Adrenal Axis Insufficiency After Endoscopic Transsphenoidal Resection of Pituitary Adenomas

Accepted Manuscript Adrenal Axis Insufficiency Following Endoscopic Transsphenoidal Resection of Pituitary Adenomas Abdulrazag Ajlan, MD, Khadeejah A. Almufawez, MD, Abdulrahman Albakr, MD, Laurence Katznelson, MD, Griffith R. Harsh, IV, MD PII:

S1878-8750(18)30225-0

DOI:

10.1016/j.wneu.2018.01.182

Reference:

WNEU 7380

To appear in:

World Neurosurgery

Received Date: 4 November 2017 Revised Date:

24 January 2018

Accepted Date: 25 January 2018

Please cite this article as: Ajlan A, Almufawez KA, Albakr A, Katznelson L, Harsh IV GR, Adrenal Axis Insufficiency Following Endoscopic Transsphenoidal Resection of Pituitary Adenomas, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.01.182. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Adrenal Axis Insufficiency Following Endoscopic Transsphenoidal Resection of Pituitary Adenomas Abdulrazag Ajlan, MD1.2; Khadeejah A Almufawez, MD 3; Abdulrahman Albakr, MD2; Laurence

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Katznelson, MD1,4, Griffith R. Harsh IV, MD1

1) Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, United States

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2) Department of Neurosurgery, King Saud University, Riyadh, Saudi Arabia 3) College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Corresponding Author: Abdulrazag M. Ajlan, MSc, MD, FRCSC,
 Assistant professor, Neurosurgery King Saud University, Riyadh, Saudi Arabia

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Adjunct Clinical Assistant Professor

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4) Department of Medicine, Stanford University, Palo Alto, California, United States

Stanford University School of Medicine
 Department of Neurosurgery


300 Pasteur Drive
Stanford, CA 94305


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Email: [email protected]

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Phone: (650) 839-3087

Conflict of interest: The author declares no competing interests. Funding: No external funding was received for this research. Running Title: Adrenal Axis Insufficiency Following Pituitary Surgery Keywords: Adrenal insufficiency; Pituitary adenoma; Transsphenoidal surgery Manuscript words: 2898

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Figures: 1 Tables: 2

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Supplementary tables: 4

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References: 32

ACCEPTED MANUSCRIPT Adrenal Axis Insufficiency Following Endoscopic Transsphenoidal Resection of Pituitary Adenomas

ABSTRACT

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INTRODUCTION: Hormonal insufficiency of one or more pituitary axes can appear after pituitary surgery. Adrenal axis impairment after surgery can lead to serious consequences if not identified and treated.

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OBJECTIVE: Assess early and late post-operative adrenal insufficiency (AI) and identify the

adenomas.

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risk factors predicting their occurrence after endoscopic transsphenoidal resection of pituitary

METHOD: Retrospective review identified 176 pituitary adenomas resected using an endoscopic transsphenoidal approach. Patients on steroids preoperatively, Cushing’s disease patients, and patients with incomplete records were excluded. 69 patients were excluded

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according to our exclusion criteria.

RESULTS: The study group thus included 107 patients (total of 111 operations). The median age was 50 years (range 18-89 years). The median duration of follow up was 30 months

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(range 6-74 months). 83 (74.7%) had macroadenomas, and 89 (59.3%) had nonfunctional

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adenomas. Of these 111 procedures, 61 (55%) had early AI. Of the 61 patients, 48 patients (79%) were off steroids in long-term follow-up and only 13 (21%) required long-term replacement. 16/111 (14.4%) had AI on long-term follow-up. Out of these 16 patients, 13 were already on steroids and 3 were newly diagnosed with AI. Age, male gender and cerebrospinal fluid (CSF) leaks were associated with persistent post-operative AI (P=0.018, P=0.001, P=0.007, respectively) CONCLUSION: Hypothalamic pituitary adrenal axis insufficiency is common following endoscopic transsphenoidal surgery. Male gender, age greater than 50 years, visual

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ACCEPTED MANUSCRIPT impairment and intraoperative CSF leak were correlated with late postoperative AI. More

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than two-thirds of patients who developed early AI did not require steroids long-term.

