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No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The estimated prevalence of pituitary lesions is 10% to 38.5% in radiologic studies. However, how frequently these incidental lesions should be monitored by serial pituitary magnetic resonance imaging (MRI) remains unclear., Objective: To evaluate changes in pituitary microadenomas over time., Design: Retrospective, longitudinal cohort study., Setting: Mass General Brigham, Boston, Massachusetts., Patients: Evidence of pituitary microadenoma from MRI., Measurements: Dimensions of pituitary microadenomas., Results: During the study period (from 2003 to 2021), 414 patients with pituitary microadenomas were identified. Of the 177 patients who had more than 1 MRI, 78 had no change in the size of the microadenoma over time, 49 had an increase in size, 34 had a decrease in size, and 16 had both an increase and decrease in size. By linear mixed model analysis, the estimated slope was 0.016 mm/y (95% CI, -0.037 to 0.069). In the subgroup analysis, pituitary adenomas with a baseline size of 4 mm or less tended to increase in size. The estimated slope was 0.09 mm/y (CI, 0.020 to 0.161). In contrast, in the subgroup with baseline tumor size greater than 4 mm, the size tended to decrease. The estimated slope was -0.063 mm/y (CI, -0.141 to 0.015)., Limitation: Retrospective cohort, some patients were lost to follow-up for unknown reasons, and data were limited to local large institutions., Conclusion: During the study period, approximately two thirds of the microadenomas remained unchanged or decreased in size. The growth, if any, was slow. These findings suggest that less frequent pituitary MRI surveillance for patients with incidental pituitary microadenomas may be safe., Primary Funding Source: None.

