Long-term pituitary function following transsphenoidal surgery for nonfunctioning pituitary adenomas with apoplexy: a single- center retrospective analysis

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Methods A retrospective analysis was performed on patients with non-functional pituitary adenomas who underwent transsphenoidal surgery from January 2016 to September 2020. The patients were divided into apoplexy group and non-apoplexy group based on magnetic resonance imaging(MRI), surgical, and pathological findings. A comparative analysis of pituitary endocrine function was conducted between the two groups at three years postoperatively. Results A total of 563 patients were initially screened, and 50 matched pairs were included in the study following propensity score matching.Preoperatively, 35 patients in the apoplexy group exhibited pituitary hormone deficiencies, including 2 cases of panhypopituitarism and 14 cases with deficiencies in two or more hormones.In contrast, the non- apoplexy group had 30 patients with pituitary hormone deficiencies, of which 8 had deficiencies in two or more hormones, with no cases of panhypopituitarism.A significant difference was observed in the incidence of ACTH axis deficiency between the two groups (36% vs 14%, p = 0.011). This trend persisted at the 3-year follow-up, where the apoplexy group continued to show a significantly higher prevalence of ACTH deficiency (34% vs 16%, p = 0.038).No significant difference was found in the incidence of preoperative LH/FSH axis insufficiency between the groups (38% vs 40%, p = 0.838).However, at the 3-year follow-up, the apoplexy group exhibited a significantly higher incidence of LH/FSH axis insufficiency compared to the non-apoplexy group (30% vs 12%, p = 0.027). Additionally, there was no significant difference in the incidence of deficiencies in two or more hormones between the two groups after 3 years of follow-up (39.1% vs 27.3%, p = 0.705). Conclusion Pituitary apoplexy is commonly associated with pituitary insufficiency. Patients with preoperative apoplexy are more susceptible to ACTH axis dysfunction compared to those without apoplexy, and they demonstrate significantly poorer recovery of ACTH axis function following transsphenoidal surgery. Additionally, among patients with apoplexy, the postoperative recovery of LH/FSH axis function is also notably inferior to that observed in non-apoplexy patients. Health sciences/Endocrinology/Endocrine system and metabolic diseases Health sciences/Neurology/Neurological disorders nonfunctioning pituitary adenomas pituitary apoplexy hypopituitarism Transsphenoidal surgery Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Pituitary adenoma apoplexy is an acute and potentially life-threatening clinical syndrome caused by hemorrhage and/or infarction of a pituitary adenoma. Headache of sudden and severe onset is the main symptom, sometimes associated with visual disturbances or ocular palsy. Previously, pituitary apoplexy was considered a neurosurgical emergency and was always treated with emergency surgery. Conservative treatment is now increasingly used in patients without visual field impairment.It is well-established that pituitary apoplexy can lead to hypopituitarism; However, the data regarding its impact on hypopituitarism remain inconsistent.Previous studies have shown that surgical treatment is more beneficial for the recovery of visual acuity and visual field compared to conservative treatment[ 1 – 3 ], while the data regarding hypopituitarism remain inconsistent[ 4 ]. A multi-center study involving 245 patients with nonfunctioning pituitary adenomas (NFPAs) demonstrated that patients who experienced apoplexy had a lower rate of complete pituitary function recovery compared to those without apoplexy. Additionally, the incidence of new-onset pituitary deficits and permanent diabetes insipidus was higher in patients with apoplexy than in those without[ 5 ]. Another study compared the outcomes of microadenoma apoplexy versus macroadenoma apoplexy. The results indicated that upon admission, hyponatremia, reduced random cortisol levels, and secondary hypothyroidism were the predominant clinical findings. After a 3-year follow-up, patients with microadenoma apoplexy exhibited a lower incidence of corticotropic deficiency and secondary hypothyroidism compared to those with macroadenoma apoplexy[ 6 ]. Although decision-making in treatment remains controversial, surgical intervention primarily aims at neurological recovery; however, its impact on endocrine function requires further investigation. In this study, we examined the pituitary function in patients who underwent transsphenoidal surgery for nonfunctioning pituitary adenomas with apoplexy. The objectives were to evaluate long-term postoperative pituitary function and the potential for recovery of pituitary function following treatment. Methods Study population This retrospective study was approved by the Ethics Committee of the General Hospital of Western Theater Command, and obtained written informed consent from all participating patients.It included patients with histopathologically confirmed pituitary adenomas who underwent transnasal surgery at the Department of Neurosurgery, General Hospital of Western Theater Command, from January 2016 to September 2020. All patients underwent preoperative evaluation of pituitary function, and systematic follow-up assessments were conducted at 3 months, 6 months, 1 year, and 3 years post-surgery to monitor changes in pituitary function. The inclusion criteria for this study were as follows: (1) Patients who underwent transsphenoidal surgery for nonfunctioning pituitary adenomas (NFPAs) between January 2016 and September 2020. (2) Pathological confirmation of nonfunctioning NFPAs, classified according to the 2022 WHO classification of pituitary tumors[ 7 ]. (3) Patients aged 18 years or older at the time of diagnosis. The diagnostic criteria for pituitary apoplexy were as follows: (i) Evidence of hemorrhage and/or necrosis on cranial MRI in patients presenting with acute symptoms suggestive of pituitary apoplexy, such as severe headache, visual field deficits, or altered mental status. (ii) Intraoperative confirmation of hemorrhage and necrosis during surgical exploration. Exclusion criteria included: (1) Functional pituitary adenomas. (2) Posterior pituitary tumors. (3) Patients under 18 years of age. (4) Patients who had undergone craniotomy. (5) Patients with a history of previous radiotherapy. (6) Patients with other endocrine disorders. In the aftermath of pituitary apoplexy, pituitary hormone secretion may be impaired to varying degrees. Consequently, the diagnosis and management of these patients necessitate a multidisciplinary approach. At our pituitary center, the treatment plan for each patient with pituitary apoplexy is formulated through Multidisciplinary Team (MDT) discussions. Furthermore, all surgical procedures are conducted by two senior surgeons, both of whom possess over 20 years of experience. Assessment of pituitary function All patients underwent comprehensive pituitary hormone assessment, which included laboratory measurements of adrenocortical hormone (ACTH), cortisol (08:00–16:00–00:00), thyroid-stimulating hormone (TSH), free thyroxine (FT4),growth hormone (GH), insulin-like growth factor 1 (IGF-1),prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and either estradiol or total and free testosterone levels. Hormone assessments were repeated at 3 months, 6 months, 1 year, and 3 years following the surgery. According to the results of hormone assessment and the patient's clinical symptoms, necessary hormone replacement therapy was conducted in accordance with the Endocrine Society's Clinical Practice Guidelines[ 8 ]. In this study, the functional status of the anterior pituitary was categorized as either deficient or non-deficient. The reference ranges were determined based on the specific analytical methods employed at the time of detection, utilizing distinct cut-off values. If morning cortisol levels fall below the normal range (6.7–22.6 µg/dL) in patients receiving hormone-replacement therapy, at least 24 hours post-final dose administration, additional insulin tolerance tests should be conducted to confirm ACTH deficiency, while also considering the patient's clinical symptoms and signs. Central hypothyroidism was defined as FT4 levels below the normal range (4.89–11.09 ug/dL) in conjunction with TSH levels that were low, within the normal range, or mildly elevated (0.55–4.78 mIU/L). In males, hypogonadism was defined as testosterone levels below the normal range (1.75–7.81 ng/ml) in conjunction with clinical signs and symptoms. In premenopausal women, hypogonadism was characterized by estradiol levels below 15.16 pg/mL, FSH levels above the normal range (1.27–19.26 mIU/ml), and LH levels within the normal