Co-secretion of growth hormone and prolactin defines a high-risk acromegaly phenotype

Co-secretion of growth hormone and prolactin defines a high-risk acromegaly phenotype | 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 Co-secretion of growth hormone and prolactin defines a high-risk acromegaly phenotype Won Kyu Lee, Hyeong-Cheol Oh, Jin-Kyung Shim, Hyeyeon Oh, So Young Won, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9255559/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Data on GH and prolactin (PRL) co-secreting pituitary neuroendocrine tumors (GH/PRL-PitNETs), a subtype of acromegaly, remain limited. In particular, comparative analyses of clinical outcomes, including remission rates, between GH/PRL-PitNETs and GH-secreting pituitary neuroendocrine tumors (GH-PitNETs) are scarce. Objective This study aimed to characterize and compare the clinical course and remission outcomes of GH/PRL-PitNETs and GH-PitNETs. Methods We retrospectively analyzed 188 patients with acromegaly who underwent surgery between 2018 and 2024. GH/PRL-PitNETs (n = 46) were compared with GH-PitNETs (n = 142) in terms of their clinical, biochemical, and radiological features. Kaplan–Meier analysis was used to assess differences in biochemical remission between the groups, after which Cox proportional hazards modeling—including a time-dependent treatment variable—was used to identify covariates independently associated with remission. Results GH/PRL-PitNETs were significantly larger and more invasive than GH-PitNETs. The surgical remission rate was lower in the GH/PRL-PitNET group ( P = .023). In multivariable Cox analysis, tumor size and cavernous sinus invasion independently predicted inferior outcome in biochemical remission. GH-PitNETs showed a higher incidence of medical comorbidities such as hypertension and thyroid carcinoma. Conclusion GH/PRL-PitNETs demonstrated greater tumor burden and more pronounced structural invasiveness, resulting in a significantly lower likelihood of endocrinological remission. Growth hormone Pituitary neuroendocrine tumor Prolactin Remission Figures Figure 1 Introduction Acromegaly is a chronic endocrine disorder caused by excessive secretion of GH from pituitary neuroendocrine tumors (PitNET), leading to elevated insulin-like growth factor 1 (IGF1) production and increased morbidity and mortality [ 1 ]. The disease manifests with typical acral and soft-tissue overgrowth accompanied by metabolic and cardiovascular comorbidities [ 2 ]. In addition, multiple reports have described higher incidences of benign and malignant tumors [ 3 , 4 ], including colorectal cancer [ 5 – 7 ], in this population. Among the tumors characterized by GH hypersecretion, the subset that co-secretes prolactin (PRL) is referred to as GH/PRL-PitNETs [ 8 ]. These tumors account for approximately one-quarter of acromegaly cases according to previous studies, and often present additional manifestations of hyperprolactinemia, such as amenorrhea or galactorrhea, which often lead to initial medical management before acromegaly is fully recognized. A few studies have reported that they exhibit larger size, higher invasiveness, and elevated PRL levels compared with GH-PitNETs [ 9 , 10 ]. However, their prevalence and clinical implications remain uncertain, largely due to heterogeneous diagnostic criteria and inconsistent definitions across studies [ 11 ]. Furthermore, despite advances in surgery and adjuvant treatments, achieving biochemical remission remains a major challenge, particularly in patients with invasive or large tumors. Prior reports have seldom provided standardized remission data or comprehensive clinical correlations, limiting the understanding of GH/PRL-PitNETs in the context of acromegaly management. In this study, we aimed to characterize the clinical differences between GH-PitNETs and GH/PRL-PitNETs. We conducted a retrospective single-center cohort analysis of surgically treated acromegaly patients, integrating clinical, radiological, and pathological data to delineate the biological and therapeutic determinants of remission outcomes. Methods Study design and patient selection We retrospectively reviewed consecutive patients diagnosed with acromegaly who underwent surgery between January 2018 and December 2024 in our institution. Of the 202 patients, those with missing GH immunohistochemistry (IHC) or unavailable serum PRL measurements, and those who were lost to follow-up were excluded. After applying the exclusion criteria, 188 patients were included in the final analysis. Patients were categorized into two groups. Tumors showing both GH and PRL positivity on IHC with concomitant serum PRL elevation, or tumors showing GH positivity on IHC without PRL immunoreactivity but accompanied by a serum PRL level >150 ng/mL, were classified as GH/PRL-PitNETs. When PRL IHC data were not available, patients with conditions that could cause secondary hyperprolactinemia (e.g., prolactin-elevating medications, renal failure, untreated hypothyroidism, or pregnancy) were excluded. Tumors with GH positivity on IHC that did not meet the criteria for GH/PRL-PitNETs were categorized as GH-PitNETs. Data collection Demographic, clinical, pathological, and radiological data were obtained from the institutional registry. Pathological evaluation included IHC for GH, PRL, Ki-67 labeling index, and three lineage-specific transcription factors: pituitary-specific transcription factor 1 (PIT1), steroidogenic factor 1, and T-box transcription factor 19. PIT1 was positive in all cases. Magnetic resonance imaging (MRI) results were reviewed for tumor size, measured as the largest value among the transversal, anteroposterior, and craniocaudal diameters. The presence of cavernous sinus invasion was determined not only by preoperative MRI findings but also by intraoperative observation. Suprasellar extension was defined as tumor penetration through the diaphragma sellae, and sphenoid invasion was defined as a visible tumor mass extruded from the bony and dural defect of the sellar floor. Hormonal and clinical evaluation The normal reference range for serum prolactin was defined as <15 ng/mL in male patients and <25 ng/mL in female patients. Postoperative remission was assessed using 75 g oral glucose tolerance test (OGTT) performed on postoperative day 3 and 6 months after surgery. Remission was defined as a nadir GH < 1 ng/mL during the