CONGRESS OF NEUROLOGICAL SURGEONS SYSTEMATIC REVIEW AND EVIDENCE-BASED GUIDELINES FOR THE ROLE OF MEDICAL MANAGEMENT FOR PATIENTS WITH FUNCTIONING PITUITARY ADENOMAS

Neurosurgery, 2025 Summary of Methods and Intro

Sponsored by: Congress of Neurological Surgeons (CNS) and the AANS/CNS Section on Tumors

Endorsement: Reviewed for evidence-based integrity and endorsed by the Congress of Neurological Surgeons (CNS), American Association of Neurological Surgeons (AANS)

Authors:

Christie G Turin, MD¹, Janice M Kerr, MD¹, Kalmon D Post, MD², Gabriel Zada, MD³, Isabelle M Germano, MD, MBA⁴ D. Ryan Ormond, MD, PhD⁵

Departmental and institutional affiliations:

1. Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
2. Mount Sinai Health System, New York, NY, United States
3. Department of Neurosurgery, Keck Medicine at University of Southern California, Los Angeles, CA, United States
4. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
5. Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, United States

Corresponding Author contact information:

Christie G Turin, MD

Department of Medicine, Division of Endocrinology, Metabolism and Diabetes

University of Colorado School of Medicine – Anschutz Medical Campus

Keywords: pituitary adenoma, transsphenoidal surgery, hyponatremia, fluid restriction, growth hormone secreting pituitary adenoma, acromegaly, medical therapy, Cushing’s disease.

Abbreviations:

TSS: transsphenoidal surgery

SIADH: syndrome of inappropriate antidiuretic hormone secretion

GH: growth hormone

FPA: functioning pituitary adenomas

ACTH: adrenocorticotropic hormone

SSA: somatostatin analogue

POD: postoperative day

IGF-1: insulin-like growth factor-1

CD: Cushing’s disease

OCT: octreotide

NPV: negative predictive value

PPV: positive predictive value

Conflicts of Interest

All Guideline Task Force members were required to disclose all potential COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs.

Funding 

These evidence-based clinical practice guidelines were funded exclusively by the Congress of Neurological Surgeons, which received no funding from outside commercial sources to support the development of this document.

The AANS/CNS Section on Tumors funded the cost of publication for the supplement. 

Disclosure

See Supplemental Digital Content 5 for a complete list of disclosures.

ABSTRACT

Background: Standardized perioperative management of patients with functioning pituitary adenomas is important for optimal medical and surgical outcomes.

Objective: Review of the literature to evaluate the impacts of: 1) postoperative fluid restriction and sodium level checks to prevent delayed hyponatremia and hospital-related readmissions, 2) preoperative somatostatin analog (SSA) medical treatment in patients with growth hormone (GH) secreting tumors and its effects on surgical and medical outcomes, and 3) immediate postoperative pituitary hormone testing in patients with adrenocorticotropic hormone (ACTH)-secreting tumors to predict adrenal insufficiency and disease remission.

Methods: Systematic literature search using EMBASE and PUBMED from 1946 to June 2021.

Results: A total of 1953 abstracts were identified for review: 124 studies were selected for full text review and 44 studies were included in the analyses. Overall, based on predominantly level III evidence, the literature supported: 1) fluid restriction (1000-1500 mL/day for ~7 postoperative days), with/without a routine serum sodium check, to lower risk of delayed hyponatremia and hospital-related readmission, and 2) basal morning serum cortisol (+/- ACTH levels), within the immediate postoperative period (< 72 hours) for patients with ACTH-secreting tumors to predict adrenal insufficiency and disease remission. Conversely, perioperative treatment of patients with GH-secreting tumors with a SSA is not recommended to improve surgical or medical outcomes.

Conclusion: Limited fluid restriction is recommended for all patients after transsphenoidal surgery (without diabetes insipidus), as is routine postoperative morning cortisol testing in Cushing’s patients, but not somatostatin pre-surgical treatment in acromegalic patients.

RECOMMENDATIONS

Target Population: Adult patients with functioning pituitary adenomas (FPAs) who undergo transsphenoidal surgery (TSS)

Key Question 1: In adult patients with FPAs who undergo TSS, does postoperative fluid restriction and/or a serum sodium level check during the first postoperative week decrease complications/readmission rates for hyponatremia compared to ad libitum fluid intake?

Recommendation, Level III: In adult patients with FPAs who undergo TSS, fluid restriction after surgery is a suggested effective approach to prevent delayed hyponatremia and reduce hospital readmission for hyponatremia .There is not enough evidence to support serum sodium check without fluid restriction as a preventative strategy to reduce hyponatremia.

Target Population: Adult patients with signs/symptoms suggestive of FPAs

Key Question 2. In adult patients with signs/symptoms suggestive of FPAs, specifically GH-tumors, does the administration of preoperative medical therapy to control serum level of hyper-secreted pituitary hormones provide a better control of serum level of hyper-secreted pituitary hormones and/or extent of surgical resection and/or decreased medical co-morbidities compared to no medical therapy?

Recommendation, Level III: Preoperative medical treatment with somatostatin analogs (SSA) for patients with GH-secreting tumors is not routinely suggested, as there is insufficient evidence demonstrating a benefit to long-term biochemical remission, medical co-morbidities or surgical complications.

Target Population: Adult patients with Cushing’s disease (CD) who have undergone pituitary surgery

Key Question 3. In adult patients with CD who have undergone pituitary surgery, does the timing of the postoperative pituitary hormone(s) assessment lead to a better prediction of postoperative adrenal insufficiency, need for steroids, and/or remission?