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ACCEPTED MANUSCRIPT INTRODUCTION Pituitary adenomas represent 10% to 15 % of all primary intracranial tumors.

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Although medical therapy is an option for some patients, the definitive treatment for most symptomatic pituitary adenomas is primarily surgical.

2

For sellar lesions, transsphenoidal

techniques.

3,4

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surgery (TSS) is typically preferred, with a notable trend towards using endoscopic For many large and giant pituitary adenomas with suprasellar and parasellar

extension, traditionally approached by open craniotomy

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, the extended endoscopic

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transnasal, transsphenoidal approach is now often preferred. 6,7

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Postoperative dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis is a recognized complication in patients undergoing surgical resection of pituitary adenomas. The overall risk of de novo adrenal insufficiency following TSS of pituitary adenomas has ranged from 0.8% to 44%.

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This large range of rates of reported adrenal insufficiency (AI) may

reflect differences in timing of assessment, study populations, tumors’ size, surgical

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techniques, and the diagnostic criteria used in the studies. Adrenal insufficiency during the postoperative period presents with vague symptoms

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such as fatigue, anorexia, nausea, vomiting, arthralgia, and, in some cases, hypotension and even death. Unnecessary replacement may produce iatrogenic suppression of ACTH and

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exposes the patients to potential complications of exogenous steroids.15 Adrenal insufficiency is the third leading cause of unplanned readmission to the hospital within the first 30 days following TSS. 16

Here, we report the incidence of early and late HPA axis insufficiency, and seek specific factors predictive of postoperative adrenal insufficiency. METHODS We retrospectively reviewed the Stanford Pituitary Database for surgical cases of 2

ACCEPTED MANUSCRIPT pituitary adenomas between 2007 and 2012. The project was approved by the Stanford University Institutional Review Board. The study included patients with complete records who underwent endoscopic resection of a pituitary tumor by a single senior surgeon (G.H). This cohort represents a subset of patients from our previous published data (270 procedures 17

Among 176, 107 met inclusion criteria. Exclusions were for

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performed by 4 surgeons).

incomplete records (n=30), Cushing’s disease (n=12), preoperative use of steroids for detection of AI prior to surgery or symptomatic optic compression (n=26), and chronic

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steroid use for rheumatoid arthritis (n=1). The remaining study cohort includes 107 eligible patients who underwent a total of 111 transsphenoidal operations. All tumors were

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pathologically confirmed to be a pituitary adenoma.

Hormonal assessment included preoperative measurement of adrenal function, thyroid-stimulating hormone /free thyroxine, prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin-like growth factor-1 (IGF-1), and clinical and biochemical

postoperatively.

17

The same tests were repeated within 12 weeks

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assessment for diabetes insipidus (DI).

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Preoperative morning serum cortisol <5 mcg/dL or a peak serum cortisol <18 mcg/dL following 250 mcg of cosyntropin administered intramuscularly was taken as evidence of AI.

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Patients with intact HPA did not receive peri-operative stress dose steroids. If AI was documented,

glucocorticoids

were

administered

at

stress

doses

perioperatively

(hydrocortisone 50 mg IV every 8 hours), and then tapered over the next few days. According to our protocol, fasting morning serum cortisol was measured every day during the hospital course for the first 1 to 4 days. Post-operatively, glucocorticoids (GCs) were administered at stress doses if the postoperative serum cortisol was less than 5 mcg/dL, if the postoperative serum cortisol was 3

ACCEPTED MANUSCRIPT between 5 and 12 mcg/dL in association with significant clinical symptoms of AI (hypotension, nausea, or fatigue), or if serum cortisol was more than 12 mcg/dL in the presence of severe headaches refractory to standard pain management, protracted vomiting, or severe hyponatremia (<125 mmol/L) that developed during the hospital stay or within the

