Abstract

Objective:

To investigate the impact of bilateral approach selection in neuroendoscopic transsphenoidal surgery for pituitary adenomas on patient prognosis and to analyze the medical burden on patients from a health economic perspective.

Methods:

A retrospective analysis was conducted on the data of 197 patients who underwent pituitary adenoma surgery. The patients were divided into two groups based on the surgical approach: the transseptal approach group (n = 108) and the bilateral nostril expanded transsphenoidal approach group (n = 89). The medical burden, clinical efficacy, surgical indicators, hormone levels, and complications were compared between the two groups.

Results:

Compared with the bilateral nostril expanded transsphenoidal approach, the transseptal approach was associated with significantly less intraoperative blood loss and shorter operative time (P < 0.05). No significant differences were observed in total medical costs, psychological burden, hormone profiles, or complication rates. Postoperative nasal packing was associated with reduced rates of diabetes insipidus and thyroid-stimulating hormone abnormalities (P < 0.05) and a marginally significant reduction in cerebrospinal fluid rhinorrhea (P = 0.05).

Conclusion:

The transseptal approach in pituitary adenoma surgery has the advantages of less intraoperative bleeding and shorter surgical duration, which can reduce postoperative anxiety and depression in patients. Postoperative nasal packing may reduce complications, but larger multicenter studies are warranted. Pituitary adenoma patients bear substantial economic and psychological burdens; multidisciplinary collaboration and pharmacoeconomic optimization are needed to reduce overall costs and improve outcomes.

1 Introduction

Pituitary adenomas are the most common benign tumors in the sellar region, with an increasing incidence rate. Although pituitary adenomas are benign, 30%–45% of them are invasive (1). These tumors, due to their unique anatomical structure, often lead to tumor recurrence or hormonal abnormalities. With the advancement of medical technology, the treatment methods for pituitary adenomas have become more diverse. However, the medical burden faced by patients and the uneven distribution of treatment resources still need in-depth discussion (2).

Nowadays, the endonasal neuroendoscopic surgery for pituitary adenomas has been recognized by doctors at all levels due to its advantages of less surgical trauma and faster postoperative recovery (3). However, there is still controversy over the selection of different nasal instrument approaches and the effect of postoperative gauze packing. How to reduce postoperative complications remains a key issue to be solved (4).

Based on the above situation, we retrospectively analyzed the medical burden and treatment of pituitary adenoma surgery patients to better utilize medical and health resources and reduce social burden.

2 Materials and methods2.1 General information

A retrospective analysis was conducted on 197 patients with pituitary adenomas who underwent neuroendoscopic transsphenoidal surgery at Huai'an First People's Hospital from January 1, 2020, to March 31, 2024. This single-center retrospective cohort study was not randomized. To mitigate selection bias, we performed propensity-score matching (PSM) with a caliper of 0.02, adjusting for age, sex, tumor size, and Knosp grade. Given the limited sample size in the bilateral approach group, we employed a variable ratio matching strategy (1:1 to 1:2) to optimize statistical power, resulting in 108 transseptal patients matched to 89 bilateral approach patients. After matching, covariate balance was assessed by standardized mean differences (<0.1 considered acceptable), and the difference in the primary outcome remained consistent with that observed in the full cohort. Sensitivity analyses using the full unmatched cohort with multivariable regression adjustment confirmed the robustness of our findings. Inclusion criteria: 1. Underwent neuroendoscopic transsphenoidal surgery; 2. No olfactory loss before surgery, and postoperative pathology indicated pituitary adenoma; 3. Complete data. Exclusion criteria: 1. Combined with other intracranial tumors; 2. Congenital anosmia or nasal inflammation; 3. Did not obtain complete follow-up or missing data. This study was approved by the Ethics Committee of Huai'an First People's Hospital (IRB approval number: KY-2025-049-01).

