ENDOCRINE OUTCOMES OF TRANS-SPHENOIDAL SURGERY FOR PITUITARY APOPLEXY VERSUS ELECTIVE SURGERY FOR PITUITARY ADENOMA

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP ENDOCRINE OUTCOMES OF TRANS-SPHENOIDAL SURGERY FOR PITUITARY APOPLEXY VERSUS ELECTIVE SURGERY FOR PITUITARY ADENOMA Paul Marcet, MSc 1, Jason Paluzzi, MD 2, Anthony Morrison, MD 3, Fernando L. Vale, MD 2 From: 1 Morsani College of Medicine, 2 Department of Neurological Surgery, 3 Department of Internal Medicine; University of South Florida Running title: HRT after TSS for PA versus NC Macroadenoma Corresponding author: Fernando L. Vale, MD Professor Department of Neurosurgery and Brain Repair 2 Tampa General Circle, 7 th floor University of South Florida-STC Tampa, FL fvale@health.usf.edu Key Words: Trans-sphenoidal surgery, Pituitary tumor, Pituitary apoplexy, Hormonal replacement

2 Abstract (maximum 250 words): Objective: To determine the rate of hormone replacement therapy (HRT) after transsphenoidal surgery (TSS) for pituitary apoplexy (PA) vs. elective resection of a null cell (NC) macroadenoma. Methods: A retrospective cohort study was performed. Data was collected on all consecutive patients who underwent TSS surgery from December 31, 2000 to December 31, Patients were split into two groups: 1) patients that presented with PA, and 2) patients that underwent elective TSS for NC macroadenoma. Postoperative pituitary function was determined by examining HRT, hormone lab values, and an evaluation by an endocrinologist for each patient. The odds ratio was calculated to determine if there was an association between PA and the need for HRT after surgery when compared to elective resection of a NC macroadenoma. Results: The need for HRT was significantly higher in surgery for PA compared to resection of a NC macroadenoma (14.7% vs. 2.9% OR = 5.690; 95% CI to ; p = 0.013). Conclusion: There is an increased need for hormone replacement therapy after surgery in patients with PA versus patients undergoing elective resection of NC macroadenoma. Further studies are warranted to strengthen this data and help determine further predictors of the need for HRT.

3 Abbreviations: HRT= Hormone replacement therapy; TSS = Trans-sphenoidal surgery; PA = Pituitary apoplexy; NC = null cell (adenoma); HPA= hypothalamic-pituitary adrenal (axis); IRB = institutional review board; OR = odds ratio; MRI = magnetic resonance image; ACTH = adrenocorticotrophic hormone; LH = leutenizing hormone; FSH = follicle stimulating hormone; TSH = thyroid stimulating hormone; IGF = insulin like growth factor; T3 = triiodothyronine; T4 = thyroxine; CI = confidence interval; DDAVP = desmopressin acetate; BNP = brain natriuretic peptide. Introduction: Pituitary adenomas are benign tumors of the anterior pituitary gland. Though their prevalence is approximately 16.7% in the general population, the majority remain asymptomatic and undetected.(1) These tumors are usually detected if they affect the hypothalamic-pituitary axis, if they are large enough to exert a mass effect on surrounding structures within the brain, or if they suddenly hemorrhage causing a rapid expansion within the sella turcica. Pituitary adenomas are classified by endocrine function, light microscopy with histologic staining, size, or electron microscopic appearance.(2) When describing pituitary adenomas according to endocrine function, tumors are classified as either functional (hormone secreting) or non-functional (non-hormone secreting or null cell). Non-functional tumors can cause hormone dysfunction due to their size and physical compression of surrounding vascular and neurologic

