Pituitary Metastasis as an Endocrine–Neuro-Ophthalmologic Emergency: Clinical Red Flags and Outcomes From a Contemporary Tertiary-Center Series

Pituitary Metastasis as an Endocrine–Neuro-Ophthalmologic Emergency: Clinical Red Flags and Outcomes From a Contemporary Tertiary-Center Series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pituitary Metastasis as an Endocrine–Neuro-Ophthalmologic Emergency: Clinical Red Flags and Outcomes From a Contemporary Tertiary-Center Series José Llumiquinga, Jacqueline Miyuki Viel, Matheo Augusto Morandi Stumpf, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9122936/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Purpose To characterize the clinical presentation, endocrine phenotype, and outcomes of pituitary metastasis in a contemporary tertiary-center cohort, with emphasis on clinically actionable diagnostic red flags. Methods We conducted a retrospective single-center case series of 14 consecutive patients diagnosed with pituitary metastasis between 2010 and 2025. Presenting manifestations, endocrine features, radiologic findings, primary tumor origin, treatment patterns, and overall survival were assessed. In patients without histopathologic confirmation, diagnosis was adjudicated using the validated clinicoradiologic model proposed by Yuzkan et al. Results Median age was 52.5 years, and 71.4% of patients were women. Hypopituitarism (64.3%), arginine vasopressin deficiency (50.0%), and visual impairment (50.0%) were frequent at presentation. One patient presented with sudden bilateral visual loss and hemodynamic instability, mimicking an apoplexy-like sellar emergency. Breast cancer was the most common primary tumor (28.6%). Serum prolactin levels, available in 11 patients, were uniformly below the range typically expected for macroprolactinoma despite large sellar masses. Histopathologic confirmation was obtained in 35.7% of cases, whereas the remainder fulfilled high-likelihood clinicoradiologic criteria. Median overall survival after pituitary metastasis diagnosis was 6.5 months, and 92.9% of patients died during follow-up. Conclusion Pituitary metastasis frequently presents with combined endocrine dysfunction and neuro-ophthalmologic compromise, occasionally as an acute sellar emergency. In oncologic patients with sellar lesions, the combination of AVP-D, visual deterioration, and non-prolactinoma-range hyperprolactinemia should raise suspicion for pituitary metastasis and prompt urgent endocrine and local evaluation. pituitary metastasis sellar lesion neuro-oncology arginine vasopressin deficiency Pituitary adenoma Pituitary carcinoma Pituitary neuroendocrine tumors Figures Figure 1 Figure 2 Introduction Pituitary metastases represent a rare but clinically consequential oncologic event, typically arising in the setting of advanced systemic malignancy [ 1 , 2 ]. Despite their rarity relative to pituitary adenomas, they carry disproportionate bedside relevance because they may precipitate rapid clinical decompensation [ 3 ]. A high-stakes presentation may involve convergent endocrine and neuro-ophthalmologic instability—including acute hypopituitarism, central arginine-vasopressin deficiency (AVP-D), and chiasmal or cranial nerve compression—sometimes resembling an apoplexy-like sellar emergency and requiring timely recognition and coordinated multidisciplinary decision-making [ 4 , 5 ]. However, guidance for day-to-day clinical management remains limited and largely experience-based. Population-level datasets provide important epidemiological context, but they seldom capture the bedside phenotype that drives urgent decisions—such as the tempo of visual decline, cranial neuropathies, and the severity of endocrine dysfunction. Conversely, published institutional series are necessarily small and heterogeneous in diagnostic confirmation and treatment approaches, which limits direct comparisons and the development of practical, clinically anchored frameworks. In this study, we aimed to characterize the clinically actionable presentation of pituitary metastasis in a contemporary tertiary-center cohort. We describe presenting manifestations, endocrine dysfunction, radiologic features, primary tumor origins, and outcomes, with particular emphasis on diagnostic clues that may sharpen bedside suspicion. We further anchor these cohort-level findings in two illustrative clinical vignettes selected because they capture two particularly consequential facets of pituitary metastasis in practice: an acute endocrine–neuro-ophthalmologic emergency that may mimic other sellar crises, and a biologically distinct metastatic presentation in which the significance of sellar involvement is shaped by the underlying primary tumor. Rather than presenting pituitary metastasis solely as a rare oncologic endpoint, we aim to frame it as a recognizable clinical syndrome in which endocrine dysfunction, neuro-ophthalmologic compromise, and cancer context intersect in ways that should directly influence diagnostic suspicion and multidisciplinary evaluation. Methods Study design and eligibility We conducted a retrospective, single-center case series of patients with pituitary metastasis. Patients were eligible if pituitary metastasis was diagnosed between 2010 and 2025 based on histopathology and/or radiologic and clinical criteria in the context of known systemic malignancy. Exclusion criteria were: (1) sellar/suprasellar lesions not consistent with metastatic disease (e.g., primary pituitary tumors or other non-metastatic sellar pathologies); (2) insufficient clinical, imaging, and/or pathology information to support the diagnosis; and (3) incomplete records precluding ascertainment of key presentation variables and/or survival outcomes. The diagnosis was confirmed by histopathology (n = 5) or considered as highly likely because of underlying advanced malignant disease, rapid progression of the sellar mass, and/ or imaging findings considered atypical for benign sellar lesions (n = 9). Data collection We extracted the following variables from medical records: demographics (age, sex), performance status (ECOG - Eastern Cooperative Oncology Group [ 6 ]) at pituitary metastasis diagnosis, primary tumor type, interval from primary tumor diagnosis to pituitary metastasis diagnosis, presenting symptoms (visual impairment, headache, cranial nerve deficits), endocrine dysfunction (hypopituitarism, AVP-D), evidence of other intracranial and systemic metastases, treatments (systemic therapy, radiotherapy, surgery/biopsy), survival after pituitary metastasis diagnosis, and outcome at last follow-up. Definitions Hypopituitarism evaluation . Hypopituitarism was defined by clinician-documented central hormone deficiencies and/or initiation of pituitary hormone replacement [ 7 , 8 ]. When laboratory data were available, deficiencies were adjudicated using standard endocrine criteria, prioritizing clinically actionable axes: central adrenal insufficiency (low morning serum cortisol in the appropriate clinical context and/or requirement for glucocorticoid replacement), central hypothyroidism (low free T4 with low/normal TSH), and central hypogonadism (low sex steroids with low/normal LH and FSH, interpreted in the clinical context) [ 7 ]. Because of the retrospective design and the advanced oncologic setting, endocrine testing, including dynamic stimulation tests, was not uniformly performed; therefore, ascertainment emphasized documented diagnoses, treatment decisions, and available objective laboratory data. AVP-D was defined by clinician-documented AVP-D and/or desmopressin initiation in the setting of polyuria/polydipsia, supported by available biochemical data and/or documented response to desmopressin when available. Visual impairment . Visual impairment was defined as decreased visual acuity and/or a visual field deficit at presentation, as documented by the treating team and corroborated, when performed, by neuro-ophthalmologic assessment. Neuro-ophthalmologic evaluation included best-corrected visual acuity testing and standardized automated perimetry. Radiology features. For patients without histopathologic confirmation (n = 9), the diagnosis of pituitary metastasis was considered highly likely when at least two of the following three criteria were simultaneously fulfilled, based on the validated model proposed by Yuzkan et al. [ 9 ] : rapid growth on serial MRI, defined as a > 20% increase in maximum tumor diameter within six months; nodular or mass-like expansion of the pituitary stalk; and a known history of malignancy. This combination has been shown to discriminate pituitary metastasis from pituitary tumors with high sensitivity and specificity [ 9 ]. In all cases, imaging studies were re-reviewed by an experienced neuroradiologist (MP). Additional radiologic features supporting the diagnosis included cavernous sinus invasion, adjacent bone destruction, optic nerve edema, irregular infiltrative tumor contour, and leptomeningeal enhancement, consistent with locally