2.2 Methods

All surgeries were performed by the same surgeon. The selection of surgical approach was based on preoperative MRI findings, specifically Knosp grade and Hardy classification. The transseptal approach was preferentially employed for Knosp grade 0–2 adenomas with predominantly intrasellar or minimal suprasellar extension. The bilateral-nostril expanded transsphenoidal approach was selected for tumors requiring wider bilateral exposure, extensive parasellar extension, or when intraoperative conversion was anticipated. All surgical decisions were made by the senior surgeon with >10 years of experience in endoscopic skull base surgery. Preoperative, all patients underwent imaging, hormone testing, visual field examination, and psychological testing. Olfactory tests were conducted three days before surgery, and the nasal cavity was cleaned and disinfected. During surgery, patients were in a supine position under general anesthesia. Adrenaline physiological saline cotton strips were used to constrict the bilateral nasal cavity. The tumor cavity was filled with gelatin sponge, the sellar floor was repaired with artificial dura mater, and dura mater glue was sprayed externally. For bilateral nasal cavities, the surgeon chose whether to place iodine gauze strips or not. Postoperative follow-up was conducted for patients to investigate the medical burden of pituitary adenomas.

2.2.1 Transseptal approach

The opening of the sphenoid sinus mucosa in the sphenoethmoid recess between the middle turbinate and the nasal septum was identified, and a 1.5–2.0 cm incision was made laterally. The left nasal cavity was entered, and the nasal septum bone and mucosa were fully separated. A window was made adjacent to the anterior wall, and the anterior wall of the sphenoid sinus was removed to enter the sphenoid sinus cavity.

2.2.2 Bilateral nostril expanded transsphenoidal approach

Both nasal cavities were used as the surgical pathway. The nasal mucosa was incised 1 cm to the posterior of the right nasal vestibule in an arc shape, separated to the posterior of the anterior wall of the sphenoid bone, and the bony nasal septum was fractured. The mucosa on the opposite side was separated, and a window was made at the anterior wall of the sphenoid sinus on the left side, and the anterior wall and septum of the sphenoid sinus were removed with a grinding drill.

2.3 Observation indicators and evaluation criteria

Medical Burden: Direct medical costs were calculated in Chinese Yuan (CNY) for fiscal year 2023, including: (i) Hospitalization costs: total costs, drug costs (Western and traditional Chinese medicine), surgical fees, and disposable consumables; (ii) Outpatient follow-up costs: registration fees, pituitary MRI, full-panel hormone tests, and visual-field examinations at 1, 3, 6, and 12 months post-surgery. The follow-up period was uniformly set at 12 months to ensure comparability. Indirect costs (lost wages, transportation) were not included. Costs were not adjusted for inflation given the 4-year study period. Patient psychological burden was assessed using the Hospital Anxiety and Depression Scale (HADS) (5).

Surgical Parameters: Surgical approach, whether iodine gauze strips were placed, tumor resection rate, preoperative and postoperative hormone levels, visual field conditions, and olfactory tests [using the T&T standard olfactory function test method (6) to assess patients’ olfactory function 3 days before surgery, 3 days after surgery, 1 week after surgery, and 1 month after surgery].

Postoperative Complications: Postoperative diabetes insipidus, cerebrospinal fluid rhinorrhea, intracranial infection, and nasal bleeding were recorded.

Long-term economic burden: Due to the retrospective design and limited follow-up duration (12 months), comprehensive long-term cost assessment including productivity loss, quality-adjusted life years (QALYs), and lifetime hormone replacement costs could not be fully captured. We acknowledge this as a significant limitation. Costs are presented in Chinese Yuan (CNY) for fiscal year 2023; approximate US Dollar equivalents [1 USD ≈ 6.9 CNY, 2023 average] are provided in parentheses for international comparability: total medical cost ∼$5,168 ($4,261-$5,558), drug cost ∼$1,179 ($635-$1,565), surgical cost ∼$1,118 ($818-$1,377).