range (1.24–8.62 mIU/ml), all accompanied by menstrual irregularities. In postmenopausal women, hypogonadism was defined by reduced FSH levels (below the normal range of 1.27–19.26 mIU/ml) and LH levels (below the normal range of 1.24–8.62 mIU/ml). If a patient exhibits symptoms suggestive of growth hormone deficiency, such as fatigue, depression, increased fat mass, and decreased muscle mass, and if insulin-like growth factor 1 (IGF-1) levels are within the normal range or below the lower limit of normal (60–350 ng/ml), an insulin stimulation test should be conducted to confirm the diagnosis of growth hormone deficiency. The assessment and management of hormone levels are critically important during the perioperative period. At our institution, steroid medications are withheld during this period unless patients have pre-existing adrenal insufficiency. This practice is supported by scientific evidence indicating that administering steroids during the perioperative period does not affect the incidence of adrenal insufficiency in patients with normal adrenal function prior to surgery[ 9 – 11 ]. Statistical Analysis Data analysis was conducted using IBM SPSS Statistics version 25.0. Continuous variables are expressed as means ± standard deviation (SD), whereas categorical variables are summarized as percentages. For continuous variables that were normally distributed, independent samples t-tests were used for comparisons; for those that deviated from normality, the Mann-Whitney U test was applied to evaluate group differences. Categorical variables were analyzed using either the chi-square test or Fisher's exact test, depending on the expected cell frequencies. All data visualizations were created using GraphPad Prism version 8. Statistical significance was set at a p-value threshold of less than 0.05. Results A total of 563 patients who underwent transnasal surgery were included in this study. Of these, 65 patients were lost to follow-up, 5 patients were under 18 years of age, 94 patients had functional pituitary adenomas,19 patients had received radiotherapy, and 1 patient had a posterior pituitary tumor. These patients were excluded from the analysis. The final study population comprised 323 patients without apoplexy and 56 patients with non-functional pituitary adenomas and a history of apoplexy. The following variables were utilized for propensity score matching: age, sex, headache status, and maximum tumor diameter, with a matching tolerance set at 0.02, resulting in the successful matching of 50 pairs of patients. Figure 1 presents a flowchart outlining the inclusion process of patients in the study. Baseline demographic and preoperative imaging and biochemical characteristics The demographic and preoperative baseline characteristics are summarized in Table 1. Prior to propensity score matching, a higher proportion of males was observed in the apoplexy group compared to the non-apoplexy group. Additionally, there was a significant difference in disease type between the two groups (p = 0.046). MRI findings revealed that the mean maximum tumor diameter in the apoplexy group (2.64 ± 0.93 cm) was significantly larger than that in the non-apoplexy group (2.38 ± 0.91 cm; p = 0.047). The incidence of headache was also significantly higher in the apoplexy group (76.79%) compared to the non-apoplexy group (52.13%; p = 0.001). Conversely, the prevalence of alcohol consumption history was significantly greater in the non-apoplexy group (26.89%) compared to the apoplexy group (14.29%; p = 0.045). No significant differences were noted between the two groups regarding age, visual impairment, hypertension, diabetes, smoking status, panhypopituitarism, diabetes insipidus, cranial nerve palsy, or preoperative Knosp classification. After propensity score matching, no significant differences in baseline characteristics were observed between the two groups. Comparison of pituitary function before surgery between the two groups Prior to surgery, 35 patients in the apoplexy group exhibited pituitary hormone deficiencies, including 2 cases of panhypopituitarism and 14 cases with deficiencies in two or more hormones. In contrast, in the non-apoplexy group, 30 patients had pituitary hormone deficiencies, with 8 cases involving deficiencies in two or more hormones and no instances of panhypopituitarism. Notably, the incidence of ACTH axis deficiency differed significantly between the two groups (36% vs. 14%, p = 0.011), while there were no significant differences in the occurrence rates of LH/FSH, TSH, and GH deficiencie (Table 2). Comparison of pituitary function after surgery between the two groups In this study, the preoperative prevalence of hypopituitarism was 70% in the apoplexy group and persisted in 46% of patients three years post-surgery, compared to 60% preoperatively and 22% at three years in the non-apoplexy group. Complete pituitary function data were collected for both groups at 3 months and 3 years post-surgery. We conducted a comparative analysis of the ACTH, TSH, GH, and LH/FSH axes between the two groups. TSH axis deficiency Preoperative thyroid-stimulating hormone (TSH) deficiency was observed in 12% (6/50) of patients in both the apoplexy and non-apoplexy groups. However, at 3 months post-surgery, TSH deficiency was noted in 10% (5/50) of patients in the apoplexy group, including 3 new cases that developed after surgery. Among those with preoperative TSH deficiency, 66.67% (4/6) experienced recovery. In contrast, only 6% (3/50) of patients in the non-apoplexy group had TSH deficiency at 3 months post-surgery, with 2 new cases developing after surgery. Notably, 83.33% (5/6) of patients with preoperative TSH deficiency in this group recovered. Three years post-surgery, TSH deficiency persisted in 4% (2/50) of patients in the apoplexy group, all of whom had preoperative TSH deficiency. In the non-apoplexy group, no patients exhibited TSH deficiency at the 3-year follow-up(Table 3). GH axis deficiency Before the operation, 14% (7/50) of patients in the apoplexy group exhibited growth hormone deficiency. At the 3-month follow-up post-operation, 14% (7/50) still had growth hormone deficiency, with 57.14% (4/7) of these cases being newly diagnosed after surgery. By the 3-year follow-up, this proportion decreased to 6% (3/50), including 2 cases that were already deficient preoperatively (Table 3). In the non-apoplexy group, 8% (4/50) of patients had GH deficiency before surgery.At the 3-month follow-up, only 4% (2/50) remained GH deficient, with 1 new case developing post-surgery and 3 preoperative cases recovering.By the 3-year follow-up, no patients in the non-apoplexy group exhibited growth hormone deficiency. LH/FSH axis deficiency In the apoplexy group, 38% (19/50) of patients exhibited LH/FSH deficiency prior to surgery. Three months post-surgery, this proportion increased slightly to 42% (21/50), with 5 new cases emerging. Among those with preoperative LH/FSH deficiency, 84.21% (16/19) continued to exhibit persistent LH/FSH deficiency. By three years post-operation, 30% (15/50) of patients still had LH/FSH deficiency, with 12 of these cases having been present preoperatively. In the non-apoplexy group, 40% (20/50) of patients had LH/FSH deficiency before surgery. At three months post-surgery, this proportion decreased to 32% (16/50), including 7 new-onset cases. Among those with preoperative LH/FSH deficiency, 45% (9/20) still had LH/FSH deficiency. By three years post-surgery, only 12% (6/50) of patients had LH/FSH deficiency, with 4 cases being preoperative and 2 newly diagnosed postoperatively.