Distinct clinical characteristics and prognosis of pediatric-onset GHPA patients compared with adult-onset patients

Distinct clinical characteristics and prognosis of pediatric-onset GHPA patients compared with adult-onset patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Distinct clinical characteristics and prognosis of pediatric-onset GHPA patients compared with adult-onset patients Xue-Qing Zheng, Sheng-Min Yang, Tong-Xin Xiao, Ying-Ying Yang, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4551046/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Sep, 2024 Read the published version in Endocrine → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose To explore the clinical characteristics, treatment, and prognosis of growth hormone-secreting pituitary adenoma (GHPA) patients with pediatric-onset, so as to facilitate the clinical management. Methods A retrospective cohort study was carried out between 102 pediatric-onset GHPA patients admitted to our hospital from January 2013 to June 2022 and 204 adult-onset GHPA patients who were randomly matched. Results GHPA with pediatric-onset was predominantly male, associated with higher proportion of genetic syndromes, longer course, and delay on diagnosis. Clinical symptoms of visual field defects and menstrual abnormality were more common. The pediatric-onset group presented with higher growth hormone (GH) nadir during oral glucose tolerance test (OGTT), higher rates of hyperprolactinemia, larger maximum diameter of adenoma, higher rates of optic chiasm compression, suprasellar invasion, and pituitary apoplexy. Hypertension, diabetes, and obstructive sleep apnea-hypopnea syndrome (OSAHS) were more common in the adult-onset group. Echocardiography results were similar between the two groups. The pediatric-onset group owned significantly higher treatment scores and proportions of multimodal therapy modality, more surgical complications, and a higher proportion of ki67 ≥ 3%. There was no significant difference in the final cure rate, but male patients with adult-onset had a worse prognosis. The recurrence rate was also similar between two groups. Hypopituitarism was more prevalent in the pediatric-onset group, while the adult-onset group had a higher rate of combining other tumors. Conclusion The clinical characteristics of pediatric-onset GHPA patients were different from adult-onset patients. Multimodal therapy modalities could help to achieve a cure rate similar to that of adult-onset patients. pediatric-onset growth hormone secreting pituitary adenoma clinical characteristics metabolism treatment prognosis Figures Figure 1 Introduction Excess growth hormone (GH) secreted by growth hormone-secreting pituitary adenoma (GHPA) stimulates the over synthesis of insulin-like growth factor 1 (IGF-1). Classically, pathologic GH excess causes acromegaly in adults and causes gigantism before the fusion of the epiphyseal growth plate in children.[ 1 ] Compared with adult-onset GHPA, earlier onset is associated with multiple genetic causes and syndromes, predicting different biological properties of the adenoma.[ 2 ] Also, premature exposure to pathologically excess GH and IGF-1 may result in more profound harmful effects on patients.[ 3 ] Due to the rarity of GHPA with pediatric-onset, previous cohort studies were insufficient, and the numbers of patients included was generally small. Comparative studies with adult-onset patients are extremely rare, which limits clinicians’ understanding of the differences in clinical characteristics, treatment, and prognosis between these two groups. Here we systematically compare GHPA patients with pediatric- and adult-onset for the first time from clinical manifestations, hormone levels, pituitary imaging, cardiovascular function, to treatment and prognosis, hoping to assist clinical management and future research of pediatric-onset GHPA. Patients and methods 1. Patient population This is a retrospective cohort study. 1555 patients were discharged from the pituitary center in Peking Union Medical College Hospital (PUMCH) with the diagnosis of “GHPA” for the first time from January 2013 to June 2022. Among them, 102 patients were selected according to the following criteria: (1) the initial symptom which related to GHPA appeared before 18-year-old, including growth acceleration, facial change, limbs enlargement, and headache; (2) mammosomatotroph adenoma, mixed somatotroph, and lactotroph adenoma were excluded according to WHO classification of pituitary tumors in 2017.[ 4 ] To ensure that patients with pediatric-onset and adult-onset GHPA received the same level of treatment, we used random numbers to match these two groups by 1:2 based on the year of patients’ initial visit to PUMCH. Therefore 204 patients with adult-onset GHPA were randomly selected. Study measures The criteria for biochemical remission of GHPA were as follows: IGF-1 decreased to the normal range, along with random GH or GH nadir during oral glucose tolerance test (OGTT) < 1.0 ng/ml. Here we use the upper limit of normal (ULN) based on the reference range matched by age and sex to describe the relative level of IGF-1. However, because changes in IGF-1 take time, immediate surgical remission was defined as random GH or OGTT GH nadir < 1.0 ng/ml within a week after surgery. The definition of hypopituitarism was described in detail in our previous work.[ 5 ] Diagnostic criteria for menstrual abnormalities among adult patients were referenced to 2018 revisions of the international Federation of Gynecology and Obstetrics (FIGO) systems, while patients < 18 years old were judged to have abnormal menstruation if they presented with amenorrhea (menarche had not occurred by 15 years old).[ 6 , 7 ] For obesity and hypertension at age < 18 years old, the diagnostic criteria referred to international obesity task force (IOTF)[ 8 ] and 2018 Chinese guidelines for the management of hypertension[ 9 ]. Giant adenomas were defined as pituitary adenomas with maximum diameters ≥ 4 cm. The homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were calculated by the formulae respectively: HOMA-IR = [insulin (mIU/L) × fasting glucose (mmol/L)]/22.5; HOMA-β (%) = [20 × insulin (mIU/L)]/[glucose (mmol/L) – 3.5].[ 10 ] The cardiovascular function was measured by M-mode, two-dimensional, and pulsed Doppler echocardiography. Parameters including left ventricular ejection fraction (LVEF), anteroposterior left atrial diameter (AP-LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular posterior wall thickness (LVPWT), interventricular septum diastolic thickness (IVST), and regurgitation of each valve were recorded. Left ventricular mass (LVM) was calculated according to Devereux’s formula: LVM (g) = 1.04 × [(LVEDD + IVST + LVPWT) 3 – LVEDD 3 ] × 0.8 + 0.6. Left ventricular hypertrophy (LVH) was considered when LVM values, corrected for body surface area as LVMi, were ≥ 115 g/m 2 in males and ≥ 95 g/m 2 in females.[ 11 ] Dilated left ventricle was defined when LVEDD was > 55 mm in males and > 50 mm in females (or LVEDD > 2 standard deviation (SD) + 5% of the predicted value according to age and body surface area). In this article we use treatment score to measure the types of treatment modalities that each patient received in total, which was calculated as the sum of each surgery and radiotherapy, the use of SSAs, dopamine agonists, and temozolomide (each was allocated one point). If a patient has used the same class of medication multiple times during the course, only one point would be recorded. A treatment score ≥ 3 was considered a multimodal therapy approach.[ 2 ] Surgical complications include cerebrospinal fluid rhinorrhea, central nervous system infection, postoperative vision impairment, and impairment of extraocular muscle function. 3. Statistical analysis The statistical and analytical procedures were performed using SPSS software version 25.0. After normality examination using Kolmogorov–Smirnov test, continuous variables were compared by t -test or Wilcoxon rank sum test. Categorical variables were analyzed by Chi-square test of Fisher exact test. The threshold of statistical significance was set to be 0.05. Results 1. Characterization of the study population A total of 102 GHPA patients with pediatric-onset were admitted to PUMCH from January 2013 to June 2022, accounting for 6.6% of the total GHPA patients. Female patients accounted for 30.3% and 50.4% in pediatric-onset and adult-onset groups respectively ( p = 0.001, Table 1 ). The median ages at first admission were 21.0 (17.0, 27.0) and 43.0 (34.0, 53.0) for the two groups, and the mean age of onset was 14.0 (11.0, 16.0) and 37.0 (28.0, 45.0) respectively. Compared with adult-onset GHPA patients, the median duration of disease and delay of diagnosis were significantly longer (7.0 (3.0, 14.0) years vs. 4.5 (2.0, 8.8) years, p < 0.001; 5.0 (2.0, 10.0) years vs. 4.0 (2.0, 7.0) years, p = 0.003), and a greater proportion of patients had received prior treatment before first admission in PUMCH (45.1% vs. 27.0%, p = 0.001). The final heights of male and female patients in younger group were also significantly higher (male: 185.8 ± 12.6 cm vs. 175.0 (170.0, 178.5) cm, p < 0.001; female: 172.1 ± 10.9 cm vs. 162.4 ± 5.9 cm, p < 0.001). 47 patients with pediatric-onset (47.5%) were taller than the 97th percentile at their first visit to PUMCH and thus could be diagnosed with gigantism. As for the occupying effect, more patients manifested as visual field defects in the younger group (20.8% vs. 9.3%, p = 0.005), which was more pronounced in male patients (Supplementary Table 1, 21.4% vs. 6.9%, p = 0.005). For female patients, younger onset was associated with a higher rate of menstrual abnormality (64.5% vs. 35.0%, p = 0.003). 2 pediatric-onset and 4 adult-onset GHPA patients had a family history of pituitary adenomas (2.0% vs. 2.0%). 12 patients in pediatric-onset group were with genetic pathogenesis (1 multiple endocrine neoplasia type 1 (MEN1), 9 McCune-Albright syndrome (MAS), and 2 X-linked acrogigantism (X-LAG)), which was significantly more than 1 MEN1 adult-onset patient (11.8% vs. 0.5%, p < 0.001). Table 1 Baseline clinical parameters between pediatric- and adult-onset GHPA Pediatric-onset (n = 102) Adult-onset (n = 204) P value Female (%) 31(30.3%) 103(50.4%) 0.001 Age at first admission (years) 21.0 (17.0, 27.0) 43.0 (34.0, 53.0) < 0.001 Age of onset (years) 14.0 (11.0, 16.0) 37.0 (28.0, 45.0) < 0.001 Course of disease (years) 7.0 (3.0, 14.0) 4.5 (2.0, 8.8) < 0.001 Delay of diagnosis (years) 5.0 (2.0, 10.0) 4.0 (2.0, 7.0) 0.003 Patients treated before (%) 46(45.1%) 55(27.0%) 0.001 Headache (%) 40/101 (39.6%) 73/204 (35.8%) 0.516 Vision impairment (%) 33/101 (32.7%) 66/204 (32.4%) 0.955 Visual field defects (%) 21/101 (20.8%) 19/204 (9.3%) 0.005 Menstrual abnormality (%) 20/31 (64.5%) 36/103 (35.0%) 0.003 Final height in male (cm) 185.8 ± 12.6 175.0 (170.0, 178.5) < 0.001 Final height in female (cm) 172.1 ± 10.9 162.4 ± 5.9 < 0.001 Family history of pituitary adenoma (%) 2/102 (2.0%) 4/204 (2.0%) 1.000 Genetic syndromes (%) 12/102 (11.8%) 1/204 (0.5%) < 0.001 Random GH (ng/ml) 20.10 (10.30, 47.3) 15.6 (7.4, 27.9) 0.031 OGTT-GH nadir (ng/ml) 14.60 (6.43, 39.60) 10.90 (5.22, 19.70) 0.030 IGF-1×ULN 2.41 ± 1.12 2.98 ± 0.99 < 0.001 PRL (ng/ml) 25.47 (12.37, 62.40) 13.20 (8.67, 26.87) < 0.001 Hyperprolactinemia (%) 51/75 (68.0%) 47/148 (31.8%) < 0.001 Macroadenoma (%) 77/90 (85.6%) 140/173 (80.9%) 0.348 Giant adenoma (%) 10/90 (11.1%) 4/173 (2.3%) 0.006 Maximum diameter (mm) 22.9 ± 11.2 15.0 (11.0, 21.0) < 0.001 Knosp ≥ 3 (%) 22/57 (38.6%) 36/124 (29.0%) 0.200 Optic chiasma compression (%) 50/79 (63.3%) 43/145 (29.7%) < 0.001 Suprasellar invasion (%) 30/51 (58.9%) 29/108 (26.9%) < 0.001 Sellar bottom erosion (%) 37/53 (69.8%) 63/115 (54.8%) 0.065 Hypointensity on T2 (%) 21/75 (28.0%) 42/136 (30.9%) 0.661 Pituitary apoplexy (%) 13/85 (15.3%) 10/172 (5.8%) 0.012 2. Comparison of hormone levels Compared with the adult-onset group, the baseline median random GH and the median GH nadir during OGTT were all higher in the pediatric-onset group (20.10 (10.30, 47.30) ng/ml vs. 15.6 (7.4, 27.9) ng/ml, p = 0.031; 14.60 (6.43, 39.60) ng/ml vs. 10.90 (5.22, 19.70) ng/ml, p = 0.030). In addition, the PRL level and the proportion of patients with hyperprolactinemia were also higher in the younger-onset group (25.47 (12.37, 62.40) ng/ml vs. 13.20 (8.67, 26.87) ng/ml, p < 0.001; 68.0% vs. 31.8%, p < 0.001). However, patients in the adult-onset group presented a higher level of IGF-1×ULN (2.98 ± 0.99 vs. 2.41 ± 1.12, p < 0.001). Comparing the differences between genders, mean IGF-1 x ULN was significantly higher in males in patients with adult-onset (3.27 ± 1.04 vs. 2.73 ± 0.87, p = 0.001), while hyperprolactinemia was more common in males in patients with adult-onset (41.4% vs. 23.1%, p = 0.017), other differences on hormone levels between genders were not found. 3. Pituitary magnetic resonance imaging (MRI) 85.6% (77/90) of pediatric-onset patients and 80.9% (140/173) of adult-onset patients had macroadenomas. However, a significantly higher percentage of patients in the pediatric-onset group presented with giant adenomas (11.1% vs. 2.3%, p = 0.006) and larger maximum diameters (22.9 ± 11.2 mm vs, 15.0 (11.0, 21.0) mm, p < 0.001). Although the proportion of patients with Knosp ≥ 3 was not significantly different between the two groups, more patients in the pediatric-onset group demonstrated optic chiasma compression (63.3% vs. 29.7%, p < 0.001), suprasellar invasion (58.9% vs. 26.9%, p < 0.001), and pituitary apoplexy (15.3% vs. 5.8%, p = 0.012) on MRI. Interestingly, in both groups, the proportions of female patients showing optic chiasma compression were all significantly higher (pediatric-onset: 80.8% vs. 54.7%, p = 0.024; adult-onset: 39.7% vs. 19.4%, p = 0.008). No other differences on MRI were found between male and female patients. 