aggressive sellar disease. Time-to-event definitions. Overall survival (OS) was defined from the date of pituitary metastasis diagnosis to death or last follow-up. OS was estimated using the Kaplan–Meier method. Exploratory subgroup descriptions were performed according to clinically relevant baseline variables, including ECOG performance status and the presence of other intracranial metastases. Given the small sample size and limited statistical power, all survival analyses were considered exploratory and descriptive. Statistical analysis. We used descriptive statistics. Continuous variables are reported as median (IQR) and categorical variables as n (%). Survival was summarized from the pituitary metastasis diagnosis to death or last follow-up. Ethics approval. This study was approved by the Ethics Committee of Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (CAAE: 86575324.3.0000.0068). Results Cohort characteristics and primary tumors. Fourteen patients with pituitary metastasis were included. Median age at diagnosis was 52.5 years (IQR 40.5–64.3), and 10 patients (71.4%) were women. Breast cancer was the most frequent primary tumor (4/14, 28.6%). In most patients, pituitary metastasis occurred in the setting of advanced systemic malignancy, although the interval between primary tumor diagnosis and pituitary involvement was heterogeneous. Clinical and endocrine presentation. Clinical presentation was dominated by combined endocrine and neuro-ophthalmologic dysfunction. Hypopituitarism was present in 9/14 patients (64.3%), arginine vasopressin deficiency (AVP-D) in 7/14 (50%), and visual impairment in 7/14 (50%). Headache, cranial nerve dysfunction, and other symptoms of sellar mass effect were variably observed. This pattern supports pituitary metastasis as a clinically actionable syndrome in which endocrine failure and visual compromise frequently coexist at presentation. Serum prolactin levels were available in 11 patients and were uniformly below the range typically expected for macroprolactinoma, despite the presence of large sellar lesions and, in several cases, suprasellar extension and visual pathway compression [10, 11]. This profile was more consistent with disconnection hyperprolactinemia than with a lactotroph tumor. Radiologic features and diagnostic confirmation. Histopathologic confirmation was obtained in 5/14 cases (35.7%). In the remaining 9 patients, the diagnosis was adjudicated as highly likely on the basis of the clinical context and imaging findings, incorporating the validated clinicoradiologic model proposed by Yuzkan et al. Specifically, these patients fulfilled the combination of known malignancy together with radiologic features favoring pituitary metastasis, including rapid interval growth and/or nodular or mass-like pituitary stalk involvement. Additional imaging findings supporting metastatic disease included cavernous sinus invasion, bone destruction, optic pathway involvement, irregular infiltrative contours, and leptomeningeal enhancement when present. Treatment and outcomes. Local and systemic treatments were used according to the overall oncologic context. Systemic therapy was administered in 8/14 patients (57.1%), radiotherapy in 8/14 (57.1%), and surgery and/or biopsy in 5/14 patients (35.7%). With a median follow-up of 6.5 months, 13 of 14 patients (92.9%) died and one was censored at last follow-up. Median overall survival after pituitary metastasis diagnosis was 6.5 months (IQR, 3.5–9.5), consistent with pituitary metastasis as a manifestation of advanced systemic disease. In exploratory survival analyses, poorer performance status and the presence of other intracranial metastases were associated with shorter observed survival. Median OS was 9 months in patients with ECOG <2 versus 3 months in those with ECOG ≥2, and 10 months in patients without other intracranial metastases versus 3 months in those with additional intracranial disease. Given the small sample size, these findings should be interpreted as descriptive and hypothesis-generating only. Illustrative clinical vignettes Clinical Vignette 1. Apoplexy-like pituitary metastasis unveiling clinically meaningful receptor switching A 43-year-old woman with a history of invasive micropapillary breast carcinoma previously classified as luminal A developed abrupt bilateral visual loss, severe headache, polyuria, and hemodynamic instability three years after initial treatment, while receiving endocrine therapy with letrozole. MRI revealed an invasive sellar lesion with supra-, para-, and infrasellar extension, optic chiasm compression, and aggressive local features (Figure 2A–C). Endocrine evaluation supported panhypopituitarism and AVP-D, prompting urgent hormone replacement. Partial transsphenoidal resection confirmed pituitary metastasis from breast carcinoma; importantly, the metastatic lesion had lost ER and PR expression and displayed a triple-negative phenotype, in contrast to the original luminal A primary tumor. The patient subsequently received whole-brain radiotherapy for concomitant meningeal involvement but experienced rapid clinical decline and died three months later. This vignette illustrates two particularly consequential aspects of pituitary metastasis emphasized in this study: its capacity to present as an acute endocrine–neuro-ophthalmologic emergency closely mimicking other sellar crises, and the potential value of tissue confirmation in revealing biologically meaningful tumor evolution not apparent from the primary tumor alone. Clinical Vignette 2. Pituitary metastasis from a rare but potentially treatable primary tumor A 27-year-old man with a non-seminomatous testicular germ cell tumor presented with widely metastatic disease, including pulmonary, nodal, retroperitoneal, and hepatic involvement. Staging brain MRI disclosed a solid-cystic sellar mass with suprasellar extension (Figure 2D–E). Although he had no visual deficits, endocrine assessment supported hypopituitarism and AVP-D, and hormone replacement was initiated. He then received systemic chemotherapy with etoposide–cisplatin followed by etoposide–ifosfamide–cisplatin, after which tumor markers declined substantially and follow-up sellar MRI demonstrated marked interval reduction of the pituitary lesion, consistent with radiologic response. This highlights that the clinical significance of sellar metastatic involvement is not uniform across tumor types and should be interpreted in light of the biology and potential treatability of the underlying primary tumor. Unfortunately, the patient subsequently abandoned systemic therapy and died 13 months after the pituitary metastasis diagnosis. This outcome, while shaped by treatment discontinuation rather than tumor refractoriness, does not negate the central observation: in selected tumors with favorable biology, pituitary metastasis may retain meaningful sensitivity to systemic therapy. Discussion In this contemporary tertiary-center series, pituitary metastasis emerged not only as a manifestation of advanced systemic malignancy, but also as a clinically recognizable endocrine–neuro-ophthalmologic syndrome. Hypopituitarism, AVP-D, and visual impairment were common at presentation, reinforcing that the bedside relevance of pituitary metastasis lies less in its rarity than in the combination of diagnostic difficulty and potential for rapid clinical deterioration. Within the differential diagnosis of sellar lesions, this pattern matters because it differs from the more indolent and often anterior-pituitary–predominant presentation expected of most non-metastatic pituitary tumors. The distribution of primary tumors in our cohort was broadly consistent with prior literature, in which breast and lung cancers predominate among the most frequent sources of pituitary metastasis [ 1 , 3 , 5 , 12 , 13 ]. At the same time, the presence of less common primaries [ 14 – 17 ] reinforces an important practical point: while knowledge of the most likely oncologic sources is useful for pre-test reasoning, pituitary metastasis should not be excluded solely because the underlying malignancy is unusual. In real-world practice, the diagnosis remains anchored not only in tumor origin, but in the convergence of cancer context, clinical tempo, endocrine dysfunction, and imaging pattern. Among these clues, AVP-D remains particularly informative. Prior series have consistently shown a strong association between pituitary metastasis and posterior pituitary or infundibular involvement, which helps explain why AVP-D is encountered far more often in metastatic sellar disease than in common pituitary adenomas [ 18 , 19 ]. Our findings are aligned with that literature. In practical terms, AVP-D should be regarded as a high-yield red flag in oncologic patients with sellar lesions, especially when accompanied by visual symptoms and a short clinical course. Its diagnostic value is not that it is pathognomonic, but that it is disproportionately uncommon in the main competing diagnoses, particularly