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first 2 postoperative weeks. Steroid replacement started at hydrocortisone 50 mg IV every 8 hours for 24 hours and was tapered rapidly over the next 3 to 4 days to a stable daily dose of oral hydrocortisone ≤25 mg. HPA was reassessed post-operatively during follow-up, at least

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6 weeks after hospital discharge, and considered normal if a morning serum cortisol was >12 mcg/dL or a peak serum cortisol was >18 mcg/dL following 250 mcg of cosyntropin

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administered intramuscularly. GCs were withheld for 24 hours prior to these tests. We diagnosed early adrenal insufficiency if steroid replacement was started according to the above criteria during the first two weeks following surgery. Criteria for the diagnosis of late adrenal insufficiency were continuation of need for GCs replacement among those

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deficient preoperatively or the development of new adrenal insufficiency at latest follow-up (at least two weeks following surgery).

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Data analysis was performed using IBM SPSS (Version 22.0, IBM, Armonk, NY). Statistical tests included Pearson’s chi-square tests of association between predictor and

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outcome variables, with a p-value ≤0.05 considered significant. Univariate logistic regression was used to analyze the risk factors for adrenal insufficiency such as age, gender, tumor size, previous surgery, tumor resection, the rate of cerebrospinal fluid (CSF) leak, the rate of early DI, hormonal outcome, and visual status. Multivariable analysis was used to further define the effects of gender, visual status, steroids use on discharge, steroids use on follow-up, and the rate of CSF leak. RESULTS

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ACCEPTED MANUSCRIPT After excluding patients according to our criteria, 107 patients who underwent 111 operations were analyzed. There were 47 men and 64 women. The median patient age was 50 years (range, 18-89 years). The study included 83 patients with macroadenomas and 28 with microadenomas. 62 (55.8%) were nonfunctional adenomas and 49 (44.2%) were

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endocrinologically active, including, prolactinomas (n=24), GH-secreting adenomas (n=23), and TSH secreting adenomas (n=2). Overall, 107 (96%) patients had one operation and 4 (4%) had a second surgery for recurrent or residual tumor. In 111 transsphenoidal operations median

duration

of

follow-up

was

30

months

(range,

6-74

months).

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the

The patients' demographics, surgical characteristics, and adrenal function outcome are

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summarized in (Table 1)

Early AI necessitating steroid replacement in the first two weeks after surgery was noted after 61 of 111 (55%) operations. In those 61 cases, 48 (79%) patients were weaned off steroids in long-term follow-up, while the remaining 13 (21%) continued to have AI at late

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follow-up. At long-term follow-up, 16 cases (14.4%) had late AI; 13 who had shown early AI and 3 who were later diagnosed with late AI despite having normal indices within the postoperative period (Table 1, Figure 1). Therefore, among 50 cases with normal HPA axis at

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the time of discharge from the hospital, only 3 cases were started on steroids at late follow-up

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(i.e. 3/50 = 6%). Overall, these patients were similar to the rest of the cohort. All of them were diagnosed with non-functional pituitary macroadenomas. The reason for diagnosis was incidental finding in two patients, and headache in one patient. The mean age at the time of diagnosis for these 3 patients was 63 years. There were no postoperative complications. There was no significant difference in gender, age (mean age in both groups was 49 years), hormonal activity (functional vs non-functional) or tumor size (microadenoma vs macroadenoma) between the 61 patients with early AI and the 50 without it. There was a

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ACCEPTED MANUSCRIPT trend toward association of early DI with both preoperative visual impairment and CSF leak (P= 0.059). Regarding late AI, female gender was significantly associated with a normal HPA axis, as only 3 out of 16 documented late AI were females (19%, p=0.001). Additionally,

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unlike our finding with early AI, increasing age (≥50 years) was a significant predictive factor for long-term requirement for of steroids (P=0.018). The prevalence of visual impairment at presentation was significantly higher in those with late AI [9 (56%) vs. 28

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(30%); P = 0.036]. At late follow-up, the majority of patients who require steroid treatment at late follow-up were given steroids at the time of discharge [13 (81%) vs. 3 (19 %); p=0.022].

adrenal insufficiency (Table 2).