4. Metabolic and cardiovascular functions. There were no significant differences on median BMI (26.90 (23.83, 29.67) vs. 26.12 (23.61, 28.37) and obesity rate (39.0% vs. 29.7%, p = 0.052) between two groups. Hypertension and diabetes mellitus were more prevalent in GHPA patients with adult-onset (Table 2 , 30 .9% vs. 17.6%, p = 0.013; 27.5% vs. 16.7%, p = 0.037), and this trend was more pronounced in males (35.6% vs. 19.7%, p = 0.024; 30.7% vs. 16.9%, p = 0.040). The prevalence of obstructive sleep apnea-hypopnea syndrome (OSAHS) was also higher in the adult-onset group (75.4% vs. 53.6%, p = 0.039), and this age-related difference was more pronounced in females (73.9% vs. 33.3%, p = 0.049). Interestingly, the correlation of OSAHS and obesity was only observed in pediatric-onset patients (Supplementary table 2, 73.3% vs. 30.8%, p = 0.024). Fasting glucose (5.30 (5.00, 5.85) mmol/L vs. 5.80 (5.40, 6.70) mmol/L, p < 0.001) was significantly lower in pediatric-onset group, while fasting insulin levels (36.88 ± 22.51 mIU/L vs. 17.21 (10.60, 25.00) mIU/L, p = 0.004), HOMA-IR (20.43 ± 16.58 vs. 4.50 (2.78, 6.77), p = 0.023), and HOMA-β (420.14 ± 265.83 vs. 111.72 (75.29, 201.81), p < 0.001) were all significantly higher in the pediatric-onset group. Regarding the lipid profile, except for a higher mean high-density lipoprotein cholesterol (HDL-C) in the adult-onset group (1.14 ± 0.26 mmol/L vs. 0.98 (0.80, 1.17) mmol/L, p = 0.007), there was no significant difference on total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) between two groups. Table 2 Metabolism and cardiovascular functions between pediatric- and adult-onset GHPA Pediatric-onset (n = 102) Adult-onset (n = 204) P value BMI (kg/m 2 ) 26.90 (23.83, 29.67) 26.12 (23.61, 28.37) 0.151 Obesity (%) 39/100 (39.0%) 55/197 (29.7%) 0.052 Hypertension (%) 18/102 (17.6%) 63/204 (30.9%) 0.013 Diabetes mellitus (%) 17/102 (16.7%) 56/204 (27.5%) 0.037 IFG or IGT 7/102 (6.9%) 17/204 (8.3%) 0.652 OSAHS (%) 15/28 (53.6%) 46/61 (75.4%) 0.039 Fasting glucose (mmol/L) 5.30 (5.00, 5.85) 5.80 (5.40, 6.70) < 0.001 HbA1c (%) 5.70 ± 0.38 5.90 (5.60, 6.60) 0.130 Fasting Insulin (mIU/L) 36.88 ± 22.51 17.21 (10.60, 25.00) 0.004 HOMA-IR 20.43 ± 16.58 4.50 (2.78, 6.77) 0.023 HOMA-β 420.14 ± 265.83 111.72 (75.29, 201.81) < 0.001 TC (mmol/L) 4.00 (3.56, 4.56) 4.31 ± 0.90 0.054 TG (mmol/L) 1.20 (1.02, 2.14) 1.27 (0.89, 1.79) 0.469 LDL-C (mmol/L) 2.45 ± 0.70 2.57 ± 0.69 0.374 HDL-C (mmol/L) 0.98 (0.80, 1.17) 1.14 ± 0.26 0.007 LVEF < 50% (%) 2/60 (3.3%) 1/128 (0.8%) 0.244 Enlarged left atrial (%) 20/60 (33.3%) 38/125 (30.4%) 0.687 Enlarged left ventricle (%) 16/60 (26.7%) 28/125 (22.4%) 0.523 Thickened IVST (%) 5/60 (8.3%) 9/126 (7.1%) 0.772 Thickened LVPWT (%) 2/60 (3.3%) 5/126 (4.0%) 1.000 Abnormal LVMi (%) 7/58 (12.1%) 12/121 (9.9%) 0.662 Valvular regurgitation (%) 21/61 (34.4%) 51/129 (39.5%) 0.498 On echocardiography, there were no significant differences in the proportions of patients presenting with LVEF < 50% (3.3% vs. 0.8%), enlarged AP-LAD (33.3% vs. 30.4%), enlarged LVEDD (26.7% vs. 22.4%), thickened IVST (8.3% vs. 7.1%), thickened LVPWT (3.3% vs. 4.0%), abnormal LVMi (12.1% vs. 9.9%), and valvular regurgitation (34.4% vs. 39.5%) between pediatric- and adult-onset groups. In patients with adult-onset acromegaly, more males showed enlarged AP-LAD (38.8% vs. 20.7%, p = 0.028) and thickened IVST (11.8% vs. 1.7%, p = 0.038). All these above cardiac structural abnormalities shown on echocardiograms were associated with hypertension (Supplementary table 3). 5. Treatment Compared with the adult-onset group, the pediatric-onset group had a significantly higher median treatment score (2.0 (1.0, 3.0) vs. 1.0 (1.0, 2.0), p < 0.001) and proportion of patients receiving a multimodal therapy modality (Table 3 , treatment score ≥ 3, 29.6% vs. 13.4%, p < 0.001), as well as a higher proportion of surgical complications (19.0% vs. 9.2%, p = 0.021). Gender-related analysis showed that younger-onset patients were observed to be more prone to surgical complications only in males (19.3% vs. 8.2%, p = 0.042). The proportion of patients who received at least 2 surgeries (26.5% vs. 19.3%) or radiotherapy (23.5% vs. 16.3%) were similar between two groups. But among adult-onset patients, more male patients who received at least 2 surgeries (27.0% vs. 11.8%, p = 0.006) or radiotherapy (23.0% vs. 9.8%, p = 0.002) than that of female patients. The immediate GH nadir (1.77 (0.50, 6.06) ng/ml vs. 0.99 (0.50, 2.11) ng/ml, p = 0.075) and the proportion of patients with immediate GH nadir < 1.0 ng/ml after the first surgery (30.9% vs. 42.4%, p = 0.078) in the pediatric- and adult-onset groups were not significantly different. However, in male patients, younger onset was associated with higher immediate GH nadir (2.78 (0.50, 8.74) ng/ml vs. 0.93 (0.43, 2.33) ng/ml, p = 0.024) and a lower proportion of patients with immediate GH nadir < 1.0 ng/ml after the first surgery (29.8% vs. 47.7%, p = 0.033). Postoperative histopathological analysis showed no significant difference on the proportion of p53 positive between the pediatric- and adult-onset groups (14.1% vs. 14.7%), while more patients in the pediatric-onset group presented Ki-67 ≥ 3% (41.0% vs. 27.7%, p = 0.034). Table 3 Treatment and prognosis between pediatric- and adult-onset GHPA Pediatric-onset (n = 102) Adult-onset (n = 204) P value Treatment score 2.0 (1.0, 3.0) 1.0 (1.0, 2.0) < 0.001 Treatment score ≥ 3 (%) 29/98 (29.6%) 27/202 (13.4%) < 0.001 Surgical complications (%) 16/84 (19.0%) 18/195 (9.2%) 0.021 Received ≥ 2 surgeries (%) 26/98 (26.5%) 39/202 (19.3%) 0.154 Received radiotherapy (%) 23/98 (23.5%) 33/202 (16.3%) 0.137 Immediate GH nadir after initial surgery (ng/ml) 1.77 (0.50, 6.06) 0.99 (0.50, 2.11) 0.075 Immediate GH after initial surgery < 1.0 ng/ml (%) 25/81 (30.9%) 73/172 (42.4%) 0.078 P53 positive (%) 11/78 (14.1%) 27/184 (14.7%) 0.904 Ki67 ≥ 3% (%) 32/78 (41.0%) 51/184 (27.7%) 0.034 Duration of follow-up (years) 1.4 (0.3, 3.9) 1.1 (0.3, 3.4) 0.588 GH nadir after 3 months (ng/ml) 1.58 (0.16, 3.93) 0.51 (0.12, 1.74) 0.074 IGF-1×ULN after 3 months 1.16 (0.89, 1.69) 1.18 (0.85, 1.84) 0.679 Cure rate after 3 months (%) 21/68 (30.9%) 49/145 (33.8%) 0.673 GH nadir after 1 year (ng/ml) 0.95 (0.24, 3.68) 0.70 (0.10, 2.07) 0.174 IGF-1×ULN after 1 year 1.13 ± 0.70 1.07 (0.82, 1.83) 0.233 Cure rate after 1 year (%) 18/45 (40.0%) 30/87 (34.5%) 0.532 GH nadir at last follow-up (ng/ml) 0.60 (0.16, 2.36) 0.58 (0.10, 1.07) 0.631 IGF-1×ULN at last follow-up 0.77 (0.48, 1.33) 0.85 (0.69, 1.30) 0.117 Cure rate at last follow-up (%) 33/56 (58.9%) 56/111 (50.5%) 0.300 Recurrence (%) 8/86 (9.3%) 37/170 (21.8%) Hypopituitarism (%) 48/100 (48.0%) 49/191 (25.7%) < 0.001 Hypogonadotropic hypogonadism (%) 44/100 (44.0%) 40/191 (20.9%) < 0.001 Secondary hypothyroidism (%) 18/100 (18.0%) 16/191 (8.4%) 0.015 Secondary hypoadrenocorticism (%) 12/100 (12.0%) 12/191 (6.3%) 0.092 Other tumors (%) 1/102 (1.0%) 20/204 (9.8%) 0.004 6. Follow-up The median follow-up was 1.1 (0.3, 3.6) years for all patients, with 54.6% patients’ follow-up more than 1 year. We measured GH nadir, IGF-1×ULN, and cure rate at 3 months, 1 year, and at the final follow-up after the initial surgical treatment (Fig. 1 ). We found that there were no significant differences on GH/IGF-1, cure rate at any time, and recurrence rate between two groups. Significantly higher GH nadir at 1-year follow-up (2.67 ± 2.47 years vs. 0.50 (0.06, 1.68) years, p = 0.013) was observed in the pediatric-onset group in male patients. However, no correlation between age of onset and prognosis was observed in female patients. In addition, we also found that the cure rate at the last follow-up was significantly higher in females than males in the adult-onset group (53.2% vs. 39.0%, p = 0.010). Hypopituitarism developed in some GHPA patients during the course and follow-up. Compared with the adult-onset group, patients in the pediatric-onset group developed higher proportions of hypopituitarism (48% vs. 25.7%, p < 0.001), hypogonadotropic hypogonadism (44.0% vs. 20.9%. p < 0.001), and secondary hypothyroidism (18.0% vs. 8.4%, p = 0.015). In adult-onset patients, hypopituitarism was more common in male patients than the female patients (26.6% vs. 14.4%, p = 0.037). Additionally, by the time of the last follow-up, 1 patient in the pediatric-onset group had developed thyroid cancer, while 20 patients in the adult-onset group developed tumors (1.0% vs. 9.8%, p = 0.004), 12 of which had thyroid cancer, others including thymoma, breast tumor, adrenal adenoma, kidney cancer, colon tumor, parotid cancer, and bladder cancer. Clinical features of pediatric-onset GHPA patients with genetic syndromes We further compared the clinical parameters between pediatric-onset GHPA patients with or without genetic syndromes (Table 4 ). Limited by the sample size, we only found that the onset age was significantly earlier (6.4 ± 5.3 vs. 15.0 (12.0, 16.0), p < 0.001), and both the rates of gigantism (75.0% vs. 43.7%, p = 0.042) and hypertension (50.0% vs. 13.3%, p = 0.006) were significantly higher in GHPA patients with genetic syndromes. No difference was found in hormone levels, MRI features, and prognosis between two groups. Table 4 Clinical parameters between pediatric-onset patients with or without genetic syndromes With genetic syndromes (n = 12) Without genetic syndromes (n = 90) P value Female (%) 6/12 (50%) 25/90 (27.8%) 0.178 Age at first admission (years) 19.2 ± 13.9 21.0 (17.0, 27.0) 0.165 Age of onset (years) 6.4 ± 5.3 15.0 (12.0, 16.0) < 0.001 Delay of diagnosis (years) 4.5 (3.0, 17.3) 5.0 (2.0, 10.5) 0.685 Gigantism (%) 9/12 (75.0%) 38/87 (43.7%) 0.042 Random GH (ng/ml) 14.80 (6.00, 68.90) 25.00 (13.00, 50.00) 0.685 OGTT-GH nadir (ng/ml) 12.95 (6.52, 74.90) 15.75 (6.43, 39.53) 0.675 IGF-1×ULN 2.95 ± 1.33 2.38 ± 1.11 0.884 Hyperprolactinemia (%) 10/11(90.9%) 41/64 (64.1%) 0.093 Maximum diameter (mm) 19.48 ± 12.52 23.21 ± 11.03 0.920 Knosp ≥ 3 (%) 5/10 (50.0%) 17/47 (36.2%) 0.485 Optic chiasma compression (%) 6/8 (75.0%) 44/71 (62.0%) 0.703 Hypertension (%) 6/12 (50.0%) 12/90 (13.3%) 0.006 Diabetes mellitus (%) 2/12 (16.7%) 15/90 (16.7%) 1.000 Treatment score 2.6 ± 0.97 2.0 (1.0, 3.0) 0.090 Treatment score ≥ 3 (%) 5/12 (41.7%) 24/86 (27.9%) 0.331 Immediate GH after initial surgery < 1.0 ng/ml (%) 2/8 (25.0%) 23/73 (31.5%) 1.000 Cure rate at last follow-up (%) 5/10 (50.0%) 34/76 (44.7%) 1.000 Hypopituitarism (%) 6/12 (50.0%) 42/88 (47.7%) 0.882 Discussion In adults, chronic GH and IGF-1 excess causes local bone and soft tissue overgrowth, which leads to acromegaly. In children and adolescents, excess GH and IGF-1 before the fusion of the epiphyseal growth plate results in gigantism by causing excessive linear growth which can be further facilitated by secondary hypogonadism.[ 3 , 12 ] However, for children with GHPA, the most common presentation was acromegaly, whereas only about half of them presented with growth acceleration.[ 1 ] Unlike the balanced gender ratio in the adult-onset group, the majority of the pediatric-onset group was male, which is consistent with previous findings.[ 2 ] The median course of GHPA and delay of diagnosis in the pediatric-onset group were both longer than the adult-onset group, which may increase the harmful effects of prolonged GH and IGF-1 excess.[ 2 , 3 ] Thus, early diagnosis and treatment are particularly important for younger-onset patients.[ 13 ] In accordance with previous literature, the tumor mass effect in the pediatric-onset group was obvious, especially for visual field defects.[ 12 ] Amenorrhea was also more common in pediatric-onset girls due to the compression of gonadotrophs by GHPA and hyperprolactinemia caused by the pituitary stalk effect.[ 14 ] Regarding the hormone levels, in addition to higher PRL levels, OGTT GH nadir was also significantly higher in the pediatric-onset group.[ 15 ] However, the mean IGF-1×ULN was higher in the adult-onset group, which may be related to the higher upper limit of IGF-1 in younger patients. Additionally, we also observed that in the adult-onset group, male GHPA patients presented with higher mean IGF-1×ULN. As for genetic testing, here we only tested patients who presented with manifestations associated with genetic syndromes or who had a very early onset and found that the most common genetic syndrome was MAS (9%), followed by X-LAG (2%), and MEN1 (1%). As different genetic syndromes or mutations present with different clinical features, GHPA patients with early onset need to be sequenced according to their manifestations for making ideal treatment plans and scheduling follow-up visits. We also compared clinical parameters between early-onset patients with or without genetic syndromes. It was not surprising that patients with genetic syndromes presented with earlier onset and higher rates of gigantism. Also, hyperprolactinemia was probably more common (90.9% vs. 64.1%, p = 0.093). Interestingly, there might be a correlation between genetic syndromes and metabolic abnormalities just like hypertension. After potentially more complex treatments ((2.6 ± 0.97) vs. 2.0 (1.0, 3.0), p = 0.090), the prognosis of patients with genetic syndromes could be similar to patients without. The proportion of giant adenomas and the maximum diameter of adenomas in the pediatric-onset group in this study are consistent with previous studies and were significantly higher than those in the adult-onset group, explaining the higher level of PRL related to the pituitary stalk effect.[ 1 ] Patients in the pediatric-onset group demonstrated a higher proportion of optic chiasma compression and suprasellar invasion on pituitary MRI, which is consistent with higher rates of visual field defects. We also unexpectedly observed a higher percentage of female patients presenting with optic chiasma compression on MRI. Previous studies have found that younger patients with pituitary adenomas were more likely to develop pituitary apoplexy. Our analysis also found that the incidence of pituitary apoplexy was significantly higher in the pediatric-onset group, which might be related to larger tumor size and greater blood requirements.