All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: No prospective epidemiologic studies have examined associations between use of oral contraceptives (OCs) or menopausal hormone therapy (MHT) and risk of pituitary adenoma in women., Objective: Our aim was to determine the association between use of OC and MHT and risk of pituitary adenoma in two separate datasets., Methods: We evaluated the association of OC/MHT with risk of pituitary adenoma in the Nurses' Health Study and Nurses' Health Study II by computing multivariable-adjusted hazard ratios (MVHR) of pituitary adenoma by OC/MHT use using Cox proportional hazards models. Simultaneously, we carried out a matched case-control study using an institutional data repository to compute multivariable-adjusted odds ratios (MVOR) of pituitary adenoma by OC/MHT use., Results: In the cohort analysis, during 6 668 019 person-years, 331 participants reported a diagnosis of pituitary adenoma. Compared to never-users, neither past (MVHR = 1.05; 95% CI, 0.80-1.36) nor current OC use (MVHR = 0.72; 95% CI, 0.40-1.32) was associated with risk. For MHT, compared to never-users, both past (MVHR = 2.00; 95% CI, 1.50-2.68) and current use (MVHR = 1.80; 95% CI, 1.27-2.55) were associated with pituitary adenoma risk, as was longer duration (MVHR = 2.06; 95% CI, 1.42-2.99 comparing more than 5 years of use to never, P trend = .002). Results were similar in lagged analyses, when stratified by body mass index, and among those with recent health care use. In the case-control analysis, we included 5469 cases. Risk of pituitary adenoma was increased with ever use of MHT (MVOR = 1.57; 95% CI, 1.35-1.83) and OC (MVOR = 1.27; 95% CI, 1.14-1.42) compared to never., Conclusion: Compared to never use, current and past MHT use and longer duration of MHT use were positively associated with higher risk of pituitary adenoma in 2 independent data sets. OC use was not associated with risk in the prospective cohort analysis and was associated with only mildly increased risk in the case-control analysis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: No studies have examined the association between body habitus and incidence of pituitary adenoma., Objective: To determine if body mass index (BMI), waist circumference, body somatotype, or height are associated with risk of pituitary adenoma., Design: Pooled analysis of 3 prospective cohort studies., Setting: Population-based study., Participants: Participants of the Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), and the Health Professionals Follow-Up Study (HPFS), totaling 284 946 American health professionals., Exposures: BMI, waist circumference, body somatotype, and height., Outcome Measures: Self-reported incident pituitary adenoma. Multivariable (MV)-adjusted hazard ratios (HRs) of pituitary adenoma were estimated using Cox proportional hazards models., Results: During 7 350 156 person-years of follow-up, 387 incident pituitary adenomas were reported. Comparing BMI of ≥30 to <25 kg/m2, higher adult BMI was associated with higher risk of pituitary adenoma (MV HR = 1.74; 95% CI, 1.33-2.28), as was higher maximum adult BMI (MV HR = 1.76; 95% CI, 1.34-2.30), higher waist circumference (MV HR = 1.06; 95% CI, 1.04-1.09 per inch), and higher BMI during early adulthood (at age 18 to 21, MV HR = 2.65; 95% CI, 1.56-4.49). Taller adult height was associated with pituitary adenoma (MV HR = 1.05; 95% CI, 1.01-1.09 per inch). Overall findings were similar in women and men, although power was limited in men (n = 62 cases). Sensitivity analyses demonstrated that the association between adult BMI and pituitary adenoma extended to at least 14 years prior to diagnosis and that the results were not affected when analyses were restricted to participants with similar healthcare utilization., Conclusion: Higher BMI and waist circumference, from early adulthood to the time of diagnosis, were associated with higher risk of pituitary adenoma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified a number of genetic determinants of pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether pituitary tumors could be stratified based on objective molecular characteristics using a clinical genomics assay. We performed a retrospective analysis of patients operated on at the Brigham and Women's Hospital from 2012 to 2016 whose pituitary tumors were profiled using multiplexed next-generation sequencing. We analyzed 127 pituitary tumors, including 114 adenomas, 5 craniopharyngiomas, and 8 tumors of other histologies. We observed recurrent BRAFV600E mutations in papillary craniopharyngiomas, CTNNB1 mutations in adamantinomatous craniopharyngiomas, and activating GNAS mutations in growth hormone-secreting adenomas. Furthermore, we validated the presence of two distinct genomic subclasses in adenomas (i.e., those with disrupted or quiet copy-number profiles) and the significant association of disruption with functional hormone status (P < 0.05). We report the clinical implementation of next-generation sequencing of pituitary tumors. We confirmed previously identified molecular subclasses for these tumors and show that routine screening as part of clinical practice is both feasible and informative. This large-scale proof-of-principle study may help to guide future institutional efforts for pituitary tumor classification as well as the incorporation of such techniques into prospective analysis as part of clinical trials., (Copyright © 2017 Endocrine Society.)

Background: Functional gonadotroph adenomas (FGAs) are rare tumors of the pituitary gland that secrete biologically active gonadotropins., Objective: To advance clinical understanding of FGAs., Methods: We performed a retrospective review of adult patients who underwent resection of a pituitary lesion between August 1997 and October 2014 and remain under care at our center. We identified patients who had pathologic and biochemical confirmation of FGAs, as defined by a lack of serum follicle-stimulating hormone/luteinizing hormone suppression in the setting of elevated gonadal steroids, associated clinical symptoms, or both., Results: FGAs were documented in 7 patients (5 men, 2 women) over a 17-year period. Clinical findings at presentation included visual field deficits in 5 patients, headache in 3, sexual dysfunction in 3, and ovarian cysts in both women. Each patient underwent lesion resection (6 via the endonasal transsphenoidal approach and 1 via a craniotomy with transsphenoidal reoperation). Analysis of tumor samples revealed immunopositivity for follicle-stimulating hormone/luteinizing hormone in 5 patients and FSH only in 2 patients. Postoperative follow-up (median, 10 months; range, 4-213 months) indicated remission in 6 of 7 patients., Conclusion: An FGA can pose both a diagnostic and a therapeutic challenge. The tumor is often diagnosed as a nonfunctioning macroadenoma after presenting with nonspecific symptoms and is the cause of significant morbidity. An FGA should be considered in the differential diagnosis of patients harboring pituitary adenomas with reproductive dysfunction. Transsphenoidal resection is the initial treatment of choice and can reduce endocrine dysfunction, resolve headaches, improve visual impairment, and provide tissue for detailed analysis., Abbreviations: FGA, functional gonadotroph adenomaFSH, follicle-stimulating hormoneLH, luteinizing hormoneTSH, thyroid-stimulating hormone.