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Neither the tumor size nor the tumor type shows significant correlation with early or late

Documentation of CSF leak showed significant association with late AI [10 (63%) vs. 27 (28%); p =0.007]. For the entire cohort, 7 cases developed CSF leak postoperativly,

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requiring reoperation in 2 patients and lumbar drain insertion for the rest; all of them were discharged with steroids. Out of these 7 patients, two patients continue to require steroids at late follow-up.

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Data concerning postoperative DI were only available in 98 patients. In those patients,

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early DI was more likely to be diagnosed in patients with early AI than in those with normal HPA axis at the time of discharge (34.7% compared with 20.4%, respectively). Similarly, the incidence of persistent DI requiring long term treatment was slightly higher in patients with late AI (14.2% in patients with late AI compared with 8.3% in those with normal HPA axis at late follow up). Based on a multivariable analysis, males with visual impairment were more likely to require new steroids at discharge (OR=5.9, 95% CI 1.6-21.5). Among patients who needed steroids at discharge, males were more likely to have steroids prescribed at follow-up

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ACCEPTED MANUSCRIPT (OR=11.1, 95% CI 2.9-50). Additionally, males with CSF leaks more often require long-term steroids replacement [OR=6.3, 95% CI 1.7- 25 (supplementary tables 1- 4)]. DISCUSSION Careful assessment of HPA function in the postoperative setting is essential, as both

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recovery and development of adrenal insufficiency may follow. In addition to clinical evaluation for symptoms and signs of adrenal insufficiency, several methods for the assessment of the HPA axis function have evolved.

13,18-20

However, at present, there is no

particular test.

21

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agreement as to which test is considered superior or when is the optimal time to perform a Insulin tolerance test (ITT) is generally regarded as the ‘gold standard’

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assay to test HPA axis function; though, it requires medical supervision and may be associated with significant adverse effects. 15 In accordance with many reports and in spite of the variations in the timing of assessment and the cutoff values, the early postoperative AM serum cortisol level following pituitary surgery appears to be a safe and efficient method for

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evaluating the HPA axis function.15,18,22,23 In the present study, the diagnosis of adrenal insufficiency was based on clinical symptoms, postoperative AM serum cortisol level, and, weeks later, the cosyntropin stimulation test.

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The overall risk of new adrenal insufficiency following TSS of pituitary adenomas

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has ranged from 0.8% to 44%.

6,8-14

Relatively few studies have detailed rates of early and

late adrenal insufficiency, with reports of an early risk ranging from 10% to 51% and 2.3% to 36% for late adrenal insufficiency.

9,22-25

In this study of 107 consecutive patients with

normal preoperative adrenal function who had an endoscopic transnasal resection of a pituitary adenoma, the incidence of early AI was 55% and 14.4% for late AI. We observed a high incidence of early AI in our cohort, which is similar to some reports but much higher than in others, perhaps due to the use of different cut-off values, differences in the reported populations, tumors' characteristics and size, and surgical strategies.8

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ACCEPTED MANUSCRIPT Both the microscopic and endoscopic transsphenoidal approaches appear equally effective in experienced hands, in addition to sharing similar results with respect to outcomes and rate of resection. Though, the latter has a number of advantages, including wider and extended view, additional theoretical benefit for visualizing tumors with significant 3,4,26

In accordance with many

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extrasellar extension, and significantly shorter hospital stay.

reports, the endoscopic transsphenoidal approach in pituitary tumors is superior to the microscopic approach in term of preservation of anterior pituitary function. Yet, the risk of

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postoperative adrenal insufficiency was not different between these approaches. 4,26,27

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The risk for de novo adrenal insufficiency following pituitary surgery is commonly seen in those with macroadenomas. 9,23 In the large study by Fatemi et al. of 444 patients who had undergone transsphenoidal surgery for pituitary adenoma, larger tumor size was a predictor of new hypopituitarism. In the present study, we failed to detect any statistically significant difference in the risk of adrenal insufficiency between macro and microadenoma

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patients. However, a considerable proportion of our patients had macroadenomas with relatively fewer microadenomas, 74.7% Vs 25.3%, respectively. This finding may explain the