[ 16 , 17 ] Chronically elevated concentrations of GH and IGF-1 in GHPA patients are associated with many cardiovascular risk factors. For example, hypertension could be observed in about 1/3 acromegaly patients, and 12–35% of patients were found to have diabetes at the time of diagnosis.[ 18 ] OSAHS is also a common comorbidity of acromegaly and has long-term implications for cardiovascular remodeling. [ 3 , 19 , 20 ] Interestingly, we only found a higher rate of OSAHS related with obesity in pediatric-onset group, indicating that more importance should be attached to OSAHS screening on younger-onset obese GHPA patients. HOMA-IR and HOMA-β are good indexes of insulin resistance and β-cell function respectively. According to previous studies, patients with active acromegaly presented with higher levels of HOMA-IR and HOMA-β than people of the same ages, while those who have undergone surgical or somatostatin control could show a significant reduction in HOMA-IR and HOMA-β.[ 12 , 21 ] Here we observed significantly higher insulin levels, HOMA-IR, and HOMA-β in pediatric-onset GHPA patients compared to the adult-onset group for the first time. This might indicate that the function of β cells in pediatric-onset patients was in a compensatory state, and timely attention should be paid to protect pancreatic beta cells function and reduce insulin resistance in this group of patients. Previous studies have reported a higher prevalence of LVH in acromegaly patients compared to the same age group.[ 18 ]Also, AP-LAD, IVST, LVPWD, and LVMi were higher in acromegaly patients.[ 3 , 22 ] In this study, the percentage of LVMi abnormalities was calculated to be 12.1% and 9.9% in patients with pediatric- and adult-onset, while the common echocardiographic abnormalities included valvular regurgitation [ 23 ], left atrial enlargement, and enlarged LVEDD. Previously reported abnormalities of cardiac structure in patients with acromegaly mainly focused on ventricular hypertrophy, and descriptions of ventricular enlargement were uncommon. In the present study, although ventricular enlargement was observed, with normal ventricular systolic function, dilated cardiomyopathy could not be diagnosed. Changes in cardiac systolic function should be monitored during subsequent follow-up. Similar to previous results, no clear relationship was found between the probability of developing decreased LVEF, left ventricular dilation, LVH, and valvular regurgitation in GHPA patients and the age of onset. [ 3 ] But the risks of cardiac structural abnormalities were clearly higher in patients with hypertension.[ 24 ] Excess GH/IGF-1 has effects on cardiac morphology and function that can’t be completely reversed after biochemical control, [ 25 ] and therefore abnormal alterations in the echocardiography should receive equal attention irrespective of the onset of GHPA. [ 26 ] Surgical resection is the first-line treatment of GHPA. According to previous cohort studies, the remission rate of transsphenoidal surgery (TSS) for GHPA in children ranges from 25–65%.[ 1 , 27 , 28 ] The immediate remission rate for initial surgery in pediatric-onset GHPA patients in this study was 30.9%, which is broadly consistent with the previous studies. [ 15 ] Although the difference was not significant, in the present study we still observed a lower rate of immediate remission for initial surgery in the pediatric-onset group compared to the adult-onset group (30.9% vs. 42.4%, p = 0.078).[ 27 ] Here we also observed that GHPA patients with pediatric onset presented with significantly higher rates of surgery complications which could be explained by anatomical differences and the larger volume of pituitary adenomas in children.[ 25 , 29 ] In patients with younger onset, the most common surgical complication was cerebrospinal rhinorrhea, [ 27 ] whereas for patients with older onset, the most common complication shifted to intracranial infection. This age-related incidence of complications coincided with the difference in suprasellar invasion presented in pituitary MRI between the two groups. In the present study, the proportion of patients with ki67 ≥ 3% in the pediatric-onset group was higher, suggesting that GHPA with younger onset was more proliferative. Due to the large size, high GH secretion level, and high proliferative capacity, pediatric-onset GHPA patients presented with higher median treatment scores and higher proportions of multimodal therapy.[ 2 ] However, the remission rates at the last follow-up and recurrence rates between pediatric- and adult-onset groups were essentially equal, suggesting that multimodal therapy was worthwhile for younger-onset patients to achieve satisfying clinical outcomes. [ 1 ] It should be noted that after the course of the disease and the subsequent multimodal therapy, patients with pediatric onset showed a significantly higher rate of hypopituitarism. Thus, regular follow-up and assessment of pituitary function for younger onset patients is essential, and necessary hormone replacement therapy should be administered over time.[ 27 ] Interestingly, we found some gender-related differences in the treatment and prognosis of GHPA during analysis. In the adult-onset group, more male patients received ≥ 2 surgeries and radiotherapy, which might be an explanation of why hypopituitarism was more common in males. Prognostic differences were also more pronounced in male patients between pediatric- and adult-onset groups. For example, the immediate remission rate of initial surgery was significantly lower in the pediatric-onset group in males. Surprisingly, the final remission rate was much lower in males than in females in patients with adult-onset, indicating that male GHPA patients might own a relatively worse prognosis. We haven’t found similar discoveries due to the limited number of patients included in previous cohort studies. This article provided a systematic comparison of the clinical features, treatment, and prognosis between pediatric- and adult-onset GHPA patients for the first time. However, since this is retrospective research, the clinical data was not complete, especially for the comprehensive screening of combined tumors and follow-up. In addition, in clinical practice, we usually screen all GHPA patients with early onset for genetic syndromes with clinical manifestations first, and then consider to perform genetic testing for suspected patients. Therefore, asymptomatic patients with genetic syndromes might be missed in our cohort. In conclusion, pediatric-onset GHPA was rare, predominantly male, and featured by longer course and delayed diagnosis compared to adult-onset patients. GHPAs with early onset were larger, able to secrete high levels of GH, and associated with more obvious tumor mass effects and more surgical complications. But after multimodal therapies, a cure rate similar to that of adult-onset patients could eventually be achieved. It should be noted that the proportion of hypopituitarism in pediatric-onset patients was higher, and the impact of long-term GH and IGF-1 excess on cardiac structure and function was similar to patients with adult-onset, calling for long-term follow-up and management. Additionally, we found that among patients with adult-onset, male patients might have a worse prognosis. Declarations Funding Provided by National High Level Hospital Clinical Research Funding（2022-PUMCH-B-016）. Author contributions All authors contributed to the study conception and design. Writing—original draft preparation: X-QZ; Methodology: X-QZ, Y-XS, H-GH; Data collection and analyzation: Y-YY, S-MY, T-XX; Investigation: RL, JL, YY, KD, HY, ; Writing—review and editing: LD, H-JZ; Supervision: LD, H-JZ. All authors read and approved the final manuscript. Data availability Original data generated and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval This is a retrospective research. The PUMCH Research Ethics Committee has confirmed that no ethical approval is required. Consent to participate Informed consent was obtained from all the study participants. References Nagata, Y., et al., Growth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes. Pituitary, 2018. 21 (1): p. 1-9. Rostomyan, L., et al., Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer, 2015. 22 (5): p. 745-57. Bondanelli, M., et al., Cardiac and metabolic effects of chronic growth hormone and insulin-like growth factor I excess in young adults with pituitary gigantism. Metabolism, 2005. 54 (9): p. 1174-80. Mete, O. and Lopes, M.B., Overview of the 2017 WHO Classification of Pituitary Tumors. Endocr Pathol, 2017. 28 (3): p. 228-243. Zhang, K., et al., Recovery of hypothalamus-pituitary-gonadal dysfunction after the treatment of suprasellar germ cell tumors. Eur J Endocrinol, 2021. 184 (4): p. 617-625. Munro, M.G., Critchley, H.O.D., and Fraser, I.S., The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet, 2018. 143 (3): p. 393-408. Klein, D.A., Paradise, S.L., and Reeder, R.M., Amenorrhea: A Systematic Approach to Diagnosis and Management. Am Fam Physician, 2019. 100 (1): p. 39-48. Cole, T.J., et al., Establishing a standard definition for child overweight and obesity worldwide: international survey. Bmj, 2000. 320 (7244): p. 1240-3. League, C.H., et al., Writing Group of 2018 Chinese Guidelines for the Management of Hypertension. Chin J Cardiovasc Med, 2019(1): p. 24-56. Matthews, D.R., et al., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985. 28 (7): p. 412-9. Lazzeroni, D., Rimoldi, O., and Camici, P.G., From Left Ventricular Hypertrophy to Dysfunction and Failure. Circ J, 2016. 80 (3): p. 555-64. Colao, A., et al., Growth hormone excess with onset in adolescence: clinical appearance and long-term treatment outcome. Clin Endocrinol (Oxf), 2007. 66 (5): p. 714-22. Mangupli, R., et al., Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening. Pituitary, 2016. 19 (5): p. 507-14. Bhansali, A., et al., Adolescent acromegaly: clinical parameters and treatment outcome. J Pediatr Endocrinol Metab, 2010. 23 (10): p. 1047-54. García-Uría Santos, M., et al., Gigantism: microsurgical treatment by transsphenoidal approach and prognostic factors. Pituitary, 2023. 26 (1): p. 51-56. Mehrazin, M., Pituitary tumors in children: clinical analysis of 21 cases. Childs Nerv Syst, 2007. 23 (4): p. 391-8. Zheng, X.Q., et al., Acromegaly complicated with fulminant pituitary apoplexy: clinical characteristic analysis and review of literature. Endocrine, 2023. 81 (1): p. 160-167. Wolf, P., et al., Acromegalic Cardiomyopathy: An Entity on its own? The Effects of GH and IGF-I Excess and Treatment on Cardiovascular Risk Factors. Arch Med Res, 2023: p. 102921. Filchenko, I., et al., Cardiovascular remodeling in active and controlled acromegaly: association with sleep-disordered breathing. Sleep Breath, 2023. 27 (6): p. 2305-2314. Rajesh, S., Wonderling, D., and Simonds, A.K., Obstructive sleep apnoea/hypopnoea syndrome and obesity hyperventilation syndrome in over 16s: summary of NICE guidance. Bmj, 2021. 375 : p. n2360. Biagetti, B., et al., HOMA-IR in acromegaly: a systematic review and meta-analysis. Pituitary, 2021. 24 (2): p. 146-158. Uziȩbło-Życzkowska, B., et al., Left Heart Dysfunction in Acromegaly Revealed by Novel Echocardiographic Methods. Front Endocrinol (Lausanne), 2020. 11 : p. 418. Ságová, I., et al., Filling the gap between the heart and the body in acromegaly: a case-control study. Endocrine, 2023. 79 (2): p. 365-375. Park, B.E., et al., Comparison of the efficiency between electrocardiogram and echocardiogram for left ventricular hypertrophy evaluation in patients with hypertension: Insight from the Korean Hypertension Cohort Study. J Clin Hypertens (Greenwich), 2022. 24 (11): p. 1451-1460. Kelly, A.P., et al., Pediatric pituitary adenomas are more aggressive, more likely to be hormone producing and are more difficult to cure than adult pituitary adenomas: case series and systematic literature review. Childs Nerv Syst, 2022. 38 (4): p. 729-738. Cansu, G.B., et al., ASSESSMENT OF DIASTOLIC DYSFUNCTION, ARTERIAL STIFFNESS, AND CAROTID INTIMA-MEDIA THICKNESS IN PATIENTS WITH ACROMEGALY. Endocr Pract, 2017. 23 (5): p. 536-545. Xia, Z., et al., Somatotrophic Adenoma in Children Younger than 14 Years: Clinical Features and Treatment of 22 Cases at a Large Pituitary Center. World Neurosurg, 2018. 112 : p. e561-e568. Creo, A.L. and Lteif, A.N., Pituitary gigantism: a retrospective case series. J Pediatr Endocrinol Metab, 2016. 29 (5): p. 597-602. Barzaghi, L.R., et al., Pediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive Patients. Neurosurgery, 2019. 