pituitary adenomas [ 20 ]. An additional exploratory observation was that the interval from primary tumor diagnosis to pituitary metastasis appeared longer in patients with AVP-D than in those without it. Although this finding should be interpreted with considerable caution given the very small sample size and heterogeneity of primary tumors, it raises the possibility that clinically overt posterior pituitary involvement may, in some cases, follow a different temporal trajectory from pituitary metastasis without AVP-D. This observation is hypothesis-generating only and requires validation in larger cohorts. This point becomes even more relevant in the acute setting, where AVP-D may be clinically under-recognized in the presence of concomitant adrenal insufficiency [ 21 ]. Glucocorticoid deficiency can mask hypotonic polyuria by impairing renal free-water clearance, such that AVP-D may only become clinically apparent after steroid replacement [ 22 ]. For this reason, the absence of overt polyuria at first assessment should not be overinterpreted in unstable patients with suspected sellar metastatic disease. Rather, clinicians should maintain suspicion when the overall endocrine and radiologic pattern suggests posterior pituitary involvement. The hormonal profile also provides a useful differential clue. In our cohort, prolactin levels were consistently below the range typically expected for macroprolactinoma despite large sellar lesions and, in several cases, substantial suprasellar extension. This pattern strongly favors disconnection hyperprolactinemia rather than autonomous lactotroph secretion. Although mild-to-moderate prolactin elevation may also be seen in non-functioning pituitary tumors with stalk effect [ 23 , 24 ], the coexistence of such prolactin levels with AVP-D and rapidly evolving neuro-ophthalmologic compromise should heighten suspicion for pituitary metastasis. Stated differently, the combination of AVP-D, visual deterioration, and non-prolactinoma-range hyperprolactinemia appears more informative than any of these features in isolation. A second clinically important message from this series is that pituitary metastasis may present as a time-sensitive sellar emergency. Visual compromise in metastatic pituitary disease often evolves over days to weeks, but abrupt deterioration can occur, particularly in apoplexy-like presentations or in lesions with hemorrhagic or infarctive change [ 25 ]. Our first illustrative vignette was selected because it captures this acute end of the clinical spectrum particularly well: sudden bilateral visual loss, hemodynamic instability, and acute hypopituitarism created a presentation that could easily have been interpreted through a non-metastatic sellar framework. This is precisely why pituitary metastasis must remain in the differential diagnosis of acute visual decline in patients with known malignancy, and also in patients whose clinical or imaging features raise suspicion for an occult cancer. The immediate clinical implication is straightforward: when this scenario is encountered, endocrine safeguarding and urgent local assessment should not await complete etiologic certainty. The value of tissue confirmation, when feasible, is also illustrated by that same vignette. In that patient, biopsy did more than establish the diagnosis of metastasis: it revealed loss of ER and PR expression and conversion from a luminal phenotype in the primary breast tumor to a triple-negative phenotype at the pituitary site. We believe this observation is important not because it should be generalized from a single case, but because it shows that sellar metastatic tissue may occasionally provide biologically consequential information not evident from the primary tumor alone. This interpretation is consistent with broader evidence from breast cancer brain metastases, in which receptor discordance between primary and metastatic sites is well documented [ 26 ]. In our case, pituitary metastasis developed while the patient was receiving letrozole, making endocrine escape biologically plausible. Accordingly, the case supports a measured but clinically relevant point: when tissue is obtained from a pituitary metastasis, biomarker reassessment may add value beyond simple diagnostic confirmation. The second vignette was chosen for a different reason. Whereas the first underscores acute urgency, the germ cell testicular case highlights that the clinical meaning of pituitary metastasis is not identical across primary tumors. In most patients, pituitary involvement occurs in the context of advanced disseminated malignancy and aligns with limited survival, as also reflected in our cohort [ 12 , 27 ]. However, pituitary metastasis from a non-seminomatous germ cell tumor illustrates that a rare but biologically treatable primary may alter the implications of the sellar lesion. The relevance of this observation is not to suggest that pituitary metastasis is frequently reversible or favorable, but to caution against an overly uniform interpretation of pituitary involvement as a purely terminal event. In selected contexts, tumor biology still matters enough to shape the balance between endocrine support, local symptom control, and systemic treatment intent. Because histopathologic confirmation is not always feasible in this population, especially in patients with poor performance status or heavy systemic disease burden, the availability of validated clinicoradiologic criteria has practical importance. In our series, most patients were diagnosed without tissue confirmation but fulfilled a high-likelihood clinicoradiologic framework based on malignancy history and characteristic imaging findings. The model proposed by Yuzkan et al. [ 9 ] is particularly helpful in this context, as it formalizes what has often been handled informally in practice: rapid sellar growth, nodular or mass-like stalk involvement, and a known history of malignancy substantially increase the probability that a sellar lesion represents metastatic disease rather than a primary pituitary tumor. We view this not as a substitute for pathology when pathology is clinically indicated and safely obtainable, but as a rational tool for diagnostic adjudication in situations where biopsy is not justified or would not change management. As expected, overall survival after pituitary metastasis diagnosis was short in our cohort, supporting the interpretation of pituitary involvement as a marker of advanced cancer burden in most patients [ 1 , 28 , 29 ]. This finding is consistent with previous reports and should temper overly aggressive causal inferences about the apparent effect of local therapies. Although surgery, biopsy, or radiotherapy may be essential for diagnosis or symptom control in selected patients, survival comparisons in cohorts of this size are highly susceptible to confounding by indication and performance-status bias. For that reason, our data are best interpreted as descriptive rather than as evidence for the superiority of any particular local intervention. The same caution applies to exploratory stratification by clinical variables such as ECOG status or intracranial disease burden: these factors are likely relevant, but our series is too small to support stable prognostic modeling. This study has several limitations. Its retrospective single-center design imposes the usual risks of incomplete ascertainment and selection bias. The cohort is necessarily small, reflecting the rarity of pituitary metastasis, and primary tumors were heterogeneous. Histopathologic confirmation was not available in all cases, although this limitation partly reflects the real-world clinical context in which tissue sampling is often not feasible or not justified. In addition, treatment exposures were described but not analyzed in a way that permits therapeutic inference. These constraints should be acknowledged explicitly, but they do not negate the main contribution of the study, which is clinical rather than interventional. In summary, our data support pituitary metastasis as a recognizable and clinically actionable syndrome at the intersection of endocrinology, neuro-ophthalmology, and oncology. In oncologic patients with sellar lesions, the combination of AVP-D, rapidly evolving visual compromise, and non-prolactinoma-range hyperprolactinemia should raise suspicion for pituitary metastasis and prompt urgent endocrine and local evaluation. The illustrative vignettes reinforce why this diagnosis matters at the bedside: pituitary metastasis may present as an acute sellar emergency, and in selected cases, tissue confirmation may also uncover biologically meaningful information not predictable from the primary tumor alone. Declarations Competing Interests: The authors declare no conflict of interest. Funding. RLB is supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grant 444825/2024-0. RLB is also supported by the American Association for Cancer Research (AACR), grant 23-15-01-BATI. Author Contribution J.L. and J.M.V. contributed equally to this work and share first authorship. J.L., J.M.V., and R.L.B. conceived and designed the study. J.L., J.M.V., M.A.M.S., B.S.B., M.M.P., M.P., E.B.T., M.N., and M.B.C.