Guidelines on the Management of Patients with Nonfunctioning Pituitary Adenomas
3. Pretreatment Endocrine Evaluation
Congress of Neurological Surgeons (CNS) and the Section on Tumors
Joint Guidelines Committee of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS)
Maria Fleseriu, MD1, Mary E. Bodach, MLIS2, Luis M. Tumialan MD3, Vivien Bonert, MD4, Nelson M. Oyesiku, MD, PhD5, Chirag G. Patil, MD6, Zachary Litvack, MD7, Manish K. Aghi, MD, PhD8*, Gabriel Zada, MD9*
1Departments of Medicine and Neurological Surgery, OHSU Northwest Pituitary Center, Oregon Health Science University, Portland, Oregon, USA
2Guidelines Department, Congress of Neurological Surgeons, Schaumburg, Illinois, USA
3Barrow Neurological Institute, Phoenix, Arizona, USA
4Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
5Department of Neurosurgery, Emory University, Atlanta, Georgia, USA
6Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
7Department of Neurosurgery, George Washington University, Washington, DC, USA
8Department of Neurosurgery, University of California, San Francisco, San Francisco, California, USA
9Department of Neurosurgery, University of Southern California, Los Angeles, California, USA
* These authors contributed equally to this work.
Gabriel Zada, MD
Department of Neurosurgery
University of Southern California
1200 N State St, Suite 3300
Los Angeles, CA 90033
Background: Nonfunctioning pituitary adenomas (NFPAs) are among the most common pituitary lesions and may present with hypopituitarism and/or hyperprolactinemia. The authors reviewed the existing literature as it pertains to preoperative endocrine assessment in the work-up for NFPAs.
Objective: To review the existing literature as it pertains to preoperative endocrine assessment in the workup for NFPAs.
Methods: A systematic review methodology was utilized to identify and screen articles assessing the role and results of preoperative laboratory assessment in patients with NFPAs. The prevalence of individual pituitary hormonal axis deficiencies was reviewed.
Results: Twenty-nine studies met inclusion criteria for analysis. No Class I evidence was available, and all studies met criteria for Class II evidence. Baseline serum laboratory assessment showed a prevalence of overall hypopituitarism in 37% to 85% of patients. The most common hormonal axis deficiency was growth hormone deficiency, prevalent in 61% to100% of patients. The next most common deficit was hypogonadism, seen in 36% to 95% of patients. Adrenal insufficiency was diagnosed in 17% to 62% of patients. Finally, hypothyroidism was seen in 8% to 81% of patients. Hyperprolactinemia was seen in 25% to 65% of patients, with a mean level of 39 ng/mL and with a minority of patients exceeding a serum prolactin level of 200 ng/mL. No evidence supporting routine biomarker testing (eg, alpha-subunit or chromogranin A) or genetic testing in patients with sporadic NFPAs was available.
Conclusion: Despite a paucity of Class I evidence, multiple retrospective studies have demonstrated a high prevalence of hypopituitarism in patients with NFPAs. Routine endocrine analysis of all anterior pituitary axes to assess for hypopituitarism is recommended, with prolactin and IGF-1 evaluation also valuable to assess for hypersecretion states that might not be clinically suspected.
Which endocrine axes should be checked preoperatively in NFPA patients?
These recommendations apply to adult patients with recurrent or residual nonfunctioning pituitary adenomas (NFPAs).
Level II Recommendations
- Routine endocrine evaluation of all anterior pituitary axes to assess for hypopituitarism is recommended because, beyond revealing a significant rate of deficits beyond the level of clinical suspicion for all pituitary axes, the cutoff values to initiate thyroid and adrenal replacement might be different in a patient with panhypopituitarism versus isolated deficiencies.
- Routine prolactin testing is recommended in all patients with suspected NFPA to rule out hypersecretion that might not be clinically suspected.
Level III Recommendations
- Routine insulin-like growth factor 1 (IGF-1) evaluation is recommended in all patients with suspected NFPA to rule out growth hormone (GH) hypersecretion that might not be clinically suspected.