4 structures, which can lead to hypopituitarism.(3) Depending on the clinical presentation, surgery can be indicated as a means of treatment.(3) The transsphenoidal surgical (TSS) approach is the preferred method of treating pituitary tumors, yet it can lead to endocrine complications.(4) Manipulation or damage of the pituitary gland, pituitary stalk, or rarely the hypothalamus during surgery can result in temporary or even permanent disruption of the hypothalamic-pituitary hormonal axis. Complications from surgery can result in significant morbidity.(4) Assessing postoperative sequelae and treating patients with the appropriate hormone replacement therapy is an important component of the postoperative follow up in these patients. Preoperative prognostic indicators can help guide the postoperative management of these patients. Studies show that size is an independent risk factor for new hormonal dysfunction after surgery.(5,6,7) The purpose of this study is to find other preoperative prognostic indicators of hormone replacement therapy (HRT). In this paper, HRT refers to any replacement of pituitary controlled hormones, not just sex hormone replacement. The clinical presentation of these tumors drives the urgency of surgical intervention and may affect the outcome of the surgery. For example, pituitary apoplexy, a condition that occurs in 2-12% of pituitary adenomas, is a rare but potentially life-threatening event.(3,8) Pituitary apoplexy (PA) most often occurs in a nonfunctioning macroadenoma.(3,8,9) It is caused by a sudden infarction or hemorrhage of pituitary adenomas, often requiring emergency surgical intervention. It is postulated that the loss of pituitary hormone function due to apoplexy is caused by the rapid increase in intrasellar pressure causing ischemic necrosis of the pituitary.(8) In addition, surgical decompression and manipulation of the pituitary may cause additional endocrine dysfunction. Because of the nature of pituitary apoplexy, some believe that the surgical intervention required to relieve it can be more traumatic to the surrounding pituitary

5 tissue and can lead to an increased number of patients with hormone dysfunction after surgery. One study showed that TSS surgery for PA resulted in a greater increase in hypopituitarism compared to TSS surgery for similar tumors that did not present with apoplexy.(8) Because of the small sample size of this study, further studies are warranted to verify these findings. Here, we compared endocrine outcomes of surgically treated patients that underwent elective resection of null cell pituitary adenoma versus those who required surgery for pituitary apoplexy. The primary goal was to determine if there was a significant difference of new pituitary HRT after surgery for pituitary apoplexy vs. elective resection of a null cell macroadenoma. Secondarily, we looked at the differences in specific hormone requirements between the two groups. In addition, we also analyzed pre-operative tumor size and the need for HRT. Methods: Data was collected retrospectively on all consecutive patients who underwent TSS in our institution for pituitary tumor resection from January 1, 2001 to December 31, 2016 obtained from a prospective database after approval from the Institutional Review Board. All patients provided informed consent. Patients were split into two groups: the PA group consisted of patients that underwent TSS for pituitary apoplexy, and the NC macroadenoma group consisted of patients that underwent elective surgery for null cell (NC) pituitary macroadenoma. Patients were followed regularly in the Adult Comprehensive Pituitary Clinic. The surgical technique consisted of endoscopic-assisted microscopic trans-nasal, trans-sphenoidal tumor resection. All surgical specimens were sent to pathology to determine pituitary hormonal stains. Pituitary hormone levels and hormone replacement therapies were recorded before