-N. collected and curated the clinical data. M.P. performed the neuroradiological review and contributed to imaging interpretation. 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Supplementary Files Table1pit2.docx Table2.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 07 Apr, 2026 Reviews received at journal 06 Apr, 2026 Reviews received at journal 26 Mar, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviewers agreed at journal 18 Mar, 2026 Reviewers invited by journal 16 Mar, 2026 Editor assigned by journal 16 Mar, 2026 Submission checks completed at journal 16 Mar, 2026 First submitted to journal 14 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9122936","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":607085534,"identity":"3d86c675-284b-4cb1-8189-f176b7741045","order_by":0,"name":"José Llumiquinga","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"","lastName":"Llumiquinga","suffix":""},{"id":607085535,"identity":"525db137-3439-4647-b969-8c791b68ef1d","order_by":1,"name":"Jacqueline Miyuki Viel","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Jacqueline","middleName":"Miyuki","lastName":"Viel","suffix":""},{"id":607085540,"identity":"0f111599-439d-4fd8-ac29-ec65ffc8ddc4","order_by":2,"name":"Matheo Augusto Morandi Stumpf","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Matheo","middleName":"Augusto Morandi","lastName":"Stumpf","suffix":""},{"id":607085543,"identity":"ad39d61a-73a0-470c-8635-b407dd6a4889","order_by":3,"name":"Bibiana Souza Boger","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Bibiana","middleName":"Souza","lastName":"Boger","suffix":""},{"id":607085547,"identity":"895c6c24-6f9b-49c1-bf4a-88a952695c63","order_by":4,"name":"Matheus Moreli Porceban","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Matheus","middleName":"Moreli","lastName":"Porceban","suffix":""},{"id":607085548,"identity":"884753e1-ddab-4960-befa-000374d572f2","order_by":5,"name":"Mario Padula","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Mario","middleName":"","lastName":"Padula","suffix":""},{"id":607085557,"identity":"4683a802-10dc-475c-8ad1-f22b2dc4e945","order_by":6,"name":"Ericka Barbosa Trarbach","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Ericka","middleName":"Barbosa","lastName":"Trarbach","suffix":""},{"id":607085563,"identity":"c8599332-3d9b-4f20-b5d1-4f6d6d215e8b","order_by":7,"name":"Marilena Nakaguma","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Marilena","middleName":"","lastName":"Nakaguma","suffix":""},{"id":607085573,"identity":"649b4609-abde-4ffd-bb11-ef60b9069df5","order_by":8,"name":"Malebranche Berardo Carneiro Cunha-Neto","email":"","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Malebranche","middleName":"Berardo Carneiro","lastName":"Cunha-Neto","suffix":""},{"id":607085575,"identity":"a4daee2e-7b91-4feb-b376-965d1e20af51","order_by":9,"name":"Rafael Loch Batista","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYFACxgcMDAUMMgwMPIyPgVx+qPABPFqYDRgYDBh4gFqYjYFcyQZStLBJE6XFvP0w44cPQC387GePVRfUMEjoNvAYfy5guJOPS4vMmWRmyRlALZI9eWm3ZxxjkDA7wGMmPYPhmWUDDi0SDPkHpHmAWgxu8Jjd5m1gqANpYeZhOGyAyxYJ/sfMv/9AtRQDtYBsMf6MV4tEMtDXUC3MUC0G0vi1PGaz7DGQAPolx1ia55iEhNlhtjLpGQbP8DgsmfnGjwobOX72M4afeWpsJMyON2/+XFBxB6cWeCggGMwgREgDBmAmVcMoGAWjYBQMawAAw9lDu1COoa0AAAAASUVORK5CYII=","orcid":"","institution":"Faculdade de Medicina da Universidade de São Paulo","correspondingAuthor":true,"prefix":"","firstName":"Rafael","middleName":"Loch","lastName":"Batista","suffix":""}],"badges":[],"createdAt":"2026-03-14 13:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9122936/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9122936/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104995932,"identity":"14e3ad6f-91b1-44b4-bbcf-e32f17d23b50","added_by":"auto","created_at":"2026-03-19 16:10:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85863,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier estimate of overall survival after pituitary metastasis diagnosis. Shaded area represents the 95% confidence interval.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9122936/v1/d036cae5812d8d6c7afa6d90.png"},{"id":104995937,"identity":"bdf64ed4-70b5-4c3f-b4f2-a3f9f5222611","added_by":"auto","created_at":"2026-03-19 16:10:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":451983,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative MRI findings from the illustrative clinical vignettes. Case 1 (A–C). Baseline MRI in a patient with breast cancer presenting with hypopituitarism and AVP-D. (A) Coronal contrast-enhanced T1-weighted image demonstrating an expansile sellar lesion with suprasellar extension. (B) Coronal T2-weighted image further depicting the lesion. (C) Sagittal contrast-enhanced T1-weighted image showing locally aggressive behavior with clival involvement/destruction and suprasellar extension (arrows), supportive of pituitary metastasis.\u003cbr\u003e\n \u0026nbsp;Case 2 (D–E). Pituitary metastasis from a non-seminomatous testicular germ cell tumor in a patient presenting with hypopituitarism and AVP-D. (D) Baseline coronal contrast-enhanced T1-weighted MRI demonstrating a solid-cystic sellar mass with suprasellar extension. (E) Follow-up coronal contrast-enhanced T1-weighted MRI after systemic chemotherapy showing marked interval reduction of the sellar lesion, consistent with radiologic response.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9122936/v1/0da491f5b9cc2eb7580785a1.png"},{"id":104996073,"identity":"419ea798-7985-4ffd-8aa7-9c7c21121054","added_by":"auto","created_at":"2026-03-19 16:11:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1722591,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9122936/v1/da002a39-c712-418c-aa4e-376d95d6f24b.pdf"},{"id":104995936,"identity":"387ee03c-59af-4432-a933-84fa401d33e4","added_by":"auto","created_at":"2026-03-19 16:10:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11045,"visible":true,"origin":"","legend":"","description":"","filename":"Table1pit2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9122936/v1/0809a8679f1b7c618c1f66cf.docx"},{"id":104995926,"identity":"f0e95c52-8dba-42cd-b493-70b5d15dda15","added_by":"auto","created_at":"2026-03-19 16:10:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7932,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9122936/v1/3edc7362fc7295f8559c7448.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pituitary Metastasis as an Endocrine–Neuro-Ophthalmologic Emergency: Clinical Red Flags and Outcomes From a Contemporary Tertiary-Center Series","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePituitary metastases represent a rare but clinically consequential oncologic event, typically arising in the setting of advanced systemic malignancy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite their rarity relative to pituitary adenomas, they carry disproportionate bedside relevance because they may precipitate rapid clinical decompensation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A high-stakes presentation may involve convergent endocrine and neuro-ophthalmologic instability\u0026mdash;including acute hypopituitarism, central arginine-vasopressin deficiency (AVP-D), and chiasmal or cranial nerve compression\u0026mdash;sometimes resembling an apoplexy-like sellar emergency and requiring timely recognition and coordinated multidisciplinary decision-making [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, guidance for day-to-day clinical management remains limited and largely experience-based. Population-level datasets provide important epidemiological context, but they seldom capture the bedside phenotype that drives urgent decisions\u0026mdash;such as the tempo of visual decline, cranial neuropathies, and the severity of endocrine dysfunction. Conversely, published institutional series are necessarily small and heterogeneous in diagnostic confirmation and treatment approaches, which limits direct comparisons and the development of practical, clinically anchored frameworks.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to characterize the clinically actionable presentation of pituitary metastasis in a contemporary tertiary-center cohort. We describe presenting manifestations, endocrine dysfunction, radiologic features, primary tumor origins, and outcomes, with particular emphasis on diagnostic clues that may sharpen bedside suspicion. We further anchor these cohort-level findings in two illustrative clinical vignettes selected because they capture two particularly consequential facets of pituitary metastasis in practice: an acute endocrine\u0026ndash;neuro-ophthalmologic emergency that may mimic other sellar crises, and a biologically distinct metastatic presentation in which the significance of sellar involvement is shaped by the underlying primary tumor. Rather than presenting pituitary metastasis solely as a rare oncologic endpoint, we aim to frame it as a recognizable clinical syndrome in which endocrine dysfunction, neuro-ophthalmologic compromise, and cancer context intersect in ways that should directly influence diagnostic suspicion and multidisciplinary evaluation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and eligibility\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective, single-center case series of patients with pituitary metastasis.