OGTT with normalization of serum IGF1 adjusted for age and sex. For patients who underwent gamma knife radiosurgery (GKS), the OGTT results obtained after discontinuation of somatostatin receptor ligand or cabergoline therapy were used. Hypopituitarism was assessed by using the combined pituitary function test (CPFT) obtained before surgery and at the most recent outpatient follow-up at least 6 months postoperatively, thereby minimizing confounding by perioperative stress [12, 13]. Four categories were applied to patients assessed by CPFT: Normal to normal, defined as no pituitary hormone deficiency before and after surgery; improved hypopituitarism; persistent hypopituitarism; or aggravated hypopituitarism, defined as an increase in the degree and/or number of pituitary hormone deficiencies after surgery [14]. Statistical analysis Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were analyzed using the Student’s t-test or the Mann–Whitney U test depending on their distribution. Kaplan–Meier survival curves were generated, and group differences were evaluated with the log-rank test. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals. The proportional hazards assumption for time-fixed covariates was evaluated using Schoenfeld residuals (Supplementary Table 1). Results Demographic characteristics The GH-PitNET group represented 75.5% (n=142) of the total acromegaly patients, and the GH/PRL-PitNET group represented 24.5% (n=46). Among the 46 patients in the GH/PRL-PitNET group, 45 demonstrated both GH and PRL immunohistochemical positivity with hyperprolactinemia, whereas 1 patient showed very weak PRL immunopositivity with serum PRL levels exceeding 200 ng/mL. The GH-PitNET group had a mean age of 45 years, and the GH/PRL-PitNET group had a mean age of 40 years, which was significantly lower ( P = .02). Patient comorbidities were comparable between the two groups, except for hypertension, which was more frequent in the GH-PitNET group ( P = .009). Among associated neoplasms, thyroid cancer was more prevalent in the GH-PitNET group than in the GH/PRL-PitNET group ( P = .01) (Table 1). Table 1. Demographic characteristics of patients with GH-secreting pituitary neuroendocrine tumor (GH-PitNET) and GH & PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET) GH-PitNET (n=142) GH/PRL-PitNET (n=46) P -value Age, yrs 45 (54.0 – 36.3) 40 (47.8 - 32) 0.02* Female sex 57.7% (82) 56.5% (26) 0.11 Comorbidity Hypertension 33.1% (47) 13.0% (6) 0.009 * Cardiovascular disease 4.9% (7) 6.5% (3) 0.67 Dyslipidemia 12.0% (17) 2.2% (1) 0.05 * Diabetes mellitus 24.6% (35) 23.9% (11) 0.94 Sleep apnea syndrome 3.5% (5) 2.2% (1) 0.66 Hyper- or hypothyroidism 2.8% (4) 2.2% (1) 0.82 Benign & Malignant neoplasm 46.5% (66) 26.1% (12) 0.02 * Thyroid nodule 17.6% (25) 10.9% (5) 0.29 Thyroid cancer 12.0% (17) 0.0% (0) 0.01 * Colon polyp 12.0% (17) 4.3% (2) 0.14 Other cancer 4.9% (7) 10.9% (5) 0.15 Malocclusion 4.9% (7) 0.0% (0) 0.13 Carpal tunnel syndrome 5.6% (8) 2.2% (1) 0.34 Septoplasty 3.5% (5) 4.3% (2) 0.79 Cerebral aneurysm 2.1% (3) 0.0% (0) 0.32 *, P -value < .05 GH, growth hormone; PitNET, pituitary neuroendocrine Preoperative clinical presentation MRI-based tumor size was larger in the GH/PRL-PitNET group when evaluated using the maximum diameter among the transverse, laterolateral, and craniocaudal dimensions ( P < .001). Extrasellar invasion was present in 84.8% of GH/PRL-PitNETs and 50.7% of GH-PitNETs ( P < .001). Cavernous sinus invasion was identified in 56.5% of GH/PRL-PitNETs and 36.6% of GH-PitNETs, demonstrating a significantly higher frequency ( P = .01). Preoperatively, the GH nadir level was significantly higher in the GH/PRL-PitNET group (median 17.05 ng/mL [6.73–39.08]) than in the GH-PitNET group (median 9.92 ng/mL [4.31–22.93], P = .03). Consistently, IGF1 levels expressed as % of the upper limit of normal (ULN), were also greater in the GH/PRL-PitNET group compared with the GH-PitNET group ( P < .001). Visual involvement occurred more often in the GH/PRL-PitNET group than in the GH-PitNET group (19.6% vs 4.2%, P = .001). The median PRL level was 9.7 ng/mL (6.7–13.7) in the GH-PitNET group, whereas the GH/PRL-PitNET group showed markedly elevated PRL concentrations (median 37.8 ng/mL [27.7–74.7], P < .001) (Table 2). Table 2. Clinical characteristics between patients with GH-secreting pituitary neuroendocrine tumor (GH-PitNET) and GH & PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET) GH-PAs (n=142) GH & PRL-PAs (n=46) P -value Maximum tumor size, cm 1.79±0.86 2.38±0.97 p<0.001 * Total extrasellar invasion 50.7% (72) 84.8% (39) p<0.001 * Cavernous sinus invasion 36.6% (52) 56.5% (26) 0.01 * Extrasellar invasion other than cavernous sinus 13.4% (19) 28.3% (13) 0.02 * IGF-1, %ULN 2.48 (1.92–2.95) 2.74 (2.11–3.27) p<0.001 * GH, ng/dL 9.92 (4.31–22.93) 17.05 (6.73–39.08) 0.03 * Visual involvement 4.2% (6) 19.6% (9) 0.001 * Serum prolactin, ng/dL 9.7 (6.7–13.7) 37.8 (27.7–74.7) p<0.001 * *, P -value < .05 GH, growth hormone; IGF-1, insulin-like growth factor-1; PitNET, pituitary neuroendocrine tumor; ULN, upper limit of normal Postoperative outcomes In line with the earlier noted tendencies toward larger tumors, greater invasiveness, and higher biochemical activity in GH/PRL-PitNETs, subtotal resection was more frequent in the GH/PRL-PitNET group (30.4%) than in the GH-PitNET group (16.9%, P = .05). Consistent with these surgical challenges, the Kaplan–Meier analyses demonstrated significantly lower cumulative remission in the GH/PRL-PitNET group ( P = .023) (Fig. 1A). Postoperative GH nadir levels were significantly higher in the GH/PRL-PitNET group (median 0.25 ng/mL [0.10–0.77] vs. 0.10 ng/mL [0.10–0.29], P = .02), and a Ki-67 labeling index >3% was more frequently observed in GH/PRL-PitNETs (11.1% vs. 1.4%, P = .003) (Table 3). Despite these aggressive tumor characteristics, postoperative changes in anterior pituitary function following transsphenoidal surgery were comparable between the two groups (Table 4). Table 3. Differences in post-surgical variables between patients with GH-secreting pituitary neuroendocrine tumor (GH-PitNET) and GH & PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET) GH-PAs (n=142) GH & PRL-PAs (n=46) P -value Subtotal resection 16.9% (24) 30.4% (14) 0.05 * GKS after surgery 9.9% (14) 28.3% (13) 0.002 * Rate of IGF-1 normalization ** 77.3% (99) 78.8% (26) 0.86 GH nadir level, ng/mL ** 0.10 (0.10–0.29) 0.25 (0.10–0.77) 0.02 * Major complications Cerebrospinal fluid leakage 0.7% (1) 0.0% (0) 0.57 Postsurgical bleeding 4.2% (6) 4.3% (2) 0.96 Ki-67 > 3% 1.4% (2) 11.1% (5) 0.003 * *, P -value < .05 **, GKS patients excluded GH, growth hormone; GKS, gamma knife surgery; IGF-1, insulin-like growth factor-1; PitNET, pituitary neuroendocrine; ULN, upper limit of normal Table 4. Multivariable Cox regression HR 95% CI P -value Group 0.90 0.59 – 1.37 0.613 Treatment 0.87 0.24 – 3.19 0.830 Group × Treatment 0.45 0.07 – 2.97 0.409 Age 1.00 0.99 – 1.02 0.844 Hypertension 1.08 0.75 – 1.56 0.682 Tumor size 0.68 0.54 – 0.86 0.001 * Cavernous sinus invasion 0.53 0.36 – 0.78 0.001 * Cox model with time-dependent treatment indicator; event = remission. HR<1 indicates delayed remission. *, P -value < .05 CI, confidential interval; HR, hazard ratio In multivariable Cox regression, tumor size and cavernous sinus invasion remained independent predictors of delayed remission (HR 0.62, P < .001; HR 0.57, P = .005) (Table 5). In line with the preoperative characteristics summarized in Table 2, inferior surgical remission in GH/PRL-PitNETs was observed alongside larger tumor burden and higher invasiveness. Postoperative adjuvant GKS was required more often in the GH/PRL-PitNET group (28.3%) than in the GH-PitNET group (9.9%, P = .002). However, among the 27 patients treated with adjuvant GKS, the Kaplan–Meier curves showed no significant difference in post-GKS remission between the two groups (Fig. 1B). Table 5. Postoperative hormonal outcome between patients with GH-secreting pituitary neuroendocrine tumor (GH-PitNET) and GH & PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET) Postoperative hormone outcome GH-PAs GH & PRL-PAs P -value Preserved normal pituitary function (n = 20, 19.0%) 19 (22.1%) 1 (5.3%) Improved hypopituitarism (n = 36, 34.3%) 26 (30.2%) 10 (52.6%) Persistent hypopituitarism (n = 35, 33.3%) 28 (32.6%) 7 (36.8%) Aggravation of hypopituitarism (n = 14, 13.3%) 13 (15.1%) 1 (5.3%) Total (n = 105) 86 19 0.12 *, P -value < .05 GH, growth hormone; PitNET, pituitary neuroendocrine Discussion GH/PRL-PitNETs have consistently been reported to have larger size [ 15 – 17 ] and a greater tendency toward invasiveness [ 16 , 17 ] across multiple studies. However, recent large series have shown similar long-term remission rates between GH/PRL- and GH-PitNETs [ 16 ], while other studies have reported markedly lower surgical remission in GH/PRL-PitNET [ 9 , 15 ]. Despite these discrepancies, these studies suggest shared biological features of PRL co-secretion in acromegaly patients, such as an immature PIT1 lineage and a propensity for invasive growth [ 9 , 16 , 18 , 19 ]. These variations are likely due to methodological differences, including heterogeneous diagnostic criteria, endpoint definitions, and adjustments for baseline tumor characteristics. Our study aimed to address these limitations by applying stringent group definitions and performing time-to-event analyses using multivariable Cox proportional hazards models, adjusting for key confounders. The definition and prevalence of GH/PRL-PitNETs have not yet been firmly established, and the criteria used across studies remain heterogeneous [ 20 ]. In our cohort, we identified many patients who showed positive staining for PRL on IHC but no increased serum PRL level. We first grouped our patients based on the presence of PRL-positive tumor cells on IHC, although it did not demonstrate clinically meaningful differences in tumor behavior or treatment outcomes, consistent with the observations reported by Araujo-Castro et al [ 16 ]. Thus, for our endocrinologically and pathologically proven acromegalic patients, GH/PRL-PitNETs were defined as meeting one of two conditions; (1) dual positive staining for GH and PRL on IHC together with serum PRL concentrations above the ULN, or (2) PRL levels > 150 ng/mL when PRL staining was not conclusive on IHC. Also, in all tumors of our cohort, PIT1 transcription factor expression was confirmed to be positive, as recommended in the WHO classification of pituitary tumors [ 21 ]. By this definition, GH/PRL-PitNETs accounted for 24.5% of our cohort, a prevalence comparable to that reported in previous studies [ 9 , 10 ]. Based on this definition, further characterization of tumor biology revealed that GH/PRL-PitNETs exhibit more aggressive features compared with GH-PitNETs. Tumors in the GH/PRL-PitNET group were larger and more invasive. In addition to typical manifestations such as amenorrhea or galactorrhea caused by hyperprolactinemia, visual field defects, which reflect tumor size [ 22 , 23 ], were significantly more frequent in GH/PRL-PitNET patients. Cavernous sinus invasion was much more common in the GH/PRL-PitNET group. In addition, tumor invasion into other regions such as the suprasellar area and sphenoid sinus, was also more common in GH/PRL-PitNET patients. Taken together, these findings suggest that GH/PRL-PitNETs exhibit inherently invasive and biologically unfavorable characteristics. Consequently, in patients with GH/PRL-PitNETs, complete tumor removal and endocrinological remission was achieved less frequently. In these patients with sustained acromegalic condition, adjuvant GKS was more often required ( P = .002). Considering that the efficacy of GKS in patients with GH/PRL-PitNETs was not inferior to that in patients with GH-PitNETs, and that tumors were generally larger and more invasive in the GH/PRL-PitNET group, early adjuvant GKS may represent a rational strategy to counteract the adverse tumor biology of GH/PRL-PitNETs. Notably, despite their more aggressive tumor behavior, GH/PRL‑PitNETs exhibited significantly low prevalence of medical comorbidities such as hypertension and thyroid carcinoma, compared with GH‑PitNETs. One plausible explanation is that the more rapid tumor progression in GH/PRL‑PitNETs may result in a shorter duration of exposure to the acromegalic condition prior to diagnosis [ 16 ]. Additionally, dopamine agonists and somatostatin analogues, which are more frequently prescribed in patients with GH/PRL‑PitNETs, are known to suppress TSH secretion through central mechanisms, leading to attenuation of hypothalamic–pituitary–thyroid axis activity [ 24 ]. Although these agents rarely induce overt central hypothyroidism, even modest reductions in TSH may attenuate proliferative signaling