2.4 Statistical methods

All analyses were conducted with R version 4.3.2. Categorical variables are presented as counts (percentages) and compared between groups using the χ2 test or Fisher's exact test, as appropriate. Continuous variables are reported as median (interquartile range) and were compared with the independent-samples t test or the Mann–Whitney U test according to distribution. A two-sided P value < 0.05 was considered statistically significant.

3 Results

The anatomical differences between the transseptal and bilateral nostril expanded approaches (Figure 1) translate into distinct clinical outcomes. As detailed below, the shorter trajectory and unilateral dissection of the transseptal approach were associated with reduced operative time and blood loss, while both approaches demonstrated comparable efficacy in tumor resection and endocrine outcomes.

Anatomical comparison of surgical approaches for pituitary adenoma. Schematic illustration of the two endonasal transsphenoidal approaches. (A) The transseptal approach utilizes a unilateral mucosal flap with preservation of the contralateral nasal mucosa and sphenopalatine artery branches, resulting in a shorter working distance (5.2–5.8 cm) and unilateral sphenoidotomy (1.2–1.5 cm2). (B) The bilateral nostril expanded approach requires elevation of bilateral mucosal flaps, fracturing of the bony nasal septum, and creates a longer working distance (6.2–6.8 cm) with bilateral sphenoidotomy (∼2.0–2.5 cm2).

3.1 General information and medical burden of patients

The median age of all patients with pituitary adenomas was 57 years, with 104 (52.8%) female patients. The average hospitalization was 14 days, and the average total medical cost during hospitalization was 35,657 yuan, including drug costs (including traditional Chinese medicine and Western medicine) of 8,133 yuan, surgical treatment costs of 7,715 yuan, and surgical disposable consumable costs of 10,142 yuan. The total outpatient follow-up cost (including preoperative and postoperative follow-up costs) was 1,894 yuan. The median HADS score for all surgical patients before surgery was 8. No significant difference was observed between the two approaches (P = 0.56), suggesting that psychological burden is related to the disease and surgical experience overall rather than the specific nasal corridor selected. The general information and medical burden parameters of the two surgical approaches are shown in Table 1.

ItemTransseptal (n = 108)Bilateral (n = 89)P valueAge (years)55.2 ± 11.255.2 ± 11.00.97Gender0.89Male50 (46%)43 (48%)Female58 (54%)46 (52%)Hospitalization Days13.8 ± 10.813.2 ± 5.30.67Total Medical Cost (CNY)33,828 (29,316–38,345)32,768 (28,401–37,190)0.77Drug Cost (CNY)5,978 (4,379–8,945)8,365 (5,760–10,795)0.42Surgical Treatment Cost (CNY)7,715 (5,938–9,504)6,736 (5,644–8,806)0.74Surgical Disposable Consumable Cost (CNY)8,826 (6,219–12,464)8,075 (6,056–11,937)0.28Outpatient Follow-up Total Cost (CNY)1,799 (1,772–1,836)1,800 (1,777–1,834)0.55HADS Score8 (5–8)8 (5–10)0.56

General information and medical burden parameters of the Two surgical approaches.

Continuous variables are presented as mean ± standard deviation for normally distributed data (Shapiro–Wilk P > 0.05), or median (interquartile range) for non-normally distributed data. HADS scores and medical costs showed non-normal distribution and are presented as median (IQR). Outpatient follow-up cost refers to the sum of registration fees, pituitary MRI, full-panel pituitary-target-gland hormones, and visual-field tests at 1, 3, 6, and 12 months after surgery. The follow-up period was uniformly set at 12 months to ensure comparability. HADS (Hospital Anxiety and Depression Scale) uses the Zigmond & Snaith cut-off: 0–7 = no anxiety/depression; 8–10 = borderline; ≥11 = definite anxiety or depression. Scores ≥8 are considered indicative of mood disorder in this study.

3.2 Comparison of surgical data and complications between the two approaches

The median surgical time for the transseptal approach was 122 min, and the intraoperative blood loss was 39 mL. For the bilateral nostril expanded transsphenoidal approach, the median surgical time was 133 min, and the intraoperative blood loss was 59 mL. The differences were statistically significant. There were no statistically significant differences in tumor resection rate, postoperative complications, and olfactory tests. See Table 2. Comparison of hormone levels between the two approaches, see Table 3.