6 elective surgeries or at the time of an apoplectic event. Postoperative hormone values and therapy administration were recorded at three and twelve months during follow-up visits to the clinic and yearly as necessary. In addition, the clinical notes from the board-certified endocrinologist was used for the assessment of HRT. To examine the endocrine effects of surgical manipulation of the pituitary gland we opted to study surgical outcomes of nonfunctioning adenomas. This is because the postoperative hormonal outcomes are not confounded by preoperative hyper functioning hormonal axes. For this reason, only non-functional macroadenomas were included in this study. Patients were excluded in the review if they met the following criteria: (1) patient received post-operative radiation of the pituitary; (2) if the adenoma was of secretory pathology; (3) if they were lost to follow up. The following data was extracted from patient charts: demographics; tumor morphology; preoperative hormone replacement therapy; magnetic resonance imaging (MRI) radiographic findings before and after surgery; pre and postoperative hormone levels including: (i) adrenocorticotropic hormone (ACTH); (ii) cortisol; (iii) follicle stimulating hormone (FSH); (iv) luteinizing hormone (LH); (v) testosterone; (vi) estrogen; (vii) prolactin; (viii) growth hormone (GH); (ix) insulin-like growth factor-1 (IGF-1); (x) triiodothyronine (T3); (xii) free thyroxine (free T4); (xiii) thyroid stimulating hormone (TSH). A complete hormonal pituitary panel was obtained before surgery, and postoperatively at three months and 12 months after surgery. Surgical evaluation of tumor resection was completed by high-resolution pituitary MRI assessment at three months and yearly as necessary after surgery. Per institutional protocol prior to 2017, all patients were discharged routinely on cortisol replacement (hydrocortisone: 20mg in AM/10 mg in PM) and tapered by the patient and endocrinologist as tolerated.

7 Statistical Analysis Data was collected from patient charts and inserted it into an Excel spreadsheet. This data was then uploaded into IBM SPSS for statistical analysis. Patient data was converted into a categorical system for statistical analysis. Number values were assigned to hormone replacements, hormone levels (low, within normal limits, high), and apoplexy status. In addition, we generated a variable to represent a patient s change in hormone status (no change vs. loss of function) to reflect hormone function after the surgery. Postoperative pituitary function was determined by evaluating hormone replacement therapy and hormone lab values for each patient. An odds ratio (OR) was calculated to compare the loss of pituitary hormone function in apoplexy vs. elective pituitary surgery after surgery. Within each population (apoplexy and null cell), we examined the percentage of patients that were on hormone replacement therapy before and after surgery. Results: Study Cohort: Out of three hundred fifty patients who underwent consecutive TSS for pathology proven benign pituitary adenoma, one hundred seventy patients were eligible for study inclusion. Thirtyfour patients underwent TSS for apoplexy and one hundred thirty-six patients received TSS for elective NC macroadenoma resection. Demographics: In the PA group, the average age was 51, ranging from 18 to 81 years. In the NC macroadenoma group, the average age was 56, ranging from 25 to 83 years. An independent sample t test was conducted to compare the mean age between the two groups; there was no

8 significance between age in the PA group (M = 51) and the NC macroadenoma group (M = 56); t(-1.607), p = The mean tumor size was 1.81 ( 0.45) cm 3 in the apoplexy group and 1.95 ( 0.61) cm 3 in the NC macroadenoma group (MD = -0.13; 95% CI = to 0.10; p = 0.266). Outcome Data: Primary endpoint: The need for additional HRT after TSS was higher for patients presenting with apoplexy compared to elective tumor resection of a null cell macroadenoma (14.7% vs. 2.9% OR = 5.690; 95%CI to ; p = 0.013) (Table 1). Only patients with permanent loss of function (>1 year) were included in this analysis. Analysis of preoperative HRT between Groups: Analysis of the patient data revealed that 14 of 34 (41%) patients in the PA group were on HRT before surgery, whereas 28/136 (20.6%) patients in the NC macroadenoma group were on HRT before surgery (Table 2). The most common replacement therapy was thyroid hormone (Table 2). However, this was most often due to primary hypothyroidism, and rarely caused by central hypothyroidism. When accounting for both clinical need and lab values to determine true hormonal axis dysfunction, the most common hormonal dysfunction was cortisol in the PA group (17.7%) and testosterone (for hypogonadism) in the NC macroadenoma group (8.8% total or 19.3% of men) (Table 2). Analysis of postoperative HRT in PA and NC macroadenoma groups: In the PA group, 24 of 34 (70.5%) patients were on hormone replacement therapy after surgery, whereas 60/136 (44.1%) patients in the NC macroadenoma group were on hormone replacement therapy after surgery (Table 2). In the PA group, 6 of 34 (17.6%) patients had a