in thyroid follicular cells that would otherwise act synergistically with GH/IGF‑1, thereby potentially contributing to the lower incidence of thyroid carcinoma observed in this group. The unfavorable outcomes associated with GH/PRL-PitNETs may reflect a shift toward a less differentiated state along the PIT1 lineage spectrum, with PRL co-secreting tumors representing a more aggressive phenotype. While the precise mechanism by how tumor cells benefit from PRL co-secretion remains unclear, one plausible hypothesis is that these cells undergo transdifferentiation between somatotrophs and lactotrophs. Physiological and experimental data suggest that such transdifferentiation can occur in specific contexts, such as pregnancy [ 25 ], and epithelial-mesenchymal transition‑related pathways may play a role in facilitating these processes [ 26 ]. However, it remains uncertain whether PRL co-secretion directly drives these unfavorable behaviors or simply reflects an already aggressive cellular state. Therefore, future studies involving human pituitary tumor tissues and cell models are needed to better elucidate the role of PRL co-secretion. Ultimately, these investigations will be essential for determining the position of PRL co-secreting tumors within the spectrum of immature PIT1 lineage neoplasms and for providing a molecular basis for their distinct clinical behaviors. This study has several limitations. First, serum PRL elevation could be caused not only by PRL secretion from the tumors, but also by the stalk effect in cases with large enough tumors to compress the pituitary stalk. As it is not clear whether the unfavorable clinical outcomes of GH/PRL-PitNETs are based on their intrinsic tumor biology or hyperprolactinemia itself, GH/PRL-PitNETs may not represent a single disease entity but possibly a rather heterogeneous group. Second, the retrospective and single-center design inherently reduces generalizability, and the limited subgroup events further lower the statistical power, which may be overcome by future multicenter prospective studies. Third, the analyses involving adjuvant GKS were subject to structural and statistical limitations. Patients receiving GKS represent a conditional subset defined by surgical non-remission, introducing selection (collider) bias. In addition, the small number of post-GKS events and correlations between key covariates (tumor size and cavernous sinus invasion) limit the statistical power and preclude definitive conclusions regarding time-dependent treatment effects or treatment sequencing strategies. Lastly, although the proportional hazards assumption was not violated globally, a mild non-proportionality signal was observed for cavernous-sinus invasion, for which HRs should be interpreted as time-averaged effects. These analytic and design-related limitations highlight the need for standardized remission criteria and confirmatory evidence from larger, multicenter, prospective studies. Declarations Disclosure statement: The authors have nothing to disclose. Ethics approval This study was approved by the Institutional Review Board of Severance hospital (approval No 4-2025-1720), and the requirement for informed consent was waived. Competing interest The authors declare no competing interests. Funding This research was supported by the Bio/Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2023-00261820) and the Technology Innovation Program (RS-2025-02308375) funded by the Ministry of Trade, Industry / Energy (MOTIE, Korea). Author Contribution Won Kyu Lee: data curation, formal analysis, writing - original draft, formal analysis; Hyeong-Cheol Oh: conceptualization, writing - review & editing; Jin-Kyung Shim: conceptualization; Hyeyeon Oh: conceptualization; So Young Won: data curation; Seonah Choi: data curation; Yoon-a Hwang: data curation; Ju Hyung Moon: data curation; Cheol Ryong Ku: data curation; Eun Jig Lee: data curation; Sun Ho Kim: writing - review & editing; Eui Hyun Kim: conceptualization, Formal Analysis, Writing - Review & Editing, Funding Acquisition, Resources, Project Administration Data Availability Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. References Fleseriu M, Langlois F, Lim DST, Varlamov EV, Melmed S (2022) Acromegaly: Pathogenesis, diagnosis, and management. 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Mol Clin Oncol 1(1):3–11. https://doi.org/10.3892/mco.2012.28 Additional Declarations No competing interests reported. Supplementary Files SupplemantaryTableforsubmission.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Apr, 2026 Reviews received at journal 20 Apr, 2026 Reviews received at journal 09 Apr, 2026 Reviewers agreed at journal 06 Apr, 2026 Reviewers agreed at journal 03 Apr, 2026 Reviewers invited by journal 03 Apr, 2026 Editor assigned by journal 31 Mar, 2026 Submission checks completed at journal 31 Mar, 2026 First submitted to journal 28 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. 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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-9255559","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":618126811,"identity":"ab333869-fa7a-4c7e-9676-847f025e0dcc","order_by":0,"name":"Won Kyu Lee","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Won","middleName":"Kyu","lastName":"Lee","suffix":""},{"id":618126812,"identity":"74429ddc-fdba-4eca-8337-fab3a4f19a3d","order_by":1,"name":"Hyeong-Cheol Oh","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hyeong-Cheol","middleName":"","lastName":"Oh","suffix":""},{"id":618126813,"identity":"3e920515-d982-44e5-b1b4-a0cc34f112f6","order_by":2,"name":"Jin-Kyung Shim","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jin-Kyung","middleName":"","lastName":"Shim","suffix":""},{"id":618126814,"identity":"9b6f890f-5910-4f47-911d-0ff92bc51f47","order_by":3,"name":"Hyeyeon Oh","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hyeyeon","middleName":"","lastName":"Oh","suffix":""},{"id":618126815,"identity":"3e85ea4d-8bc5-4c46-ac81-de21975b18ea","order_by":4,"name":"So Young Won","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"So","middleName":"Young","lastName":"Won","suffix":""},{"id":618126816,"identity":"c7698f69-bf91-4b35-adcc-24a2dc1c93ca","order_by":5,"name":"Seonah Choi","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Seonah","middleName":"","lastName":"Choi","suffix":""},{"id":618126817,"identity":"6ec06a29-2295-4b3f-ab3a-f1b93520742b","order_by":6,"name":"Yoon-a