Recommendation, Level III:  Postoperative serum cortisol monitoring within the immediate postoperative period (< 72 hours) is suggested using a cut-off level of <2 ug/dl as a predictor of remission and an indicator for glucocorticoid replacement. 

INTRODUCTION

 Pituitary adenomas are the second most frequent type of primary intracranial neoplasms,

accounting for ~10-20% of tumors¹. Lactotroph adenomas are the most common subtype of pituitary adenomas, followed by non-functioning adenomas (NFPAs), somatotroph, corticotroph, and thyrotroph adenomas. Functional pituitary adenomas (FPAs) account for ~60% of pituitary tumors and are defined by the clinical and biochemical evidence of pituitary hormonal excess. These pituitary adenomas typically present with classic signs and symptoms specific to their target hormone excess (e.g., acromegaly with growth hormone (GH)-secreting tumors and Cushing’s disease (CD) with adrenocorticotropic hormone (ACTH)-secreting tumors). In addition, large pituitary tumors/macroadenomas may be associated with mass effects secondary to local compressive effects (e.g., headaches, visual loss from optic chiasm compression, and/or cranial nerve palsies).  The optimal preoperative and postoperative management of functional tumors lack standardization but is an important consideration for optimal medical and surgical outcomes.

Goals and Rationale

This guideline has been created as an educational tool to guide qualified physicians through a series of diagnostic and treatment decisions to improve the quality and efficiency of care of patients with FPAs.

Objectives

The aim of this chapter of the guideline is to highlight 3 specific questions relevant to perioperative endocrine management of FPAs:  firstly, to evaluate the impact of fluid restriction and serum sodium monitoring in TSS patients during the early postoperative period on readmission for delayed hyponatremia; secondly, to determine the potential role of pre-surgical SSA treatment to improve surgical outcomes (i.e., biochemical remission and extent of surgical resection) and medical/surgical complications in patients with GH-secreting adenomas; last, to evaluate if the timing of postoperative hormonal assessment could lead to a better prediction of postoperative adrenal insufficiency and biochemical remission. Questions were asked following a population, intervention, comparison, outcome (PICO) format and approved by the CNS Guidelines Committee prior to performing the literature search or systematic review.

Importantly, in selecting the topics for review of preoperative medical therapy, this question focused exclusively on GH-secreting tumors and somatostatin presurgical treatment. This is because there was either insufficient data to support preoperative medical therapy for the other functional tumors (i.e., ACTH, thyroid stimulating hormone, and follicle stimulating hormone/ luteinizing hormone-secreting tumors) or non-standardized care (e.g., prolactinomas). A flow chart summarizing the study selection and screening process is shown in Supplemental Digital Content 3. Additional information about the methods utilized in this systematic review is provided below.

Methodology

The guidelines task force initiated a systematic review of the literature and evidence-based guideline relevant to the treatment of patients with FPAs. The Guidelines Task Force used DistillerSR (which utilizes artificial intelligence) to cull, narrow and aid its review of the relevant literature.  All abstracts were reviewed and relevant full text articles were retrieved and graded (by individuals of the guideline task force).  Through objective evaluation of the evidence and transparency in the process of making recommendations, this evidence-based clinical practice guideline was developed for the diagnosis and treatment of adult patients with FPAs. These guidelines were developed for educational purposes to assist practitioners in their clinical decision-making processes.

Literature Search

The task force members identified search terms/parameters and a medical librarian implemented the literature search, consistent with the literature search protocol (see Supplemental Digital Content 1: Appendix I), using the National Library of Medicine/PubMed database and Embase for the period from 1946 (inception of the database) to June 8, 2021 using the search strategies provided in Supplemental Digital Content 1: Appendix I.

RESULTS   

The literature search yielded 1953 abstracts. Task force members conducted a double-blind review of the abstracts yielded from the literature search and identified 124 studies for full text review and extraction, addressing the clinical questions. Task force members identified 44 articles that met criteria for inclusion.  Overall, based on predominantly level III evidence, the literature supported: 1) fluid restriction (1000-1500 mL/day for ~7 postoperative days), with/without a routine serum sodium check, to lower risk of delayed hyponatremia and hospital-related readmission, and 2) basal morning serum cortisol (+/- ACTH levels), within the immediate postoperative period (< 72 hours) for patients with ACTH-secreting tumors to predict adrenal insufficiency and disease remission. Conversely, perioperative treatment of patients with GH-secreting tumors with a SSA is not recommended to improve surgical or medical outcomes.

CONCLUSIONS

Limited fluid restriction is recommended for all patients after transsphenoidal surgery (without diabetes insipidus), as is routine postoperative morning cortisol testing in Cushing’s patients, but not somatostatin pre-surgical treatment in acromegalic patients.

Disclaimer of Liability

          This clinical systematic review and evidence-based guideline was developed by a physician volunteer task force as an educational tool that reflects the current state of knowledge at the time of completion. Each chapter is designed to provide an accurate review of the subject matter covered. This guideline is disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in their development are not meant to replace the individualized care and treatment advice from a patient's physician(s). If medical advice or assistance is required, the services of a competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

Acknowledgments

          The guidelines task force would like to acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Review Committee, as well as the contributions of Trish Rehring, MPH, Director for Evidence-Based Practice Initiatives for the CNS, and Janet Waters, MLS, BSN, RN, for assistance with the literature searches. Throughout the review process, the reviewers and authors were blinded from one another. At this time the guidelines task force would like to acknowledge the following individual peer reviewers for their contributions:  Brandon Lucke-Wold, MD, Koji Ebersole, MD, Andrew Carlson, MD, MS, Andrew Ryu, MD, Vincent Alentado, MD and Jeffrey Olson, MD.

References

1. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro-oncology. 2021;23(12 Suppl 2):iii1-iii105.