9 new HRT compared to their preoperative hormone status, and 5 of 34 (14.7%) required this replacement for greater than 1 year. In the NC macroadenoma group, 11 of 136 (8.1%) patients had a new HRT compared to their preoperative hormone status, and 4 of 136 (2.9%) required this replacement for greater than one year. Those that no longer required replacement were successfully weaned off their replacement and had normal HPA function of those hormones. Cortisol demonstrated the largest replacement rate pre- and postoperatively (32.4% and 17.4% increase in the PA group vs. NC macroadenoma group respectively), followed by testosterone in the PA group and thyroid hormone in the NC macroadenoma group (Table 2). In the PA group, 1 patient was on DDAVP preop, and 2 patients required new DDAVP therapy postop (1 permanent, 1 transient). In the NC macroadenoma group, 1 patient was on DDAVP preoperatively, and 8 required new DDAVP therapy postoperatively (2 permanent, 6 transient). In men (PA group), the most common postoperative hormone replacement in the apoplexy group was cortisol (11/20, 55%), followed by testosterone (8/20, 40%). In the NC macroadenoma group, the most common postoperative replacement in men was testosterone (14/62, 22.6%) followed by cortisol (12/62, 19.5%). In women, the most common postoperative hormone replacement in the PA group was cortisol (6/14, 42.9%), followed by DDAVP (2/14, 14.3%). In the NC macroadenoma group, the most common postoperative replacement in women was cortisol (15/74, 20.3%) followed by DDAVP (5/74, 6.8%). DDAVP required replacement postoperatively in 3/34 (8.8%) of the patients in the apoplexy group, and 9/136 (6.6%) of the NC macroadenoma group. Overall, there was no significant difference in the rate of postoperative DDAVP replacement between the apoplexy and NC macroadenoma groups (8.8% vs. 6.6%; OR = 1.37; 95% CI 0.35 to 5.34; p = 0.654).

10 Tumor size and HRT (Apoplexy and NC macroadenoma groups included): Although pre-operative tumor size cannot be well predicted in the apoplexy group (due to the presence of acute hemorrhage), we used the dimensions reported by the neuroradiologist to calculate volume of the hemorrhagic mass in the apoplexy group and the tumor in the NC macroadenoma group. Binary logistic regression shows a statistically non-significant relationship between tumor size and need for additional hormone replacement therapy postoperatively at three months [Chi square = 1.496; df = 1; p = 0.221] or one year [Chi square = 0.020; df = 1; p = 0.886]. The Odds ratio for size at three months is (95% CI = to 8.074), and at one year is (95%CI = to ). Size data was not available for 5 apoplexy cases, and 17 NC macroadenoma cases. Discussion: Postoperative endocrine complications of pituitary surgery remain a challenge for neurosurgeons and endocrinologists. Extensive follow-up and testing are needed to rule out endocrine abnormalities following TSS. Preoperative prognostic indicators for postoperative hormone replacement are lacking. Identifying those indicators can help facilitate postoperative management and preoperative education for these patients. Delineating the risk of hormonal dysfunction in these patients would allow endocrinologists and neurosurgeons to prepare patients for and adequately treat endocrine derangements. To better assess clinical needs in our population, the focus of this study was hormonal replacement therapy (clinically significant) not necessarily hormonal dysfunction. Current healthcare socioeconomics allows for replacement of only symptomatic hormonal requirements, and treatment algorithms are based on a strict clinical-