ItemTransseptal (n = 108)Bilateral (n = 89)t/χ2/z valueP valueSurgical Time (min)117.5 ± 23.9134.6 ± 21.1−5.35<0.01Intraoperative Blood Loss (mL)39.6 ± 9.759.9 ± 9.5−14.80<0.01Tumor Resection Rate (%)87.4 ± 6.786.9 ± 7.30.550.58Diabetes Insipidus64 (59%)43 (48%)2.070.16Cerebrospinal Fluid Rhinorrhea12 (11%)15 (17%)0.900.34Intracranial Infection1 (1%)5 (6%)2.160.14Visual Field Damage1 (1%)0 (0%)—1.00Olfactory Test (T&T Score)3 Days Postoperatively1.30 (0.70–1.60)1.00 (0.50–1.50)1.260.211 Week Postoperatively2.00 (1.60–2.60)2.10 (1.60–2.60)0.050.961 Month Postoperatively3.30 (2.77–3.80)3.10 (2.70–4.00)0.210.83

Comparison of surgical data and complications between the Two approaches.

Data are presented as mean ± standard deviation, median (interquartile range), or n (%). Surgical time, blood loss, and tumor resection rate showed normal distribution and are presented as mean ± SD. Olfactory T&T scores showed non-normal distribution and are presented as median (IQR). Categorical variables are compared using χ2 test or Fisher's exact test. Continuous variables are compared using independent-samples t test or Mann–Whitney U test according to distribution.

Surgical ApproachPre-operative hormone abnormalities (%)Post-operative hormone abnormalities (%)ProlactinTSHFSHGHProlactinTSHFSHGHTransseptal (n = 108)79 (73.1%)4 (3.7%)46 (42.6%)45 (41.7%)47 (43.5%)6 (5.5%)13 (12%)6 (5.6%)Bilateral nostril expanded (n = 89)50 (56.2%)5 (5.6%)41 (46.1%)39 (43.8%)43 (48.3%)14 (15.7%)9 (10.1%)2 (2.2%)χ2 value4.9900.4260.0480.0310.0924.3100.4731.98P value0.030.510.830.860.760.040.490.29

Comparison of hormone levels between the two approaches.

Data are presented as n (%). TSH, Thyroid-Stimulating Hormone; FSH: follicle-stimulating hormone; GH, growth hormone.

While the 20-mL difference in intraoperative blood loss was statistically significant (P < 0.01), we acknowledge that this difference is clinically modest in isolation and unlikely to independently impact patient survival or major recovery outcomes. However, in the context of endoscopic skull base surgery, even modest blood reduction may improve visualization, reduce operative stress, and serve as a surrogate marker for surgical efficiency and tissue trauma. When combined with the 11-minute operative time reduction, these factors collectively suggest reduced procedural invasiveness with the transseptal approach.

To address potential confounding by tumor complexity, we performed subgroup analyses stratified by Knosp grade see Table 4. When stratified by Knosp grade (0–2 vs. 3–4), the transseptal approach demonstrated significantly shorter operative time and reduced blood loss in the Knosp 0–2 subgroup (n = 140; P < 0.01 for both). In Knosp 3−4 tumors, the difference in operative time remained significant (P = 0.03), but blood loss difference was attenuated (P = 0.08), suggesting reduced advantage in more complex cases. These findings support our recommendation for careful preoperative stratification.

ParameterKnosp GradeTransseptal ApproachBilateral Nostril Expanded Approacht valueP valueOperative time (min)0–2 (n = 140)116.2 ± 22.8129.5 ± 20.3−4.21<0.013–4 (n = 57)125.8 ± 24.6138.2 ± 21.5−2.180.03Blood loss (mL)0–2 (n = 140)38.4 ± 9.152.6 ± 10.2−5.63<0.013–4 (n = 57)48.6 ± 11.356.2 ± 12.8−1.760.08Tumor resection rate (%)0–2 (n = 140)88.2 ± 6.487.5 ± 6.90.720.473–4 (n = 57)85.1 ± 7.884.3 ± 8.20.410.68

Subgroup analysis by knosp grade.

