide necessary evidence for clinicians and pharmacist managers to be vigilant about the safety of rhGH. Key Points 1. First large-scale pharmacovigilance study: systematically analyzing recombinant human growth hormone (rhGH) safety using FAERS data spanning 2014-2024. 2. Novel methodology: Combined traditional disproportionality analysis with time-to-onset (TTO) modeling to identify both acute and delayed risks. 3. Critical findings: Identified unexpected signals (e.g., seizures, dementia) and validated known risks (e.g., scoliosis, intracranial hypertension). 4. Clinical impact: Provides evidence for stratified monitoring strategies based on risk timelines (e.g., neurological AEs within 1 month vs. musculoskeletal AEs after 1 year). Plain Language Summary This study investigated the safety of recombinant human growth hormone (rhGH), a medication used to treat growth disorders in children and adults. By analyzing over 50,000 real-world reports from the FDA Adverse Event Reporting System (2014-2024), we identified both expected and unexpected side effects. Common issues like headaches and joint pain often occurred within the first month of treatment. Surprisingly, we also found potential links to seizures and memory problems, which were not previously highlighted in drug labels. Additionally, some side effects, such as spine curvature, could develop even after a year of use. These findings suggest that doctors should monitor patients more closely, especially for neurological symptoms early in treatment and long-term bone health. Our results aim to help healthcare providers improve rhGH safety by tailoring monitoring plans to individual risks. Introduction Growth hormone (GH) is a non-glycosylated protein hormone necessary for normal growth, comprising approximately 95%; it is a peptide with 191 amino acid residues and a molecular weight of approximately 22,000D, aptly named the 22K-hGH. weight of approximately 22,000D, aptly named the 22K-hGH. The remaining 5%, called the 20K-hGH, has an amo-molecular weight of approximately 20,000D(Jørgensen et al., 1991; McKenna and Doward, 1994). Growth hormone In addition to its linear growth-promoting effects, it also has the effects of improving body components and metabolism, increasing bone density, and improving the quality of life, and thus has been applied to adult patients with growth hormone deficiency (GHD). However, the clinical application of growth hormone is highly specialized, and strict control of the indications, treatment, and safety monitoring is required to ensure the drug’s rational, effective, and safe application(Shalet and Holmes, 1994). In 1985, human growth hormone ( rhGH ) was successfully developed. rhGH is produced by recombinant DNA technology, and its sequence is identical to human growth hormone (hGH). The Food and Drug Administration (FDA) has approved rhGH to treat growth hormone deficiency (GHD). Hormone deficiency (GHD), growth retardation due to chronic kidney failure (CKF), Turner syndrome (TS), Prader-Willi syndrome (PWS), Diagnosing idiopathic short stature (ISS), growth retardation associated with a defect in the Short Stature HOmeoboX Containing (SHOX) gene, growth retardation in infants born small for gestational age (SGA), etc.(Blethen and MacGillivray, 1997; Bryant et al., 2007). According to surveys, the prevalence of childhood dwarfism in China can be up to 3%, and the number of children aged 4 to 15 years who need treatment is approximately 7 million out of the total dwarf population(Fang et al., 2019). Results of a retrospective study covering nine epidemiologic studies published from 1974 to 2022 showed that the prevalence of growth hormone deficiency in the European region ranges from 1/1107 to 1/8646, with an average incidence of 1/28,800 to 1/46,700 cases per year(Mameli et al., 2024). The prevalence of GHD in Italian children ranges from 1/(1000-2000), Turner syndrome (TS) from 1/2500 births, and Prader-Willi syndrome (PWS) from 1/15000 births(Orso et al., 2022). Growth hormone is the drug of choice for GHD, and it is widely used, mainly in children. While an increasing number of children with relatively short stature but normal growth hormone production are joining the ranks of growth hormone users, this group of patients may be categorized as Diagnosing idiopathic short stature (ISS)(Schena et al., 2017), with approximately 23 out of 1,000 people having this diagnosis(Cohen et al., 2008). With the widespread use of recombinant human growth hormone, adverse drug reaction (ADR) reports have gradually increased, attracting the attention of physicians and drug administration. According to clinical results, recombinant human growth hormone is usually well tolerated, and most treatment-induced ADRs are transient mild or moderate ADRs.Adverse drug reactions in patients treated with recombinant human growth hormone include headache, arthralgia, localized edema, benign intracranial hypertension, slipped capital femoral epiphysis, and worsening of established scoliosis(Blethen et al., 1996; Clayton and Cowell, 2000; 2001; Darendeliler et al., 2007; Yuen et al., 2018). However, most of the current studies on recombinant human growth hormone are centered on the efficacy of a particular indication and its safety, or on the analysis of the known incidence of adverse events of recombinant human growth hormone(Tritos and Biller, 2009; Gaillard et al., 2012). There is no literature on the statistical analysis of the association of growth hormone with individual AEs through the FAERS database, especially for some rare adverse events. Therefore, in this paper, we analyzed and explored the strength of the association between recombinant human growth hormone and related AEs by mining the FDA database for adverse reactions related to recombinant human growth hormone. Our findings may provide a reference for physicians and health regulators to monitor the adverse reactions and to promote the rational use of recombinant human growth hormone. Drug safety assessment through data mining of a significant adverse event spontaneous reporting system database has recently become an important means of pharmacovigilance research. The FAERS is a public, accessible, and free database in the United States that contains tens of millions of AE reports voluntarily submitted by health professionals, consumers, manufacturers, and others, which is designed to support the FDA’s safety monitoring for post-marketing drugs and biological products(Anand et al., 2019; Yu et al., 2021; Zhou et al., 2023). This study aimed to quantitatively measure AE signal intensity by disproportionality analysis and assess the risk caused by rhGH. Materials and methods This is a retrospective study based on the FAERS database, which contains seven datasets: patient demographics and administration (DEMO), drug details (DRUG), records of AEs (REAC), patient outcomes ( OUTC), sources of reports (RPSR), start and end dates of therapy for the reported drugs (THER), and indications for drug usage (INDI). We downloaded and extracted all data from the FDA website in ASCII format from the first quarter of 2014 through the second quarter of 2024 (the latest update of the FAERS database at the time of the study). We then transferred the data to MySQL 8.0 for further analysis.16,231,751 adverse event reports were collected from the FAERS database. The FAERS database is regularly updated every quarter, resulting in duplication of early AE reports that need to be reprocessed. According to the FDA recommendation(Sakaeda et al., 2013), the most recent FDA_DT was selected when CASEID was the same, and the higher PRIMARYID was selected when CASEID and FDA_DT were the same, and the duplicates were removed before further analysis, which resulted in a final number of reports of 13,951,938 (Figure 1). The AEs in the FAERS database are organized by the Medical Dictionary for Regulatory Activities 27.0 (MedDRA)(Brown et al., 1999). The hierarchical structure of MedDRA The hierarchical structure of MedDRA terms is organized into five levels: lowest-level term (LLT), preferred term (PT), high-level term (HLT), high-level group term (HLGT), and system organ class (SOC). We obtained all Recombinant human growth hormone AE reports from the FAERS database for use in this study based on MedDRA signal intensity at the PT levels. MedDRA’s system organ class (SOC) and preferred term (PT) were used in this study. To improve the accuracy of the analysis, only the generic name ”growth hormone,” ”somatropin,” ”lonapegsomatropin-tcgd” and the trade name ”GENOTROPIN,” ”GENOTROPINPRESERVATIVEFREE,” ”HUMATROPE,” ”NORDITROPIN,” ”NUSPIN,” ”OMNITROPE,” ”SAIZEN,” ”SEROSTIM,” ”SKYTROFA,” ”ZOMACTON,” ”ZORBTIVE,” ”SAIZENPREP” as the first suspected drugs in this study [role_cod field is ’Primary suspected (PS)’] for AE (PS)’] for AE reports. Disproportionality analysis is a key tool in pharmacovigilance research, which is based on the four-cell table of the proportional imbalance method, the formula of the proportional imbalance analysis, and the threshold table to calculate the threshold value(Shu et al., 2022; Fusaroli et al., 2024) if the rate of AEs associated with the target drug is significantly higher than the rate of all other drug-associated AEs and is greater than the threshold value, it is called a disproportionality, we then recognize it as a positive signal. In the present study, we analyzed the odds ratio by [ reporting odds ratio (ROR)(Rothman et al., 2004) and proportional reporting ratio (PRR)(Evans et al., 2001)], Bayesian methods [information component (IC)(Kidwell et al., 2022) and empirical Bayes geometric mean (EBGM)(Bate and Evans, 2009)], a total of four methods for disproportionate analysis to detect growth hormone-related AE signals. Non-Bayesian methods (e.g., ROR) may show better results in early signal detection, while Bayesian methods have strong detection capabilities even in the case of rare drug ADEs(Mazhar et al., 2021)。To further avoid false-positive signals, meaningful AE signals were considered to be generated only when the thresholds of all four algorithms were reached simultaneously. Specific formulas are shown in Supplementary Table 1. We have calculated the time to adverse events and their proportion of serious consequences. Specifically, time to adverse event was defined as the interval between EVENT_DT (date of AE occurrence) and START_DT (date of initiation of treatment with rhGH). During this process, we excluded reports with reporting errors (EVENT_DT before START_DT), inaccurate dates, or missing entries to ensure the accuracy and reliability of the data. The frequency of adverse events after the start of treatment depends on the mechanism of action of the drug and may fluctuate over time. In contrast, the incidence of adverse events not related to drug treatment is consistent(Burman et al., 1996).The wear failure type curve determines the proportional change in the rate of adverse events, indicating whether the risk increases or decreases over time. The wear failure type curve is defined by two main parameters: the scale parameter (α) and the shape parameter (β). For this study, only the parameter β is considered and discussed. If the shape parameter β < 1 and its 95% confidence interval (CI) < 1, the risk of an adverse reaction is considered to decrease over time (early failure type curve). If the shape parameter β is approximately equal to or close to 1 and its 95% CI includes the value 1, the risk is estimated to increase over time (random failure type curve); if the shape parameter β >1 and its 95% CI excludes the value 1, the risk is considered to increase over time (wear failure type curve)(Hong et al., 2023). Serious outcomes included those that were life-threatening and resulted in hospitalization, disability, or death. After identifying these serious outcomes, we further counted the relevant reports and compared them to the total number of all reports. This resulted in a proportion of serious outcomes. For data processing, we use MySQL 8.0, Navicat Premium 15, and Microsoft Excel 2023. Results From the first quarter of 2014 to the second quarter of 2024, a total of 13,951,938 AE reports were recorded in the FAERS database after deduplication. The specific demographic and clinical details are shown in Table 1. Among them, 50,707 adverse event reports were mainly related to recombinant human growth hormone. A total of 46,301 adverse event reports reported the patient’s gender, including 18,594 female patients (36.67%) and 27,707 male patients (54.64%). In terms of age distribution, patients under 18 years of age were the leading group, with 26,974 cases (53.20%). 