\u003c/p\u003e \u003cp\u003ePatients were eligible if pituitary metastasis was diagnosed between 2010 and 2025 based on histopathology and/or radiologic and clinical criteria in the context of known systemic malignancy.\u003c/p\u003e \u003cp\u003eExclusion criteria were: (1) sellar/suprasellar lesions not consistent with metastatic disease (e.g., primary pituitary tumors or other non-metastatic sellar pathologies); (2) insufficient clinical, imaging, and/or pathology information to support the diagnosis; and (3) incomplete records precluding ascertainment of key presentation variables and/or survival outcomes.\u003c/p\u003e \u003cp\u003eThe diagnosis was confirmed by histopathology (n\u0026thinsp;=\u0026thinsp;5) or considered as highly likely because of underlying advanced malignant disease, rapid progression of the sellar mass, and/ or imaging findings considered atypical for benign sellar lesions (n\u0026thinsp;=\u0026thinsp;9).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eWe extracted the following variables from medical records: demographics (age, sex), performance status (ECOG - Eastern Cooperative Oncology Group [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]) at pituitary metastasis diagnosis, primary tumor type, interval from primary tumor diagnosis to pituitary metastasis diagnosis, presenting symptoms (visual impairment, headache, cranial nerve deficits), endocrine dysfunction (hypopituitarism, AVP-D), evidence of other intracranial and systemic metastases, treatments (systemic therapy, radiotherapy, surgery/biopsy), survival after pituitary metastasis diagnosis, and outcome at last follow-up.\u003c/p\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eHypopituitarism evaluation\u003c/b\u003e. Hypopituitarism was defined by clinician-documented central hormone deficiencies and/or initiation of pituitary hormone replacement [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. When laboratory data were available, deficiencies were adjudicated using standard endocrine criteria, prioritizing clinically actionable axes: central adrenal insufficiency (low morning serum cortisol in the appropriate clinical context and/or requirement for glucocorticoid replacement), central hypothyroidism (low free T4 with low/normal TSH), and central hypogonadism (low sex steroids with low/normal LH and FSH, interpreted in the clinical context) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Because of the retrospective design and the advanced oncologic setting, endocrine testing, including dynamic stimulation tests, was not uniformly performed; therefore, ascertainment emphasized documented diagnoses, treatment decisions, and available objective laboratory data. AVP-D was defined by clinician-documented AVP-D and/or desmopressin initiation in the setting of polyuria/polydipsia, supported by available biochemical data and/or documented response to desmopressin when available.\u003c/p\u003e \u003cp\u003e \u003cb\u003eVisual impairment\u003c/b\u003e. Visual impairment was defined as decreased visual acuity and/or a visual field deficit at presentation, as documented by the treating team and corroborated, when performed, by neuro-ophthalmologic assessment. Neuro-ophthalmologic evaluation included best-corrected visual acuity testing and standardized automated perimetry.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRadiology features.\u003c/b\u003e For patients without histopathologic confirmation (n\u0026thinsp;=\u0026thinsp;9), the diagnosis of pituitary metastasis was considered highly likely when at least two of the following three criteria were simultaneously fulfilled, based on the validated model proposed by Yuzkan et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] : rapid growth on serial MRI, defined as a\u0026thinsp;\u0026gt;\u0026thinsp;20% increase in maximum tumor diameter within six months; nodular or mass-like expansion of the pituitary stalk; and a known history of malignancy. This combination has been shown to discriminate pituitary metastasis from pituitary tumors with high sensitivity and specificity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In all cases, imaging studies were re-reviewed by an experienced neuroradiologist (MP). Additional radiologic features supporting the diagnosis included cavernous sinus invasion, adjacent bone destruction, optic nerve edema, irregular infiltrative tumor contour, and leptomeningeal enhancement, consistent with locally aggressive sellar disease.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTime-to-event definitions.\u003c/b\u003e Overall survival (OS) was defined from the date of pituitary metastasis diagnosis to death or last follow-up. OS was estimated using the Kaplan\u0026ndash;Meier method. Exploratory subgroup descriptions were performed according to clinically relevant baseline variables, including ECOG performance status and the presence of other intracranial metastases. Given the small sample size and limited statistical power, all survival analyses were considered exploratory and descriptive.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analysis.\u003c/b\u003e We used descriptive statistics. Continuous variables are reported as median (IQR) and categorical variables as n (%). Survival was summarized from the pituitary metastasis diagnosis to death or last follow-up.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval.\u003c/strong\u003e \u003cp\u003e This study was approved by the Ethics Committee of Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u0026atilde;o Paulo (CAAE: 86575324.3.0000.0068).\u003c/p\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCohort characteristics and primary tumors.\u003c/strong\u003eFourteen patients with pituitary metastasis were included. Median age at diagnosis was 52.5 years (IQR 40.5\u0026ndash;64.3), and 10 patients (71.4%) were women. Breast cancer was the most frequent primary tumor (4/14, 28.6%). In most patients, pituitary metastasis occurred in the setting of advanced systemic malignancy, although the interval between primary tumor diagnosis and pituitary involvement was heterogeneous.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical and endocrine presentation.\u003c/strong\u003e Clinical presentation was dominated by combined endocrine and neuro-ophthalmologic dysfunction. Hypopituitarism was present in 9/14 patients (64.3%), arginine vasopressin deficiency (AVP-D) in 7/14 (50%), and visual impairment in 7/14 (50%). Headache, cranial nerve dysfunction, and other symptoms of sellar mass effect were variably observed. This pattern supports pituitary metastasis as a clinically actionable syndrome in which endocrine failure and visual compromise frequently coexist at presentation. Serum prolactin levels were available in 11 patients and were uniformly below the range typically expected for macroprolactinoma, despite the presence of large sellar lesions and, in several cases, suprasellar extension and visual pathway compression [10, 11]. This profile was more consistent with disconnection hyperprolactinemia than with a lactotroph tumor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiologic features and diagnostic confirmation.\u0026nbsp;\u003c/strong\u003eHistopathologic confirmation was obtained in 5/14 cases (35.7%). In the remaining 9 patients, the diagnosis was adjudicated as highly likely on the basis of the clinical context and imaging findings, incorporating the validated clinicoradiologic model proposed by Yuzkan et al. Specifically, these patients fulfilled the combination of known malignancy together with radiologic features favoring pituitary metastasis, including rapid interval growth and/or nodular or mass-like pituitary stalk involvement. Additional imaging findings supporting metastatic disease included cavernous sinus invasion, bone destruction, optic pathway involvement, irregular infiltrative contours, and leptomeningeal enhancement when present.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment and outcomes.