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high incidence of adrenal insufficiency in our cohort. Additionally, among 16 patients with late adrenal insufficiency, there was only one patient with microadenoma. Somewhat

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surprisingly, gender, age, and hormonal function of the adenoma did not appear to be independent predictive factors of early adrenal insufficiency. We did, however, find that increasing age (≥50 years) was a significant predictive

factor for late adrenal insufficiency. Overall, the rate of hormonal deficiency further increases with advancing age.28 Furthermore, women are less likely to develop late adrenal insufficiency than men. In patients with late adrenal insufficiency, only 3/16 (19%) were females. A similar finding was observed in a study by Caputo et al., in which the authors found that men were more likely than women to develop secondary adrenal insufficiency 8

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29

Similarly, men tend to have a lower likelihood of recovery of

preexisting adrenal insufficiency. 29

Both preoperative visual impairment and postoperative CSF leaks were associated

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with higher numbers of AI (56% and 63% respectively). Although a statistically significant difference was only noted with late AI. Perhaps, one of the explanations for these findings is related to the mass effects of the pituitary tumor rather than the surgical intervention. Based

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on our multivariable analysis, we found that males with visual impairment were more likely to be started on steroids at the time of discharge (OR=5.9, CI 1.6-21.5). In addition, among

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patients who needed steroids at discharge, males were more likely to have steroids prescribed at follow-up. Lastly, our data revealed that, among males with CSF leaks, 46% will require long-term steroids replacement. Individuals with multiple risk factors (i.e., pituitary macroadenoma in a 65- year-old man with visual impairment and documented CSF leak)

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should be carefully monitored in the postoperative period and during later follow-up.

Among 50 cases with normal HPA axis at the time of discharge from the hospital, 3 patients were later diagnosed with late AI despite having normal indices within the

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postoperative period. The etiology behind the development of late-onset, new AI following

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pituitary surgery is not well understood, primarily because of the rarity of this event. One previous study has identified 2 patients who required new cortisol replacement at the last follows up. Both of them had Gamma Knife radiosurgery for residual pituitary adenomas.25 Moreover, generally, advanced patient age, larger tumors, and non-functional pituitary lesions have been reported as predictors of new postoperative pituitary failure.30 In the current study, all the 3 patients who develop late-onset, new AI did not receive radiation therapy, but they were all elderly with non-functional pituitary macroadenomas.

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ACCEPTED MANUSCRIPT Early diagnosis of HPA axis insufficiency is essential for early treatment and avoidance of excessive intake of glucocorticoids.

31

Fatigue, anxiety, depression and lack of

energy are common symptoms of untreated adrenal insufficiency.

32

Adrenal crisis usually

presents with fever, abdominal pain, nausea, vomiting, diarrhea, hypotension and even death 33

Hydrocortisone is the preferred replacement therapy in

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if left undiagnosed or untreated.

case of adrenal insufficiency. Less commonly used alternative drugs are cortisone acetate, prednisolone and dexamethasone. A physiologically normal cortisol level is achieved by

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using the hydrocortisone regimen: 10 mg in the morning, 5 mg in the afternoon and 5 mg in the early evening.33 Using our protocol, we identified no complication related to HPA

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insufficiency, re-admissions, or steroid induced long-term side effects.

The major limitations of this study are its retrospective nature and loss of follow up of some patients (N=30). In addition, the extent of resection was not assessed in the current study and therefore we were not able to correlate the extent of resection with the

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endocrinological outcome. CONCLUSION

Hypothalamic pituitary adrenal axis insufficiency can follow endoscopic transsphenoidal

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resection of a pituitary tumor. Male gender, age greater than 50 years, visual impairment and

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CSF leak correlated with development of late postoperative adrenal insufficiency but not with early AI. Neither tumor size nor tumor hormonal function was significantly associated with either early or late adrenal insufficiency. More than two-thirds of patients who developed early adrenal insufficiency did not require long term steroid replacement. Acknowledgments: None Disclosure of funding: None

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Figure 1. The incidence of early and late adrenal insufficiency