(Fig. 2 and Table 3). There was no statistically significant difference in LH/FSH axis insufficiency between the two groups prior to surgery (38% vs 40%, p = 0.838). However, three years post-surgery, the apoplexy group exhibited a significantly higher incidence of LH/FSH axis insufficiency compared to the non-apoplexy group (30% vs 12%, p = 0.027). ACTH axis deficiency In patients with apoplexy, the incidence of ACTH deficiency was 36% (18/50) preoperatively and increased to 42% (21/50) at 3 months postoperatively. Among those with normal preoperative ACTH levels, 18.75% (6/32) developed new-onset ACTH deficiency (Table 3). Extended follow-up to 3 years postoperatively revealed that a total of 34% (17/50) of patients exhibited ACTH deficiency. Specifically, among patients who had preoperative ACTH deficiency, 83.33% (15/18) continued to have deficiency during the 3-year follow-up period, while 16.67% (3/18) regained ACTH function (Fig. 3 and Table 3). In the non-apoplexy group, the incidence of ACTH deficiency rose from 14% (7/50) preoperatively to 28% (14/50) at 3 months postoperatively. Among patients with normal preoperative ACTH levels, 9.3% (4/43) developed new-onset ACTH deficiency (Table 3). After 3 years of follow-up, a total of 16% (8/50) of patients in this group had ACTH deficiency. Specifically, among patients who had preoperative ACTH deficiency, 71.43% (5/7) continued to have deficiency during the 3-year follow-up period, while 28.57% (2/7) regained ACTH function (Fig. 3 and Table 3). Prior to surgery, a significantly higher proportion of patients in the apoplexy group exhibited ACTH deficiency compared to those in the non-apoplexy group (36% vs 14%, p = 0.011). Three years post-surgery, this trend persisted, with the apoplexy group still demonstrating a significantly higher prevalence of ACTH deficiency (34% vs 16%, p = 0.038) (Table 3). Two or more axes deficiency At 3 months post-surgery, a total of 24 patients in the apoplexy group developed hypopituitarism. Specifically, 8 patients exhibited deficiencies in both the LH/FSH and ACTH axes, 1 patient had deficiencies in the LH/FSH and GH axes, 2 patients showed insufficiencies in the ACTH and GH axes, and 1 patient experienced deficiencies in all three axes: LH/FSH, GH, and ACTH. Two patients continued to have panhypopituitarism. In contrast, in the non-apoplexy group, 15 patients developed pituitary dysfunction, with 3 patients exhibiting combined deficiencies in the LH/FSH and ACTH axes, while the remaining 12 patients had single hormone deficiencies (Fig. 4). Three years post-surgery, a total of 23 patients in the apoplexy group exhibited pituitary dysfunction. Specifically, 2 patients still had persistent panhypopituitarism, 6 patients exhibited deficiencies in both the LH/FSH and ACTH axes, and 1 patient showed deficiencies in the LH/FSH, GH, and ACTH axes. In contrast, in the non-apoplexy group, 6 patients had isolated LH/FSH axis deficiency, 8 patients had isolated ACTH axis deficiency, and only 3 patients exhibited combined deficiencies in both the LH/FSH and ACTH axes(Fig. 4). Discussion In this study, we examined the long-term outcomes of pituitary function in patients with nonfunctional pituitary adenomas who underwent endonasal surgery, comparing those with and without apoplexy events. Our findings are as follows: 1) Male patients have a higher incidence of pituitary adenoma apoplexy, and tumors in the apoplexy group tend to be larger compared to those in the non-apoplexy group. 2) Preoperatively, the apoplexy group exhibited a significantly higher incidence of ACTH axis dysfunction than the non-apoplexy group. 3) At the 3-year postoperative follow-up, patients in the apoplexy group demonstrated significantly poorer recovery of both ACTH axis and LH/FSH axis compared to the non-apoplexy group. 4) There was no significant difference in the occurrence of deficiencies involving two or more axes between the apoplexy and non-apoplexy groups. Demographically, our data indicate a higher prevalence of nonfunctional pituitary adenoma apoplexy in male patients, consistent with findings from other studies on pituitary apoplexy. For example, Marta Araujo-Castro's research demonstrated that the incidence of pituitary apoplexy was significantly higher in males compared to females (70% vs. 48.1%)[ 5 ]. A sudden headache is the most prominent clinical manifestation of pituitary adenoma apoplexy. Our data revealed that 76.79% of patients in the apoplexy group experienced headaches, which was significantly higher than the 52.13% in the non-apoplexy group (p = 0.001). Other studies have reported that the incidence of headache in patients with pituitary adenoma apoplexy ranges from approximately 80% to as high as 89% [ 12 , 13 ]. Research suggests that the sudden increase in intrasellar pressure following pituitary adenoma apoplexy, leading to traction on the dura mater and subsequent meningeal irritation, may be the primary cause of headache[ 14 ]. The recovery of pituitary function following pituitary apoplexy is challenging. Our study demonstrated that among patients with pre-existing preoperative ACTH axis dysfunction, 28.57% of non-apoplexy patients exhibited recovery of the ACTH axis function three years post-surgery, a finding consistent with previous research [ 15 , 16 ]. However, in the apoplexy group, the recovery rate of the ACTH axis was significantly lower, at only 16.67%, compared to non-apoplexy patients, indicating that apoplexy may affect the recovery of ACTH axis function in patients. Furthermore, when evaluating the ACTH axis function three years post-surgery, the apoplexy group exhibited a significantly higher prevalence of ACTH axis insufficiency compared to the non-apoplexy group, with the difference being statistically significant.This indicates a markedly poorer recovery of ACTH axis function in apoplexy patients.This phenomenon may be attributed to the rapid elevation of intrasellar pressure following pituitary apoplexy, which compromises pituitary blood supply and compresses the portal venous system,these changes can result in irreversible damage to the anterior pituitary gland, ultimately impairing the recovery of pituitary function[ 14 ]. The recovery of the adrenocorticotropic hormone (ACTH) axis following pituitary apoplexy is a critical determinant of long-term endocrine function and patient outcomes.Numerous studies suggest that the recovery of ACTH axis function after pituitary adenoma apoplexy is influenced by multiple factors. For example, some research indicates that younger age, smaller tumor size (< 2 cm), normal blood pressure, and the absence of intraoperative cerebrospinal fluid leakage may positively impact ACTH axis recovery[ 17 – 19 ]. Furthermore, in the pituitary microenvironment, ischemia and inflammatory responses secondary to hemorrhage and ischemia are also associated with ongoing pituitary tissue damage, thereby impeding functional recovery[ 20 ]. Patients with pituitary apoplexy are at a heightened risk of developing adrenal insufficiency, which can manifest as fatigue, hypotension, hyponatremia, and, in severe cases, life-threatening adrenal crises[ 21 ]. Therefore, close postoperative monitoring of adrenal function is essential, and the multidisciplinary team (MDT) model is helpful. Early initiation of glucocorticoid replacement therapy may be necessary in patients with persistent ACTH axis dysfunction. After pituitary adenoma apoplexy, insufficiency of the LH/FSH axis should not be overlooked. In our study, the recovery of LH/FSH axis function post-surgery was significant in the non-apoplexy group, whereas it was notably unsatisfactory in the apoplexy group. The incidence of LH/FSH axis dysfunction following transsphenoidal surgery for pituitary adenomas varies widely. Maria's study reported an incidence of 35.7% [ 22 ], while Alexopoulou found it to be as high as 68%[ 23 ]. Data regarding the impact of transsphenoidal surgery on anterior pituitary function are inconsistent, and this variability becomes even more pronounced when compounded by the effects of pituitary apoplexy. Pituitary adenomas are the most frequent cause of hypopituitarism, which can be further aggravated by pituitary apoplexy and/or surgical intervention. According to O'Sullivan's study, 51% of patients with pituitary adenomas exhibited preoperative anterior pituitary insufficiency, increasing to 74.5% postoperatively[ 24 ]. Another study reported a significant increase in pituitary function insufficiency among patients with pituitary apoplexy during follow-up (from 45% at baseline to 71% at follow-up, OR = 4.7, CI = 1.30–25.33) [ 25 ], with some reports indicating that up to 80% of these patients experienced postoperative decline in pituitary function[ 26 ]. Currently, hormone replacement therapy (HRT) remains the primary treatment for pituitary function decline. It is recommended to use the minimum effective dose to alleviate clinical symptoms and optimize the patient's quality of life[ 27 , 28 ]. Recently, a prospective study by Adsm et al. demonstrated that there was no significant difference in the recovery of anterior pituitary function between surgical and medically conservative treatments in patients with pituitary apoplexy. However, surgery is generally preferred for patients presenting with visual field defects.