11 laboratory analysis. Tables 4 and 5 outline some relevant studies on the endocrine outcomes of transsphenoidal surgery. This cohort study examines whether a specific preoperative pathology like pituitary apoplexy has a higher likelihood of postoperative endocrine dysfunction compared to other patients undergoing elective TSS. Pituitary apoplexy is a sudden, destructive event that can cause a rapid change in hormonal function. The acute loss of hormonal function is a significant concern in this population. On the other hand, pituitary macroadenoma growth affects function slowly over time through local invasion and progressive mass effect. In our series, pituitary apoplexy patients undergoing TSS had a statistically significant higher likelihood of needing additional HRT more than one year after surgery compared to those undergoing elective surgery, possibly owing to the differences in the pathological mechanism of action and clinical presentation (14.7% vs. 2.9% OR = 5.690; 95% CI to ; p = 0.013). This is consistent with another study in which postoperative hormonal outcomes of 39 patients with pituitary apoplexy were compared via matched case-control study to patients within a cohort of pituitary tumors (matched for sex, tumor type, tumor size, and age).(8) These authors found that patients with pituitary apoplexy experienced a greater change in pituitary dysfunction after surgery compared to the control group.(8) In this study, the frequency of hypopituitarism increased significantly from 45% at presentation to 71% after surgery in patients with pituitary apoplexy, compared to the control group (from 48% at presentation to 55% after surgery).(8) Our study showed that the two groups did not differ in lesion size, age, or sex.(3) Other studies report rates of new pituitary dysfunction after TSS for null cell adenoma to be somewhere between 1-13%, which is consistent with our results.(5, 6, 7) Tables 4 and 5 outline several papers that

12 report the endocrine outcomes and hormone deficiencies associated with TSS in null cell adenomas and apoplexy. In our study, rates of hormone replacement do not accurately reflect rates of pituitary dysfunction. This is because hormone replacement rates that we recorded include any hormone replacements taken by the patient not only for central hormonal derangements but also for primary disorders requiring hormonal replacement such as primary hypothyroidism. Despite this, we reported rates of specific hormone replacements in order to give a general idea of the hormone replacements required by the two groups within our study. 70.5% patients in the PA group were on HRT after surgery, and 44.1% in the NC macroadenoma group were on HRT after surgery. These results are consistent with literature reporting rates of hormone replacement and hypopituitarism after surgery.(10, 11) A literature review of 186 cases of pituitary apoplexy reported rates of hypopituitarism as high as 40-80% regardless of the type of treatment.(10) One study reported 65% of patients with at least one hormone deficit after surgical treatment of 466 patients for non-functioning macroadenomas (91.8% of these patients underwent TSS, the rest underwent transcranial surgery).(11) The endocrine outcomes of pituitary apoplexy vary. Acutely, endocrine insufficiencies can result from destruction of the pituitary or the rapid increase in pressure on the gland.(3,12) The most common and most life-threatening of these endocrine dysfunctions is a corticotrophic deficiency (50-80%) (3), leading to hypotension and hyponatremia. In the absence of circulating cortisol, vessels become insensitive to catecholamines, leading to severe hypotension.(13) Hyponatremia can result from glucocorticoid insufficiency due to diminished inhibition of posterior pituitary release of vasopressin, or from cerebral salt wasting caused either by impaired sympathetic neural input to the kidneys or circulating hormones (i.e., BNP) that impair renal

13 tubular absorption of sodium.(14,15,16,17,18) Other endocrine deficiencies may have significant acute or long-term effects, including diabetes insipidus and thyrotropic, gonadotropic, growth hormone, and prolactin deficiencies. With regards to specific hormone replacements, cortisol was the most common postoperative hormone requirement (50.0% and 19.9% respectively) in both the PA and NC macroadenoma groups (though thyroid hormone replacement rates were higher, this was due to primary hypothyroidism). One study reported an outcome of secondary adrenal failure in 55% of patients with pituitary apoplexy, 39/42 of these patients were treated surgically.(8) In our experience, patients diagnosed with pituitary adenoma receive HRT with or without hormonal assessment due to the potential risks of adrenal-pituitary axis dysfunction. This extension of therapy may account for the substantial increase in patients taking steroid replacement postoperatively, rather than true secondary cortisol deficiency. The thyroid hormonal axis was more difficult to assess since many of the patients were on thyroid hormone replacement for primary hypothyroidism, and as such not all patients had TSH levels closely monitored. The values in Table 2 represent all patients taking thyroid hormone replacement for both primary and secondary hypothyroidism, and thus do not all reflect a pituitary deficiency. One study reported that 52% of patients experienced secondary hypothyroidism after surgery for pituitary apoplexy.(8) Overall there is insufficient evidence to show an association between tumor size and postoperative hormone replacement. Other studies have shown tumor size to be the strongest predictor of new hypopituitarism after surgery.(5,11) Several studies showed a significant increase in the need for postoperative hormone replacement with tumors larger than 20mm.(5,7) These studies included microadenomas and macroadenomas in their