85 (1): p. 65-74. Additional Declarations No competing interests reported. Supplementary Files EJPsupplementarymaterial.docx Cite Share Download PDF Status: Published Journal Publication published 24 Sep, 2024 Read the published version in Endocrine → Version 1 posted Editorial decision: Revision requested 19 Aug, 2024 Reviews received at journal 22 Jun, 2024 Reviewers agreed at journal 17 Jun, 2024 Reviewers invited by journal 17 Jun, 2024 Editor assigned by journal 10 Jun, 2024 Submission checks completed at journal 10 Jun, 2024 First submitted to journal 08 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4551046","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":317637029,"identity":"3d42c53b-47be-4689-87b2-c431970c4921","order_by":0,"name":"Xue-Qing Zheng","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xue-Qing","middleName":"","lastName":"Zheng","suffix":""},{"id":317637030,"identity":"47f5844d-336d-48a5-b024-274ef2813d33","order_by":1,"name":"Sheng-Min 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College","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hui-Juan","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2024-06-08 14:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4551046/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4551046/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12020-024-04044-3","type":"published","date":"2024-09-24T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":59435215,"identity":"8b65996e-4c00-4043-8be2-ed912da7f971","added_by":"auto","created_at":"2024-07-01 19:08:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47444,"visible":true,"origin":"","legend":"\u003cp\u003eChanges on remission rate after surgery for different groups\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4551046/v1/49ca8f72f1b7f2cbc176d88b.png"},{"id":65627041,"identity":"267c46aa-3ec8-4a9b-84e5-a91e15e3d19c","added_by":"auto","created_at":"2024-09-30 16:08:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":875162,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4551046/v1/8b4e58cc-ca31-4b5d-86ad-9e400727aa10.pdf"},{"id":59435216,"identity":"ba0042ce-6ba4-42c9-a73e-cdfc9f115a65","added_by":"auto","created_at":"2024-07-01 19:08:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30194,"visible":true,"origin":"","legend":"","description":"","filename":"EJPsupplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4551046/v1/c0f9369c95e0ee3e89916b1e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Distinct clinical characteristics and prognosis of pediatric-onset GHPA patients compared with adult-onset patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eExcess growth hormone (GH) secreted by growth hormone-secreting pituitary adenoma (GHPA) stimulates the over synthesis of insulin-like growth factor 1 (IGF-1). Classically, pathologic GH excess causes acromegaly in adults and causes gigantism before the fusion of the epiphyseal growth plate in children.[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e] Compared with adult-onset GHPA, earlier onset is associated with multiple genetic causes and syndromes, predicting different biological properties of the adenoma.[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e] Also, premature exposure to pathologically excess GH and IGF-1 may result in more profound harmful effects on patients.[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e] Due to the rarity of GHPA with pediatric-onset, previous cohort studies were insufficient, and the numbers of patients included was generally small. Comparative studies with adult-onset patients are extremely rare, which limits clinicians’ understanding of the differences in clinical characteristics, treatment, and prognosis between these two groups. Here we systematically compare GHPA patients with pediatric- and adult-onset for the first time from clinical manifestations, hormone levels, pituitary imaging, cardiovascular function, to treatment and prognosis, hoping to assist clinical management and future research of pediatric-onset GHPA.\u003c/p\u003e\n\n\n\n\n\n\n\n\n\n"},{"header":"Patients and methods","content":"\u003cp\u003e1. Patient population\u003c/p\u003e\u003cp\u003eThis is a retrospective cohort study. 1555 patients were discharged from the pituitary center in Peking Union Medical College Hospital (PUMCH) with the diagnosis of “GHPA” for the first time from January 2013 to June 2022. Among them, 102 patients were selected according to the following criteria: (1) the initial symptom which related to GHPA appeared before 18-year-old, including growth acceleration, facial change, limbs enlargement, and headache; (2) mammosomatotroph adenoma, mixed somatotroph, and lactotroph adenoma were excluded according to WHO classification of pituitary tumors in 2017.[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e] To ensure that patients with pediatric-onset and adult-onset GHPA received the same level of treatment, we used random numbers to match these two groups by 1:2 based on the year of patients’ initial visit to PUMCH. Therefore 204 patients with adult-onset GHPA were randomly selected.\u003c/p\u003e\u003cp\u003eStudy measures\u003c/p\u003e\u003cp\u003eThe criteria for biochemical remission of GHPA were as follows: IGF-1 decreased to the normal range, along with random GH or GH nadir during oral glucose tolerance test (OGTT) \u0026lt; 1.0 ng/ml. Here we use the upper limit of normal (ULN) based on the reference range matched by age and sex to describe the relative level of IGF-1. However, because changes in IGF-1 take time, immediate surgical remission was defined as random GH or OGTT GH nadir \u0026lt; 1.0 ng/ml within a week after surgery.\u003c/p\u003e\u003cp\u003eThe definition of hypopituitarism was described in detail in our previous work.[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e] Diagnostic criteria for menstrual abnormalities among adult patients were referenced to 2018 revisions of the international Federation of Gynecology and Obstetrics (FIGO) systems, while patients \u0026lt; 18 years old were judged to have abnormal menstruation if they presented with amenorrhea (menarche had not occurred by 15 years old).[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e] For obesity and hypertension at age \u0026lt; 18 years old, the diagnostic criteria referred to international obesity task force (IOTF)[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e] and 2018 Chinese guidelines for the management of hypertension[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGiant adenomas were defined as pituitary adenomas with maximum diameters ≥ 4 cm. The homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) were calculated by the formulae respectively: HOMA-IR = [insulin (mIU/L) × fasting glucose (mmol/L)]/22.5; HOMA-β (%) = [20 × insulin (mIU/L)]/[glucose (mmol/L) – 3.5].[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe cardiovascular function was measured by M-mode, two-dimensional, and pulsed Doppler echocardiography. Parameters including left ventricular ejection fraction (LVEF), anteroposterior left atrial diameter (AP-LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular posterior wall thickness (LVPWT), interventricular septum diastolic thickness (IVST), and regurgitation of each valve were recorded. Left ventricular mass (LVM) was calculated according to Devereux’s formula: LVM (g) = 1.04 × [(LVEDD + IVST + LVPWT)\u003csup\u003e3\u003c/sup\u003e – LVEDD\u003csup\u003e3\u003c/sup\u003e] × 0.8 + 0.6. Left ventricular hypertrophy (LVH) was considered when LVM values, corrected for body surface area as LVMi, were ≥ 115 g/m\u003csup\u003e2\u003c/sup\u003e in males and ≥ 95 g/m\u003csup\u003e2\u003c/sup\u003e in females.[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e] Dilated left ventricle was defined when LVEDD was \u0026gt; 55 mm in males and \u0026gt; 50 mm in females (or LVEDD \u0026gt; 2 standard deviation (SD) + 5% of the predicted value according to age and body surface area).\u003c/p\u003e\u003cp\u003eIn this article we use treatment score to measure the types of treatment modalities that each patient received in total, which was calculated as the sum of each surgery and radiotherapy, the use of SSAs, dopamine agonists, and temozolomide (each was allocated one point). If a patient has used the same class of medication multiple times during the course, only one point would be recorded. A treatment score ≥ 3 was considered a multimodal therapy approach.[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e] Surgical complications include cerebrospinal fluid rhinorrhea, central nervous system infection, postoperative vision impairment, and impairment of extraocular muscle function.\u003c/p\u003e\u003ch2\u003e3. Statistical analysis\u003c/h2\u003e\u003cp\u003eThe statistical and analytical procedures were performed using SPSS software version 25.0. After normality examination using Kolmogorov–Smirnov test, continuous variables were compared by \u003cem\u003et\u003c/em\u003e-test or Wilcoxon rank sum test. Categorical variables were analyzed by Chi-square test of Fisher exact test. The threshold of statistical significance was set to be 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e1. Characterization of the study population\u003c/p\u003e\n\u003cp\u003eA total of 102 GHPA patients with pediatric-onset were admitted to PUMCH from January 2013 to June 2022, accounting for 6.6% of the total GHPA patients. Female patients accounted for 30.3% and 50.4% in pediatric-onset and adult-onset groups respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The median ages at first admission were 21.0 (17.0, 27.0) and 43.0 (34.0, 53.0) for the two groups, and the mean age of onset was 14.0 (11.0, 16.0) and 37.0 (28.0, 45.0) respectively. Compared with adult-onset GHPA patients, the median duration of disease and delay of diagnosis were significantly longer (7.0 (3.0, 14.0) years vs. 4.5 (2.0, 8.8) years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 5.0 (2.0, 10.0) years vs. 4.0 (2.0, 7.0) years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), and a greater proportion of patients had received prior treatment before first admission in PUMCH (45.1% vs. 27.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). The final heights of male and female patients in younger group were also significantly higher (male: 185.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6 cm vs. 175.0 (170.0, 178.5) cm, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; female: 172.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 cm vs. 162.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9 cm, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). 47 patients with pediatric-onset (47.5%) were taller than the 97th percentile at their first visit to PUMCH and thus could be diagnosed with gigantism. As for the occupying effect, more patients manifested as visual field defects in the younger group (20.8% vs. 9.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), which was more pronounced in male patients (Supplementary Table 1, 21.4% vs. 6.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). For female patients, younger onset was associated with a higher rate of menstrual abnormality (64.5% vs. 35.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). 2 pediatric-onset and 4 adult-onset GHPA patients had a family history of pituitary adenomas (2.0% vs. 2.0%). 12 patients in pediatric-onset group were with genetic pathogenesis (1 multiple endocrine neoplasia type 1 (MEN1), 9 McCune-Albright syndrome (MAS), and 2 X-linked acrogigantism (X-LAG)), which was significantly more than 1 MEN1 adult-onset patient (11.8% vs. 0.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline clinical parameters between pediatric- and adult-onset GHPA\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePediatric-onset (n\u0026thinsp;=\u0026thinsp;102)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eAdult-onset (n\u0026thinsp;=\u0026thinsp;204)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u003cem\u003eP\u003c/em\u003e value\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFemale (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e31(30.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e103(50.4%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eAge at first admission (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e21.0 (17.0, 27.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e43.0 (34.0, 53.0)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eAge of onset (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e14.0 (11.0, 16.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e37.0 (28.0, 45.0)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eCourse of disease (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e7.0 (3.0, 14.0)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.5 (2.0, 8.8)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eDelay of diagnosis (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e5.0 (2.0, 10.0)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.0 (2.0, 7.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.003\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003ePatients treated before (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e46(45.1%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e55(27.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHeadache (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e40/101 (39.6%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e73/204 (35.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.516\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eVision impairment (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e33/101 (32.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e66/204 (32.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.955\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eVisual field defects (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e21/101 (20.8%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e19/204 (9.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.005\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eMenstrual abnormality (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e20/31 (64.5%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e36/103 (35.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.003\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFinal height in male (cm)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e185.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e175.0 (170.0, 178.5)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFinal height in female (cm)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e172.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e162.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFamily history of pituitary adenoma (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2/102 (2.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4/204 (2.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.000\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eGenetic syndromes (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e12/102 (11.8%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1/204 (0.