34,662 consumers submitted 68.26% of the adverse event reports, and 7,735 doctors submitted 15.25% of the adverse event reports. Regarding sources of reports, the United States reported the highest number of adverse events, with 34,701 cases (68.43%). The most commonly reported therapeutic indication for recombinant human growth hormone was growth hormone deficiency (11,410 cases, 22.50%), with 5,225 cases (10.30%) Product used for unknown indication, followed by hypopituitarism (4,124 cases, 8.13%). In addition, serious outcomes were reported in 28.61% of patients (n=14,507 cases), the most common being Other Serious (Important Medical Events) (n=9,418, 18.57%), followed by Hospitalization (n=4,049, 7.99%) and Death (n=539, 1.06%). Figure 2B shows the annual distribution of reports of adverse events (ADEs) associated with recombinant human growth hormone. The year with the fewest reports recorded was 2014 (1,309), while the year with the most reports was 2023 (8,923). From 2014 to 2021, the number of ADE reports showed an upward trend and remained high from 2022 to 2024. rhGH-related ADEs occurred in 26 SOCs. The number of case reports for trofinetide-related SOCs is shown in Figure 2A. The top 5 SOCs were General disorders and administration site conditions (n = 6,546, 23.71%), Nervous system disorders (n = 4,988, 18.07%), Gastrointestinal disorders (n = 2,134, 7.73%), Musculoskeletal and connective tissue disorders (n = 2,123, 7.69%), and Psychiatric disorders (n = 1,918, 6.95%). A total of 6524 AE reports accurately recorded the time of initial administration and the time of the adverse event, and we excluded any erroneous, missing, or unknown reports. The median onset duration was 37.5 days, and the interquartile range was 0-395 days. As shown in Figure 3, most cases of patients receiving recombinant human growth hormone occurred within the first month of administration (n = 3,148, 48.25%). There were 392 cases (6.01%) in the second month and 225 cases (3.45%) in the third month. After 3 months, the incidence of adverse events seems to increase with time gradually, and in nearly 26.67% of cases, adverse drug events may still occur even after 1 year of treatment with recombinant human growth hormone. We performed a wear failure type curve test on the overall patient population to examine whether the risk of rhGH-related ADEs increased or decreased over time. For the overall analysis, the shape parameter (β) was calculated to be 0.53, and its upper 95% confidence interval (CI) was 0.55. Both values were below 1, indicating that the prevalence of ADEs decreased over time (Supplementary Table 2). To determine the time to onset of ADEs in more detail, we analyzed the TTO at the SOC level (Figure 4A). The SOC with the longest median time to onset was Blood and lymphatic system disorders, with a median time to onset of 395 days (IQR 10.5-1252 days). In contrast, General disorders and administration site conditions, Immune system disorders, and Hepatobiliary disorders, which were associated with recombinant human growth hormone, had the shortest median time to onset, all at 3 days. The median time to onset of other systemic adverse reactions, such as Injury, poisoning and procedural complications, Infections and infestations, Psychiatric disorders, Skin and subcutaneous tissue disorders, Respiratory, thoracic and mediastinal disorders, Renal and urinary disorders, and Reproductive system and breast disorders, was 1–2 months. It is worth noting that the median time to onset of 7 SOCs was more than 6 months (Supplementary Table 3). SOCs often include multiple types of PTs. To clarify the onset time of individual PTs in SOCs and determine whether there are differences in the onset time of PTs within the same SOC, we analyzed and compared the detailed onset times of PTs at the SOC level (Figure 4B). The earliest mean onset time of Injection site erythema was 18.13 days, and the latest mean onset time of Epiphysiolysis was 918.45 days. More detailed and complete results are supplemented in Table 3. These TTO analyses at the SOC and PT levels provide more precise guidance for detecting adverse events after the administration of recombinant human growth hormone. The extracted ADEs targeting growth hormones were screened using the disproportionality method. After meeting the threshold criteria of the four algorithms, we detected 355 rhGH-induced AE signals in 24 SOCs. The most significant signals were generated by various neurological diseases, followed by infectious and parasitic diseases sys,temic diseases, and various reactions at the administration site. Since FAERS collects all medical and health-related PTs, we detected some AE signals that are not related to the drug’s adverse reactions, as shown in Supplementary Table 4. After removing these interfering signals, 22 SOCs containing 327 valid positive AE signals were finally included in our analysis. Next, we classified the PTs of more than 20 cases of ADE and selected 146 cases of ADE that met the screening criteria, including 19 corresponding SOCs. To improve visualization, we presented the PT signals as a forest plot, sorted in descending order by the number of cases (Figure 5). In addition, we identified 102 AEs that were consistent with the known safety information in the medication instructions. The more frequently occurring PTs included headache (n=2,268), fatigue (n=1,336), malaise (n=1,253), arthralgia (n=1,123), pain (n=898), and pyrexia (n=635). We also considered the IC025 values, as the Bayesian approach provides a calculation that increases stability in the case of a small number of adverse events(Kubota et al., 2004). Despite the small number of cases, high IC025 values were found for scoliosis (n=235, IC025 6.21), neoplasm (n=105, IC025 5.83), papilloedema (n=95, IC025 4.80), epiphysiol ysis (n=46, IC025 4.74), hypothyroidism (n=81, IC025 4.71) were found to have higher IC025 values, which indicates a close relationship with the use of recombinant human growth hormone. These PT signals are also consistent with the warning information in the instructions. These data are detailed in Supplementary Table 5. Interestingly, we found some unexpected significant ADEs, among which the more frequently occurring PTs included seizure (n=405, ROR 11.19(10.13-12.36), PRR 11.11(3583.02), IC 3.42(3.24), EBGM 10.71(9.70)), depression (n=263, ROR 22.25(19.61-25.23), PRR 22.14(4912.62), IC 4.36(4.07), EBGM 20.56(18.13)), Dyspnoea (n=226, ROR 9.53(8.35-10.89), PRR 9.50(1661.37), IC 3.20(2.95), EBGM 9.21(8.07)). We also examined these data in terms of signal strength and found higher ROR values in signals such as Dementia (n=21, ROR 2879.75(675.20-12282.24)) and Nocturia (N=43, ROR 737.40(415.34-1309.19)). Discussion This study is the first thorough pharmacovigilance analysis of Recombinant human growth hormone (rhGH) through the FAERS database. We provide a comprehensive analysis of the high frequency and high risk of AEs associated with rhGH to date. rhGH is produced by recombinant DNA technology and has the same sequence as GHD, which is the first choice for patients with primary or secondary growth hormone deficiency(Blethen and MacGillivray, 1997). Globally, the number of patients with growth hormone deficiency continues to be high, leading to the escalating use of recombinant human growth hormone (rhGH)(Cohen et al., 2008; Schena et al., 2017; Orso et al., 2022; Mameli et al., 2024), along with a gradual increase in the reports of adverse drug reactions (ADRs), which underscores the need for continuous monitoring of its safety in real-world applications. During long-term clinical use of recombinant human growth hormone, it is usually generally well tolerated, and its known serious adverse effects are relatively rare(2001). The most common adverse effects include transient somatic reactions such as headache, arthralgia, localized edema, and benign intracranial hypertension(Blethen et al., 1996; Clayton and Cowell, 2000; 2001). Serious AEs were experienced by 3.7% of patients in a follow-up trial of patients receiving long-term clinical treatment with rhgGH, most commonly including acute respiratory infections and tumor recurrence(Maghnie et al., 2022). In addition, another long-term clinical trial of patients with Prader-Willi syndrome treated with rhGH showed an even higher percentage of serious adverse events (SAEs), with 9.4% of patients experiencing SAEs that were considered to be related to the treatment, and 50% of SAEs occurring in the first year of treatment(Lämmer et al., 2024). Our findings, based on the FAERS database, provide a more comprehensive reference for the safety of human recombinant growth hormone. 