\u0026nbsp;\u003c/strong\u003eLocal and systemic treatments were used according to the overall oncologic context. Systemic therapy was administered in 8/14 patients (57.1%), radiotherapy in 8/14 (57.1%), and surgery and/or biopsy in 5/14 patients (35.7%). With a median follow-up of 6.5 months, 13 of 14 patients (92.9%) died and one was censored at last follow-up. Median overall survival after pituitary metastasis diagnosis was 6.5 months (IQR, 3.5\u0026ndash;9.5), consistent with pituitary metastasis as a manifestation of advanced systemic disease. In exploratory survival analyses, poorer performance status and the presence of other intracranial metastases were associated with shorter observed survival. Median OS was 9 months in patients with ECOG \u0026lt;2 versus 3 months in those with ECOG \u0026ge;2, and 10 months in patients without other intracranial metastases versus 3 months in those with additional intracranial disease. Given the small sample size, these findings should be interpreted as descriptive and hypothesis-generating only.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIllustrative clinical vignettes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Vignette 1. Apoplexy-like pituitary metastasis unveiling clinically meaningful receptor switching\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 43-year-old woman with a history of invasive micropapillary breast carcinoma previously classified as luminal A developed abrupt bilateral visual loss, severe headache, polyuria, and hemodynamic instability three years after initial treatment, while receiving endocrine therapy with letrozole. MRI revealed an invasive sellar lesion with supra-, para-, and infrasellar extension, optic chiasm compression, and aggressive local features (Figure 2A\u0026ndash;C). Endocrine evaluation supported panhypopituitarism and AVP-D, prompting urgent hormone replacement. Partial transsphenoidal resection confirmed pituitary metastasis from breast carcinoma; importantly, the metastatic lesion had lost ER and PR expression and displayed a triple-negative phenotype, in contrast to the original luminal A primary tumor. The patient subsequently received whole-brain radiotherapy for concomitant meningeal involvement but experienced rapid clinical decline and died three months later. This vignette illustrates two particularly consequential aspects of pituitary metastasis emphasized in this study: its capacity to present as an acute endocrine\u0026ndash;neuro-ophthalmologic emergency closely mimicking other sellar crises, and the potential value of tissue confirmation in revealing biologically meaningful tumor evolution not apparent from the primary tumor alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Vignette 2. Pituitary metastasis from a rare but potentially treatable primary tumor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 27-year-old man with a non-seminomatous testicular germ cell tumor presented with widely metastatic disease, including pulmonary, nodal, retroperitoneal, and hepatic involvement. Staging brain MRI disclosed a solid-cystic sellar mass with suprasellar extension (Figure 2D\u0026ndash;E). Although he had no visual deficits, endocrine assessment supported hypopituitarism and AVP-D, and hormone replacement was initiated. He then received systemic chemotherapy with etoposide\u0026ndash;cisplatin followed by etoposide\u0026ndash;ifosfamide\u0026ndash;cisplatin, after which tumor markers declined substantially and follow-up sellar MRI demonstrated marked interval reduction of the pituitary lesion, consistent with radiologic response. This highlights that the clinical significance of sellar metastatic involvement is not uniform across tumor types and should be interpreted in light of the biology and potential treatability of the underlying primary tumor. Unfortunately, the patient subsequently abandoned systemic therapy and died 13 months after the pituitary metastasis diagnosis. This outcome, while shaped by treatment discontinuation rather than tumor refractoriness, does not negate the central observation: in selected tumors with favorable biology, pituitary metastasis may retain meaningful sensitivity to systemic therapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this contemporary tertiary-center series, pituitary metastasis emerged not only as a manifestation of advanced systemic malignancy, but also as a clinically recognizable endocrine\u0026ndash;neuro-ophthalmologic syndrome. Hypopituitarism, AVP-D, and visual impairment were common at presentation, reinforcing that the bedside relevance of pituitary metastasis lies less in its rarity than in the combination of diagnostic difficulty and potential for rapid clinical deterioration. Within the differential diagnosis of sellar lesions, this pattern matters because it differs from the more indolent and often anterior-pituitary\u0026ndash;predominant presentation expected of most non-metastatic pituitary tumors.\u003c/p\u003e \u003cp\u003eThe distribution of primary tumors in our cohort was broadly consistent with prior literature, in which breast and lung cancers predominate among the most frequent sources of pituitary metastasis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. At the same time, the presence of less common primaries [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] reinforces an important practical point: while knowledge of the most likely oncologic sources is useful for pre-test reasoning, pituitary metastasis should not be excluded solely because the underlying malignancy is unusual. In real-world practice, the diagnosis remains anchored not only in tumor origin, but in the convergence of cancer context, clinical tempo, endocrine dysfunction, and imaging pattern.\u003c/p\u003e \u003cp\u003eAmong these clues, AVP-D remains particularly informative. Prior series have consistently shown a strong association between pituitary metastasis and posterior pituitary or infundibular involvement, which helps explain why AVP-D is encountered far more often in metastatic sellar disease than in common pituitary adenomas [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our findings are aligned with that literature. In practical terms, AVP-D should be regarded as a high-yield red flag in oncologic patients with sellar lesions, especially when accompanied by visual symptoms and a short clinical course. Its diagnostic value is not that it is pathognomonic, but that it is disproportionately uncommon in the main competing diagnoses, particularly pituitary adenomas [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAn additional exploratory observation was that the interval from primary tumor diagnosis to pituitary metastasis appeared longer in patients with AVP-D than in those without it. Although this finding should be interpreted with considerable caution given the very small sample size and heterogeneity of primary tumors, it raises the possibility that clinically overt posterior pituitary involvement may, in some cases, follow a different temporal trajectory from pituitary metastasis without AVP-D. This observation is hypothesis-generating only and requires validation in larger cohorts.\u003c/p\u003e \u003cp\u003eThis point becomes even more relevant in the acute setting, where AVP-D may be clinically under-recognized in the presence of concomitant adrenal insufficiency [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Glucocorticoid deficiency can mask hypotonic polyuria by impairing renal free-water clearance, such that AVP-D may only become clinically apparent after steroid replacement [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For this reason, the absence of overt polyuria at first assessment should not be overinterpreted in unstable patients with suspected sellar metastatic disease. Rather, clinicians should maintain suspicion when the overall endocrine and radiologic pattern suggests posterior pituitary involvement.\u003c/p\u003e \u003cp\u003eThe hormonal profile also provides a useful differential clue. In our cohort, prolactin levels were consistently below the range typically expected for macroprolactinoma despite large sellar lesions and, in several cases, substantial suprasellar extension. This pattern strongly favors disconnection hyperprolactinemia rather than autonomous lactotroph secretion. Although mild-to-moderate prolactin elevation may also be seen in non-functioning pituitary tumors with stalk effect [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], the coexistence of such prolactin levels with AVP-D and rapidly evolving neuro-ophthalmologic compromise should heighten suspicion for pituitary metastasis. Stated differently, the combination of AVP-D, visual deterioration, and non-prolactinoma-range hyperprolactinemia appears more informative than any of these features in isolation.\u003c/p\u003e \u003cp\u003eA second clinically important message from this series is that pituitary metastasis may present as a time-sensitive sellar emergency. Visual compromise in metastatic pituitary disease often evolves over days to weeks, but abrupt deterioration can occur, particularly in apoplexy-like presentations or in lesions with hemorrhagic or infarctive change [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our first illustrative vignette was selected because it captures this acute end of the clinical spectrum particularly well: sudden bilateral visual loss, hemodynamic instability, and acute hypopituitarism created a presentation that could easily have been interpreted through a non-metastatic sellar framework. This is precisely why pituitary metastasis must remain in the differential diagnosis of acute visual decline in patients with known malignancy, and also in patients whose clinical or imaging features raise suspicion for an occult cancer. The immediate clinical implication is straightforward: when this scenario is encountered, endocrine safeguarding and urgent local assessment should not await complete etiologic certainty.