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ACCEPTED MANUSCRIPT Table 1. Demographic, surgical characteristics, and adrenal function outcome of the study population 107

Number of surgeries

111

Median age, years (range)

50 (18–89)

Sex, M (%)


47 (42.3)

Sex, F (%)

64 (57.6)

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Number of patients

83 (74.7)

Microadenoma

28 (25.3)

Tumor type # (%)

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Macroadenoma

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Tumor size # (%)

62 (55.8%)

Prolactinoma

24 (21.6)

TSH-secreting adenoma Previous surgery # (%)

No

2 (1.8)

4 (4%)

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Yes

23 (20.7)

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GH-secreting adenoma

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Nonfunctional adenoma

103 (96%)

Timing of adrenal insufficiency # (%) Early * Late *

61 (55%) 16 (14.4%)

Abbreviations: GH: Growth hormone, TSH: Thyroid-stimulating hormone, M: Male, F: Female *Early adrenal insufficiency is considered if the diagnosis is made during the first two weeks following surgery, whereas late adrenal insufficiency is considered in those who continue to have glucocorticoid replacement or develop new adrenal insufficiency at late follow-up.

ACCEPTED MANUSCRIPT Table 2. Predictive factors of early or late postoperative adrenal insufficiency New steroids at Discharge no (N=50)

yes (N=61)

p-value

no (N=95)

yes (N=16)

p-value

Age (mean ±SD)

49±15

49±16

0.84

48±15

58±16

0.018

Gender (female)

26 (52%)

38 (62%)

0.28

61 (64%)

3 (19%)

0.001

Vision affected

12 (24%)

25 (41%)

0.059

28 (30%)

9 (56%)

0.036

Size (Macro vs.

37 (74%)

46 (75%)

0.865

68 (72%)

15 (94%)

0.059

12 (24%)

25 (41%)

0.059

27 (28%)

10 (63%)

0.007

48 (51%)

13 (81%)

0.022

19 (20%)

4 (25%)

Microadenoma) CSF leak

SC

New steroids at DC Hormone secretion 14 (28%)

9 (15%)

Prolactin (n=24)

10 (20%)

14 (23%)

0 (0%)

2 (3%)

Non-functional (n=62)

26 (52%)

36 (59%)

Functional (n=49)

24 (48%)

25 (41%)

TSH (n=2)

M AN U

GH (n=23)

RI PT

Factor

Steroids on Follow-up

0.25

0.46

24 (25%)

0 (0%)

2 (2%)

0 (0%)

50 (53%)

12 (75%)

45 (47%)

4 (25%)

0.079

0.096

AC C

EP

TE D

Abbreviations: GH: Growth hormone, CSF: Cerebrospinal fluid, DC: Discharge, TSH: Thyroid stimulating hormone

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT -

Of 111 endoscopic transsphenoidal surgery for pituitary adenoma, 61 (55%) had early adrenal insufficiency (AI). Of the 61 patients, 48 patients (79%) were off steroids in long-term follow-up and only 13 (21%) required long-term replacement. 16/111 (14.4%) had AI on long-term follow-up. Out of these 16 patients, 13 were already on steroids and 3 were newly diagnosed with AI.

-

Male gender, age greater than 50 years, visual impairment and intraoperative CSF leak were correlated with late postoperative AI.

SC

More than two-thirds of patients who developed early AI did not require steroids

EP

TE D

M AN U

long-term.

AC C

-

RI PT

-

ACCEPTED MANUSCRIPT

Abbreviations and Acronyms: AI: Adrenal insufficiency, CSF: Cerebrospinal fluid, DI: Diabetes insipidus, FSH: Follicle-

RI PT

stimulating hormone, GCs: Glucocorticoids, GH: Growth hormone, HPA: Hypothalamic– pituitary–adrenal, IGF-1: Insulin-like growth factor-1, ITT: Insulin tolerance test, LH: luteinizing

AC C

EP

TE D

M AN U

SC

hormone, TSH: Thyroid stimulating hormone, TSS: Transsphenoidal surgery