4.1 ADEs related to nervous system disorders Headache is the most common neurological adverse reaction, consistent with this study’s real data. Headaches caused by recombinant human growth hormone are usually complications caused by benign intracranial hypertension(Yuen et al., 2018). Benign intracranial hypertension (BIH) or pseudotumor cerebri is caused by an increase in cerebrospinal fluid pressure without a space-occupying lesion and may present with headache, vision loss, nausea, vomiting, and papilledema(Yuen et al., 2018), usually in the early stages of rhGH treatment(Chesnokova and Melmed, 2019). The cause of benign intracranial hypertension or pseudotumor cerebri induced by rhGH is uncertain and may be due to increased secretion or decreased drainage of cerebrospinal fluid. Earlier studies have speculated that growth hormone has a fluid retention property, which may lead to expansion of the cerebrospinal fluid volume. In addition, growth hormone may act to increase local IGF-1 after passing through the cerebrospinal fluid, thereby producing more cerebrospinal fluid(Malozowski et al., 1995; Crock et al., 1998; Zhou et al., 2024). Interestingly, we detected positive signals related to epilepsy in various neurological-related SOCs, such as Seizure (n=405, ROR 11.19 (10.13-12.36)), Epilepsy (n=104, ROR 14.93 (12.26-18.19)). There were also 140 cases of tremor (ROR 13.30 (11.22-15.76)) that we believe are related to epilepsy, possibly because the reporter’s identity was different, resulting in different descriptions. These AEs were not indicated in the package insert. In a recent retrospective case analysis, epilepsy occurred in 2 children undergoing rhGH treatment and returned to normal after adjusting the treatment plan. The study assessed the causal relationship between epilepsy and rhGH treatment according to the World Health Organization-Uppsala Monitoring Centre Standardized Case Causality Assessment System. The causal relationship between epilepsy and rhGH treatment in the 2 cases was considered possible(Kato et al., 2009). An earlier animal study showed that rhGH injections into the hippocampus of male mice could lead to significantly enhanced seizures(Arámburo et al., 2014). Subsequent studies have found that growth hormone can cross the blood-brain barrier, and GH receptors are expressed in multiple regions of the rodent and human brain, including the hippocampal region(Johannsson et al., 2022). Another study showed that growth hormone can significantly increase asparagine concentration in the cerebrospinal fluid, and asparagine is the main mediator of excitatory synaptic transmission(Maghnie et al., 2022). Therefore, we believe that this is a valuable clue, and the possibility that rhGH induces seizures cannot be ignored. The patient’s risk factors for potential neurological diseases should be carefully assessed before rhGH treatment is given. During treatment, if symptoms similar to epilepsy occur, rhGH treatment should be immediately discontinued and symptomatic treatment provided. After a comprehensive assessment of the child’s condition, a decision should be made as to whether rhGH treatment can continue in the future. In addition, we also found significantly correlated positive signals in nervous system disorders, but the number was relatively small, including Dementia (n=21, ROR 2879.75 (675.20-12282.24)), Amnesia (n=68, ROR 50.31 (38.85-65.17)). The available data indicate that dementia is rare. An earlier study exploring the neuroprotective effects of recombinant human growth hormone (rhGH) on neuronal function and the improvement of learning and memory deficits in mice concluded that the neuroprotective effects of rhGH have potential application value in the treatment of Alzheimer’s disease (AD)(Ling et al., 2007). The link between growth hormone and Alzheimer’s disease has also received attention. In a prospective cohort study, researchers found that lower insulin-like growth factor 1 (IGF-1) levels were associated with decreased memory(Bell et al., 2010). However, in contrast, a small study of patients with growth hormone receptor deficiency (GHRD) and their unaffected relatives revealed the opposite result, i.e., that GHRD patients showed better memory(Villarejo et al., 2008). Dementia can also be a manifestation of hypopituitarism or small glioma(Duchen and Treip, 1969; Dalbeth et al., 2021). Another interesting hypothesis is that the literature currently indicates that diabetic patients are more likely to develop dementia than normal people, which may be related to insulin resistance in diabetic patients. Patients receiving growth hormone therapy are at risk of triggering insulin resistance, which can lead to chronic neuroinflammation in patients. Of course, this is only a hypothesis, and at present, we can only confirm a significant correlation between dementia-related AE signals and recombinant human growth hormone (rhGH), which needs to be further verified through more experiments. 