[ 29 ]. In our study, the non-apoplexy group exhibited significant improvement in pituitary function following surgery, whereas the apoplexy group showed limited improvement and required long-term or lifelong hormone replacement therapy. Therefore, when surgical intervention is warranted due to pituitary adenoma apoplexy, careful deliberation is essential. Although surgical treatment provides notable improvements in vision, its potential impact on pituitary function must be carefully considered. Our study has several limitations that warrant consideration. Firstly, this was a retrospective, single-institution study, which may introduce selection bias within the patient cohort. Secondly, all surgical procedures were conducted by neurosurgeons at our institution, potentially limiting the generalizability of our findings to other pituitary centers. Lastly, hormone assessments in some female patients during follow-up were influenced by menstrual cycles and menopause, which could have introduced variability into the data. Additionally,future research should focus on elucidating the molecular mechanisms underlying the development of pituitary insufficiency after pituitary apoplexy and exploring potential therapeutic interventions to enhance pituitary function recovery.At the same time, longitudinal studies with larger patient cohorts are warranted to validate our findings and to assess the impact of various treatment modalities on pituitary function recovery. Conclusion Pituitary apoplexy is frequently associated with long-term pituitary dysfunction. Compared to non-apoplexy patients, those with preoperative apoplexy are more prone to ACTH axis dysfunction, and exhibit significantly poorer recovery of ACTH axis function following surgical treatment. Furthermore, among patients with preoperative apoplexy, the recovery of LH/FSH axis function is also inferior to that in non-apoplexy patients. Declarations Study approval statement: The studies involving humans were approved by The General Hospital of Western Theater Command. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Conflict of Interest Statement: The authors have no conflicts of interest to declare. Funding Sources: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the The construction of the army's key clinical specialty – neurosurgery(4156Z5A2). Author Contribution DB. Z,JN. L and Z.Z collected the data.RT.G and YQ.O performed the data analyses.DB. Z and YX. Y interpreted the data and drafted the manuscript. JM.C and T.Y designed the Study.All authors reviewed the manuscript critically for intellectual content and gave final approval of the current version of the manuscript. Data Availability The raw data supporting the conclusions of this article will be made available upon reasonable request from the authors. For further inquiries, please contact the corresponding author. References Saktiwarawat, K., Tunthanathip, T., Oearsakul, T. & Taweesomboonyat, C. Comparing neuroendocrine recovery between surgical and conservative management in pituitary apoplexy patients: a propensity score-matched analysis. Neurosurg. Rev. 47 (1), 236 (2024). Kim, Y. H. et al. Postoperative Neurologic Outcome in Patients with Pituitary Apoplexy After Transsphenoidal Surgery. World Neurosurg. 111 , e18–e23 (2018). Tu, M., Lu, Q., Zhu, P. & Zheng, W. 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Arafah, B. M., Prunty, D., Ybarra, J., Hlavin, M. L. & Selman, W. R. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J. Clin. Endocrinol. Metab. 85 (5), 1789–1793 (2000). Yedinak, C. et al. Recovery rate of adrenal function after surgery in patients with acromegaly is higher than in those with non-functioning pituitary tumors: a large single center study. Pituitary 18 (5), 701–709 (2015). Al-Shamkhi, N. et al. Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register. Eur. J. Endocrinol. 189 (2), 217–224 (2023). Kelly, D. F., Fatemi, N. & Dusick, J. Pituitary Hormonal Loss and Recovery After Transsphenoidal Adenoma Removal. Neurosurgery 67 (1), E221 (2010). Munro, V. et al. Recovery of adrenal function after chronic secondary adrenal insufficiency in patients with hypopituitarism. Clin. Endocrinol. (Oxf) . 85 (2), 216–222 (2016). Hwang, J. Y. et al. Axis-specific analysis and predictors of endocrine recovery and deficits for non-functioning pituitary adenomas undergoing endoscopic transsphenoidal surgery. Pituitary 23 (4), 389–399 (2020). Glezer, A. & Bronstein, M. D. Pituitary apoplexy: pathophysiology, diagnosis and management. Arch. Endocrinol. Metab. 59 (3), 259–264 (2015). Husebye, E. S., Pearce, S. H., Krone, N. P. & Kampe, O. Adrenal insufficiency. Lancet 397 (10274), 613–629 (2021). Mavromati, M. et al. The impact of transsphenoidal surgery on pituitary function in patients with non-functioning macroadenomas. Endocrine 81 (2), 340–348 (2023). Alexopoulou, O. et al. Outcome of pituitary hormone deficits after surgical treatment of nonfunctioning pituitary macroadenomas. Endocrine 73 (1), 166–176 (2021). O'Sullivan, E. P. et al. The natural history of surgically treated but radiotherapy-naive nonfunctioning pituitary adenomas. Clin. Endocrinol. (Oxf) . 71 (5), 709–714 (2009). Moller-Goede, D. L., Brandle, M., Landau, K., Bernays, R. L. & Schmid, C. Pituitary apoplexy: re-evaluation of risk factors for bleeding into pituitary adenomas and impact on outcome. Eur. J. Endocrinol. 164 (1), 37–43 (2011). Gondim, J. A. et al. Endoscopic Endonasal Surgery for Treatment of Pituitary Apoplexy: 16 Years of Experience in a Specialized Pituitary Center. World Neurosurg. 108 , 137–142 (2017). Higham, C. E., Johannsson, G. & Shalet, S. M. Hypopituitarism Lancet , 388 (10058): 2403–2415. (2016). Tritos, N. A. & Miller, K. K. Diagnosis and Management of Pituitary Adenomas: A Review. JAMA 329 (16), 1386–1398 (2023). Mamelak, A. N. et al. A Prospective, Multicenter, Observational Study of Surgical vs Nonsurgical Management for Pituitary Apoplexy. J. Clin. Endocrinol. Metab. 109 (2), e711–e725 (2024). Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx Table3.xlsx Cite Share Download PDF Status: Published Journal Publication published 01 Jun, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 25 Apr, 2025 Reviews received at journal 24 Apr, 2025 Reviewers agreed at journal 24 Apr, 2025 Reviews received at journal 15 Apr, 2025 Reviewers agreed at journal 14 Apr, 2025 Reviewers invited by journal 03 Apr, 2025 Editor assigned by journal 02 Apr, 2025 Editor invited by journal 17 Mar, 2025 Submission checks completed at journal 15 Mar, 2025 First submitted to journal 15 Mar, 2025 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. 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Command","correspondingAuthor":false,"prefix":"","firstName":"Yongxiang","middleName":"","lastName":"Yang","suffix":""},{"id":446377601,"identity":"8bf6311c-ebae-4d35-adbf-7cf0999b3711","order_by":2,"name":"Ruiting Gao","email":"","orcid":"","institution":"The General Hospital of Western Theater Command","correspondingAuthor":false,"prefix":"","firstName":"Ruiting","middleName":"","lastName":"Gao","suffix":""},{"id":446377602,"identity":"9344d9a6-e7aa-46ed-af61-f1003696e855","order_by":3,"name":"Yangqing Ou","email":"","orcid":"","institution":"The General Hospital of Western Theater Command","correspondingAuthor":false,"prefix":"","firstName":"Yangqing","middleName":"","lastName":"Ou","suffix":""},{"id":446377603,"identity":"13e85522-7203-44bd-af2f-ee5645d5bf86","order_by":4,"name":"Jianing Luo","email":"","orcid":"","institution":"The General Hospital of Western Theater 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2","display":"","copyAsset":false,"role":"figure","size":88945,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/0585a5d6d1d36039c3b41c46.jpg"},{"id":82079893,"identity":"b7deac4a-2a0b-47ed-bf9d-dc109b10eabe","added_by":"auto","created_at":"2025-05-06 14:19:20","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":89947,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/484debd352bd404722ffdaf2.jpg"},{"id":82079167,"identity":"ac502ae0-8658-4b07-a42b-0719b40bbc7d","added_by":"auto","created_at":"2025-05-06 14:11:20","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":328110,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/093324518c2697290e2b3bb3.jpg"},{"id":83783014,"identity":"92c36bd4-63ec-4223-9e87-e5622a6ea197","added_by":"auto","created_at":"2025-06-02 16:09:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1402628,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/30221ea7-0989-4fd5-9349-3ca2fc3b39d0.pdf"},{"id":82079168,"identity":"24304a62-c22b-48c2-9f87-0b48fdf2bffa","added_by":"auto","created_at":"2025-05-06 14:11:20","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":10857,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/894d84da328ab59c5ff8d209.xlsx"},{"id":82077505,"identity":"642916f7-0ff0-4819-b31f-d1fc49d2a452","added_by":"auto","created_at":"2025-05-06 14:03:20","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":9488,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/1c4c84c7c7cb834bad7302d3.xlsx"},{"id":82077509,"identity":"8ae33aa4-7f7b-465a-9179-fcf1d70a3355","added_by":"auto","created_at":"2025-05-06 14:03:20","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":9816,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6231669/v1/054d92e1f146f8d093f541c4.