14 analyses, whereas our study did not include any microadenomas, and instead included only macroadenomas and cases of apoplexy. Size data in the PA group was based on the neuroradiologist s measurements of the hemorrhagic mass. We were able to identify several patients who were over treated with hormonal replacement due to segmentation of their care across multiple specialties and locations. This extension of therapy may account for such a large increase in patients taking HRT postoperatively (usually steroid replacement). While it remains to be seen which factors at presentation may help predict the hormonal outcomes of these patients, postoperative management in a coordinated, comprehensive pituitary clinic could help optimize hormonal therapies. This information can help guide practitioners in the community that are managing postoperative patients that are not managed by a comprehensive pituitary clinic. It is important to evaluate patients for hormonal deficiency rather than keeping them on hormone replacement postoperatively. As a single institution, single surgeon retrospective analysis, this study is limited by the confounding factors associated with all patients being subject to a similar treatment paradigm without randomization. While all efforts were made to ensure close follow-up, some patients elected to follow with their primary care provider or an outside endocrinologist for their hormonal therapy over our comprehensive pituitary clinic. Despite this, very few patients were ultimately lost to follow up in our clinic. In addition, growth hormone is conjectured to be a common hormonal dysfunction; however, not many patients received replacement therapy. Many patients seem to be clinically asymptomatic. Nevertheless, current costs and insurance constraints make GH replacement a clinical challenge in most cases.

15 Conclusion: Patients undergoing transsphenoidal surgery have a low rate of new hormonal replacement therapy postoperatively. Our analysis demonstrated an increased need for hormone replacement therapy after surgery in patients with pituitary apoplexy when compared to patients undergoing elective resection of a NC macroadenoma. A larger sample size may strengthen this data and help determine if preoperative pathology is an independent risk factor for the need for postoperative hormone replacement therapy. Factors such as type of adenoma, the severity of hemorrhage in apoplexy, and extent of surgical decompression may also play a significant role. Further multicenter studies are warranted to help determine predictors of hormonal dysfunction after TSS. Management of these patients in a comprehensive pituitary clinic could potentially lower the need for unnecessary hormonal replacement.

16 Citations: 1. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004;101: Greenberg MS. Pituitary Tumors General Information and Classification. In: Handbook of Neurosurgery. 8 th ed. New York: Thieme, 2016: Briet C, Salenave S, Bonneville JF, Laws E, Chanson P. Pituitary Apoplexy. Endocr Rev. 2015;36: Charalampaki P, Ayyad A, Kockro RA, Perneczky A. Surgical complications after endoscopic transsphenoidal pituitary surgery. J Clin Neurosci. 2009;16: Fatemi N, Dusick J, Matozzo C, et al. Pituitary hormonal loss and recovery after transsphenoidal adenoma removal. Neurosurgery. 2008;63: Jahangiri A, Wagner J, Han SW, et al. Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis. J Neurosurg. 2016;124:

17 7. Nomikos P, Ladar C, Fahlbusch R, Buchfelder M. Impact of primary surgery on pituitary function in patients with non-functioning pituitary adenomas A study on 721 patients. Acta Neurochir (Wien). 2004;146: Moller-Goede DL, Brandle M, Landau K, Bernays R, Schmid C. Pituitary apoplexy: reevaluation of risk factors for bleeding into pituitary adenomas and impact on outcome. Eur J Endocrinol. 2011;164: Randeva HS, Schoebel J, Byrne J, et al. Classical pituitary apoplexy: clinical features, management and outcome. Clin Endocrinol (Oxf). 1999;51: Turgut M, Özsunar Y, Başak S, Güney E, Kır E, Meteog lu I. Pituitary apoplexy: an overview of 186 cases published during the last century. Acta Neurochir (Wien). 2010;152: Vargas G, Gonzalez B, Ramirez C, et al. Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas. Int J Endocrinol. 2015; 2015: Arafah BM, Harrington JF, Madhoun ZT, Selman WR. Improvement of pituitary function after surgical decompression for pituitary tumor apoplexy. J Clin Endocrinol Metab. 1990;71: Bouachour G, Tirot P, Varache N, Gouello JP, Harry P, Alquier P. Hemodynamic changes in acute adrenal insufficiency. Intensive Care Med. 1994;20: Bradley MD, Olliff JF, Winer JB, Franklyn JA. An unusual cause of hyponatraemia. Clin Endocrinol (Oxf). 1999;50: Chanson P. Severe hyponatremia as a frequent revealing sign of hypopituitarism after 60 years of age. Eur J Endocrinol. 2003;149:

18 16. Diederich S, Franzen NF, Bähr V, Oelkers W. Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases. Eur J Endocrinol. 2003;148: Palmer BF. Hyponatraemia in a neurosurgical patient: syndrome of inappropriate antidiuretic hormone secretion versus cerebral salt wasting. Nephrol Dial Transplant. 2000;15: Raff H. Glucocorticoid inhibition of neurohypophysial vasopressin secretion. Am J Physiol. 1987;252: Comtois R, Beauregard H, Somma M, Serri O, Aris-Jilwan N, Hardy J. The clinical and endocrine outcome to trans-sphenoidal microsurgery of nonsecreting pituitary adenomas. Cancer. 1991;68: Marazuela M, Astigarraga B, Vicente A, et al. Recovery of visual and endocrine function following transsphenoidal surgery of large nonfunctioning pituitary adenomas. J Endocrinol Invest. 1994;17: Wichers-Rother M, Hoven S, Kristof RA, Bliesener N, Stoffel-Wagner B. Nonfunctioning pituitary adenomas: endocrinological and clinical outcome after transsphenoidal and transcranial surgery. Exp Clin Endocrinol Diabetes. 2004;112: Webb SM, Rigla M, Wa gner A, Oliver B, Bartumeus F. Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas. J Clin Endocrinol Metab. 1999;84:

19 23. Ayuk J, McGregor EJ, Mitchell RD, Gittoes NJL. Acute management of pituitary apoplexy surgery or conservative management? Clin Endocrinol (Oxf). 2004;61: Chuang CC, Chang CN, Wei KC, et al. Surgical treatment of severe visual compromised patients after pituitary apoplexy. J Neuro-oncol. 2006:80:39 47.

20 Table 1: Postoperative loss of pituitary hormone function in the PA group and NC macroadenoma groups Group No loss of Transient loss Permanent Loss of Function (> 1 function of function (>3 year) months and < 1 year) PA group 28/34 1/34 5/34 (14.7%) NC 125/136 7/136 4/136 (2.9%) macroadenoma group

21 Table 2: Number of patients receiving each modality of hormone replacement therapy Replacement PA group NC macroadenoma group Preoperative Postoperative Preoperative Postoperative Replacement Replacement Replacement Replacement HRT 14 (41.0%) 24 (70.5%) 28 (20.6%) 60 (44.1%) Cortisol 6 (17.7%) 17 (50.0%) 8 (5.9%) 27 (19.9%) Thyroid Hormone 11 (32.3%) 13 (38.2%) 23 (16.9%) 33 (24.3%) Testosterone 4 (11.8%) 8 (23.5%) 12 (8.8%) 14 (10.1%) Growth Hormone 0 (0.0%) 0 (0.0%) 1 (0.7%) 0 (0.0%) DDAVP 1 (2.9%) 3 (8.8%) 1 (0.3%) 9 (6.6%) HRT = total number of patients on hormone replacement therapy PA = Pituitary Apoplexy NC = Null Cell (Elective surgery group)