4.2 ADEs related to Infections and infestations Infections and infestations: The three most common ADEs were nasopharyngitis (n = 327, ROR 28.01 (24.99-31.40)), pneumonia (n = 257, ROR 12.61(11.13-14.30)) and Influenza (n = 245, ROR 25.57(22.43-29.15)). One of the severe adverse reactions listed in the warnings and precautions of the drug instructions that patients need to be alert to is acute respiratory infection caused by rhGH treatment. Up to 11% of patients may develop respiratory infections. Similar statistics were shown in the results of a large-scale, real-world study on the long-term use of growth hormone to treat growth hormone deficiency in children, which included a total of 1,170 patients from 81 research centers in China who had participated in four phase IV clinical trials and received 0.2 mg/kg or 0.1-0.2 mg/kg rhGH for 30 months. Ultimately, 18.72% of patients experienced upper respiratory tract infections, and 10% experienced upper respiratory tract viral infections(Ruokonen and Takala, 2000). Similarly, the results of a randomized, double-masked placebo-controlled trial from Finland and multiple European centers showed that compared with the placebo group, patients treated with growth hormone had an increase in ICU length of stay, mechanical ventilation time, and hospitalization time, as well as a significant increase in mortality. The most common cause was uncontrolled infection, which may be related to the effect of GH on the immune system(Warwick-Davies et al., 1995). The effect of growth hormone on the immune system is controversial, and it may either promote(Edwards et al., 1988; Kappel et al., 1994)or inhibit(Hammarqvist et al., 1992)the production of proinflammatory cytokines and reactive oxygen species, resulting in either decreased(Liao et al., 1996)or increased(Malozowski et al., 1993). Resistance to endotoxin challenge. Another alternative explanation may be related to rhGH blocking the mobilization of glutamine, which leads to a decrease in glutamine supply and, in turn, affects cells with high glutamine requirements, such as leukocytes and red blood cells(Inoue et al., 1995). Through the analysis of recombinant human growth hormones, we have also discovered several new and unexpected signals, such as sepsis and cellulitis. These adverse reaction signals may be related to uncontrolled infection. The high-frequency AE signals of Nasopharyngitis, Pneumonia, and Influenza detected in this study further confirm that this is likely to cause upper respiratory tract infections during treatment and that more serious complications of infection may also occur. Therefore, for patients receiving long-term rhGH treatment, we recommend that patients who develop respiratory tract infections during treatment or who are immunocompromised may need to re-evaluate whether to adjust the dose or even discontinue rhGH to prevent uncontrolled infections. 4.3 ADEs related to Musculoskeletal and connective tissue disorders In Musculoskeletal and connective tissue disorders, our data reported adverse reactions consistent with the drug’s instructions for use, such as Arthralgia (n=1123, ROR 108.66 (101.36-116.47)), Scoliosis (n = 235 ROR 251.84 (210.96-300.64)) and Epiphysiolysis (n = 46 ROR 350.61 (226.66-542.36)). Several studies have found that recombinant human growth hormone significantly increases the risk of scoliosis in children with idiopathic short stature(Yun et al., 2017; Maghnie et al., 2022). Scoliosis and epiphysiolysis may be caused by the rapid linear growth of children(Barake et al., 2018). Osteopenia and osteoporosis are unexpected adverse effects, but this result conflicts with the conclusions of some related studies. Multiple studies have found that rhGH has a non-significant positive effect on osteoporosis and that rhGH can increase the production of osteoblasts(Bouillon, 1991; van Bunderen et al., 2010; Atkinson et al., 2017). 4.4 ADEs related to Neoplasms benign, malignant and unspecified The link between rhGH and tumors is a major research area. The data detected in this study also show a strong correlation between them. Recently, data on 15,809 patients treated with rhGH were reported. Among 14,533 patients without a history of cancer at the beginning, 471 patients were diagnosed with new cancer during follow-up, with prostate cancer (n=86) being the most common (Bell et al., 2010). Recent experimental studies have shown that endocrine and/or paracrine GH is involved in promoting “wild-type carcinogenesis” to create a pro-tumor environment, which promotes tumor growth by inhibiting tumor suppressor proteins and altering DNA damage repair(Bamba and Kanakatti Shankar, 2022). A study on the safety of recombinant human growth hormone (rhGH) came to a similar conclusion, stating that high levels of IGF-I and growth hormone may be associated with the development of breast, prostate, and colorectal cancer, suggesting that elevated IGF-I and/or growth hormone (GH) levels may promote changes in messenger RNA or other molecular changes that promote angiogenesis and inhibit apoptosis, which may exacerbate underlying carcinogenic tendencies(Swerdlow et al., 2017). Conversely, multiple studies have investigated the risk of leukemia and other non-hematological cancers in patients treated with recombinant human growth hormone (rhGH) and have consistently concluded that rhGH treatment does not increase the risk of new cancers in the absence of other tumor risk factors(Ling et al., 2007; Woodmansee et al., 2013). This study revealed a significant correlation between tumors and recombinant human growth hormone (rhGH). This finding emphasizes the importance of closely monitoring relevant indicators when administering rhGH therapy, especially for patients who have or have had cancer. 4.5 ADEs at other SOC levels Our disproportionality analyses suggest that ADEs associated with recombinant human growth hormone may also affect other organs or tissues. This study found significant signals for AEs associated with cardiovascular risk, such as thrombosis and hypertension. Two prospective cohort studies in the Netherlands and the United Kingdom, which targeted older people and adults, respectively, showed a U-shaped association between IGF-I levels and mortality, with high levels of circulating IGF-I being associated with an increased risk of death from all causes and cardiovascular disease (CVD)(Poidvin et al., 2014). One study reported an increased incidence of hemorrhagic cerebrovascular disease, particularly subarachnoid hemorrhage, among 6,874 young people with IGHD, ISS and SGA who were treated with rhGH in childhood(Wolters et al., 2020). Excess GH/IGF-1 may directly affect endothelial function through multiple mechanisms, leading to a significantly increased risk of cardiovascular disease(Leroy et al., 2014). Notably, we also identified gout (ROR 274.16 (55.33–1358.43), PRR 274.15 (408.23), IC 7.10 (0.33), EBGM 137.57 (27.77)) as a strongly correlated ae signal. Gout is a common and treatable disease caused by the deposition of urate crystals in joint and non-joint structures. Elevated serum uric acid concentrations (hyperuricemia) are the most important risk factor for the development of gout(Mo et al., 2023). A recent study on the change in serum uric acid (UA) concentration in children with idiopathic short stature treated with rhGH found that growth hormone can significantly increase UA concentration levels(Nomura et al., 2015). Similarly, a study by Caiyan Mo et al. suggests similar results(Cornelius et al., 2012). We believe it is worthwhile to closely monitor the serum uric acid levels of patients receiving rhGH. 4.6 TTO analysis The time relationship between drug administration and the onset of the disease is crucial for assessing drug safety, as it can identify specific risk windows and lead to the prevention or early