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term pituitary function following transsphenoidal surgery for nonfunctioning pituitary adenomas with apoplexy: a single- center retrospective analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePituitary adenoma apoplexy is an acute and potentially life-threatening clinical syndrome caused by hemorrhage and/or infarction of a pituitary adenoma. Headache of sudden and severe onset is the main symptom, sometimes associated with visual disturbances or ocular palsy. Previously, pituitary apoplexy was considered a neurosurgical emergency and was always treated with emergency surgery. Conservative treatment is now increasingly used in patients without visual field impairment.It is well-established that pituitary apoplexy can lead to hypopituitarism; However, the data regarding its impact on hypopituitarism remain inconsistent.Previous studies have shown that surgical treatment is more beneficial for the recovery of visual acuity and visual field compared to conservative treatment[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], while the data regarding hypopituitarism remain inconsistent[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A multi-center study involving 245 patients with nonfunctioning pituitary adenomas (NFPAs) demonstrated that patients who experienced apoplexy had a lower rate of complete pituitary function recovery compared to those without apoplexy. Additionally, the incidence of new-onset pituitary deficits and permanent diabetes insipidus was higher in patients with apoplexy than in those without[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Another study compared the outcomes of microadenoma apoplexy versus macroadenoma apoplexy. The results indicated that upon admission, hyponatremia, reduced random cortisol levels, and secondary hypothyroidism were the predominant clinical findings. After a 3-year follow-up, patients with microadenoma apoplexy exhibited a lower incidence of corticotropic deficiency and secondary hypothyroidism compared to those with macroadenoma apoplexy[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although decision-making in treatment remains controversial, surgical intervention primarily aims at neurological recovery; however, its impact on endocrine function requires further investigation.\u003c/p\u003e \u003cp\u003eIn this study, we examined the pituitary function in patients who underwent transsphenoidal surgery for nonfunctioning pituitary adenomas with apoplexy. The objectives were to evaluate long-term postoperative pituitary function and the potential for recovery of pituitary function following treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003e This retrospective study was approved by the Ethics Committee of the General Hospital of Western Theater Command, and obtained written informed consent from all participating patients.It included patients with histopathologically confirmed pituitary adenomas who underwent transnasal surgery at the Department of Neurosurgery, General Hospital of Western Theater Command, from January 2016 to September 2020.\u003c/p\u003e \u003cp\u003eAll patients underwent preoperative evaluation of pituitary function, and systematic follow-up assessments were conducted at 3 months, 6 months, 1 year, and 3 years post-surgery to monitor changes in pituitary function. The inclusion criteria for this study were as follows: (1) Patients who underwent transsphenoidal surgery for nonfunctioning pituitary adenomas (NFPAs) between January 2016 and September 2020. (2) Pathological confirmation of nonfunctioning NFPAs, classified according to the 2022 WHO classification of pituitary tumors[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. (3) Patients aged 18 years or older at the time of diagnosis. The diagnostic criteria for pituitary apoplexy were as follows: (i) Evidence of hemorrhage and/or necrosis on cranial MRI in patients presenting with acute symptoms suggestive of pituitary apoplexy, such as severe headache, visual field deficits, or altered mental status. (ii) Intraoperative confirmation of hemorrhage and necrosis during surgical exploration. Exclusion criteria included: (1) Functional pituitary adenomas. (2) Posterior pituitary tumors. (3) Patients under 18 years of age. (4) Patients who had undergone craniotomy. (5) Patients with a history of previous radiotherapy. (6) Patients with other endocrine disorders.\u003c/p\u003e \u003cp\u003eIn the aftermath of pituitary apoplexy, pituitary hormone secretion may be impaired to varying degrees. Consequently, the diagnosis and management of these patients necessitate a multidisciplinary approach. At our pituitary center, the treatment plan for each patient with pituitary apoplexy is formulated through Multidisciplinary Team (MDT) discussions. Furthermore, all surgical procedures are conducted by two senior surgeons, both of whom possess over 20 years of experience.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssessment of pituitary function\u003c/h3\u003e\n\u003cp\u003eAll patients underwent comprehensive pituitary hormone assessment, which included laboratory measurements of adrenocortical hormone (ACTH), cortisol (08:00\u0026ndash;16:00\u0026ndash;00:00), thyroid-stimulating hormone (TSH), free thyroxine (FT4),growth hormone (GH), insulin-like growth factor 1 (IGF-1),prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and either estradiol or total and free testosterone levels. Hormone assessments were repeated at 3 months, 6 months, 1 year, and 3 years following the surgery. According to the results of hormone assessment and the patient's clinical symptoms, necessary hormone replacement therapy was conducted in accordance with the Endocrine Society's Clinical Practice Guidelines[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, the functional status of the anterior pituitary was categorized as either deficient or non-deficient. The reference ranges were determined based on the specific analytical methods employed at the time of detection, utilizing distinct cut-off values.\u003c/p\u003e \u003cp\u003eIf morning cortisol levels fall below the normal range (6.7\u0026ndash;22.6 \u0026micro;g/dL) in patients receiving hormone-replacement therapy, at least 24 hours post-final dose administration, additional insulin tolerance tests should be conducted to confirm ACTH deficiency, while also considering the patient's clinical symptoms and signs.\u003c/p\u003e \u003cp\u003eCentral hypothyroidism was defined as FT4 levels below the normal range (4.89\u0026ndash;11.09 ug/dL) in conjunction with TSH levels that were low, within the normal range, or mildly elevated (0.55\u0026ndash;4.78 mIU/L).\u003c/p\u003e \u003cp\u003eIn males, hypogonadism was defined as testosterone levels below the normal range (1.75\u0026ndash;7.81 ng/ml) in conjunction with clinical signs and symptoms. In premenopausal women, hypogonadism was characterized by estradiol levels below 15.16 pg/mL, FSH levels above the normal range (1.27\u0026ndash;19.26 mIU/ml), and LH levels within the normal range (1.24\u0026ndash;8.62 mIU/ml), all accompanied by menstrual irregularities. In postmenopausal women, hypogonadism was defined by reduced FSH levels (below the normal range of 1.27\u0026ndash;19.26 mIU/ml) and LH levels (below the normal range of 1.24\u0026ndash;8.62 mIU/ml).\u003c/p\u003e \u003cp\u003eIf a patient exhibits symptoms suggestive of growth hormone deficiency, such as fatigue, depression, increased fat mass, and decreased muscle mass, and if insulin-like growth factor 1 (IGF-1) levels are within the normal range or below the lower limit of normal (60\u0026ndash;350 ng/ml), an insulin stimulation test should be conducted to confirm the diagnosis of growth hormone deficiency.\u003c/p\u003e \u003cp\u003eThe assessment and management of hormone levels are critically important during the perioperative period. At our institution, steroid medications are withheld during this period unless patients have pre-existing adrenal insufficiency. This practice is supported by scientific evidence indicating that administering steroids during the perioperative period does not affect the incidence of adrenal insufficiency in patients with normal adrenal function prior to surgery[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData analysis was conducted using IBM SPSS Statistics version 25.0. Continuous variables are expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), whereas categorical variables are summarized as percentages. For continuous variables that were normally distributed, independent samples t-tests were used for comparisons; for those that deviated from normality, the Mann-Whitney U test was applied to evaluate group differences. Categorical variables were analyzed using either the chi-square test or Fisher's exact test, depending on the expected cell frequencies. All data visualizations were created using GraphPad Prism version 8. Statistical significance was set at a p-value threshold of less than 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 563 patients who underwent transnasal surgery were included in this study. Of these, 65 patients were lost to follow-up, 5 patients were under 18 years of age, 94 patients had functional pituitary adenomas,19 patients had received radiotherapy, and 1 patient had a posterior pituitary tumor. These patients were excluded from the analysis. The final study population comprised 323 patients without apoplexy and 56 patients with non-functional pituitary adenomas and a history of apoplexy. The following variables were utilized for propensity score matching: age, sex, headache status, and maximum tumor diameter, with a matching tolerance set at 0.02, resulting in the successful matching of 50 pairs of patients. Figure\u0026nbsp;1 presents a flowchart outlining the inclusion process of patients in the study.