Hwang","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yoon-a","middleName":"","lastName":"Hwang","suffix":""},{"id":618126818,"identity":"92fa7623-9ea0-4342-8a51-968ee61a465f","order_by":7,"name":"Ju Hyung Moon","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ju","middleName":"Hyung","lastName":"Moon","suffix":""},{"id":618126819,"identity":"d113d070-9dd6-4a97-af0d-7308ea134dfb","order_by":8,"name":"Cheol Ryong Ku","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Cheol","middleName":"Ryong","lastName":"Ku","suffix":""},{"id":618126820,"identity":"c840d546-ddd6-4e00-8e61-14020f2f6f73","order_by":9,"name":"Eun Jig Lee","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Eun","middleName":"Jig","lastName":"Lee","suffix":""},{"id":618126821,"identity":"8494f698-b3aa-48e0-b2b6-972931c54ea0","order_by":10,"name":"Sun Ho Kim","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sun","middleName":"Ho","lastName":"Kim","suffix":""},{"id":618126822,"identity":"a0fa47b2-d819-428f-bc08-40e079d20c99","order_by":11,"name":"Eui Hyun Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYFACxjYQacDGwHyAgbGBNC1sCcRqYWADa2Fg4DEgTgu/RHLbY962O8Z8Yme+SfPuqGPgbz+AX4vkjMR2Y962Z2Zs0rnbpHnPHGaQOJOAX4vBjcQ2ad62wzYQLW1AG24QcJg9QkvOMyCjjkGekBYDCYgWoMNy2IAMZqC9BLRInHnYJjnn3GFjNuk0Y8u5bYd5DAn5hb89/ZnEm7LDhvNnJz+88batTk7u+AEC1gABEw+EZpEAEjyE1QMB4w8IzfyBKOWjYBSMglEw4gAANdw+jkpX0NcAAAAASUVORK5CYII=","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Eui","middleName":"Hyun","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2026-03-28 23:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9255559/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9255559/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106581245,"identity":"d0fcdf60-f320-4b19-bb0d-d225c965e5d3","added_by":"auto","created_at":"2026-04-10 06:42:25","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87270,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve for endocrinological remission after surgical treatment. (A) Probability of postoperative endocrinological remission after surgery in patients with GH-secreting pituitary neuroendocrine tumor (GH-PitNET) and GH and prolactin co-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET). GH/PRL-PitNETs had a significantly lower remission probability than GH-PitNETs (log-rank \u003cem\u003eP\u003c/em\u003e = .023). (B) Probability of endocrinological remission after adjuvant GKS in patients with residual disease following surgery. 3 of 14 GH-PitNET and 2 of 13 GH/PRL-PitNET patients achieved remission, and remission probability did not differ significantly between subtypes (log-rank \u003cem\u003eP\u003c/em\u003e = .40).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9255559/v1/c0f4b78f5376911d7f26d3de.jpeg"},{"id":106581254,"identity":"e4255c43-9248-4cea-9e9c-ba4a0d89b934","added_by":"auto","created_at":"2026-04-10 06:42:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":732012,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9255559/v1/fe09742c-9a5c-4bda-8a0a-ee3743ebdd07.pdf"},{"id":106581237,"identity":"9809221f-59c8-479f-b84e-05627380c922","added_by":"auto","created_at":"2026-04-10 06:42:21","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":20544,"visible":true,"origin":"","legend":"","description":"","filename":"SupplemantaryTableforsubmission.docx","url":"https://assets-eu.researchsquare.com/files/rs-9255559/v1/a38d66da1ce7675c217b6a66.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Co-secretion of growth hormone and prolactin defines a high-risk acromegaly phenotype","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcromegaly is a chronic endocrine disorder caused by excessive secretion of GH from pituitary neuroendocrine tumors (PitNET), leading to elevated insulin-like growth factor 1 (IGF1) production and increased morbidity and mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease manifests with typical acral and soft-tissue overgrowth accompanied by metabolic and cardiovascular comorbidities [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In addition, multiple reports have described higher incidences of benign and malignant tumors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], including colorectal cancer [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], in this population.\u003c/p\u003e \u003cp\u003eAmong the tumors characterized by GH hypersecretion, the subset that co-secretes prolactin (PRL) is referred to as GH/PRL-PitNETs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These tumors account for approximately one-quarter of acromegaly cases according to previous studies, and often present additional manifestations of hyperprolactinemia, such as amenorrhea or galactorrhea, which often lead to initial medical management before acromegaly is fully recognized. A few studies have reported that they exhibit larger size, higher invasiveness, and elevated PRL levels compared with GH-PitNETs [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, their prevalence and clinical implications remain uncertain, largely due to heterogeneous diagnostic criteria and inconsistent definitions across studies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, despite advances in surgery and adjuvant treatments, achieving biochemical remission remains a major challenge, particularly in patients with invasive or large tumors. Prior reports have seldom provided standardized remission data or comprehensive clinical correlations, limiting the understanding of GH/PRL-PitNETs in the context of acromegaly management.\u003c/p\u003e \u003cp\u003eIn this study, we aimed to characterize the clinical differences between GH-PitNETs and GH/PRL-PitNETs. We conducted a retrospective single-center cohort analysis of surgically treated acromegaly patients, integrating clinical, radiological, and pathological data to delineate the biological and therapeutic determinants of remission outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and patient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively reviewed consecutive patients diagnosed with acromegaly who underwent surgery between January 2018 and December 2024 in our institution. Of the 202 patients, those with missing GH immunohistochemistry (IHC) or unavailable serum PRL measurements, and those who were lost to follow-up were excluded. After applying the exclusion criteria, 188 patients were included in the final analysis. Patients were categorized into two groups. Tumors showing both GH and PRL positivity on IHC with concomitant serum PRL elevation, or tumors showing GH positivity on IHC without PRL immunoreactivity but accompanied by a serum PRL level \u0026gt;150 ng/mL, were classified as GH/PRL-PitNETs. When PRL IHC data were not available, patients with conditions that could cause secondary hyperprolactinemia (e.g., prolactin-elevating medications, renal failure, untreated hypothyroidism, or pregnancy) were excluded. Tumors with GH positivity on IHC that did not meet the criteria for GH/PRL-PitNETs were categorized as GH-PitNETs.