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eRandom GH (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e20.10 (10.30, 47.3)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e15.6 (7.4, 27.9)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.031\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eOGTT-GH nadir (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e14.60 (6.43, 39.60)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e10.90 (5.22, 19.70)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.030\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eIGF-1\u0026times;ULN\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e2.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003ePRL (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e25.47 (12.37, 62.40)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e13.20 (8.67, 26.87)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHyperprolactinemia (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e51/75 (68.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e47/148 (31.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eMacroadenoma (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e77/90 (85.6%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e140/173 (80.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.348\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eGiant adenoma (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e10/90 (11.1%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4/173 (2.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.006\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eMaximum diameter (mm)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e22.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e15.0 (11.0, 21.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eKnosp\u0026thinsp;\u0026ge;\u0026thinsp;3 (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e22/57 (38.6%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e36/124 (29.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.200\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eOptic chiasma compression (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e50/79 (63.3%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e43/145 (29.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eSuprasellar invasion (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e30/51 (58.9%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e29/108 (26.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eSellar bottom erosion (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e37/53 (69.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e63/115 (54.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.065\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHypointensity on T2 (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e21/75 (28.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e42/136 (30.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.661\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003ePituitary apoplexy (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e13/85 (15.3%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e10/172 (5.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.012\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e2. Comparison of hormone levels\u003c/p\u003e\n\u003cp\u003eCompared with the adult-onset group, the baseline median random GH and the median GH nadir during OGTT were all higher in the pediatric-onset group (20.10 (10.30, 47.30) ng/ml vs. 15.6 (7.4, 27.9) ng/ml, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031; 14.60 (6.43, 39.60) ng/ml vs. 10.90 (5.22, 19.70) ng/ml, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030). In addition, the PRL level and the proportion of patients with hyperprolactinemia were also higher in the younger-onset group (25.47 (12.37, 62.40) ng/ml vs. 13.20 (8.67, 26.87) ng/ml, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 68.0% vs. 31.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, patients in the adult-onset group presented a higher level of IGF-1\u0026times;ULN (2.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99 vs. 2.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Comparing the differences between genders, mean IGF-1 x ULN was significantly higher in males in patients with adult-onset (3.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04 vs. 2.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), while hyperprolactinemia was more common in males in patients with adult-onset (41.4% vs. 23.1%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017), other differences on hormone levels between genders were not found.\u003c/p\u003e\n\u003cp\u003e3. Pituitary magnetic resonance imaging (MRI)\u003c/p\u003e\n\u003cp\u003e85.6% (77/90) of pediatric-onset patients and 80.9% (140/173) of adult-onset patients had macroadenomas. However, a significantly higher percentage of patients in the pediatric-onset group presented with giant adenomas (11.1% vs. 2.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) and larger maximum diameters (22.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2 mm vs, 15.0 (11.0, 21.0) mm, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Although the proportion of patients with Knosp\u0026thinsp;\u0026ge;\u0026thinsp;3 was not significantly different between the two groups, more patients in the pediatric-onset group demonstrated optic chiasma compression (63.3% vs. 29.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suprasellar invasion (58.9% vs. 26.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and pituitary apoplexy (15.3% vs. 5.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012) on MRI. Interestingly, in both groups, the proportions of female patients showing optic chiasma compression were all significantly higher (pediatric-onset: 80.8% vs. 54.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024; adult-onset: 39.7% vs. 19.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). No other differences on MRI were found between male and female patients.\u003c/p\u003e\n\u003cp\u003e4. Metabolic and cardiovascular functions.\u003c/p\u003e\n\u003cp\u003eThere were no significant differences on median BMI (26.90 (23.83, 29.67) vs. 26.12 (23.61, 28.37) and obesity rate (39.0% vs. 29.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.052) between two groups. Hypertension and diabetes mellitus were more prevalent in GHPA patients with adult-onset (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cstrong\u003e30\u003c/strong\u003e.9% vs. 17.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; 27.5% vs. 16.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037), and this trend was more pronounced in males (35.6% vs. 19.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024; 30.7% vs. 16.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040). The prevalence of obstructive sleep apnea-hypopnea syndrome (OSAHS) was also higher in the adult-onset group (75.4% vs. 53.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039), and this age-related difference was more pronounced in females (73.9% vs. 33.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049). Interestingly, the correlation of OSAHS and obesity was only observed in pediatric-onset patients (Supplementary table 2, 73.3% vs. 30.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024). Fasting glucose (5.30 (5.00, 5.85) mmol/L vs. 5.80 (5.40, 6.70) mmol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was significantly lower in pediatric-onset group, while fasting insulin levels (36.88\u0026thinsp;\u0026plusmn;\u0026thinsp;22.51 mIU/L vs. 17.21 (10.60, 25.00) mIU/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), HOMA-IR (20.43\u0026thinsp;\u0026plusmn;\u0026thinsp;16.58 vs. 4.50 (2.78, 6.77), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023), and HOMA-\u0026beta; (420.14\u0026thinsp;\u0026plusmn;\u0026thinsp;265.83 vs. 111.72 (75.29, 201.81), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were all significantly higher in the pediatric-onset group. Regarding the lipid profile, except for a higher mean high-density lipoprotein cholesterol (HDL-C) in the adult-onset group (1.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 mmol/L vs. 0.98 (0.80, 1.17) mmol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), there was no significant difference on total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) between two groups.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMetabolism and cardiovascular functions between pediatric- and adult-onset GHPA\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePediatric-onset (n\u0026thinsp;=\u0026thinsp;102)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eAdult-onset (n\u0026thinsp;=\u0026thinsp;204)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u003cem\u003eP\u003c/em\u003e value\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e26.90 (23.83, 29.67)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e26.12 (23.61, 28.37)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.151\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eObesity (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e39/100 (39.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e55/197 (29.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.052\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHypertension (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e18/102 (17.6%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e63/204 (30.9%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.013\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eDiabetes mellitus (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e17/102 (16.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e56/204 (27.5%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.037\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eIFG or IGT\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e7/102 (6.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e17/204 (8.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.652\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eOSAHS (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e15/28 (53.6%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e46/61 (75.4%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.039\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFasting glucose (mmol/L)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.30 (5.00, 5.85)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e5.80 (5.40, 6.70)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHbA1c (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.90 (5.60, 6.60)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.130\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFasting Insulin (mIU/L)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e36.88\u0026thinsp;\u0026plusmn;\u0026thinsp;22.51\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e17.21 (10.60, 25.00)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.004\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHOMA-IR\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e20.43\u0026thinsp;\u0026plusmn;\u0026thinsp;16.58\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.50 (2.78, 6.77)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.023\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHOMA-\u0026beta;\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e420.14\u0026thinsp;\u0026plusmn;\u0026thinsp;265.83\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e111.72 (75.29, 201.81)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eTC (mmol/L)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.00 (3.56, 4.56)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e4.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.054\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eTG (mmol/L)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.20 (1.02, 2.14)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.27 (0.89, 1.79)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.469\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eLDL-C (mmol/L)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.374\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHDL-C (mmol/L)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.98 (0.80, 1.17)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e1.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.007\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eLVEF\u0026thinsp;\u0026lt;\u0026thinsp;50% (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2/60 (3.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1/128 (0.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.244\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eEnlarged left atrial (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e20/60 (33.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e38/125 (30.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.687\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eEnlarged left ventricle (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e16/60 (26.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e28/125 (22.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.523\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eThickened IVST (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5/60 (8.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e9/126 (7.1%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.772\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eThickened LVPWT (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2/60 (3.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5/126 (4.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.000\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eAbnormal LVMi (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e7/58 (12.1%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e12/121 (9.