This review compares endocrine outcomes after endoscopic and microscopic transsphenoidal surgery for pituitary adenomas and highlights cautious, evidence-limited support for endoscopic approaches.
Review Article
* These authors contributed equally
This review compares endocrine outcomes after endoscopic and microscopic transsphenoidal surgery for pituitary adenomas and highlights cautious, evidence-limited support for endoscopic approaches.
Transsphenoidal surgery remains a principal treatment for most functioning and symptomatic non-functioning pituitary adenomas, but the relative endocrine and safety outcomes of endoscopic transsphenoidal surgery (ETS) and microscopic transsphenoidal surgery (MTS) remain debated. This systematic review and meta-analysis searched PubMed/MEDLINE, Embase, Web of Science Core Collection, Cochrane Library, Scopus, ClinicalTrials.gov, and reference lists for comparative studies published from January 2010 to March 2025. Eight studies comprising 769 patients were included in the endocrine-success analysis, with 392 patients treated by ETS and 377 by MTS. The pooled random-effects estimate favored ETS for the composite endocrine-success endpoint, defined as biochemical remission for functioning adenomas or preserved pituitary function in mixed and non-functioning cohorts (risk ratio [RR] 1.26, 95% confidence interval [CI] 1.13–1.41; I2 = 17.8%). The functioning-only subgroup had an imprecise, non-significant estimate (RR 1.06, 95% CI 0.63–1.80), whereas mixed cohorts favored ETS (RR 1.22, 95% CI 1.11–1.34). Diabetes insipidus and cerebrospinal fluid (CSF) leak were infrequently reported and had wide CIs. New hypopituitarism was not meaningfully pooled because events were sparse and between-study heterogeneity was substantial; raw study-level counts are therefore presented. The available literature suggests an association between ETS and improved endocrine success, but interpretation is limited by heterogeneous outcome definitions, confounding by indication, and the predominance of retrospective cohorts. Complication outcomes remain underpowered, and no definitive conclusion can be drawn regarding differences in postoperative morbidity between approaches.
Pituitary adenomas are common sellar tumors and account for a substantial proportion of primary intracranial neoplasms; population-based data also indicate that clinically recognized adenomas are less frequent than incidental radiological or autopsy findings1,2. Their clinical effects range from hormone hypersecretion, such as acromegaly or Cushing disease, to mass effect with visual compromise, headache, and hypopituitarism3. Medical therapy remains central for selected tumor subtypes, particularly prolactinomas, whereas surgical resection is frequently used for functioning adenomas requiring rapid biochemical control and for symptomatic non-functioning adenomas producing compression3,4.
Transsphenoidal surgery (TSS) has evolved from early microsurgical approaches to contemporary endonasal techniques. Historical descriptions of TSS emphasize progressive improvements in visualization, anatomical access, and perioperative safety5,6. The fully endoscopic endonasal approach was described by Jankowski and colleagues in 1992 and subsequently refined into a widely adopted technique that provides panoramic visualization and angled views of the sellar, suprasellar, parasellar, and cavernous sinus regions7,8. These visual advantages could plausibly improve selective adenomectomy and preservation of normal gland tissue, although surgical experience, tumor anatomy, and endocrine subtype remain major determinants of outcome.
Prior systematic reviews comparing ETS with MTS have reported heterogeneous conclusions for gross total resection, endocrine remission, and complications9,10,11. Endocrine endpoints are particularly difficult to synthesize because biochemical remission in functioning adenomas is clinically distinct from preservation of pituitary function in non-functioning tumors. Consensus criteria for acromegaly and disease-specific endocrine remission standards have changed over time, while reporting of pituitary axes after surgery remains inconsistent12,13. This review therefore evaluates the contemporary comparative literature with explicit attention to the conceptual heterogeneity of endocrine-success definitions, the low number of randomized data sources, and the potential for confounding by indication in observational cohorts.
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This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 framework14. The review was not registered in PROSPERO; it was registered in INPLASY (registration number: INPLASY202650157), and the eligibility criteria, outcomes, and analysis plan were specified before extraction of outcome data. Study screening, data extraction, and statistical verification were performed by two independent reviewers and adjudicated by a senior reviewer. PubMed/MEDLINE, Embase, Web of Science Core Collection, Cochrane Library, and Scopus were searched from January 1, 2010, to March 1, 2025, with additional screening of ClinicalTrials.gov and reference lists. The 2010 start date was selected to focus on contemporary ETS practice because widespread adoption of modern high-definition endoscopes, angled endoscopic visualization, and multilayer skull-base reconstruction after endoscopic pituitary surgery matured after this period. The PubMed strategy combined free-text and Medical Subject Headings (MeSH) terms for pituitary neoplasms, endoscopy, microscopic or transsphenoidal surgery, and endocrine or complication outcomes: ("Pituitary Neoplasms"[MeSH] OR "pituitary adenoma" OR "pituitary tumor" OR "pituitary tumour" OR acromegaly OR "Cushing disease") AND ("Endoscopy"[MeSH] OR endoscopic OR endonasal) AND (microscopic OR transsphenoidal OR "trans-sphenoidal") AND (endocrine OR hormone OR hypopituitarism OR remission OR "Diabetes Insipidus"[MeSH] OR "Cerebrospinal Fluid Leak"[MeSH]). Database-specific syntax was adapted without study-design filters, and English-language human studies were screened.