What is the role for preoperative hormone replacement in NFPA patients?
These recommendations apply to adult patients with recurrent or residual nonfunctioning pituitary adenomas (NFPAs).
Level II Recommendation
• Replacement for adrenal insufficiency and significant hypothyroidism is recommended in all patients preoperatively.
Nonfunctioning pituitary adenomas (NFPAs) are among the most common pituitary adenomas and are defined by a lack of any functional hormonal products. They are often diagnosed because they cause local compression of the pituitary gland and optic chiasm, and may present clinically with signs and symptoms of hypopituitarism, visual loss, and headaches, among others. Many NFPAs are also diagnosed incidentally on CT or MR studies. The aim of this systematic review and evidence-based guideline is to highlight any prior studies assessing preoperative laboratory evaluation in patients with NFPAs. Although NFPAs are partially defined by a paucity of hormonal oversecretion (with the exception of hyperprolactinemia caused by the pituitary stalk effect), we aimed to review any pertinent results relating to the role of laboratory values, including a workup for hypopituitarism, assessment of hyperprolactinemia, and other diagnostic lab or genetic evaluations that have been assessed in NFPAs in prior research studies.
The medical literature was searched systematically to identify articles focusing on the role of the preoperative laboratory evaluation in NFPAs. Abstracts from the results of these searches were screened by multiple reviewers, and full-text articles from potentially significant articles were secondarily reviewed for application of inclusion and exclusion criteria. Outcomes studied included the particular laboratory value and results for the detection of each particular endocrinopathy.
The evidence-based Clinical Practice Guideline Task Force members and the Tumor Section of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons conducted a systematic review of the literature relevant to the management of nonfunctioning pituitary adenomas (NFPAs). Additional details of the systematic review and the methods the group used to create it are provided below and within the introduction and methodology chapter of the guideline.
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. The presentations are 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 its 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 physician should be sought. The recommendations contained in this guideline may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in this guideline must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.
Potential Conflicts of Interest
All NFPA 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 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.
The guideline task force members collaborated with a medical librarian to search for articles published from January 1, 1966, to October 1, 2014. Two electronic databases were searched, PubMed and The Cochrane Central Register of Controlled Trials. Strategies for searching electronic databases were constructed by the guideline taskforce members and the medical librarian using previously published search strategies to identify relevant studies (Appendix A).1-8
Twenty-nine articles met the criteria for inclusion and were included as evidence to support the conclusions in this chapter (Table 1). A flow chart summarizing study selection can be found in Figure 1. No Class I evidence was available to support the role of specific diagnostic laboratory evaluation in the work-up and diagnosis of NFPAs. Several Class II studies were identified to support the role of specific laboratory tests in the work-up of NFPAs.
Laboratory Assessment of Serum Prolactin in Patients with NFPAs
In the work-up of patients with pituitary adenomas, the serum prolactin level is perhaps the most important laboratory level that dictates a given patient’s treatment course. The ability to distinguish between a prolactinoma (for which medical therapy represents first-line therapy in most patients) and an NFPA with hyperprolactinemia caused by the pituitary stalk effect (a surgically treated disease for most patients) is a critical one and depends on the size of the tumor and the level of clinical suspicion. According to our systematic literature review, no Class I evidence was available to support a given threshold of serum prolactin that can be used to distinguish these 2 subtypes of pituitary adenomas. However, multiple retrospective and several prospective studies reported their findings pertaining to laboratory assessment of serum prolactin in NFPA patients. Results from these studies indicate that the incidence of hyperprolactinemia in patients with histologically verified NFPAs is 25%-65% (1848 patients)9-18 (Table 2).