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.662\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eValvular regurgitation (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e21/61 (34.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e51/129 (39.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.498\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eOn echocardiography, there were no significant differences in the proportions of patients presenting with LVEF\u0026thinsp;\u0026lt;\u0026thinsp;50% (3.3% vs. 0.8%), enlarged AP-LAD (33.3% vs. 30.4%), enlarged LVEDD (26.7% vs. 22.4%), thickened IVST (8.3% vs. 7.1%), thickened LVPWT (3.3% vs. 4.0%), abnormal LVMi (12.1% vs. 9.9%), and valvular regurgitation (34.4% vs. 39.5%) between pediatric- and adult-onset groups. In patients with adult-onset acromegaly, more males showed enlarged AP-LAD (38.8% vs. 20.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) and thickened IVST (11.8% vs. 1.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.038). All these above cardiac structural abnormalities shown on echocardiograms were associated with hypertension (Supplementary table 3).\u003c/p\u003e\n\u003cp\u003e5. Treatment\u003c/p\u003e\n\u003cp\u003eCompared with the adult-onset group, the pediatric-onset group had a significantly higher median treatment score (2.0 (1.0, 3.0) vs. 1.0 (1.0, 2.0), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and proportion of patients receiving a multimodal therapy modality (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, treatment score\u0026thinsp;\u0026ge;\u0026thinsp;3, 29.6% vs. 13.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as well as a higher proportion of surgical complications (19.0% vs. 9.2%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021). Gender-related analysis showed that younger-onset patients were observed to be more prone to surgical complications only in males (19.3% vs. 8.2%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042). The proportion of patients who received at least 2 surgeries (26.5% vs. 19.3%) or radiotherapy (23.5% vs. 16.3%) were similar between two groups. But among adult-onset patients, more male patients who received at least 2 surgeries (27.0% vs. 11.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) or radiotherapy (23.0% vs. 9.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) than that of female patients. The immediate GH nadir (1.77 (0.50, 6.06) ng/ml vs. 0.99 (0.50, 2.11) ng/ml, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.075) and the proportion of patients with immediate GH nadir\u0026thinsp;\u0026lt;\u0026thinsp;1.0 ng/ml after the first surgery (30.9% vs. 42.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.078) in the pediatric- and adult-onset groups were not significantly different. However, in male patients, younger onset was associated with higher immediate GH nadir (2.78 (0.50, 8.74) ng/ml vs. 0.93 (0.43, 2.33) ng/ml, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) and a lower proportion of patients with immediate GH nadir\u0026thinsp;\u0026lt;\u0026thinsp;1.0 ng/ml after the first surgery (29.8% vs. 47.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033). Postoperative histopathological analysis showed no significant difference on the proportion of p53 positive between the pediatric- and adult-onset groups (14.1% vs. 14.7%), while more patients in the pediatric-onset group presented Ki-67\u0026thinsp;\u0026ge;\u0026thinsp;3% (41.0% vs. 27.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034).\u003c/p\u003e\n\u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment and prognosis between pediatric- and adult-onset GHPA\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003ePediatric-onset (n\u0026thinsp;=\u0026thinsp;102)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eAdult-onset (n\u0026thinsp;=\u0026thinsp;204)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u003cem\u003eP\u003c/em\u003e value\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eTreatment score\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e2.0 (1.0, 3.0)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.0 (1.0, 2.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eTreatment score\u0026thinsp;\u0026ge;\u0026thinsp;3 (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e29/98 (29.6%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e27/202 (13.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eSurgical complications (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e16/84 (19.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e18/195 (9.2%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.021\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eReceived\u0026thinsp;\u0026ge;\u0026thinsp;2 surgeries (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e26/98 (26.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e39/202 (19.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.154\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eReceived radiotherapy (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e23/98 (23.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e33/202 (16.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.137\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eImmediate GH nadir after initial surgery (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.77 (0.50, 6.06)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.99 (0.50, 2.11)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.075\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eImmediate GH after initial surgery\u0026thinsp;\u0026lt;\u0026thinsp;1.0 ng/ml (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e25/81 (30.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e73/172 (42.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.078\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eP53 positive (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e11/78 (14.1%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e27/184 (14.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.904\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eKi67\u0026thinsp;\u0026ge;\u0026thinsp;3% (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e32/78 (41.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e51/184 (27.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.034\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eDuration of follow-up (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.4 (0.3, 3.9)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.1 (0.3, 3.4)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.588\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eGH nadir after 3 months (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.58 (0.16, 3.93)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.51 (0.12, 1.74)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.074\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eIGF-1\u0026times;ULN after 3 months\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.16 (0.89, 1.69)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.18 (0.85, 1.84)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.679\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eCure rate after 3 months (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e21/68 (30.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e49/145 (33.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.673\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eGH nadir after 1 year (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.95 (0.24, 3.68)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.70 (0.10, 2.07)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.174\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eIGF-1\u0026times;ULN after 1 year\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.07 (0.82, 1.83)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.233\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eCure rate after 1 year (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e18/45 (40.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e30/87 (34.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.532\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eGH nadir at last follow-up (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.60 (0.16, 2.36)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.58 (0.10, 1.07)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.631\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eIGF-1\u0026times;ULN at last follow-up\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.77 (0.48, 1.33)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.85 (0.69, 1.30)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.117\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eCure rate at last follow-up (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e33/56 (58.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e56/111 (50.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.300\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eRecurrence (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e8/86 (9.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e37/170 (21.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHypopituitarism (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e48/100 (48.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e49/191 (25.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHypogonadotropic hypogonadism (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e44/100 (44.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e40/191 (20.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eSecondary hypothyroidism (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e18/100 (18.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e16/191 (8.4%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.015\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eSecondary hypoadrenocorticism (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e12/100 (12.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e12/191 (6.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.092\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eOther tumors (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1/102 (1.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e20/204 (9.8%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.004\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e6. Follow-up\u003c/p\u003e\n\u003cp\u003eThe median follow-up was 1.1 (0.3, 3.6) years for all patients, with 54.6% patients\u0026rsquo; follow-up more than 1 year. We measured GH nadir, IGF-1\u0026times;ULN, and cure rate at 3 months, 1 year, and at the final follow-up after the initial surgical treatment (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). We found that there were no significant differences on GH/IGF-1, cure rate at any time, and recurrence rate between two groups. Significantly higher GH nadir at 1-year follow-up (2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.47 years vs. 0.50 (0.06, 1.68) years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) was observed in the pediatric-onset group in male patients. However, no correlation between age of onset and prognosis was observed in female patients. In addition, we also found that the cure rate at the last follow-up was significantly higher in females than males in the adult-onset group (53.2% vs. 39.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010).\u003c/p\u003e\n\u003cp\u003eHypopituitarism developed in some GHPA patients during the course and follow-up. Compared with the adult-onset group, patients in the pediatric-onset group developed higher proportions of hypopituitarism (48% vs. 25.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), hypogonadotropic hypogonadism (44.0% vs. 20.9%. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and secondary hypothyroidism (18.0% vs. 8.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). In adult-onset patients, hypopituitarism was more common in male patients than the female patients (26.6% vs. 14.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037). Additionally, by the time of the last follow-up, 1 patient in the pediatric-onset group had developed thyroid cancer, while 20 patients in the adult-onset group developed tumors (1.0% vs. 9.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), 12 of which had thyroid cancer, others including thymoma, breast tumor, adrenal adenoma, kidney cancer, colon tumor, parotid cancer, and bladder cancer.\u003c/p\u003e\n\u003cp\u003eClinical features of pediatric-onset GHPA patients with genetic syndromes\u003c/p\u003e\n\u003cp\u003eWe further compared the clinical parameters between pediatric-onset GHPA patients with or without genetic syndromes (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Limited by the sample size, we only found that the onset age was significantly earlier (6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3 vs. 15.0 (12.0, 16.0), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and both the rates of gigantism (75.0% vs. 43.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042) and hypertension (50.0% vs. 13.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) were significantly higher in GHPA patients with genetic syndromes. No difference was found in hormone levels, MRI features, and prognosis between two groups.\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical parameters between pediatric-onset patients with or without genetic syndromes\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eWith genetic syndromes (n\u0026thinsp;=\u0026thinsp;12)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003eWithout genetic syndromes (n\u0026thinsp;=\u0026thinsp;90)\u003cbr\u003e\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u003cem\u003eP\u003c/em\u003e value\u003cbr\u003e\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eFemale (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/12 (50%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e25/90 (27.8%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.178\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eAge at first admission (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e19.