\u003c/p\u003e\n\u003ch3\u003eBaseline demographic and preoperative imaging and biochemical characteristics\u003c/h3\u003e\n\u003cp\u003eThe demographic and preoperative baseline characteristics are summarized in Table\u0026nbsp;1. Prior to propensity score matching, a higher proportion of males was observed in the apoplexy group compared to the non-apoplexy group. Additionally, there was a significant difference in disease type between the two groups (p\u0026thinsp;=\u0026thinsp;0.046). MRI findings revealed that the mean maximum tumor diameter in the apoplexy group (2.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93 cm) was significantly larger than that in the non-apoplexy group (2.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91 cm; p\u0026thinsp;=\u0026thinsp;0.047). The incidence of headache was also significantly higher in the apoplexy group (76.79%) compared to the non-apoplexy group (52.13%; p\u0026thinsp;=\u0026thinsp;0.001). Conversely, the prevalence of alcohol consumption history was significantly greater in the non-apoplexy group (26.89%) compared to the apoplexy group (14.29%; p\u0026thinsp;=\u0026thinsp;0.045). No significant differences were noted between the two groups regarding age, visual impairment, hypertension, diabetes, smoking status, panhypopituitarism, diabetes insipidus, cranial nerve palsy, or preoperative Knosp classification. After propensity score matching, no significant differences in baseline characteristics were observed between the two groups.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparison of pituitary function before surgery between the two groups\u003c/h2\u003e \u003cp\u003ePrior to surgery, 35 patients in the apoplexy group exhibited pituitary hormone deficiencies, including 2 cases of panhypopituitarism and 14 cases with deficiencies in two or more hormones. In contrast, in the non-apoplexy group, 30 patients had pituitary hormone deficiencies, with 8 cases involving deficiencies in two or more hormones and no instances of panhypopituitarism. Notably, the incidence of ACTH axis deficiency differed significantly between the two groups (36% vs. 14%, p\u0026thinsp;=\u0026thinsp;0.011), while there were no significant differences in the occurrence rates of LH/FSH, TSH, and GH deficiencie (Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eComparison of pituitary function after surgery between the two groups\u003c/h3\u003e\n\u003cp\u003eIn this study, the preoperative prevalence of hypopituitarism was 70% in the apoplexy group and persisted in 46% of patients three years post-surgery, compared to 60% preoperatively and 22% at three years in the non-apoplexy group. Complete pituitary function data were collected for both groups at 3 months and 3 years post-surgery. We conducted a comparative analysis of the ACTH, TSH, GH, and LH/FSH axes between the two groups.\u003c/p\u003e\n\u003ch3\u003eTSH axis deficiency\u003c/h3\u003e\n\u003cp\u003ePreoperative thyroid-stimulating hormone (TSH) deficiency was observed in 12% (6/50) of patients in both the apoplexy and non-apoplexy groups. However, at 3 months post-surgery, TSH deficiency was noted in 10% (5/50) of patients in the apoplexy group, including 3 new cases that developed after surgery. Among those with preoperative TSH deficiency, 66.67% (4/6) experienced recovery. In contrast, only 6% (3/50) of patients in the non-apoplexy group had TSH deficiency at 3 months post-surgery, with 2 new cases developing after surgery. Notably, 83.33% (5/6) of patients with preoperative TSH deficiency in this group recovered. Three years post-surgery, TSH deficiency persisted in 4% (2/50) of patients in the apoplexy group, all of whom had preoperative TSH deficiency. In the non-apoplexy group, no patients exhibited TSH deficiency at the 3-year follow-up(Table\u0026nbsp;3).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eGH axis deficiency\u003c/h2\u003e \u003cp\u003eBefore the operation, 14% (7/50) of patients in the apoplexy group exhibited growth hormone deficiency. At the 3-month follow-up post-operation, 14% (7/50) still had growth hormone deficiency, with 57.14% (4/7) of these cases being newly diagnosed after surgery. By the 3-year follow-up, this proportion decreased to 6% (3/50), including 2 cases that were already deficient preoperatively (Table\u0026nbsp;3). In the non-apoplexy group, 8% (4/50) of patients had GH deficiency before surgery.At the 3-month follow-up, only 4% (2/50) remained GH deficient, with 1 new case developing post-surgery and 3 preoperative cases recovering.By the 3-year follow-up, no patients in the non-apoplexy group exhibited growth hormone deficiency.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLH/FSH axis deficiency\u003c/h2\u003e \u003cp\u003eIn the apoplexy group, 38% (19/50) of patients exhibited LH/FSH deficiency prior to surgery. Three months post-surgery, this proportion increased slightly to 42% (21/50), with 5 new cases emerging. Among those with preoperative LH/FSH deficiency, 84.21% (16/19) continued to exhibit persistent LH/FSH deficiency. By three years post-operation, 30% (15/50) of patients still had LH/FSH deficiency, with 12 of these cases having been present preoperatively. In the non-apoplexy group, 40% (20/50) of patients had LH/FSH deficiency before surgery. At three months post-surgery, this proportion decreased to 32% (16/50), including 7 new-onset cases. Among those with preoperative LH/FSH deficiency, 45% (9/20) still had LH/FSH deficiency. By three years post-surgery, only 12% (6/50) of patients had LH/FSH deficiency, with 4 cases being preoperative and 2 newly diagnosed postoperatively.(Fig.\u0026nbsp;2 and Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eThere was no statistically significant difference in LH/FSH axis insufficiency between the two groups prior to surgery (38% vs 40%, p\u0026thinsp;=\u0026thinsp;0.838). However, three years post-surgery, the apoplexy group exhibited a significantly higher incidence of LH/FSH axis insufficiency compared to the non-apoplexy group (30% vs 12%, p\u0026thinsp;=\u0026thinsp;0.027).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eACTH axis deficiency\u003c/h2\u003e \u003cp\u003eIn patients with apoplexy, the incidence of ACTH deficiency was 36% (18/50) preoperatively and increased to 42% (21/50) at 3 months postoperatively. Among those with normal preoperative ACTH levels, 18.75% (6/32) developed new-onset ACTH deficiency (Table\u0026nbsp;3). Extended follow-up to 3 years postoperatively revealed that a total of 34% (17/50) of patients exhibited ACTH deficiency. Specifically, among patients who had preoperative ACTH deficiency, 83.33% (15/18) continued to have deficiency during the 3-year follow-up period, while 16.67% (3/18) regained ACTH function (Fig.\u0026nbsp;3 and Table\u0026nbsp;3). In the non-apoplexy group, the incidence of ACTH deficiency rose from 14% (7/50) preoperatively to 28% (14/50) at 3 months postoperatively. Among patients with normal preoperative ACTH levels, 9.3% (4/43) developed new-onset ACTH deficiency (Table\u0026nbsp;3). After 3 years of follow-up, a total of 16% (8/50) of patients in this group had ACTH deficiency. Specifically, among patients who had preoperative ACTH deficiency, 71.43% (5/7) continued to have deficiency during the 3-year follow-up period, while 28.57% (2/7) regained ACTH function (Fig.\u0026nbsp;3 and Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003ePrior to surgery, a significantly higher proportion of patients in the apoplexy group exhibited ACTH deficiency compared to those in the non-apoplexy group (36% vs 14%, p\u0026thinsp;=\u0026thinsp;0.011). Three years post-surgery, this trend persisted, with the apoplexy group still demonstrating a significantly higher prevalence of ACTH deficiency (34% vs 16%, p\u0026thinsp;=\u0026thinsp;0.038) (Table\u0026nbsp;3).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTwo or more axes deficiency\u003c/h2\u003e \u003cp\u003eAt 3 months post-surgery, a total of 24 patients in the apoplexy group developed hypopituitarism. Specifically, 8 patients exhibited deficiencies in both the LH/FSH and ACTH axes, 1 patient had deficiencies in the LH/FSH and GH axes, 2 patients showed insufficiencies in the ACTH and GH axes, and 1 patient experienced deficiencies in all three axes: LH/FSH, GH, and ACTH. Two patients continued to have panhypopituitarism. In contrast, in the non-apoplexy group, 15 patients developed pituitary dysfunction, with 3 patients exhibiting combined deficiencies in the LH/FSH and ACTH axes, while the remaining 12 patients had single hormone deficiencies (Fig.