Eligible studies enrolled adults with radiologically or histologically confirmed pituitary adenomas and directly compared pure ETS with conventional MTS. Studies limited to non-adenomatous sellar lesions, pediatric populations, reoperations, salvage surgery after radiotherapy, mixed skull-base pathologies without adenoma-specific results, or single-arm series were excluded. The primary endpoint was endocrine success, defined according to the source article as biochemical remission for functioning tumors or preservation of pituitary function for mixed or non-functioning cohorts. This composite endpoint was used for quantitative synthesis because it represented the most consistently extractable endocrine outcome across comparative studies; however, it combines clinically distinct outcomes and is interpreted as a broad comparative signal rather than a single biological endpoint. Secondary outcomes included postoperative diabetes insipidus, CSF leak requiring intervention, and new postoperative hypopituitarism.
Records were managed in a reference manager, duplicates were removed, and titles and abstracts were assessed independently by Wang WC and Zhang HD. Full texts were then evaluated against the eligibility criteria by the same reviewers, with disagreements resolved by consensus and consultation with Zhang F. The search identified 3,542 records (PubMed/MEDLINE n = 1,050; Embase n = 1,200; Web of Science Core Collection n = 750; Scopus n = 450; Cochrane Library n = 85; ClinicalTrials.gov/reference lists n = 7); 695 duplicate records were removed, leaving 2,847 records screened after duplicate removal; after title and abstract screening, 2,802 records were excluded, and 45 full-text articles were assessed for eligibility. Thirty-seven full-text articles were excluded because they lacked a microscopic comparator, did not provide stratified endocrine or complication outcomes, mixed adenomas with other pathologies, reported overlapping populations, had insufficient sample size, or were not available in English. Eight comparative studies were included in the quantitative synthesis, as shown in Figure 1. The data extraction spreadsheet and analysis script are provided as supplemental files.
Risk of bias was evaluated with Cochrane Risk of Bias 2 (RoB 2) principles for randomized data and ROBINS-I domains for observational studies15. Statistical analyses were performed in R version 4.3.0 using the meta and metafor packages, and risk-of-bias graphics were prepared with robvis and provided as Supplemental Figure S1 and Supplemental Figure S216,17,18,19. Risk ratios with 95% CIs compared ETS with MTS. Random-effects models were prespecified as primary because of clinical and methodological heterogeneity across institutions, time periods, surgical expertise, tumor types, and endocrine definitions. Heterogeneity was summarized with I2, τ2, and prediction intervals when applicable. Funnel plots were generated only as exploratory visual displays because fewer than 10 studies contributed to the primary analysis, making formal asymmetry tests unreliable.
The eight included studies were published from 2014 to 2025 and represented Germany, Denmark, Thailand, Bulgaria, India, Turkey, and Egypt20,21,22,23,24,25,26,27. One study was a randomized controlled trial, and seven were observational comparative cohorts, including retrospective, prospective, and mixed prospective-retrospective designs; the Egypt study by Ibrahim et al. was classified as a prospective cohort to match Table 127. Table 1 summarizes the study characteristics, including the analysis denominators for Moller et al. in the endocrine-success analysis and for Ibrahim et al. as displayed in the pooled forest plot. Patient demographic data were not uniformly extractable across studies. The largest available demographic description came from Noiphithak et al., in which the ETS group had a mean age of 48.8 years and 77 of 138 patients were male, whereas the MTS group had a mean age of 53.8 years and 44 of 72 patients were male22. Savik et al. reported 52 patients overall, with 23 men and 29 women, split equally between ETS and MTS25. Other studies variably reported age, sex, tumor size, hormone subtype, cavernous sinus invasion, or follow-up, limiting formal adjustment for baseline comparability.
The primary endocrine-success analysis included 392 ETS patients and 377 MTS patients. The random-effects model favored ETS over MTS (RR 1.26, 95% CI 1.13-1.41; I2 = 17.8%), with a prediction interval from 1.06 to 1.51 (Figure 2A). Subgroup analysis by tumor functional status showed a non-significant and imprecise estimate in functioning-only cohorts (RR 1.06, 95% CI 0.63-1.80), whereas mixed cohorts favored ETS (RR 1.22, 95% CI 1.11-1.34; Figure 2B). Study-design subgrouping showed that the single randomized trial had an estimate near the pooled effect, while the observational studies also favored ETS but carried greater susceptibility to residual confounding (Figure 2C). Sensitivity analysis using sequential omission of each study produced pooled RRs between 1.20 and 1.30, suggesting that the primary point estimate was not driven by a single study.