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e21.0 (17.0, 27.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.165\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eAge of onset (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u003cstrong\u003e15.0 (12.0, 16.0)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\u0026lt;\u0026thinsp;0.001\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eDelay of diagnosis (years)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e4.5 (3.0, 17.3)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e5.0 (2.0, 10.5)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.685\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eGigantism (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u003cstrong\u003e9/12 (75.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e38/87 (43.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.042\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eRandom GH (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e14.80 (6.00, 68.90)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e25.00 (13.00, 50.00)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.685\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eOGTT-GH nadir (ng/ml)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e12.95 (6.52, 74.90)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e15.75 (6.43, 39.53)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.675\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eIGF-1\u0026times;ULN\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.884\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHyperprolactinemia (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e10/11(90.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e41/64 (64.1%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.093\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eMaximum diameter (mm)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e19.48\u0026thinsp;\u0026plusmn;\u0026thinsp;12.52\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e23.21\u0026thinsp;\u0026plusmn;\u0026thinsp;11.03\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.920\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eKnosp\u0026thinsp;\u0026ge;\u0026thinsp;3 (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5/10 (50.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e17/47 (36.2%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.485\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eOptic chiasma compression (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/8 (75.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e44/71 (62.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.703\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHypertension (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u003cstrong\u003e6/12 (50.0%)\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e12/90 (13.3%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.006\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eDiabetes mellitus (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2/12 (16.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e15/90 (16.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.000\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eTreatment score\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e2.0 (1.0, 3.0)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.090\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eTreatment score\u0026thinsp;\u0026ge;\u0026thinsp;3 (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5/12 (41.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e24/86 (27.9%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.331\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eImmediate GH after initial surgery\u0026thinsp;\u0026lt;\u0026thinsp;1.0 ng/ml (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e2/8 (25.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e23/73 (31.5%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.000\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eCure rate at last follow-up (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e5/10 (50.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e34/76 (44.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e1.000\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003eHypopituitarism (%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"left\"\u003e6/12 (50.0%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e42/88 (47.7%)\u003cbr\u003e\u003c/td\u003e\n \u003ctd align=\"char\"\u003e0.882\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn adults, chronic GH and IGF-1 excess causes local bone and soft tissue overgrowth, which leads to acromegaly. In children and adolescents, excess GH and IGF-1 before the fusion of the epiphyseal growth plate results in gigantism by causing excessive linear growth which can be further facilitated by secondary hypogonadism.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] However, for children with GHPA, the most common presentation was acromegaly, whereas only about half of them presented with growth acceleration.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Unlike the balanced gender ratio in the adult-onset group, the majority of the pediatric-onset group was male, which is consistent with previous findings.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] The median course of GHPA and delay of diagnosis in the pediatric-onset group were both longer than the adult-onset group, which may increase the harmful effects of prolonged GH and IGF-1 excess.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Thus, early diagnosis and treatment are particularly important for younger-onset patients.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] In accordance with previous literature, the tumor mass effect in the pediatric-onset group was obvious, especially for visual field defects.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Amenorrhea was also more common in pediatric-onset girls due to the compression of gonadotrophs by GHPA and hyperprolactinemia caused by the pituitary stalk effect.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Regarding the hormone levels, in addition to higher PRL levels, OGTT GH nadir was also significantly higher in the pediatric-onset group.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] However, the mean IGF-1\u0026times;ULN was higher in the adult-onset group, which may be related to the higher upper limit of IGF-1 in younger patients. Additionally, we also observed that in the adult-onset group, male GHPA patients presented with higher mean IGF-1\u0026times;ULN.\u003c/p\u003e \u003cp\u003e As for genetic testing, here we only tested patients who presented with manifestations associated with genetic syndromes or who had a very early onset and found that the most common genetic syndrome was MAS (9%), followed by X-LAG (2%), and MEN1 (1%). As different genetic syndromes or mutations present with different clinical features, GHPA patients with early onset need to be sequenced according to their manifestations for making ideal treatment plans and scheduling follow-up visits. We also compared clinical parameters between early-onset patients with or without genetic syndromes. It was not surprising that patients with genetic syndromes presented with earlier onset and higher rates of gigantism. Also, hyperprolactinemia was probably more common (90.9% vs. 64.1%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.093). Interestingly, there might be a correlation between genetic syndromes and metabolic abnormalities just like hypertension. After potentially more complex treatments ((2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97) vs. 2.0 (1.0, 3.0), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.090), the prognosis of patients with genetic syndromes could be similar to patients without.\u003c/p\u003e \u003cp\u003eThe proportion of giant adenomas and the maximum diameter of adenomas in the pediatric-onset group in this study are consistent with previous studies and were significantly higher than those in the adult-onset group, explaining the higher level of PRL related to the pituitary stalk effect.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Patients in the pediatric-onset group demonstrated a higher proportion of optic chiasma compression and suprasellar invasion on pituitary MRI, which is consistent with higher rates of visual field defects. We also unexpectedly observed a higher percentage of female patients presenting with optic chiasma compression on MRI. Previous studies have found that younger patients with pituitary adenomas were more likely to develop pituitary apoplexy. Our analysis also found that the incidence of pituitary apoplexy was significantly higher in the pediatric-onset group, which might be related to larger tumor size and greater blood requirements.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eChronically elevated concentrations of GH and IGF-1 in GHPA patients are associated with many cardiovascular risk factors. For example, hypertension could be observed in about 1/3 acromegaly patients, and 12\u0026ndash;35% of patients were found to have diabetes at the time of diagnosis.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] OSAHS is also a common comorbidity of acromegaly and has long-term implications for cardiovascular remodeling. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Interestingly, we only found a higher rate of OSAHS related with obesity in pediatric-onset group, indicating that more importance should be attached to OSAHS screening on younger-onset obese GHPA patients. HOMA-IR and HOMA-β are good indexes of insulin resistance and β-cell function respectively. According to previous studies, patients with active acromegaly presented with higher levels of HOMA-IR and HOMA-β than people of the same ages, while those who have undergone surgical or somatostatin control could show a significant reduction in HOMA-IR and HOMA-β.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Here we observed significantly higher insulin levels, HOMA-IR, and HOMA-β in pediatric-onset GHPA patients compared to the adult-onset group for the first time. This might indicate that the function of β cells in pediatric-onset patients was in a compensatory state, and timely attention should be paid to protect pancreatic beta cells function and reduce insulin resistance in this group of patients. Previous studies have reported a higher prevalence of LVH in acromegaly patients compared to the same age group.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]Also, AP-LAD, IVST, LVPWD, and LVMi were higher in acromegaly patients.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] In this study, the percentage of LVMi abnormalities was calculated to be 12.1% and 9.9% in patients with pediatric- and adult-onset, while the common echocardiographic abnormalities included valvular regurgitation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], left atrial enlargement, and enlarged LVEDD. Previously reported abnormalities of cardiac structure in patients with acromegaly mainly focused on ventricular hypertrophy, and descriptions of ventricular enlargement were uncommon. In the present study, although ventricular enlargement was observed, with normal ventricular systolic function, dilated cardiomyopathy could not be diagnosed. Changes in cardiac systolic function should be monitored during subsequent follow-up. Similar to previous results, no clear relationship was found between the probability of developing decreased LVEF, left ventricular dilation, LVH, and valvular regurgitation in GHPA patients and the age of onset. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] But the risks of cardiac structural abnormalities were clearly higher in patients with hypertension.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Excess GH/IGF-1 has effects on cardiac morphology and function that can\u0026rsquo;t be completely reversed after biochemical control, [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and therefore abnormal alterations in the echocardiography should receive equal attention irrespective of the onset of GHPA. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSurgical resection is the first-line treatment of GHPA. According to previous cohort studies, the remission rate of transsphenoidal surgery (TSS) for GHPA in children ranges from 25\u0026ndash;65%.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] The immediate remission rate for initial surgery in pediatric-onset GHPA patients in this study was 30.9%, which is broadly consistent with the previous studies. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Although the difference was not significant, in the present study we still observed a lower rate of immediate remission for initial surgery in the pediatric-onset group compared to the adult-onset group (30.9% vs. 42.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.078).[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Here we also observed that GHPA patients with pediatric onset presented with significantly higher rates of surgery complications which could be explained by anatomical differences and the larger volume of pituitary adenomas in children.