In a large study involving 721 patients with NFPAs by Nomikos et al, preoperative hyperprolactinemia was noted in 25.3% of patients.16 Behan et al performed a retrospective analysis in 250 patients with NFPAs, reporting baseline hyperprolactinemia in 44.8% of patients.10 Karavitaki et al published their findings from a retrospective analysis of 226 patients with NFPAs.15 The authors found hyperprolactinemia in 38.5% of patients. The median prolactin level in the entire group was 18 ng/mL (range 0.8-73.6 ng/mL). A serum prolactin level of <94.3 ng/mL was seen in 98.7% of patients. Of the 3 subjects with a serum prolactin >94.3 ng/mL, 2 were on estrogen treatment. The authors concluded that patients with a prolactin >94.3 ng/mL almost never have NFPAs.15 In a study by Fatemi et al involving 223 patients with NFPAs, the prevalence of hyperprolactinemia caused by pituitary stalk effect was 54%.14
Comtois et al studied serum prolactin levels in 126 patients with NFPAs and identified baseline hyperprolactinemia in 65% of patients, with a mean level of 39 ng/mL.11 In a retrospective analysis of 104 patients with NFPAs by Cury et al, the prevalence of preoperative hyperprolactinemia was 38.5%.12 In a study by Drange et al involving 99 NFPA patients, 47% were found to have laboratory evidence of hyperprolactinemia.13 Tjeerdsma et al studied baseline endocrine function in 40 patients with NFPAs and reported baseline hyperprolactinemia in 50% of patients.17 In their study, hyperprolactinemia was associated with additional anterior pituitary axis deficiencies. In another study by Tominaga et al involving 33 NFPA patients, baseline hyperprolactinemia was evident in 42% of patients.18 Arafah et al reported results from a prospective study involving 26 patients with NFPAs and noted that mild hyperprolactinemia (PRL of 29-53 ng/mL) was seen in 46% of patients.9
In another large retrospective study by Gsponer et al19, the authors sought to determine a threshold of prolactin that could reliably differentiate between NFPAs and prolactinomas. They found that a basal prolactin level above 85 ng/mL in the absence of renal failure or any prolactin-enhancing drugs, and a prolactin increment less than 30% following thyrotropin-releasing hormone (TRH), reliably ruled out pituitary stalk effect from an NFPA.
In 2010, Hong et al published results from a retrospective analysis in 117 patients with prolactinomas as well as NFPAs.20 NFPAs were associated with older age, extrasellar extension, and a prolactin level <100 ng/mL, while prolactin levels above 250 ng/mL were exclusively associated with prolactinomas and never represented stalk effect from NFPAs, a more stringent cutoff than used in the studies above and felt to represent a diagnostic criteria for prolactinoma with acceptably low false positive rates. Furthermore, GH deficiency was more common in patients with NFPAs than those with prolactinomas. The authors concluded that preoperative serum prolactin levels <100 ng/mL and the presence of a hypofunctioning GH axis were predictive of NFPAs.
Endocrine Axis Testing and the Prevalence of Hypopituitarism
Multiple retrospective studies and a handful of prospective observational studies have assessed baseline function of multiple anterior pituitary axes in patients with NFPAs. The overall prevalence of partial hypopituitarism in patients with NFPAs ranged from 37%-85%13,14,16,21-23 (1240 patients) (Table 3). On the other hand, panhypopituitarism was much less frequent and was evident in 6%-29% of patients.24,25 Of the involved endocrine axes, the most commonly affected pituitary axis was the growth hormone (GH) axis, with 61%-100% of patients showing laboratory evidence of GH deficiency9,12,17,25-28 (903 patients) (Table 4). Central hypogonadism was the next most commonly affected axis and was noted in 36%-96% of patients9,11-13,16,17,24-26,28-30 (1911 patients) (Table 5). Adrenal insufficiency was the following most commonly involved axis, noted in 17%-62% of patients9,11,12,16,24,25,27-30 (1486 patients) (Table 6). Finally, 8%-81% of 1911 assessed