\u003c/p\u003e \u003cp\u003eThe value of tissue confirmation, when feasible, is also illustrated by that same vignette. In that patient, biopsy did more than establish the diagnosis of metastasis: it revealed loss of ER and PR expression and conversion from a luminal phenotype in the primary breast tumor to a triple-negative phenotype at the pituitary site. We believe this observation is important not because it should be generalized from a single case, but because it shows that sellar metastatic tissue may occasionally provide biologically consequential information not evident from the primary tumor alone. This interpretation is consistent with broader evidence from breast cancer brain metastases, in which receptor discordance between primary and metastatic sites is well documented [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In our case, pituitary metastasis developed while the patient was receiving letrozole, making endocrine escape biologically plausible. Accordingly, the case supports a measured but clinically relevant point: when tissue is obtained from a pituitary metastasis, biomarker reassessment may add value beyond simple diagnostic confirmation.\u003c/p\u003e \u003cp\u003eThe second vignette was chosen for a different reason. Whereas the first underscores acute urgency, the germ cell testicular case highlights that the clinical meaning of pituitary metastasis is not identical across primary tumors. In most patients, pituitary involvement occurs in the context of advanced disseminated malignancy and aligns with limited survival, as also reflected in our cohort [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, pituitary metastasis from a non-seminomatous germ cell tumor illustrates that a rare but biologically treatable primary may alter the implications of the sellar lesion. The relevance of this observation is not to suggest that pituitary metastasis is frequently reversible or favorable, but to caution against an overly uniform interpretation of pituitary involvement as a purely terminal event. In selected contexts, tumor biology still matters enough to shape the balance between endocrine support, local symptom control, and systemic treatment intent.\u003c/p\u003e \u003cp\u003eBecause histopathologic confirmation is not always feasible in this population, especially in patients with poor performance status or heavy systemic disease burden, the availability of validated clinicoradiologic criteria has practical importance. In our series, most patients were diagnosed without tissue confirmation but fulfilled a high-likelihood clinicoradiologic framework based on malignancy history and characteristic imaging findings. The model proposed by Yuzkan et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] is particularly helpful in this context, as it formalizes what has often been handled informally in practice: rapid sellar growth, nodular or mass-like stalk involvement, and a known history of malignancy substantially increase the probability that a sellar lesion represents metastatic disease rather than a primary pituitary tumor. We view this not as a substitute for pathology when pathology is clinically indicated and safely obtainable, but as a rational tool for diagnostic adjudication in situations where biopsy is not justified or would not change management.\u003c/p\u003e \u003cp\u003eAs expected, overall survival after pituitary metastasis diagnosis was short in our cohort, supporting the interpretation of pituitary involvement as a marker of advanced cancer burden in most patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This finding is consistent with previous reports and should temper overly aggressive causal inferences about the apparent effect of local therapies. Although surgery, biopsy, or radiotherapy may be essential for diagnosis or symptom control in selected patients, survival comparisons in cohorts of this size are highly susceptible to confounding by indication and performance-status bias. For that reason, our data are best interpreted as descriptive rather than as evidence for the superiority of any particular local intervention. The same caution applies to exploratory stratification by clinical variables such as ECOG status or intracranial disease burden: these factors are likely relevant, but our series is too small to support stable prognostic modeling.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Its retrospective single-center design imposes the usual risks of incomplete ascertainment and selection bias. The cohort is necessarily small, reflecting the rarity of pituitary metastasis, and primary tumors were heterogeneous. Histopathologic confirmation was not available in all cases, although this limitation partly reflects the real-world clinical context in which tissue sampling is often not feasible or not justified. In addition, treatment exposures were described but not analyzed in a way that permits therapeutic inference. These constraints should be acknowledged explicitly, but they do not negate the main contribution of the study, which is clinical rather than interventional.\u003c/p\u003e \u003cp\u003eIn summary, our data support pituitary metastasis as a recognizable and clinically actionable syndrome at the intersection of endocrinology, neuro-ophthalmology, and oncology. In oncologic patients with sellar lesions, the combination of AVP-D, rapidly evolving visual compromise, and non-prolactinoma-range hyperprolactinemia should raise suspicion for pituitary metastasis and prompt urgent endocrine and local evaluation. The illustrative vignettes reinforce why this diagnosis matters at the bedside: pituitary metastasis may present as an acute sellar emergency, and in selected cases, tissue confirmation may also uncover biologically meaningful information not predictable from the primary tumor alone.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eCompeting Interests:\u003c/strong\u003e \u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding.\u003c/h2\u003e \u003cp\u003eRLB is supported by the Conselho Nacional de Desenvolvimento Cient\u0026iacute;fico e Tecnol\u0026oacute;gico (CNPq), grant 444825/2024-0. RLB is also supported by the American Association for Cancer Research (AACR), grant 23-15-01-BATI.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.L. and J.M.V. contributed equally to this work and share first authorship. J.L., J.M.V., and R.L.B. conceived and designed the study. J.L., J.M.V., M.A.M.S., B.S.B., M.M.P., M.P., E.B.T., M.N., and M.B.C.-N. collected and curated the clinical data. M.P. performed the neuroradiological review and contributed to imaging interpretation. M.M.P. contributed to neurosurgical data review and clinical interpretation. J.L., J.M.V., and R.L.B. analyzed and interpreted the data. J.L., J.M.V., and R.L.B. wrote the main manuscript text. R.L.B. supervised the study. All authors reviewed the manuscript, approved the final version, and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJavanbakht A, D\u0026rsquo;Apuzzo M, Badie B, Salehian B (2018) Pituitary metastasis: a rare condition. Endocr Connect 7:1049\u0026ndash;1057\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKameda-Smith MM, Zhang E, Lannon M et al (2021) Pituitary metastasis: From pathology to clinical and radiological considerations. J Clin Neurosci 93:231\u0026ndash;240\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang K, Begley SL, Lynch D et al (2023) Pituitary metastases: a case series and scoping review. Pituitary 26:538\u0026ndash;550\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHenry A, Nugent A, Wallace IR et al (2021) Pituitary metastasis: a clinical overview. Ulster Med J 90:146\u0026ndash;150\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastle-Kirszbaum M, Goldschlager T, Ho B et al (2018) Twelve cases of pituitary metastasis: a case series and review of the literature. Pituitary 21:463\u0026ndash;473\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649\u0026ndash;655\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIglesias P (2024) An Update on Advances in Hypopituitarism: Etiology, Diagnosis, and Current Management. J Clin Med 13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jcm13206161\u003c/span\u003e\u003cspan address=\"10.3390/jcm13206161\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleseriu M, Hashim IA, Karavitaki N et al (2016) Hormonal replacement in hypopituitarism in adults: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 