\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eThree years post-surgery, a total of 23 patients in the apoplexy group exhibited pituitary dysfunction. Specifically, 2 patients still had persistent panhypopituitarism, 6 patients exhibited deficiencies in both the LH/FSH and ACTH axes, and 1 patient showed deficiencies in the LH/FSH, GH, and ACTH axes. In contrast, in the non-apoplexy group, 6 patients had isolated LH/FSH axis deficiency, 8 patients had isolated ACTH axis deficiency, and only 3 patients exhibited combined deficiencies in both the LH/FSH and ACTH axes(Fig.\u0026nbsp;4).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we examined the long-term outcomes of pituitary function in patients with nonfunctional pituitary adenomas who underwent endonasal surgery, comparing those with and without apoplexy events. Our findings are as follows: 1) Male patients have a higher incidence of pituitary adenoma apoplexy, and tumors in the apoplexy group tend to be larger compared to those in the non-apoplexy group. 2) Preoperatively, the apoplexy group exhibited a significantly higher incidence of ACTH axis dysfunction than the non-apoplexy group. 3) At the 3-year postoperative follow-up, patients in the apoplexy group demonstrated significantly poorer recovery of both ACTH axis and LH/FSH axis compared to the non-apoplexy group. 4) There was no significant difference in the occurrence of deficiencies involving two or more axes between the apoplexy and non-apoplexy groups.\u003c/p\u003e \u003cp\u003eDemographically, our data indicate a higher prevalence of nonfunctional pituitary adenoma apoplexy in male patients, consistent with findings from other studies on pituitary apoplexy. For example, Marta Araujo-Castro's research demonstrated that the incidence of pituitary apoplexy was significantly higher in males compared to females (70% vs. 48.1%)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A sudden headache is the most prominent clinical manifestation of pituitary adenoma apoplexy. Our data revealed that 76.79% of patients in the apoplexy group experienced headaches, which was significantly higher than the 52.13% in the non-apoplexy group (p\u0026thinsp;=\u0026thinsp;0.001). Other studies have reported that the incidence of headache in patients with pituitary adenoma apoplexy ranges from approximately 80% to as high as 89% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Research suggests that the sudden increase in intrasellar pressure following pituitary adenoma apoplexy, leading to traction on the dura mater and subsequent meningeal irritation, may be the primary cause of headache[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe recovery of pituitary function following pituitary apoplexy is challenging. Our study demonstrated that among patients with pre-existing preoperative ACTH axis dysfunction, 28.57% of non-apoplexy patients exhibited recovery of the ACTH axis function three years post-surgery, a finding consistent with previous research [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, in the apoplexy group, the recovery rate of the ACTH axis was significantly lower, at only 16.67%, compared to non-apoplexy patients, indicating that apoplexy may affect the recovery of ACTH axis function in patients. Furthermore, when evaluating the ACTH axis function three years post-surgery, the apoplexy group exhibited a significantly higher prevalence of ACTH axis insufficiency compared to the non-apoplexy group, with the difference being statistically significant.This indicates a markedly poorer recovery of ACTH axis function in apoplexy patients.This phenomenon may be attributed to the rapid elevation of intrasellar pressure following pituitary apoplexy, which compromises pituitary blood supply and compresses the portal venous system,these changes can result in irreversible damage to the anterior pituitary gland, ultimately impairing the recovery of pituitary function[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The recovery of the adrenocorticotropic hormone (ACTH) axis following pituitary apoplexy is a critical determinant of long-term endocrine function and patient outcomes.Numerous studies suggest that the recovery of ACTH axis function after pituitary adenoma apoplexy is influenced by multiple factors. For example, some research indicates that younger age, smaller tumor size (\u0026lt;\u0026thinsp;2 cm), normal blood pressure, and the absence of intraoperative cerebrospinal fluid leakage may positively impact ACTH axis recovery[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, in the pituitary microenvironment, ischemia and inflammatory responses secondary to hemorrhage and ischemia are also associated with ongoing pituitary tissue damage, thereby impeding functional recovery[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with pituitary apoplexy are at a heightened risk of developing adrenal insufficiency, which can manifest as fatigue, hypotension, hyponatremia, and, in severe cases, life-threatening adrenal crises[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, close postoperative monitoring of adrenal function is essential, and the multidisciplinary team (MDT) model is helpful. Early initiation of glucocorticoid replacement therapy may be necessary in patients with persistent ACTH axis dysfunction.\u003c/p\u003e \u003cp\u003eAfter pituitary adenoma apoplexy, insufficiency of the LH/FSH axis should not be overlooked. In our study, the recovery of LH/FSH axis function post-surgery was significant in the non-apoplexy group, whereas it was notably unsatisfactory in the apoplexy group. The incidence of LH/FSH axis dysfunction following transsphenoidal surgery for pituitary adenomas varies widely. Maria's study reported an incidence of 35.7% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], while Alexopoulou found it to be as high as 68%[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Data regarding the impact of transsphenoidal surgery on anterior pituitary function are inconsistent, and this variability becomes even more pronounced when compounded by the effects of pituitary apoplexy.\u003c/p\u003e \u003cp\u003ePituitary adenomas are the most frequent cause of hypopituitarism, which can be further aggravated by pituitary apoplexy and/or surgical intervention. According to O'Sullivan's study, 51% of patients with pituitary adenomas exhibited preoperative anterior pituitary insufficiency, increasing to 74.5% postoperatively[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Another study reported a significant increase in pituitary function insufficiency among patients with pituitary apoplexy during follow-up (from 45% at baseline to 71% at follow-up, OR\u0026thinsp;=\u0026thinsp;4.7, CI\u0026thinsp;=\u0026thinsp;1.30\u0026ndash;25.33) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], with some reports indicating that up to 80% of these patients experienced postoperative decline in pituitary function[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Currently, hormone replacement therapy (HRT) remains the primary treatment for pituitary function decline. It is recommended to use the minimum effective dose to alleviate clinical symptoms and optimize the patient's quality of life[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Recently, a prospective study by Adsm et al. demonstrated that there was no significant difference in the recovery of anterior pituitary function between surgical and medically conservative treatments in patients with pituitary apoplexy. However, surgery is generally preferred for patients presenting with visual field defects.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In our study, the non-apoplexy group exhibited significant improvement in pituitary function following surgery, whereas the apoplexy group showed limited improvement and required long-term or lifelong hormone replacement therapy. Therefore, when surgical intervention is warranted due to pituitary adenoma apoplexy, careful deliberation is essential. Although surgical treatment provides notable improvements in vision, its potential impact on pituitary function must be carefully considered.