patients in these studies9,11,12,16,17,24-30 (Table 7) exhibited central hypothyroidism. Central hypothyroidism is defined as inappropriately low serum TSH in the presence of low-normal serum T4 and T3 concentrations. Central hypothyroidism is typically confirmed by the thyrotropin releasing hormone stimulation test, in which serum TSH is measured serially post-TRH at 20 and 60 minutes, with a normal response defined as the 20-minute TSH value being higher than the 60-minute TSH value. A flat response is seen in pituitary disease, and delayed response, with the 60-minute value higher than the 20-minute value, is seen in hypothalamic disease. Diabetes insipidus was a very uncommon finding, reported to occur in 7% of patients with NFPAs at the time of clinical presentation.28
In the largest observational study included, Nomikos et al16 reported on 721 patients with NFPAs who had full preoperative endocrine data available. Of these patients, over 85% had evidence of preoperative hypopituitarism. Patients had evidence of secondary adrenal insufficiency (31%), hypogonadism (76.6%), and hypothyroidism (19.1%). In another large prospective observational study by Chen et al,26 baseline hypopituitarism was analyzed in 385 patients with NFPAs. Baseline hypothyroidism was noted in 35.8% of patients, hypogonadism in 41%, hypoprolactinemia in 17.9%, and GH deficiency in 61%. In 2008, Fatemi et al reported results from a retrospective analysis of 223 patients with NFPAs who underwent transsphenoidal surgical resection.14 Preoperative hormonal dysfunction was diagnosed in 194 patients (84%). In a retrospective analysis including 155 patients with NFPAs, Wichers-Rother et al determined baseline GH deficiency in 85% of patients, hypogonadism in 55% of patients, hypothyroidism in 30% of patients, and adrenal insufficiency in 31% of patients.27
In another retrospective study looking at baseline hypopituitarism in 126 patients with NFPAs by Comtois et al,11 hypogonadism was seen in 75% of patients, adrenal insufficiency in 36%, and hypothyroidism in 18%. A retrospective study by Berkmann et al included 114 patients with NFPAs.21 The authors reported preoperative hypopituitarism in 83 patients (72.8%). Dekkers et al published a retrospective analysis of 109 consecutive patients with NFPAs.25 They reported GH deficiency in 77% of patients, hypogonadism in 75%, adrenal insufficiency in 53%, hypothyroidism in 43%, and panhypopituitarism in 29% of patients. Cury et al systematically studied preoperative endocrine levels in 104 patients with NFPAs.12 They found GH deficiency in 81.4% of patients, hypogonadism in 63.3%, adrenal hypofunction in 59.5%, and hypothyroidism in 20.4%. Ebersold et al reported results following retrospective analysis of 100 patients with NFPAs and examined baseline endocrine function.29 They reported hypogonadism in 36% of patients, hypothyroidism in 32% of patients, and adrenal insufficiency in 17% of patients. Similarly, in a large retrospective registration study by Drange et al including 99 patients with NFPAs,13 hypopituitarism was evident in 44% of patients, with the gonadal axis affected in 93% of these patients. Colao et al published their findings in 84 patients with NFPAs who were assessed retrospectively.28 They reported baseline GH deficiency in 65% of patients, hypogonadism in 56%, hypoadrenalism in 23%, hypothyroidism in 8%, and diabetes insipidus in 7% of patients. Webb et al published their findings from a retrospective study including 56 NFPAs. Of these patients, 52% had some element of preoperative hypopituitarism.22 Tjeerdsma et al reported baseline endocrine function in 40 patients with NFPAs.17 They reported a prevalence of GH deficiency in 865 of patients, hypogonadism in 66.5%, and hypothyroidism in 67% of NFPA patients. In a smaller retrospective study by Marazuela et al,24,35 patients with NFPAs were analyzed for preoperative pituitary dysfunction. The authors reported baseline hypogonadism in 69% of patients, adrenal insufficiency in 20%, hypothyroidism in 23%, and panhypopituitarism in 6% of patients.