22 Table 3. Articles quantifying the endocrine outcomes of transsphenoidal surgery for null cell pituitary adenomas Citation Methods Total number of Rates of hypopituitarism Rate of new Post-operative patients HRT/New Deficit follow up Preop Postop Fatemi, N., et Retrospective analysis of 444 total, % (7.3% 3 months al. (2008). 5 endocrine function after endocrine inactive anterior, 3.1% TSS for NC adenoma. (NC) posterior) Jahangiri, A., et al. (2016). 6 Retrospective analysis of endocrine function after TSS for NC adenoma. 305 (NC) 50% 13.70% 6 weeks and 6 months Nomikos P, et Retrospective analysis of % 3 months 72%, New deficit 1.4%, 1 week, 3 months, 1 al. (2004). 7 endocrine function after One year 69% Normalized 19.6%, year TSS for pituitary adenomas. Improved 30.1%, Unchanged 48.9% Comtois R, et al. (1991). 19 Retrospective analysis of endocrine function after TSS for pituitary adenomas. 126 TSH 15%, ACTH 8%, FSH/LH 3% Marazuela Retrospective analysis of 35 Total 69%, FSH/LH Improved 46%, M, et al. endocrine function after 69%, ACTH 20%, Persistent deficits (1994). 20 TSS for NC pituitary TSH 23%, 54% macroaadenomas. Panhypopitarism 6% Wichers- Retrospective analysis of 109 TSS GH 85%, FSH/LH No improvement Rother M, et the endocrine and clinical 61%, ACTH 31%, al. (2004). 21 outcomes after TSH 32%, PRL 22% transsphenoidal and transcranial surgery for non-functioning pituitary micro and macroadenomas. Webb SM, et Retrospective analysis of 234 (56 NC, 71 Thyroid 85.5%, PRL Thyroid 82.5%, al. (1999). 22 recovery of pituitary PRL, 66 GH, %, LH/FSH PRL 79.9%, hormone function after ACTH, 1 LH/FSH, %, ACTH FSH/LH 82.5%, surgical treatment of TSH) 77.4%, GH 71.4%, ACTH 80.8%, pituitary adenomas. complete 55%; NC GH 76.9%, 42.9% complete 62%, NC 53.6%

23 Table 3. Articles quantifying the endocrine outcomes of transsphenoidal surgery for apoplexy and null cell pituitary adenomas Citation Methods Total number of Rates of hypopituitarism Rate of new Post-operative patients HRT/New Deficit follow up Preop Postop Moller- Retrospective analysis of 42 (39 underwent 45% 71% Significantly 12 months Goede D L, outcomes of TSS for TSS) higher in Apoplexy et al. (2011). 12 pituitary apoplexy. compared to control Ayuk J, et al. (2004). 23 Turgut, M., Retrospective analysis of conservative vs surgical (TSS) management of pituitary apoplexy. Case review series of TSS 87% permanent % et al. (2010). 10 cases of pituitary apoplexy. Chuang CC, Retrospective analysis of 13 (12 TSS, 1 ACTH 62%, TSH ACTH 62%, Every 6 months et al. (2006). 24 patients presenting with craniotomy) 23%, DI 8%, TSH 31%, DI visual field defects in FSH/LH 31%. 8%, FSH/LH 8%. pituitary apoplexy that were Total 62% treated conservatively vs required long surgically (TSS). term replacement.

24 Figure 1: Hormone replacement therapy before and after surgery in the PA group

25 Figure 2: Hormone replacement therapy before and after surgery in the NC macroadenoma group