The complication analyses were substantially less certain than the endocrine-success analysis. Two studies reported postoperative diabetes insipidus, and the pooled estimate did not show a statistically reliable difference between approaches (RR 1.89, 95% CI 0.72–4.96; Figure 2D). Two studies reported CSF leak requiring intervention, again with no reliable difference (RR 1.15, 95% CI 0.15-8.90; Figure 2E). These analyses are underpowered because the number of contributing studies and events was small, and the wide CIs include clinically important benefit and harm. New postoperative hypopituitarism was not meaningfully pooled. Noiphithak et al.22 reported new deficits in 24 of 138 ETS patients and 17 of 72 MTS patients, while Moller et al.21 reported 1 of 30 ETS patients and 41 of 120 MTS patients with new pituitary deficits in the endocrine-analysis subset. The heterogeneity and sparse ETS events produced a computationally unstable pooled CI; consequently, Figure 2F presents raw study-level counts and individual study estimates without a summary diamond. Leave-one-out sensitivity analysis for endocrine success is shown in Figure 2G, and the exploratory funnel plot is shown in Figure 3.
The apparent association between ETS and endocrine success is biologically plausible. Endoscopes provide improved illumination, a close-up panoramic view, and angled inspection of parasellar recesses that are difficult to visualize through the microscope. Better visualization may support more complete tumor removal while reducing traction on compressed normal pituitary tissue. Improvements in endoscopic skull-base closure, including multilayer reconstruction and selective use of vascularized flaps, also reduce concerns that early endoscopic approaches inherently carried higher CSF leak risk28.
Nevertheless, the pooled endocrine-success estimate should not be interpreted as definitive proof of superiority, because the composite endpoint merges remission and function preservation, and because most evidence derives from non-randomized cohorts. Confounding by indication is a material concern in this evidence base. Six of the eight included studies were retrospective observational cohorts, and the surgical approach was frequently determined by era, surgeon preference, institutional adoption of endoscopy, tumor anatomy, or anticipated technical difficulty rather than random allocation. Baseline tumor size, cavernous sinus invasion, Knosp grade, suprasellar extension, prior therapy, and hormone subtype were not consistently balanced or adjusted. These factors strongly influence both resection completeness and endocrine recovery29. Thus, the observed advantage for ETS may partly reflect selection of cases, accumulated institutional experience, improved imaging, or contemporary endocrine assessment rather than the visualization method alone.
Surgeon experience also shapes interpretation. The learning curve for endoscopic pituitary surgery can influence operative time, extent of resection, CSF leak, endocrine remission, and complication rates30,31,32. Several studies in the included period were conducted after endoscopic techniques had become established at high-volume centers, which may make the results more applicable to experienced pituitary teams than to low-volume settings adopting endoscopy for the first time. For this reason, the evidence supports careful institutional training, multidisciplinary skull-base collaboration, and outcome monitoring rather than automatic substitution of ETS for MTS in every clinical context.
Future comparative research should prioritize prospective designs with standardized endocrine endpoints and transparent baseline tumor characterization. Functioning adenoma cohorts should use disease-specific biochemical remission criteria, and non-functioning adenoma cohorts should report pituitary axes separately before and after surgery. Studies should record tumor size, invasiveness, Knosp grade, suprasellar extension, prior surgery or radiotherapy, surgeon experience, reconstruction technique, and follow-up duration. Adequately powered multicenter randomized or prospective registry studies would be especially valuable for complication outcomes, where current analyses remain dominated by sparse events and wide uncertainty. Cost, quality of life, visual outcomes, recurrence, and need for long-term hormone replacement should also be incorporated to clarify the patient-centered value of each approach. Additional observational work also links tumor characteristics and hormone levels to remission and underscores the need for more completely reported comparative datasets33,34.
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This systematic review and meta-analysis suggest that ETS is associated with higher endocrine success than MTS in contemporary comparative studies of pituitary adenoma surgery. The pooled primary estimate favored ETS, and leave-one-out sensitivity analysis did not identify a single study responsible for the result. However, the evidence should be interpreted cautiously because the endpoint combines biochemical remission in functioning adenomas with preservation of pituitary function in mixed and non-functioning cohorts. ...
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The authors have no conflicts of interest to declare.
No specific funding was received for this work. Language-editing assistance was used to improve grammar, formatting, and journal-style consistency; all scientific content, study selection, data extraction, statistical analysis, data interpretation, and final decisions remain the responsibility of the authors. No artificial intelligence tool was used for study screening, data extraction, statistical analysis, or scientific interpretation.
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