\u003c/p\u003e \u003cp\u003eOur study has several limitations that warrant consideration. Firstly, this was a retrospective, single-institution study, which may introduce selection bias within the patient cohort. Secondly, all surgical procedures were conducted by neurosurgeons at our institution, potentially limiting the generalizability of our findings to other pituitary centers. Lastly, hormone assessments in some female patients during follow-up were influenced by menstrual cycles and menopause, which could have introduced variability into the data. Additionally,future research should focus on elucidating the molecular mechanisms underlying the development of pituitary insufficiency after pituitary apoplexy and exploring potential therapeutic interventions to enhance pituitary function recovery.At the same time, longitudinal studies with larger patient cohorts are warranted to validate our findings and to assess the impact of various treatment modalities on pituitary function recovery.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePituitary apoplexy is frequently associated with long-term pituitary dysfunction. Compared to non-apoplexy patients, those with preoperative apoplexy are more prone to ACTH axis dysfunction, and exhibit significantly poorer recovery of ACTH axis function following surgical treatment. Furthermore, among patients with preoperative apoplexy, the recovery of LH/FSH axis function is also inferior to that in non-apoplexy patients.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003eStudy approval statement:\u003c/h2\u003e \u003cp\u003e The studies involving humans were approved by The General Hospital of Western Theater Command. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003ch2\u003eConflict of Interest Statement:\u003c/h2\u003e \u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e \u003ch2\u003eFunding Sources:\u003c/h2\u003e \u003cp\u003eThe author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the The construction of the army's key clinical specialty \u0026ndash; neurosurgery(4156Z5A2).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDB. Z,JN. L and Z.Z collected the data.RT.G and YQ.O performed the data analyses.DB. Z and YX. Y interpreted the data and drafted the manuscript. JM.C and T.Y designed the Study.All authors reviewed the manuscript critically for intellectual content and gave final approval of the current version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe raw data supporting the conclusions of this article will be made available upon reasonable request from the authors. For further inquiries, please contact the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSaktiwarawat, K., Tunthanathip, T., Oearsakul, T. \u0026amp; Taweesomboonyat, C. Comparing neuroendocrine recovery between surgical and conservative management in pituitary apoplexy patients: a propensity score-matched analysis. \u003cem\u003eNeurosurg. Rev.\u003c/em\u003e \u003cb\u003e47\u003c/b\u003e (1), 236 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, Y. H. et al. 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Pituitary apoplexy: re-evaluation of risk factors for bleeding into pituitary adenomas and impact on outcome. \u003cem\u003eEur. J. Endocrinol.\u003c/em\u003e \u003cb\u003e164\u003c/b\u003e (1), 37\u0026ndash;43 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGondim, J. A. et al. Endoscopic Endonasal Surgery for Treatment of Pituitary Apoplexy: 16 Years of Experience in a Specialized Pituitary Center. \u003cem\u003eWorld Neurosurg.\u003c/em\u003e \u003cb\u003e108\u003c/b\u003e, 137\u0026ndash;142 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHigham, C. E., Johannsson, G. \u0026amp; Shalet, S. M. \u003cem\u003eHypopituitarism Lancet\u003c/em\u003e, \u003cb\u003e388\u003c/b\u003e(10058): 2403\u0026ndash;2415. (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTritos, N. A. \u0026amp; Miller, K. K. Diagnosis and Management of Pituitary Adenomas: A Review. \u003cem\u003eJAMA\u003c/em\u003e \u003cb\u003e329\u003c/b\u003e (16), 1386\u0026ndash;1398 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMamelak, A. N. et al. A Prospective, Multicenter, Observational Study of Surgical vs Nonsurgical Management for Pituitary Apoplexy. \u003cem\u003eJ. Clin. Endocrinol. Metab.\u003c/em\u003e \u003cb\u003e109\u003c/b\u003e (2), e711\u0026ndash;e725 (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"nonfunctioning pituitary adenomas, pituitary apoplexy, hypopituitarism, Transsphenoidal surgery","lastPublishedDoi":"10.21203/rs.3.rs-6231669/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6231669/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis retrospective study aims to investigate pituitary function 3 years after transsphenoidal surgery in patients with non-functional pituitary adenomas(NFPAs) complicated by apoplexy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective analysis was performed on patients with non-functional pituitary adenomas who underwent transsphenoidal surgery from January 2016 to September 2020. The patients were divided into apoplexy group and non-apoplexy group based on magnetic resonance imaging(MRI), surgical, and pathological findings. A comparative analysis of pituitary endocrine function was conducted between the two groups at three years postoperatively.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 563 patients were initially screened, and 50 matched pairs were included in the study following propensity score matching.Preoperatively, 35 patients in the apoplexy group exhibited pituitary hormone deficiencies, including 2 cases of panhypopituitarism and 14 cases with deficiencies in two or more hormones.In contrast, the non- apoplexy group had 30 patients with pituitary hormone deficiencies, of which 8 had deficiencies in two or more hormones, with no cases of panhypopituitarism.A significant difference was observed in the incidence of ACTH axis deficiency between the two groups (36% vs 14%, p\u0026thinsp;=\u0026thinsp;0.011). This trend persisted at the 3-year follow-up, where the apoplexy group continued to show a significantly higher prevalence of ACTH deficiency (34% vs 16%, p\u0026thinsp;=\u0026thinsp;0.038).No significant difference was found in the incidence of preoperative LH/FSH axis insufficiency between the groups (38% vs 40%, p\u0026thinsp;=\u0026thinsp;0.838).However, at the 3-year follow-up, the apoplexy group exhibited a significantly higher incidence of LH/FSH axis insufficiency compared to the non-apoplexy group (30% vs 12%, p\u0026thinsp;=\u0026thinsp;0.027). Additionally, there was no significant difference in the incidence of deficiencies in two or more hormones between the two groups after 3 years of follow-up (39.1% vs 27.3%, p\u0026thinsp;=\u0026thinsp;0.705).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePituitary apoplexy is commonly associated with pituitary insufficiency. Patients with preoperative apoplexy are more susceptible to ACTH axis dysfunction compared to those without apoplexy, and they demonstrate significantly poorer recovery of ACTH axis function following transsphenoidal surgery. Additionally, among patients with apoplexy, the postoperative recovery of LH/FSH axis function is also notably inferior to that observed in non-apoplexy patients.\u003c/p\u003e","manuscriptTitle":"Long-term pituitary function following transsphenoidal surgery for nonfunctioning pituitary adenomas with apoplexy: a single- center retrospective analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 14:03:15","doi":"10.21203/rs.3.rs-6231669/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-25T19:19:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-24T14:58:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217819535619710527937043804451888662667","date":"2025-04-24T14:01:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-15T07:24:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18407819587172172550998975635046938943","date":"2025-04-14T09:10:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-03T14:04:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-02T12:27:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-17T14:47:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-15T09:10:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-03-15T08:43:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"44c3ad6a-f587-4bc7-87ef-287fdb883e28","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47513066,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases"},{"id":47513067,"name":"Health sciences/Neurology/Neurological disorders"}],"tags":[],"updatedAt":"2025-06-02T16:04:28+00:00","versionOfRecord":{"articleIdentity":"rs-6231669","link":"https://doi.org/10.1038/s41598-025-03053-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-06-01 15:57:14","publishedOnDateReadable":"June 1st, 2025"},"versionCreatedAt":"2025-05-06 14:03:15","video":"","vorDoi":"10.1038/s41598-025-03053-0","vorDoiUrl":"https://doi.org/10.1038/s41598-025-03053-0","workflowStages":[]},"version":"v1","identity":"rs-6231669","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6231669","identity":"rs-6231669","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}