Purpose: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas., Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry., Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes., Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.

Context: Several studies have reported an association between idiopathic intracranial hypertension (IIH) and deficits of the hypothalamic-pituitary-adrenal (HPA) axis., Case Illustration: A 33-yr-old woman with Cushing's disease underwent successful surgical resection of a pituitary adenoma and developed IIH 11 months later after inadvertent withdrawal of oral glucocorticoids., Methods: A review of the literature was conducted to identify previous studies pertaining to IIH in association with neuroendocrine disease, focusing on reports related to HPA axis dysfunction., Results: A number of patients developing IIH due to a relative deficiency in glucocorticoids, after surgical or medical management for Cushing's disease, withdrawal from glucocorticoid replacement, or as an initial presentation of Addison's disease, have been reported. Hypotheses regarding the underlying pathophysiology of IIH in this context and, in particular, the role of cortisol and its relationship to other neuroendocrine and inflammatory mediators that may regulate the homeostasis of cerebrospinal fluid production and absorption are reviewed., Conclusion: In a subset of patients, dysfunction of the HPA axis appears to play a role in the development of IIH. Hormonal control of cerebrospinal fluid production and absorption may be regulated by inflammatory mediators and the enzyme 11ß-hydroxysteroid dehydrogenase type 1. Further study of neuroendocrine markers in the serum and cerebrospinal fluid may be an avenue for further research in IIH.

GH-secreting pituitary adenomas can cause gigantism or acromegaly, determined by onset before or after epiphyseal fusion of the distal ends of the radius and ulna. Overlapping phenotypes can occur when the condition presents peripubertally. Gigantism is associated with identifiable hereditary causes and genetic mutations in almost 50% of cases; genetic testing should be considered in patients with gigantism and early-onset acromegaly, especially (but not only) when pituitary tumors have aggressive features and/or are refractory to standard treatments. Here, we present a case of a young adult with a giant somatotroph adenoma resistant to multiple treatment modalities and negative for mutations in AIP , which encodes aryl hydrocarbon receptor-interacting protein. [ABSTRACT FROM AUTHOR]

Context: Recurrence of Cushing disease (CD) can occur even decades after surgery. Biomarkers to predict recurrence of CD after surgery have been studied but are inconclusive.Objective: The aim of our study was to identify specific biomarkers that can predict long-term remission after neurosurgery.Design: Identification of specific biomarkers to predict long-term remission of CD was performed by logistic regression analysis followed by Kaplan-Meier survival analysis, using recurrence as the dependent variable.Setting: A total of 260 patients with CD identified from our institutional research patient data registry search tool and from patients who presented to our longitudinal multidisciplinary clinic between May 2008 and May 2018 underwent statistical analysis.Interventions: Data on clinical features, neuro-imaging study, pathology, biochemistry, and treatments were collected by reviewing digital chart records.Main Outcome Measure: Postoperative cortisol as a biomarker to predict long-term remission after surgical treatment for CD.Results: By logistic regression analysis, postoperative day 1 (POD1) morning (5-10 am) serum cortisol, female sex, and proliferative index had significant association with CD recurrence (odds ratio [OR] = 1.025, 95% CI: 1.002-1.048, P = .032). In contrast, the postoperative nadir cortisol (OR = 1.081, 95% CI: 0.989-1.181, P = .086), urinary free cortisol (OR = 1.032, 95% CI: 0.994-1.07, P = .098), and late night salivary cortisol (OR = 1.383, 95% CI: 0.841-2.274, P = .201) had no significant correlation with recurrence. A significant association between POD1 morning serum cortisol and long-term CD remission was verified by Kaplan-Meier analysis when using POD1 morning serum cortisol <5 μg/dL as the cut-off.Conclusions: The POD1 morning serum cortisol level has a significant association with CD recurrence. [ABSTRACT FROM AUTHOR]