diagnosis of adverse reactions(Kubota et al., 2004). The results showed that adverse reactions related to recombinant human growth hormone mainly occurred in the first month (48.25%), and adverse reaction events may still occur after one year (26.67%). Recombinant human growth hormone can cause various types of neurological side effects, among which the more frequent ones are headache and dizziness, with a median TTO of less than one week, while the median time to onset of osteochondrosis is 1308 days. Therefore, the requirements for early detection and follow-up of adverse reactions occurring in different systems should be different. Our study has made a valuable contribution in this area, helping to reduce patient discomfort and improve their experience of the results of drug treatment better and more quickly. This study is limited by the FAERS database and its research methods. First, FAERS is a system that collects spontaneously reported data from multiple countries. Incomplete information and uncontrollable confounding factors (such as dose, duration of use, comorbidities, and concomitant medications) may affect the accuracy of the results analysis. Second, due to the lack of data on the total number of patients treated with rhGH, we were unable to calculate the incidence of specific adverse events. Third, this study was unable to establish a causal link between rhGH and adverse events, as the non-proportionality analysis only provided an assessment of signal strength, and statistical significance does not equate to causality. Therefore, further trials are needed to validate these findings. Despite these limitations, our findings can serve as a valuable guide to help healthcare professionals closely monitor rhGH-related adverse events. conclusion This study provides an in-depth analysis of adverse event reports in the FAERS database associated with the use of recombinant human growth hormone (rhGH). As a long-term post-marketing drug safety assessment, its aim is to provide a comprehensive overview of the safety of rhGH. The results show that benign intracranial hypertension-related complications and transient pain in the general body and injection site are relatively common adverse events among rhGH users. In addition, the study also revealed some unexpected but significant adverse events, including seizures and dementia. We determined the time to onset of several common and rare adverse reactions to recombinant human growth hormone use. These findings are critical to raising clinicians’ awareness of the potential risks of rhGH. They highlight the need for active monitoring, which should focus on a comprehensive assessment of individual patient differences to reduce the risk of medication in patients, which helps ensure the safe use of rhGH. Abbreviations FDA Food and Drug Administration. rhGH Recombinant human growth hormone. AEs Adverse events. SAEs serious Adverse events. FAERS Food and Drug Administration Adverse Event Reporting System. ROR reporting odds ratio. PRR proportional reporting ratio. BCPNN Bayesian confidence propagation neural network. MGPS multi-item gamma Poisson shrinker. GH Growth hormone. GHD growth hormone deficiency. CKF chronic kidney failure. TS Turner syndrome. PWS Prader-Willi syndrome. ISS Diagnosing idiopathic short stature. SHOX Short Stature HOmeoboX. SGA gestational age. ADR adverse drug reaction. MedDRA Medical Dictionary for Regulatory Activities. PT Preferred term. SOC System organ class. PS primary suspected. LLT lowest-level term. HLT high-level term. HLGT high-level group term. BIH Benign intracranial hypertension GHRD Growth hormone receptor deficiency UA uric acid jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Authors’ contributions SYF : research design, performance of the research, data analysis, the writing of the paper. HRD: data analysis. YWZ: data analysis. QXY: managed and checked all the data. All authors read, checked, and approved the final manuscript. Funding The authors declare that the research, writing and/or publication of this article was not funded. Acknowledgments We would like to thank everyone who participated in this study. jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Data Availability Statement The data that support the findings of this study are publicly available in Figshare as ”Adverse events associated with rhGH use” (doi:10.6084/m9.figshare.27619899). The dataset can be accessed through this URL: https://figshare.com/account/items/27619899/edit. Additionally, our dataset comes from the public FDA Adverse Event Reporting System (FAERS) database, which can be found at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Supplementary material The Supplementary Material for this article can be found online at: https://figshare.com/account/items/28280858/edit. Characteristics Subgroups Case number, n Case proportion, % Number of events 50,707 Gender Female 18,594 36.67 Male 27,707 54.64 Unknown 4,406 8.69 Age ＜18 years 26,974 53.20 18-64 years 4,854 9.57 ＞65 years 1,658 3.27 Unknown 17,221 33.96 Reporter Physician(MD) 7,735 15.25 Health professional(HP) 3,868 7.63 Pharmacist(PH) 2,112 4.17 Other health-professional(OT) 1,940 3.83 Consumer(CN) 34,662 68.36 Others 390 0.76 Reported Countries America(US) 34,701 68.43 Colombia(CO) 3,757 7.41 Great Britain(GB) 2,084 4.11 Argentina(AR) 1,225 2.42 Others and Country not specified 8,940 17.63 Indications Growth hormone deficiency 11,410 22.50 Product used for unknown indication 5,225 10.30 Hypopituitarism 4,124 8.13 Short stature 1,771 3.49 Body height below normal 1,111 2.19 Others and Unknown 27,066 53.39 Serious Outcome Hospitalization(HO) 4,049 7.99 Other Serious (Important Medical Event)(OT) 9,418 18.57 Death(DE) 539 1.06 Life-Threatening(LT) 298 0.59 Disability(DS) 164 0.32 Congenital Anomaly(CA) 28 0.06 Required Intervention to Prevent Permanent Impairment/Damage(RI) 11 0.02 Unknown 36,200 71.39 rhGH,recombinant human growth hormone; FAERS, Food and Drug Administration Adverse Event Reporting System. Figure 2 Signals detection at the SOC level. Distribution of ADEs of rhGH from 2014 to the second quarter of 2024 (2023 Q2). (B) The bar chart displays the reported cases of ADEs at each SOC level. rhGH,recombinant human growth hormone; FAERS, Food and Drug Administration Adverse Event Reporting System; ADEs, adverse drug events; SOC, System Organ Class. Figure 3 Time to onset of Recombinant human growth hormone adverse events. Figure 4 Time to onset (TTO) analysis of ADEs at the SOC and PT levels. Box plot of the TTO at the SOC level for rhGH. Bold bar within the stick: median TTO; Lower end of the stick: 1/4 quantile of the TTO; Upper end of the stick: 3/4 quantile of the TTO. (B) Specific comparison of TTO in PTs at eight different SOC levels. SOC, System Organ Class; PTs, preferred term; rhGH, recombinant human growth hormone. Figure 5 Signals detection at the PT level. We selected PTs with a minimum of 20 cases and displayed the ROR and corresponding 95% CI using a forest plot. The green triangle signify that the lower limit of the 95% confidence interval of the ROR exceeds 25.PTs, preferred terms; SOC, System Organ Class; PTs, preferred terms; CI, confidence interval; ROR, reporting odds rati. References 1. (2001). Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J Clin Endocrinol Metab 86(5) , 1868-1870. K., Ensor, J., Trachtenberg, B., and Bernicker, E.H. (2019). Osimertinib-Induced Cardiotoxicity: A Retrospective Review of the FDA Adverse Events Reporting System (FAERS). JACC CardioOncol 1(2) , 172-178. C., Alba-Betancourt, C., Luna, M., and Harvey, S. (2014). Expression and function of growth hormone in the nervous system: a brief review. Gen Comp Endocrinol 203 , 35-42. H.F., Moyer, R.F., Yacoub, D., Coughlin, D., and Birmingham, T.B. (2017). Effects of Recombinant Human Growth Hormone for Osteoporosis: Systematic Review and Meta-Analysis. Can J Aging 36(1) , 41-54. V., and Kanakatti Shankar, R. (2022). Approach to the Patient: Safety of Growth Hormone Replacement in Children and Adolescents. J Clin Endocrinol Metab 107(3) , 847-861. M., Arabi, A., Nakhoul, N., El-Hajj Fuleihan, G., El Ghandour, S., Klibanski, A., et al. (2018). Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis. Endocrine 59(1) , 39-49. A., and Evans, S.J. (2009). Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 18(6) , 427-436. J., Parker, K.L., Swinford, R.D., Hoffman, A.R., Maneatis, T., and Lippe, B. (2010). Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab 95(1) , 167-177. S.L., Allen, D.B., Graves, D., August, G., Moshang, T., and Rosenfeld, R. (1996). Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab 81(5) , 1704-1710. S.L., and MacGillivray, M.H. (1997). A risk-benefit assessment of growth hormone use in children. Drug Saf 17(5) , 303-316. R. (1991). Growth hormone and bone. Horm Res 36 Suppl 1 , 49-55. E., Wood, L., and Wood, S. (1999). The medical dictionary for regulatory activities (MedDRA). Drug Saf 20(2) , 109-117. 2165/00002018-199920020-00002.Bryant, J., Baxter, L., Cave, C.B., and Milne, R. (2007). Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database Syst Rev (3) , Cd004440. P., Hetta, J., Wide, L., Månsson, J.E., Ekman, R., and Karlsson, F.A. (1996). Growth hormone treatment affects brain neurotransmitters and thyroxine [see comment]. Clin Endocrinol (Oxf) 44(3) , 319-324. V., and Melmed, S. (2019). Growth hormone in the tumor microenvironment. Arch Endocrinol Metab 63(6) , 568-575. P.E., and Cowell, C.T. (2000). Safety issues in children and adolescents during growth hormone therapy–a review. Growth Horm IGF Res 10(6) , 306-317. P., Rogol, A.D., Deal, C.L., Saenger, P., Reiter, E.O., Ross, J.L., et al. (2008). Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 93(11) , 4210-4217. V.R., Sauzet, O., and Evans, S.J. (2012). A signal detection method to detect adverse drug reactions using a parametric time-to-event model in simulated cohort data. Drug Saf 35(7) , 599-610. P.A., McKenzie, J.D., Nicoll, A.M., Howard, N.J., Cutfield, W., Shield, L.K., et al. (1998). Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand. Acta Paediatr 87(4) , 381-386. N., Gosling, A.L., Gaffo, A., and Abhishek, A. (2021). Gout. Lancet 397(10287) , 1843-1855. F., Karagiannis, G., and Wilton, P. (2007). Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. Horm Res 68 Suppl 5 , 41-47. L.W., and Treip, C.S. (1969). Microgliomatosis presenting with dementia and hypopituitarism. J Pathol 98(2) , 143-146. C.K., 3rd, Ghiasuddin, S.M., Schepper, J.M., Yunger, L.M., and Kelley, K.W. (1988). A newly defined property of somatotropin: priming of macrophages for production of superoxide anion. Science 239(4841 Pt 1) , 769-771. S.J., Waller, P.C., and Davis, S. (2001). Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 10(6) , 483-486. L., Lijun, C., and Shiling, Y. (2019). Effects of rhGH treatment of early adolescent idiopathic short stature on bone metabolism. Journal of Pediatric Pharmacology 25(06) , 26-29. M., Raschi, E., Poluzzi, E., and Hauben, M. (2024). The evolving role of disproportionality analysis in pharmacovigilance. Expert Opin Drug Saf 23(8) , 981-994. R.C., Mattsson, A.F., Akerblad, A.C., Bengtsson, B., Cara, J., Feldt-Rasmussen, U., et al. (2012). Overall and cause-specific mortality in GH-deficient adults on GH replacement. Eur J Endocrinol 166(6) , 1069-1077. F., Strömberg, C., von der Decken, A., Vinnars, E., and Wernerman, J. (1992). Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle-free glutamine, and improves whole-body nitrogen economy after operation. Ann Surg 216(2) , 184-191. H., Pan, X., Song, J., Fang, N., Yang, R., Xiang, L., et al. (2023). Idiopathic short stature and scoliosis in children treated with growth hormone. Bone Joint J 105-b(4) , 439-448. T., Saito, H., Fukushima, R., Inaba, T., Lin, M.T., Fukatsu, K., et al. (1995). Growth hormone and insulinlike growth factor I enhance host defense in a murine sepsis model. Arch Surg 130(10) , 1115-1122. G., Touraine, P., Feldt-Rasmussen, U., Pico, A., Vila, G., Mattsson, A.F., et al. (2022). Long-term Safety of Growth Hormone in Adults With Growth Hormone Deficiency: Overview of 15 809 GH-Treated Patients. J Clin Endocrinol Metab 107(7) , 1906-1919. J.T., Chirstensen, T., Jørgensen, M., and Jakobsen, G. (1991). Development, production and pharmacodynamics of human growth hormone. Indian J Pediatr 58 Suppl 1 , 23-32. M., Hansen, M.B., Diamant, M., and Pedersen, B.K. (1994). In vitro effects of human growth hormone on the proliferative responses and cytokine production of blood mononuclear cells. Horm Metab Res 26(12) , 612-614. K., Suzuki, M., Kanno, H., Sekino, S., Kusakabe, K., Okada, T., et al. (2009). Distinct role of growth hormone on epilepsy progression in a model of temporal lobe epilepsy. J Neurochem 110(2) , 509-519. K.M., Roychoudhury, S., Wendelberger, B., Scott, J., Moroz, T., Yin, S., et al. (2022). Application of Bayesian methods to accelerate rare disease drug development: scopes and hurdles. Orphanet J Rare Dis 17(1) , 186. K., Koide, D., and Hirai, T. (2004). Comparison of data mining methodologies using Japanese spontaneous reports. Pharmacoepidemiol Drug Saf 13(6) , 387-394. C., Backeljauw, P., Tauber, M., Kanumakala, S., Loche, S., Otfried Schwab, K., et al. (2024). Growth hormone treatment in children with Prader-Willi syndrome: safety and effectiveness data from the PATRO Children study. Ther Adv Endocrinol Metab 15 , 20420188241264343. F., Dauxois, J.Y., Théophile, H., Haramburu, F., and Tubert-Bitter, P. (2014). Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases. BMC Med Res Methodol 14 , 17. W., Rudling, M., and Angelin, B. (1996). Growth hormone potentiates the in vivo biological activities of endotoxin in the rat. Eur J Clin Invest 26(3) , 254-258. F.A., Hui, D.Z., and Ji, S.M. (2007). Protective effect of recombinant human somatotropin on amyloid beta-peptide induced learning and memory deficits in mice. Growth Horm IGF Res 17(4) , 336-341. M., Ranke, M.B., Geffner, M.E., Vlachopapadopoulou, E., Ibáñez, L., Carlsson, M., et al. (2022). Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort. J Clin Endocrinol Metab 107(12) , 3287-3301. S., Tanner, L.A., Wysowski, D., and Fleming, G.A. (1993). Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Engl J Med 329(9) , 665-666. S., Tanner, L.A., Wysowski, D.K., Fleming, G.A., and Stadel, B.V. (1995). Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone. J Pediatr 126(6) , 996-999. C., Guadagni, L., Orso, M., Calcaterra, V., Wasniewska, M.G., Aversa, T., et al. (2024). Epidemiology of growth hormone deficiency in children and adolescents: a systematic review. Endocrine 85(1) , 91-98. F., Battini, V., Gringeri, M., Pozzi, M., Mosini, G., Marran, A.M.N., et al. (2021). The impact of anti-TNFα agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database. Expert Opin Biol Ther 21(9) , 1281-1290. S.P., and Doward, L.C. (1994). Quality-of-life assessment of adults with growth hormone deficiency. Implications for drug therapy. Pharmacoeconomics 6(5) , 434-441. C., Chen, H., Wang, F., Guo, Y., Wang, Y., Tong, T., et al. (2023). Uric acid levels correlate with disease activity in growth hormone-secreting pituitary adenoma patients. Front Endocrinol (Lausanne) 14 , 1230852. K., Takahashi, K., Hinomura, Y., Kawaguchi, G., Matsushita, Y., Marui, H., et al. (2015). Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases. Drug Des Devel Ther 9 , 3031-3041. M., Polistena, B., Granato, S., Novelli, G., Di Virgilio, R., La Torre, D., et al. (2022). Pediatric growth hormone treatment in Italy: A systematic review of epidemiology, quality of life, treatment adherence, and economic impact. PLoS One 17(2) , e0264403. A., Touzé, E., Ecosse, E., Landier, F., Béjot, Y., Giroud, M., et al. (2014). Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. Neurology 83(9) , 780-786. K.J., Lanes, S., and Sacks, S.T. (2004). The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiol Drug Saf 13(8) , 519-523. E., and Takala, J. (2000). Dangers of growth hormone therapy in critically ill patients. Ann Med 32(5) , 317-322. T., Tamon, A., Kadoyama, K., and Okuno, Y. (2013). Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci 10(7) , 796-803. L., Meazza, C., Pagani, S., Paganelli, V., Bozzola, E., Tinelli, C., et al. (2017). Efficacy of long-term growth hormone therapy in short non-growth hormone-deficient children. J Pediatr Endocrinol Metab 30(2) , 197-201. S.M., and Holmes, S.J. (1994). Growth hormone replacement in adults. Bmj 308(6940) , 1314-1315. Y., Zhang, Q., He, X., Liu, Y., Wu, P., and Chen, L. (2022). Fluoroquinolone-associated suspected tendonitis and tendon rupture: A pharmacovigilance analysis from 2016 to 2021 based on the FAERS database. Front Pharmacol 13 , 990241. A.J., Cooke, R., Beckers, D., Borgström, B., Butler, G., Carel, J.C., et al. (2017). Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study. J Clin Endocrinol Metab 102(5) , 1661-1672. N.A., and Biller, B.M. (2009). Growth hormone and bone. Curr Opin Endocrinol Diabetes Obes 16(6) , 415-422. Bunderen, C.C., van Nieuwpoort, I.C., van Schoor, N.M., Deeg, D.J., Lips, P., and Drent, M.L. (2010). The association of serum insulin-like growth factor-I with mortality, cardiovascular disease, and cancer in the elderly: a population-based study. J Clin Endocrinol Metab 95(10) , 4616-4624. A., Díaz-Guzman, J., and Bermejo-Pareja, F. (2008). Dementia in hypopituitarism. Eur J Neurol 15(6) , e53-54. J., Lowrie, D.B., and Cole, P.J. (1995). Growth hormone is a human macrophage activating factor. Priming of human monocytes for enhanced release of H2O2. J Immunol 154(4) , 1909-1918.Wolters, T.L.C., Netea, M.G., Riksen, N.P., Hermus, A., and Netea-Maier, R.T. (2020). Acromegaly, inflammation and cardiovascular disease: a review. Rev Endocr Metab Disord 21(4) , 547-568. W.W., Zimmermann, A.G., Child, C.J., Rong, Q., Erfurth, E.M., Beck-Peccoz, P., et al. (2013). Incidence of second neoplasm in childhood cancer survivors treated with GH: an analysis of GeNeSIS and HypoCCS. Eur J Endocrinol 168(4) , 565-573. R.J., Krantz, M.S., Phillips, E.J., and Stone, C.A., Jr. (2021). Emerging Causes of Drug-Induced Anaphylaxis: A Review of Anaphylaxis-Associated Reports in the FDA Adverse Event Reporting System (FAERS). J Allergy Clin Immunol Pract 9(2) , 819-829.e812. K.C.J., Miller, B.S., and Biller, B.M.K. (2018). The current state of long-acting growth hormone preparations for growth hormone therapy. Curr Opin Endocrinol Diabetes Obes 25(4) , 267-273. Y.H., Kwon, S.S., Koh, Y., Kim, D.J., Ahn, J., and Lee, S.Y. (2017). Influence of growth hormone treatment on radiographic indices of the spine: propensity-matched analysis. J Orthop Surg Res 12(1) , 130. C., Peng, S., Lin, A., Jiang, A., Peng, Y., Gu, T., et al. (2023). Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. EClinicalMedicine 59 , 101967. Y., Jia, R., Xu, Z., and Ma, Y. (2024). Case report: Epilepsy during the use of recombinant human growth hormone: a report on two cases and a literature review. Front Pharmacol 15 , 1458487. 1 The process of selecting recombinant human growth hormone adverse events from food and drug administration adverse event reporting database. Table 1. Clinical characteristics of reports with rhGH from the FAERS database (January 2014 to June 2024). Crossref Google Scholar Information & Authors Information Version history V1 Version 1 06 February 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords adverse drug reaction5 data mining4 disproportionality analysis2 faers1 recombinant human growth hormone3 Authors Affiliations Shiyu Feng 0009-0000-5480-4336 Mianyang Orthopaedic Hospital View all articles by this author Qingxin Yang [email protected] Mianyang Orthopaedic Hospital View all articles by this author Huarong Deng Mianyang Orthopaedic Hospital View all articles by this author Yuwei Zeng Mianyang Orthopaedic Hospital View all articles by this author Metrics & Citations Metrics Article Usage 502 views 228 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shiyu Feng, Qingxin Yang, Huarong Deng, et al. Safety surveillance of recombinant human growth hormone : An observational, pharmacovigilance study leveraging FAERS database. Authorea . 06 February 2025. DOI: https://doi.org/10.22541/au.173882792.24431559/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.173882792.24431559/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ff521af3c7452ad',t:'MTc3OTM4Mjc2NQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();