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] In patients with younger onset, the most common surgical complication was cerebrospinal rhinorrhea, [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] whereas for patients with older onset, the most common complication shifted to intracranial infection. This age-related incidence of complications coincided with the difference in suprasellar invasion presented in pituitary MRI between the two groups. In the present study, the proportion of patients with ki67\u0026thinsp;\u0026ge;\u0026thinsp;3% in the pediatric-onset group was higher, suggesting that GHPA with younger onset was more proliferative. Due to the large size, high GH secretion level, and high proliferative capacity, pediatric-onset GHPA patients presented with higher median treatment scores and higher proportions of multimodal therapy.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] However, the remission rates at the last follow-up and recurrence rates between pediatric- and adult-onset groups were essentially equal, suggesting that multimodal therapy was worthwhile for younger-onset patients to achieve satisfying clinical outcomes. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] It should be noted that after the course of the disease and the subsequent multimodal therapy, patients with pediatric onset showed a significantly higher rate of hypopituitarism. Thus, regular follow-up and assessment of pituitary function for younger onset patients is essential, and necessary hormone replacement therapy should be administered over time.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Interestingly, we found some gender-related differences in the treatment and prognosis of GHPA during analysis. In the adult-onset group, more male patients received\u0026thinsp;\u0026ge;\u0026thinsp;2 surgeries and radiotherapy, which might be an explanation of why hypopituitarism was more common in males. Prognostic differences were also more pronounced in male patients between pediatric- and adult-onset groups. For example, the immediate remission rate of initial surgery was significantly lower in the pediatric-onset group in males. Surprisingly, the final remission rate was much lower in males than in females in patients with adult-onset, indicating that male GHPA patients might own a relatively worse prognosis. We haven\u0026rsquo;t found similar discoveries due to the limited number of patients included in previous cohort studies.\u003c/p\u003e \u003cp\u003eThis article provided a systematic comparison of the clinical features, treatment, and prognosis between pediatric- and adult-onset GHPA patients for the first time. However, since this is retrospective research, the clinical data was not complete, especially for the comprehensive screening of combined tumors and follow-up. In addition, in clinical practice, we usually screen all GHPA patients with early onset for genetic syndromes with clinical manifestations first, and then consider to perform genetic testing for suspected patients. Therefore, asymptomatic patients with genetic syndromes might be missed in our cohort. In conclusion, pediatric-onset GHPA was rare, predominantly male, and featured by longer course and delayed diagnosis compared to adult-onset patients. GHPAs with early onset were larger, able to secrete high levels of GH, and associated with more obvious tumor mass effects and more surgical complications. But after multimodal therapies, a cure rate similar to that of adult-onset patients could eventually be achieved. It should be noted that the proportion of hypopituitarism in pediatric-onset patients was higher, and the impact of long-term GH and IGF-1 excess on cardiac structure and function was similar to patients with adult-onset, calling for long-term follow-up and management. Additionally, we found that among patients with adult-onset, male patients might have a worse prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp; Provided by National High Level Hospital Clinical Research Funding（2022-PUMCH-B-016）.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp; All authors contributed to the study conception and design. Writing\u0026mdash;original draft preparation: X-QZ; Methodology: X-QZ, Y-XS, H-GH; Data collection and analyzation: Y-YY, S-MY, T-XX; Investigation: RL, JL, YY, KD, HY, ; Writing\u0026mdash;review and editing: LD, H-JZ; Supervision: LD, H-JZ. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability \u0026nbsp;\u003c/strong\u003eOriginal data generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp; This is a retrospective research. The PUMCH Research Ethics Committee has confirmed that no ethical approval is required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u0026nbsp; Informed consent was obtained from all the study participants.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNagata, Y., et al., \u003cem\u003eGrowth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes.\u003c/em\u003e Pituitary, 2018. \u003cstrong\u003e21\u003c/strong\u003e(1): p. 1-9.\u003c/li\u003e\n\u003cli\u003eRostomyan, L., et al., \u003cem\u003eClinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients.\u003c/em\u003e Endocr Relat Cancer, 2015. \u003cstrong\u003e22\u003c/strong\u003e(5): p. 745-57.\u003c/li\u003e\n\u003cli\u003eBondanelli, M., et al., \u003cem\u003eCardiac and metabolic effects of chronic growth hormone and insulin-like growth factor I excess in young adults with pituitary gigantism.\u003c/em\u003e Metabolism, 2005. \u003cstrong\u003e54\u003c/strong\u003e(9): p. 1174-80.\u003c/li\u003e\n\u003cli\u003eMete, O. and Lopes, M.B., \u003cem\u003eOverview of the 2017 WHO Classification of Pituitary Tumors.\u003c/em\u003e Endocr Pathol, 2017. \u003cstrong\u003e28\u003c/strong\u003e(3): p. 228-243.\u003c/li\u003e\n\u003cli\u003eZhang, K., et al., \u003cem\u003eRecovery of hypothalamus-pituitary-gonadal dysfunction after the treatment of suprasellar germ cell tumors.\u003c/em\u003e Eur J Endocrinol, 2021. \u003cstrong\u003e184\u003c/strong\u003e(4): p. 617-625.\u003c/li\u003e\n\u003cli\u003eMunro, M.G., Critchley, H.O.D., and Fraser, I.S., \u003cem\u003eThe two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions.\u003c/em\u003e Int J Gynaecol Obstet, 2018. \u003cstrong\u003e143\u003c/strong\u003e(3): p. 393-408.\u003c/li\u003e\n\u003cli\u003eKlein, D.A., Paradise, S.L., and Reeder, R.M., \u003cem\u003eAmenorrhea: A Systematic Approach to Diagnosis and Management.\u003c/em\u003e Am Fam Physician, 2019. \u003cstrong\u003e100\u003c/strong\u003e(1): p. 39-48.\u003c/li\u003e\n\u003cli\u003eCole, T.J., et al., \u003cem\u003eEstablishing a standard definition for child overweight and obesity worldwide: international survey.\u003c/em\u003e Bmj, 2000. \u003cstrong\u003e320\u003c/strong\u003e(7244): p. 1240-3.\u003c/li\u003e\n\u003cli\u003eLeague, C.H., et al., \u003cem\u003eWriting Group of 2018 Chinese Guidelines for the Management of Hypertension.\u003c/em\u003e Chin J Cardiovasc Med, 2019(1): p. 24-56.\u003c/li\u003e\n\u003cli\u003eMatthews, D.R., et al., \u003cem\u003eHomeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.\u003c/em\u003e Diabetologia, 1985. \u003cstrong\u003e28\u003c/strong\u003e(7): p. 412-9.\u003c/li\u003e\n\u003cli\u003eLazzeroni, D., Rimoldi, O., and Camici, P.G., \u003cem\u003eFrom Left Ventricular Hypertrophy to Dysfunction and Failure.\u003c/em\u003e Circ J, 2016. \u003cstrong\u003e80\u003c/strong\u003e(3): p. 555-64.\u003c/li\u003e\n\u003cli\u003eColao, A., et al., \u003cem\u003eGrowth hormone excess with onset in adolescence: clinical appearance and long-term treatment outcome.\u003c/em\u003e Clin Endocrinol (Oxf), 2007. \u003cstrong\u003e66\u003c/strong\u003e(5): p. 714-22.\u003c/li\u003e\n\u003cli\u003eMangupli, R., et al., \u003cem\u003eCombined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening.\u003c/em\u003e Pituitary, 2016. \u003cstrong\u003e19\u003c/strong\u003e(5): p. 507-14.\u003c/li\u003e\n\u003cli\u003eBhansali, A., et al., \u003cem\u003eAdolescent acromegaly: clinical parameters and treatment outcome.\u003c/em\u003e J Pediatr Endocrinol Metab, 2010. \u003cstrong\u003e23\u003c/strong\u003e(10): p. 1047-54.\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a-Ur\u0026iacute;a Santos, M., et al., \u003cem\u003eGigantism: microsurgical treatment by transsphenoidal approach and prognostic factors.\u003c/em\u003e Pituitary, 2023. \u003cstrong\u003e26\u003c/strong\u003e(1): p. 51-56.\u003c/li\u003e\n\u003cli\u003eMehrazin, M., \u003cem\u003ePituitary tumors in children: clinical analysis of 21 cases.\u003c/em\u003e Childs Nerv Syst, 2007. \u003cstrong\u003e23\u003c/strong\u003e(4): p. 391-8.\u003c/li\u003e\n\u003cli\u003eZheng, X.Q., et al., \u003cem\u003eAcromegaly complicated with fulminant pituitary apoplexy: clinical characteristic analysis and review of literature.\u003c/em\u003e Endocrine, 2023. \u003cstrong\u003e81\u003c/strong\u003e(1): p. 160-167.\u003c/li\u003e\n\u003cli\u003eWolf, P., et al., \u003cem\u003eAcromegalic Cardiomyopathy: An Entity on its own? 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adenomas: case series and systematic literature review.\u003c/em\u003e Childs Nerv Syst, 2022. \u003cstrong\u003e38\u003c/strong\u003e(4): p. 729-738.\u003c/li\u003e\n\u003cli\u003eCansu, G.B., et al., \u003cem\u003eASSESSMENT OF DIASTOLIC DYSFUNCTION, ARTERIAL STIFFNESS, AND CAROTID INTIMA-MEDIA THICKNESS IN PATIENTS WITH ACROMEGALY.\u003c/em\u003e Endocr Pract, 2017. \u003cstrong\u003e23\u003c/strong\u003e(5): p. 536-545.\u003c/li\u003e\n\u003cli\u003eXia, Z., et al., \u003cem\u003eSomatotrophic Adenoma in Children Younger than 14 Years: Clinical Features and Treatment of 22 Cases at a Large Pituitary Center.\u003c/em\u003e World Neurosurg, 2018. \u003cstrong\u003e112\u003c/strong\u003e: p. e561-e568.\u003c/li\u003e\n\u003cli\u003eCreo, A.L. and Lteif, A.N., \u003cem\u003ePituitary gigantism: a retrospective case series.\u003c/em\u003e J Pediatr Endocrinol Metab, 2016. \u003cstrong\u003e29\u003c/strong\u003e(5): p. 597-602.\u003c/li\u003e\n\u003cli\u003eBarzaghi, L.R., et al., \u003cem\u003ePediatric Pituitary Adenomas: Early and Long-Term Surgical Outcome in a Series of 85 Consecutive Patients.\u003c/em\u003e Neurosurgery, 2019. \u003cstrong\u003e85\u003c/strong\u003e(1): p. 65-74.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"pediatric-onset growth hormone secreting pituitary adenoma, clinical characteristics, metabolism, treatment, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-4551046/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4551046/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo explore the clinical characteristics, treatment, and prognosis of growth hormone-secreting pituitary adenoma (GHPA) patients with pediatric-onset, so as to facilitate the clinical management.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective cohort study was carried out between 102 pediatric-onset GHPA patients admitted to our hospital from January 2013 to June 2022 and 204 adult-onset GHPA patients who were randomly matched.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGHPA with pediatric-onset was predominantly male, associated with higher proportion of genetic syndromes, longer course, and delay on diagnosis. Clinical symptoms of visual field defects and menstrual abnormality were more common. The pediatric-onset group presented with higher growth hormone (GH) nadir during oral glucose tolerance test (OGTT), higher rates of hyperprolactinemia, larger maximum diameter of adenoma, higher rates of optic chiasm compression, suprasellar invasion, and pituitary apoplexy. Hypertension, diabetes, and obstructive sleep apnea-hypopnea syndrome (OSAHS) were more common in the adult-onset group. Echocardiography results were similar between the two groups. The pediatric-onset group owned significantly higher treatment scores and proportions of multimodal therapy modality, more surgical complications, and a higher proportion of ki67\u0026thinsp;\u0026ge;\u0026thinsp;3%. There was no significant difference in the final cure rate, but male patients with adult-onset had a worse prognosis. The recurrence rate was also similar between two groups. Hypopituitarism was more prevalent in the pediatric-onset group, while the adult-onset group had a higher rate of combining other tumors.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe clinical characteristics of pediatric-onset GHPA patients were different from adult-onset patients. Multimodal therapy modalities could help to achieve a cure rate similar to that of adult-onset patients.\u003c/p\u003e","manuscriptTitle":"Distinct clinical characteristics and prognosis of pediatric-onset GHPA patients compared with adult-onset patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-01 19:08:39","doi":"10.21203/rs.3.rs-4551046/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-19T13:24:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-22T10:59:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"195183465076904555690766490434943986600","date":"2024-06-17T11:43:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-17T06:06:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-10T17:40:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-10T17:39:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2024-06-08T14:58:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6366eee2-65c3-40ed-9469-9e52dbe2ea0f","owner":[],"postedDate":"July 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-30T15:58:41+00:00","versionOfRecord":{"articleIdentity":"rs-4551046","link":"https://doi.org/10.1007/s12020-024-04044-3","journal":{"identity":"endocrine","isVorOnly":false,"title":"Endocrine"},"publishedOn":"2024-09-24 15:56:51","publishedOnDateReadable":"September 24th, 2024"},"versionCreatedAt":"2024-07-01 19:08:39","video":"","vorDoi":"10.1007/s12020-024-04044-3","vorDoiUrl":"https://doi.org/10.1007/s12020-024-04044-3","workflowStages":[]},"version":"v1","identity":"rs-4551046","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4551046","identity":"rs-4551046","version":["v1"]},"buildId":"veTbxFhMMB0_faC6-Wkog","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}