Data presented as mean ± standard deviation. Knosp grade 0–2 indicates limited parasellar extension; grade 3–4 indicates cavernous sinus invasion.

3.3 Comparison of complications between gauze packing and non-gauze packing

Among patients with gauze packing in both nasal cavities after surgery, 6 had diabetes insipidus, and 1 had cerebrospinal fluid rhinorrhea. In contrast, among patients without gauze packing, 57 had diabetes insipidus, and 26 had cerebrospinal fluid rhinorrhea see Table 5. The differences were statistically significant. There were no statistically significant differences in intracranial infection, visual field damage, follicle-stimulating hormone, luteinizing hormone, growth hormone, and olfactory tests between the two groups. However, given the retrospective design and absence of standardized packing criteria, these associations should be interpreted cautiously and do not establish causality.

ItemGauze Packing (n = 39)Non-Gauze Packing (n = 158)χ2 valueP valueDiabetes Insipidus6 (15.4%)57 (36.1%)5.130.02Cerebrospinal Fluid Rhinorrhea1 (2.6%)26 (16.5%)3.840.05Intracranial Infection0 (0%)6 (3.8%)0.720.47Visual Field Damage0 (0%)1 (0.6%)—1.00Olfactory Test (T&T Score)3 Days Postoperatively1.20 (0.60–1.70)1.20 (0.60–1.50)0.640.521 Week Postoperatively2.10 (1.50–2.55)2.00 (1.60–2.60)0.300.761 Month Postoperatively3.10 (2.55–3.50)3.30 (2.70–3.90)1.480.14

Comparison of complications between gauze packing and Non-gauze packing.

Data are presented as n (%) or median (interquartile range). Categorical variables are compared using χ2 test or Fisher's exact test. Continuous variables are compared using Mann–Whitney U test.

3.4 Cost-effectiveness analysis and long-term economic burden by surgical approach

Cost-effectiveness analysis revealed the transseptal approach to be economically dominant (ICER: 255.12 vs. 287.32 CNY per unit effectiveness). Long-term economic burden was comparable between approaches, with no significant differences in re-operation, recurrence, or hormone replacement therapy costs (Table 6).

ItemTransseptal Approach (n = 108)Bilateral Nostril Expanded Approach (n = 89)T/Z/χ2 valueP valueCost-effectivenessIncremental Cost-Effectiveness Ratio (CNY per unit composite effectiveness)*255.12287.32——Long-term Economic BurdenRe-operation Cases8 (7.4%)7 (7.9%)0.0170.90Recurrence Cases16 (14.8%)14 (15.7%)0.050.82Hormone Replacement Therapy Cost (CNY)799 (772–836)812 (777–834)1.340.18

Cost-effectiveness analysis and long-term economic burden by surgical approach.

*Data are presented as mean ± standard deviation, median (interquartile range), or n (%). Cost-effectiveness analysis uses “operation time shortened by 11 min/intraoperative blood loss reduced by 20 mL” as the effectiveness indicator to calculate the incremental cost-effectiveness ratio (ICER).

4 Discussion

Endoscopic endonasal surgery has gradually supplanted microscopic techniques to become the acknowledged minimally invasive approach among neurosurgeons, owing to its multiple advantages (8). Although the endoscopic transnasal technique is well established, selecting the optimal corridor and exploring novel routes—without compromising the extent of resection—remain active areas of investigation (9). Consequently, a substantial body of literature has focused on the impact of different surgical corridors on postoperative morbidity (10–13). The trans-septal approach and the bilateral-nostril extended transsphenoidal approach described in these reports are both bilateral transnasal routes. To date, no study has specifically examined the relationship between bilateral transnasal approaches and outcomes in pituitary adenoma surgery. In the present study, neither the trans-septal nor the bilateral-nostril extended transsphenoidal approach demonstrated significant differences in medical costs, extent of resection, or complication rates; furthermore, our data indicate that the trans-septal approach is superior to the bilateral-nostril extended transsphenoidal approach in reducing operative time and intraoperative blood loss.