In a retrospective study published in 2007, Del Monte et al reported results from routine preoperative laboratory assessment in 27 patients with NFPAs.23 They identified global anterior hypopituitarism in 33% of patients and partial hypopituitarism in 37% of patients. Greenman et al studied baseline hormonal function in 26 patients with NFPAs.30 The authors reported baseline hypogonadism in 78% of patients, adrenal insufficiency in 43%, and hypothyroidism in 23% of patients. In a prospective study by Arafah et al that examined preoperative serum endocrine function in 26 patients with NFPAs, the authors reported GH deficiency in 100% of patients, hypogonadism in 96% of patients, hypothyroidism in 81% of patients, and adrenal insufficiency in 62% of patients.9
A study by Vierhapper et al in 1998 assessed the extent of growth hormone deficiency in 33 patients with NFPAs and evidence of hypopituitarism in at least 1 other hormonal axis.31 Following GHRH-stimulation testing, patients with NFPAs had lower levels of GH than control subjects. The authors concluded that although GH stimulation tests are superior to other biochemical tests for GH deficiency, they are still an inadequate method to reliably diagnose GH deficiency in an individual patient and should be considered only in patients with other types of hypopituitarism exhibiting symptoms of GH deficiency.31 In a prospective study by Beentjes et al,32,34 patients with NFPAs were prospectively evaluated with a peak GH to insulin tolerance test (ITT) and GHRH in relation to prolactin levels. In patients with hyperprolactinemia, an insufficient GH peak was demonstrated via ITT in 16 patients (47%) and GHRH stimulation in 7 patients (21%). Peak GH to ITT was lower in 24 patients with other hormonal axis deficiencies. The authors concluded that ITT and GHRH tests cannot be used interchangeably in diagnosing GH deficiency in patients with NFPAs.32
Assessment of Other Hormonal Oversecretion and Endocrine Biomarkers in NFPAs
A retrospective observational study of transsphenoidal pituitary surgery included 37 patients with NFPAs.33 Of these patients, 19 (45.9%) showed subsequent positivity for GH immunostaining despite a lack of clinical suspicion for acromegaly. Three of these patients (8.1%) had slightly elevated IGF-1 levels. This led the authors to conclude that preoperative laboratory assessment for NFPAs should include an IGF-1 level.
Laboratory assessment of gonadotropes and the alpha-subunit have also been made in patients with NFPAs, both at baseline and following TRH administration, recognizing that this process is different between men and women, between pre- and postmenopausal women, and between women have had a hysterectomy. Although many NFPAs exhibit positive immunochemistry for LH and/or FSH (over 90% in some series),34 only a minority (<10%) show actual evidence of hypergonadism. Popovic et al assessed the in vivo responses of LH, FSH, and alpha-subunit to TRH in 23 patients with NFPAs.34 They found that a bolus dose of TRH increased levels of FSH, LH, or alpha-subunit in 23 of 24 patients with NFPAs. In a similar study by Chanson et al,26,35 patients with NFPAs underwent LH-beta measurement following TRH stimulation. LH-beta hypersecretion was detected in 7 of 26 patients (26%), with concomitant elevations of FSH and/or alpha-subunit in an additional 3 patients. The authors concluded that assessment of LH-beta following TRH stimulation is rarely helpful for determining the gonadotropic nature of NFPAs.35 In another retrospective analysis in which TRH and LHRH was administered for provocative testing in the baseline setting,18 Tominaga et al showed GH deficiency in 97% of patients, LH deficiency in 52%, hypoadrenalism in 48%, FSH deficiency in 42%, hypothyroidism in 19%, and hypoprolactinemia in 6.5% of patients.
Although not widely used, chromogranin A (CGA) has also been assessed as a potential biomarker for NFPAs. In a prospective case-control study by Gussi et al,36 3 of 27 patients with NFPAs had elevations of serum CGA at 576, 143, and 241 ng/mL, respectively. As the authors acknowledge, the low prevalence of CGA elevations in the NFPA population makes its utility as a sensitive biomarker less reliable.