101:3888\u0026ndash;3921\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYuzkan S, Erkan B, Dogukan FM et al (2024) Distinguishing Pituitary Metastasis and Pituitary Neuroendocrine Tumors through Conventional MR Imaging and Clinical Features. AJNR Am J Neuroradiol 45:1063\u0026ndash;1069\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAuriemma RS, Pirchio R, Pivonello C et al (2023) Approach to the Patient With Prolactinoma. J Clin Endocrinol Metab 108:2400\u0026ndash;2423\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetersenn S, Fleseriu M, Casanueva FF et al (2023) Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol 19:722\u0026ndash;740\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong S, Atkinson JL, Erickson D et al (2023) Treatment outcome of metastasis to the pituitary gland: a case series of 21 patients with pathological diagnosis. Neurosurg Focus 55:E13\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaberbosch L, Schmid S, Hubertus V et al (2023) Metastases to the pituitary gland: insights from the German pituitary tumor registry. Pituitary 26:708\u0026ndash;715\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhatoe HS, Badwal S, Dutta V, Kannan N (2008) Pituitary metastasis from medullary carcinoma of thyroid: case report and review of literature. J Neurooncol 89:63\u0026ndash;67\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMerchant H, Rye DS, Smith JA (2020) Isolated pituitary fossa metastasis from a primary tonsillar squamous cell carcinoma: case report. J Laryngol Otol 134:369\u0026ndash;371\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorita A, Meyer FB, Laws ER Jr (1998) Symptomatic pituitary metastases. J Neurosurg 89:69\u0026ndash;73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKleinschmidt-DeMasters BK (2021) Metastases to the Pituitary Gland: Histological Patterns of Spread and Review of the Literature. J Neuropathol Exp Neurol 80:1033\u0026ndash;1042\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLithgow K, Siqueira I, Senthil L et al (2020) Pituitary metastases: presentation and outcomes from a pituitary center over the last decade. Pituitary 23:258\u0026ndash;265\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchill F, Nilsson M, Olsson DS et al (2019) Pituitary Metastases: A Nationwide Study on Current Characteristics With Special Reference to Breast Cancer. J Clin Endocrinol Metab 104:3379\u0026ndash;3388\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNayak P, Montaser AS, Hu J et al (2018) Predictors of Postoperative Diabetes Insipidus Following Endoscopic Resection of Pituitary Adenomas. J Endocr Soc 2:1010\u0026ndash;1019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastle-Kirszbaum M, Goldschlager T, Shi MDY, Fuller PJ (2023) Glucocorticoids and Water Balance: Implications for Hyponatremia Management and Pituitary Surgery. Neuroendocrinology 113:785\u0026ndash;794\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang D, Newman SK, Katz K, Agrawal N (2019) Central diabetes insipidus emerging after steroid replacement in pituitary apoplexy. CMAJ 191:E501\u0026ndash;E504\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyu L, Yin S, Hu Y et al (2020) Hyperprolactinemia in clinical non-functional pituitary macroadenomas: A STROBE-compliant study. Med (Baltim) 99:e22673\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSakata K, Hashimoto A, Takeshige N et al (2024) Clinical and radiographic characteristics of patients with non-functioning pituitary adenomas categorized according to their serum prolactin concentration: novel predictors of postoperative transient diabetes insipidus following surgery. Endocrine 85:837\u0026ndash;848\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Zhu M, Yan Y (2024) Neuro-ophthalmological findings of pituitary metastasis: Case series from a single center and review of the literature. Heliyon 10:e26027\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotecha R, Tonse R, Rubens M et al (2021) Systematic review and meta-analysis of breast cancer brain metastasis and primary tumor receptor expression discordance. Neurooncol Adv 3:vdab010\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbou-Al-Shaar H, Albalkhi I, Shariff RK et al (2025) Outcomes of stereotactic radiosurgery for pituitary metastases: an international multi-institutional study. Pituitary 28:69\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao Y, Lian W, Xing B et al (2018) Diagnosis, Therapy, and Therapeutic Effects in Cases of Pituitary Metastasis. World Neurosurg 117:122\u0026ndash;128\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGilard V, Alexandru C, Proust F et al (2016) Pituitary metastasis: is there still a place for neurosurgical treatment? J Neurooncol 126:219\u0026ndash;224\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pituitary","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pitu","sideBox":"Learn more about [Pituitary]()","snPcode":"11102","submissionUrl":"https://submission.nature.com/new-submission/11102/3","title":"Pituitary","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"pituitary metastasis, sellar lesion, neuro-oncology, arginine vasopressin deficiency, Pituitary adenoma, Pituitary carcinoma, Pituitary neuroendocrine tumors","lastPublishedDoi":"10.21203/rs.3.rs-9122936/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9122936/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo characterize the clinical presentation, endocrine phenotype, and outcomes of pituitary metastasis in a contemporary tertiary-center cohort, with emphasis on clinically actionable diagnostic red flags.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective single-center case series of 14 consecutive patients diagnosed with pituitary metastasis between 2010 and 2025. Presenting manifestations, endocrine features, radiologic findings, primary tumor origin, treatment patterns, and overall survival were assessed. In patients without histopathologic confirmation, diagnosis was adjudicated using the validated clinicoradiologic model proposed by Yuzkan et al.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMedian age was 52.5 years, and 71.4% of patients were women. Hypopituitarism (64.3%), arginine vasopressin deficiency (50.0%), and visual impairment (50.0%) were frequent at presentation. One patient presented with sudden bilateral visual loss and hemodynamic instability, mimicking an apoplexy-like sellar emergency. Breast cancer was the most common primary tumor (28.6%). Serum prolactin levels, available in 11 patients, were uniformly below the range typically expected for macroprolactinoma despite large sellar masses. Histopathologic confirmation was obtained in 35.7% of cases, whereas the remainder fulfilled high-likelihood clinicoradiologic criteria. Median overall survival after pituitary metastasis diagnosis was 6.5 months, and 92.9% of patients died during follow-up.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePituitary metastasis frequently presents with combined endocrine dysfunction and neuro-ophthalmologic compromise, occasionally as an acute sellar emergency. In oncologic patients with sellar lesions, the combination of AVP-D, visual deterioration, and non-prolactinoma-range hyperprolactinemia should raise suspicion for pituitary metastasis and prompt urgent endocrine and local evaluation.\u003c/p\u003e","manuscriptTitle":"Pituitary Metastasis as an Endocrine–Neuro-Ophthalmologic Emergency: Clinical Red Flags and Outcomes From a Contemporary Tertiary-Center Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 16:09:19","doi":"10.21203/rs.3.rs-9122936/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-07T08:57:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-06T14:24:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-26T09:42:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"259213206587331135559967869524769910883","date":"2026-03-26T08:40:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225728281346341925669591923616959772251","date":"2026-03-19T00:36:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-16T14:38:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T07:21:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-16T07:20:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pituitary","date":"2026-03-14T13:28:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pituitary","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pitu","sideBox":"Learn more about [Pituitary]()","snPcode":"11102","submissionUrl":"https://submission.nature.com/new-submission/11102/3","title":"Pituitary","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"49c34dc7-6fc7-4bf1-9b0c-b8e562464259","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T09:11:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 16:09:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9122936","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9122936","identity":"rs-9122936","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}