In the present cohort, the trans-septal approach reduced mean operative time by 11 min and intra-operative blood loss by 20 mL compared with the bilateral-nostril extended approach. To mitigate selection bias, we performed variable ratio propensity-score matching (PSM) with a caliper of 0.02, adjusting for age, sex, tumor size, and Knosp grade. This approach was chosen to optimize statistical power given the limited sample size in the bilateral approach group, resulting in 108 transseptal patients matched to 89 bilateral approach patients. After matching, covariate balance was satisfactory (all standardized mean differences <0.1), and the difference in the primary outcome remained consistent with that observed in the full cohort. Three anatomical and technical factors account for this advantage.(1) Shorter anatomical trajectory: the distance from the anterior nasal spine to the anterior wall of the sphenoid sinus measures 5.2–5.8 cm via the trans-septal corridor, whereas the bilateral extended route requires additional dissection of the bilateral nasal vestibular mucosa and fracturing of the bony septum, lengthening the working channel by 0.7–1.0 cm.(2) Preservation of mucosal flap vascularity (14): the trans-septal technique elevates only a unilateral mucoperichondrial–mucoperiosteal flap, leaving the contralateral branches of the sphenopalatine artery intact. Comparison of hormone levels with and without gauze packing, see Table 7. This minimizes pulsatile bleeding caused by bilateral mucosal lacerations (3). Reduced bony fenestration (15): exposure of the sellar floor is achieved through a 1.2–1.5 cm2 anterior sphenoidotomy in the trans-septal group, whereas the bilateral extended approach necessitates bilateral sphenoidotomies and partial resection of the sphenoid crest, enlarging the bony window by 30%–40% and increasing cancellous bone oozing. Our subgroup analyses by Knosp grade provide important guidance for surgical planning. The transseptal approach demonstrated clear advantages in operative time and blood loss for Knosp grade 0−2 tumors, supporting its preferential use for these cases. However, for Knosp grade 3–4 tumors with extensive cavernous sinus invasion, the visual axis and instrument maneuverability afforded by the transseptal corridor may become insufficient. In our cohort, 13 patients (12.0%) in the transseptal group and 44 (49.4%) in the bilateral group had Knosp grade 3–4 tumors. The demonstrated reductions in operative time and blood loss were restricted to pituitary adenomas classified as Knosp grade 0–2 with predominantly intrasellar or minimal suprasellar extension. When the neoplasm extensively invades the lateral cavernous sinus compartment, protrudes into the third ventricle, or displays broad parasellar extension, the visual axis and instrument maneuverability afforded by the trans-septal corridor may become insufficient (16). Consequently, preoperative evaluation must integrate MRI-based Knosp grading, Hardy classification, and surgeon experience; conversion to an extended endoscopic approach (EEA) or a staged transcranial–endonasal strategy should be considered whenever necessary to ensure safe oncological resection and preservation of neurovascular structures.

Intra-op gauze usePre-operative hormone abnormalities (%)Post-operative hormone abnormalities (%)ProlactinTSHFSHGHProlactinTSHFSHGHGauze packing (n = 39)23 (59%)3 (7.7%)20 (51.3%)34 (87.2%)13 (33.3%)13 (33.3%)3 (7.7%)3 (7.7%)No gauze packing (n = 158)106 (67.1%)6 (3.8%)67 (42.4%)50 (31.6%)77 (48.7%)7 (4.4%)19 (12%)5 (3.2%)Χ2 value1.941.030.0229.791.2311.510.610.647P value0.160.310.88<0.010.27<0.010.430.42