Genetic Testing in Patients with NFPAs
In 2012, Cazabat et al published their results from a prospective single-center observational study in which 113 patients with presumed sporadic NFPAs underwent genetic screening for germline mutations in the AIP gene.37 Of the 113 patients, only 1 patient (0.9%) had evidence of an AIP mutation.
A systematic literature review of studies performing baseline assessments of endocrine function in patients with NFPAs identified 29 research articles that evaluated the entire spectrum of anterior pituitary function. Although no Class I evidence was available, sufficient Class II evidence exists to support routine endocrine analysis of anterior pituitary hormones in patients with suspected NFPAs. The overall prevalence of hypopituitarism was 37%-85%, with deficiency in the GH axis being the most frequent hormonal axis deficiency, with a prevalence of 61-100%. The next most common finding was hypogonadism, which was prevalent in 36%-95% of NFPA patients. Adrenal insufficiency was identified in 17%-62% of patients, followed by hypothyroidism in 8%-81% of patients. Clinical evidence of hyperprolactinemia thought to be secondary to pituitary stalk effect was prevalent in 25%-65% of patients. Taken together, there is sufficient data to suggest routine endocrine axis testing of all anterior pituitary hormones in patients with newly diagnosed pituitary adenomas and clinical suspicion of NFPAs.
Although the prevalence of the overall and individual endocrine axis deficiency is apparent from the compiled data, no evidence-based recommendations can be provided to support any particular methods of working up a particular hormonal axis deficiency beyond routine laboratory screening. A random prolactin value, diluted in patients with large tumors to eliminate possible hook effect, should be sufficient for diagnosis. Multiple tests (including low-dose Cortrosyn stimulation test, high-dose Cortrosyn stimulation test, or insulin tolerance test) for cortisol stimulation testing have been used to diagnose adrenal insufficiency in patients with NFPAs, with indications for these tests limited to use as follow-up tests in patients with a fasting morning serum cortisol suggesting that their basal cortisol level is low enough to warrant further evaluation for central adrenal insufficiency. However, due to study design and absence of comparative data, we cannot assess sensitivity and specificity of each test.
The biochemical evaluation of central hypothyroidism and central hypogonadism seems more straightforward in these studies, the large majority making the diagnosis using free T4 and TSH, respectively, estradiol or testosterone, and FSH and LH. Additional stimulation testing with TRH was shown to be of limited benefit in the workup of NFPA patients. The evaluation for GH deficiency has also been done by using different stimulation tests in function of availability of stimulation agents and/or timeline of each study.
The potential for suspected NFPAs to in actuality be functional tumors causing acromegaly or Cushing’s disease without apparent clinical manifestations is a reality. The study by Pawlikowski et al revealed an elevated IGF-1 in 8.1% of patients with presumed NFPAs and immunopositivity for GH in 45.9% of their series,33 calling these tumors “silent somatotropinomas.” No studies performing exhaustive work-ups for hypercortisolemia in patients with presumed NFPAs without clinical evidence of Cushing’s syndrome were identified; thus, biochemical routine evaluation to exclude the presence of hypercortisolemia in the absence of clinical suspicion cannot be recommended based on the available data at this time. Additionally, insufficient evidence was available to support the routine testing of any clinical biomarkers in patients with NFPAs, including the alpha-subunit and chromogranin A. Similarly, routine genetic testing in patients with NFPAs without any familial history was deemed to be low yield and is not routinely recommended.
Limitations and Future Research
The current study is limited by its systematic review methodology, which is inherently susceptible to various sources of bias, including publication, selection, and information bias. Similarly, the recommendations made are based on Class II or III evidence, without any prospective randomized controlled trial data available to truly compare efficacy of the treatment modalities in question. Recommendations for checking all pituitary axes preoperatively are based on the interactions between different hormonal axes that influence decisions about replacing thyroid and cortisol hormone,38 which come from the general literature on hypopituitarism rather than adenomas specifically. And recommendations for preoperative thyroid and cortisol hormone replacement arise from studies in which slow awakening from anesthesia was reported in patients with these deficiencies undergoing non-pituitary surgeries,39 as well as studies of perioperative stress dose steroids (intraoperative and postoperative) summarized in other articles in this set of guidelines as well as in guidelines from other societies,40 from which it is reasonable to conclude about the risks of not replacing these particular hormones but not something one could safely choose to investigate in adenoma patients specifically. Nevertheless, the results of this review highlight the existing evidence available to guide a focused endocrine workup in patients with newly diagnosed pituitary adenomas without clinical evidence of hormonal hypersecretion disorders such as Cushing’s disease and acromegaly.
Baseline laboratory analysis in patients with NFPAs is an important aspect of preoperative assessment and overall comprehensive care. The prevalence of overall hypopituitarism in patients with NFPAs is high, with GH deficiency and hypogonadism being the most commonly affected axes, followed by adrenal insufficiency and hypothyroidism. Routine endocrine axis testing of all anterior pituitary hormones in patients with newly diagnosed pituitary adenomas and clinical suspicion of NFPAs is recommended.
Assessment of baseline prolactin is imperative to rule out a prolactinoma, with hyperprolactinemia secondary to stalk effect occurring in 38.7% of NFPA patients. Assessment of preoperative IGF-1 Levels is also recommended to rule out acromegaly or clinically silent GH secreting tumors. No clinical evidence is available to support the measurement of any biomarkers pertaining to NFPAs, such as alpha-subunit or chromogranin A. There is also little evidence for now to support the role of routine genetic testing in patients with sporadic NFPAs.
Disclosure of Funding
These evidence-based clinical practice guidelines were funded exclusively by the CNS and the Tumor Section of the CNS and the AANS, which received no funding from outside commercial sources to support the development of this document.
The authors acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Committee for their review, comments, and suggestions throughout peer review, and Pamela Shaw, MSLIS, MS, for assistance with the literature searches. Also, the authors acknowledge the following individual peer reviewers for their contributions: Sepideh Amin-Hanjani, MD, Kathryn Holloway, MD, Odette Harris, MD, Brad Zacharia, MD, Daniel Hoh, MD, Isabelle Germano, MD, Martina Stippler, MD, Kimon Bekelis, MD, Christopher Winfree, MD and William Mack, MD. Lastly, and most significantly, the authors would like to acknowledge Edward Laws, MD, for serving as an advisor on this nonfunctioning adenoma guidelines project and providing comprehensive critical appraisal.
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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1. MeSH descriptor Pituitary Neoplasms
2. MeSH descriptor Adenoma
3. 1 and 2
4. ((pituitary OR hypophyse* OR sellar) NEAR/4 (microadenoma* OR adenoma* OR macroadenoma* OR incidentaloma* or chromophobe*)):ti,ab,kw
5. 3 or 4 and (asymptomatic* OR nonfunction* OR non-function* OR nonsecret* OR non-secret* OR inactive OR null OR inert OR silent)
1. (("Pituitary Neoplasms"[Majr] AND Adenoma[Mesh]) OR "Adenoma, Chromophobe"[Majr] OR "Sella Turcica"[Majr])
2. (microadenoma* OR adenoma* OR macroadenoma* OR incidentaloma* OR chromophobe*[Title/Abstract]) AND (pituitary OR hypophyse* OR sellar[Title/Abstract])
3. (1 OR 2) AND (asymptomatic* OR nonfunction* OR non-function* OR nonsecret* OR non-secret* OR inactive OR null OR inert OR silent)
4. 3 AND "Hyperpituitarism"[Mesh] OR "Hypopituitarism"[Mesh] OR ("stalk effect" OR "disconnection hyperprolactinemia")
5. 4 AND "Diagnostic techniques, endocrine"[Mesh] OR diagnosis[tiab] OR (endocrine AND (function OR functioning OR status))
6. NOT Comment[pt] NOT Letter[pt] Limits: English, Humans, publication date 1966 to 10/1/2014
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