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDemographic, clinical, pathological, and radiological data were obtained from the institutional registry. Pathological evaluation included IHC for GH, PRL, Ki-67 labeling index, and three lineage-specific transcription factors: pituitary-specific transcription factor 1 (PIT1), steroidogenic factor 1, and T-box transcription factor 19. PIT1 was positive in all cases. Magnetic resonance imaging (MRI) results were reviewed for tumor size, measured as the largest value among the transversal, anteroposterior, and craniocaudal diameters. The presence of cavernous sinus invasion was determined not only by preoperative MRI findings but also by intraoperative observation. Suprasellar extension was defined as tumor penetration through the diaphragma sellae, and sphenoid invasion was defined as a visible tumor mass extruded from the bony and dural defect of the sellar floor.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHormonal and clinical evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe normal reference range for serum prolactin was defined as \u0026lt;15 ng/mL in male patients and \u0026lt;25 ng/mL in female patients. Postoperative remission was assessed using 75 g oral glucose tolerance test (OGTT) performed on postoperative day 3 and 6 months after surgery. Remission was defined as a nadir GH \u0026lt; 1 ng/mL during the OGTT with normalization of serum IGF1 adjusted for age and sex. For patients who underwent gamma knife radiosurgery (GKS), the OGTT results obtained after discontinuation of somatostatin receptor ligand or cabergoline therapy were used. Hypopituitarism was assessed by using the combined pituitary function test (CPFT) obtained before surgery and at the most recent outpatient follow-up at least 6 months postoperatively, thereby minimizing confounding by perioperative stress [12, 13]. Four categories were applied to patients assessed by CPFT: Normal to normal, defined as no pituitary hormone deficiency before and after surgery; improved hypopituitarism; persistent hypopituitarism; or aggravated hypopituitarism, defined as an increase in the degree and/or number of pituitary hormone deficiencies after surgery [14].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical variables were compared using the chi-square test or Fisher\u0026rsquo;s exact test, as appropriate. Continuous variables were analyzed using the Student\u0026rsquo;s t-test\u003cem\u003e\u0026nbsp;\u003c/em\u003eor the Mann\u0026ndash;Whitney U test depending on their distribution. Kaplan\u0026ndash;Meier survival curves were generated, and group differences were evaluated with the log-rank test. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals. The proportional hazards assumption for time-fixed covariates was evaluated using Schoenfeld residuals (Supplementary Table 1).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe GH-PitNET group represented 75.5% (n=142) of the total acromegaly patients, and the GH/PRL-PitNET group represented 24.5% (n=46). Among the 46 patients in the GH/PRL-PitNET group, 45 demonstrated both GH and PRL immunohistochemical positivity with hyperprolactinemia, whereas 1 patient showed very weak PRL immunopositivity with serum PRL levels exceeding 200 ng/mL. The GH-PitNET group had a mean age of 45 years, and the GH/PRL-PitNET group had a mean age of 40 years, which was significantly lower (\u003cem\u003eP\u003c/em\u003e = .02). Patient comorbidities were comparable between the two groups, except for hypertension, which was more frequent in the GH-PitNET group (\u003cem\u003eP\u003c/em\u003e = .009). Among associated neoplasms, thyroid cancer was more prevalent in the GH-PitNET group than in the GH/PRL-PitNET group (\u003cem\u003eP\u003c/em\u003e = .01) (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. Demographic characteristics of patients with GH-secreting\u0026nbsp;pituitary neuroendocrine tumor (GH-PitNET) and GH \u0026amp; PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eGH-PitNET (n=142)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003eGH/PRL-PitNET (n=46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eAge, yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e45 (54.0 \u0026ndash; 36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e40 (47.8 - 32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.02*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eFemale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e57.7% (82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e56.5% (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eComorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e33.1% (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e13.0% (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.009\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eCardiovascular disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e4.9% (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e6.5% (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eDyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e12.0% (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e2.2% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.05\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e24.6% (35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e23.9% (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eSleep apnea syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e3.5% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e2.2% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eHyper- or hypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e2.8% (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e2.2% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eBenign \u0026amp; Malignant neoplasm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e46.5% (66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e26.1% (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eThyroid nodule\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e17.6% (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e10.9% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eThyroid cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e12.0% (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e0.0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eColon polyp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e12.0% (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e4.3% (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eOther cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e4.9% (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e10.9% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eMalocclusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e4.9% (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e0.0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eCarpal tunnel syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e5.6% (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e2.2% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eSeptoplasty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e3.5% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e4.3% (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eCerebral aneurysm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e2.1% (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 160px;\"\u003e\n \u003cp\u003e0.0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*, \u003cem\u003eP\u003c/em\u003e-value \u0026lt; .05\u003c/p\u003e\n\u003cp\u003eGH, growth hormone; PitNET, pituitary neuroendocrine\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreoperative clinical presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMRI-based tumor size was larger in the GH/PRL-PitNET group when evaluated using the maximum diameter among the transverse, laterolateral, and craniocaudal dimensions (\u003cem\u003eP\u003c/em\u003e \u0026lt; .001). Extrasellar invasion was present in 84.8% of GH/PRL-PitNETs and 50.7% of GH-PitNETs (\u003cem\u003eP\u003c/em\u003e \u0026lt; .001). Cavernous sinus invasion was identified in 56.5% of GH/PRL-PitNETs and 36.6% of GH-PitNETs, demonstrating a significantly higher frequency (\u003cem\u003eP\u003c/em\u003e = .01). Preoperatively, the GH nadir level was significantly higher in the GH/PRL-PitNET group (median 17.05 ng/mL [6.73\u0026ndash;39.08]) than in the GH-PitNET group (median 9.92 ng/mL [4.31\u0026ndash;22.93], \u003cem\u003eP\u003c/em\u003e = .03). Consistently, IGF1 levels expressed as % of the upper limit of normal (ULN), were also greater in the GH/PRL-PitNET group compared with the GH-PitNET group (\u003cem\u003eP\u003c/em\u003e \u0026lt; .001). Visual involvement occurred more often in the GH/PRL-PitNET group than in the GH-PitNET group (19.6% vs 4.2%, \u003cem\u003eP\u003c/em\u003e = .001). The median PRL level was 9.7 ng/mL (6.7\u0026ndash;13.7) in the GH-PitNET group, whereas the GH/PRL-PitNET group showed markedly elevated PRL concentrations (median 37.8 ng/mL [27.7\u0026ndash;74.7], \u003cem\u003eP\u003c/em\u003e \u0026lt; .001) (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Clinical characteristics between patients with GH-secreting\u0026nbsp;pituitary neuroendocrine tumor (GH-PitNET) and GH \u0026amp; PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eGH-PAs\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n=142)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eGH \u0026amp; PRL-PAs\u003c/p\u003e\n \u003cp\u003e(n=46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eMaximum tumor size, cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e1.79\u0026plusmn;0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e2.38\u0026plusmn;0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eTotal extrasellar invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e50.7% (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e84.8% (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eCavernous sinus invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e36.6% (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e56.5% (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eExtrasellar invasion other than cavernous sinus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e13.4% (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e28.3% (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eIGF-1, %ULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e2.48 (1.92\u0026ndash;2.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e2.74 (2.11\u0026ndash;3.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eGH, ng/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e9.92 (4.31\u0026ndash;22.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e17.05 (6.73\u0026ndash;39.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.03\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eVisual involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e4.2% (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e19.6% (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eSerum prolactin, ng/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e9.7 (6.7\u0026ndash;13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e37.8 (27.7\u0026ndash;74.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*, \u003cem\u003eP\u003c/em\u003e-value \u0026lt; .05\u003c/p\u003e\n\u003cp\u003eGH, growth hormone; IGF-1, insulin-like growth factor-1; PitNET, pituitary neuroendocrine tumor; ULN, upper limit of normal\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostoperative outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn line with the earlier noted tendencies toward larger tumors, greater invasiveness, and higher biochemical activity in GH/PRL-PitNETs, subtotal resection was more frequent in the GH/PRL-PitNET group (30.4%) than in the GH-PitNET group (16.9%, \u003cem\u003eP\u003c/em\u003e = .05). Consistent with these surgical challenges, the Kaplan\u0026ndash;Meier analyses demonstrated significantly lower cumulative remission in the GH/PRL-PitNET group (\u003cem\u003eP\u003c/em\u003e = .023) (Fig. 1A). Postoperative GH nadir levels were significantly higher in the GH/PRL-PitNET group (median 0.25 ng/mL [0.10\u0026ndash;0.77] vs. 0.10 ng/mL [0.10\u0026ndash;0.29], \u003cem\u003eP\u003c/em\u003e = .02), and a Ki-67 labeling index \u0026gt;3% was more frequently observed in GH/PRL-PitNETs (11.1% vs. 1.4%, \u003cem\u003eP\u003c/em\u003e= .003) (Table 3). Despite these aggressive tumor characteristics, postoperative changes in anterior pituitary function following transsphenoidal surgery were comparable between the two groups (Table 4). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. Differences in post-surgical variables between patients with GH-secreting\u0026nbsp;pituitary neuroendocrine tumor (GH-PitNET) and GH \u0026amp; PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eGH-PAs\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n=142)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eGH \u0026amp; PRL-PAs\u003c/p\u003e\n \u003cp\u003e(n=46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eSubtotal resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e16.9% (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e30.4% (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.05\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eGKS after surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e9.9% (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e28.3% (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eRate of IGF-1 normalization\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e77.3% (99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e78.8% (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eGH nadir level, ng/mL\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0.10 (0.10\u0026ndash;0.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0.25 (0.10\u0026ndash;0.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eMajor complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eCerebrospinal fluid leakage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0.7% (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0.0% (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003ePostsurgical bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e4.2% (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e4.3% (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eKi-67 \u0026gt; 3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e1.4% (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e11.1% (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.003\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*, \u003cem\u003eP\u003c/em\u003e-value \u0026lt; .05\u003c/p\u003e\n\u003cp\u003e**, GKS patients excluded\u003c/p\u003e\n\u003cp\u003eGH, growth hormone; GKS, gamma knife surgery; IGF-1, insulin-like growth factor-1; PitNET, pituitary neuroendocrine; ULN, upper limit of normal\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Multivariable Cox regression\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.59 \u0026ndash; 1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.613\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.24 \u0026ndash; 3.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.830\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eGroup \u0026times; Treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.07 \u0026ndash; 2.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.409\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.99 \u0026ndash; 1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.844\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.75 \u0026ndash; 1.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.682\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.54 \u0026ndash; 0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eCavernous sinus invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.36 \u0026ndash; 0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCox model with time-dependent treatment indicator; \u003cem\u003eevent = remission.\u003c/em\u003e HR\u0026lt;1 indicates delayed remission.\u003c/p\u003e\n\u003cp\u003e*, \u003cem\u003eP\u003c/em\u003e-value \u0026lt; .05\u003c/p\u003e\n\u003cp\u003eCI, confidential interval; HR, hazard ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn multivariable Cox regression, tumor size and cavernous sinus invasion remained independent predictors of delayed remission (HR 0.62, \u003cem\u003eP\u003c/em\u003e \u0026lt; .001; HR 0.57, \u003cem\u003eP\u003c/em\u003e = .005) (Table 5). In line with the preoperative characteristics summarized in Table 2, inferior surgical remission in GH/PRL-PitNETs was observed alongside larger tumor burden and higher invasiveness. Postoperative adjuvant GKS was required more often in the GH/PRL-PitNET group (28.3%) than in the GH-PitNET group (9.9%, \u003cem\u003eP\u003c/em\u003e = .002). However, among the 27 patients treated with adjuvant GKS, the Kaplan\u0026ndash;Meier curves showed no significant difference in post-GKS remission between the two groups (Fig. 1B).\u003c/p\u003e\n\u003cp\u003eTable 5. Postoperative hormonal outcome between patients with GH-secreting pituitary neuroendocrine tumor (GH-PitNET) and GH \u0026amp; PRL-secreting pituitary neuroendocrine tumor (GH/PRL-PitNET)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003ePostoperative hormone outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eGH-PAs\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eGH \u0026amp; PRL-PAs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003ePreserved normal pituitary function (n = 20, 19.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e19 (22.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eImproved hypopituitarism\u003c/p\u003e\n \u003cp\u003e(n = 36, 34.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e26 (30.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e10 (52.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003ePersistent hypopituitarism\u003c/p\u003e\n \u003cp\u003e(n = 35, 33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e28 (32.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e7 (36.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eAggravation of hypopituitarism\u003c/p\u003e\n \u003cp\u003e(n = 14, 13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e13 (15.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 246px;\"\u003e\n \u003cp\u003eTotal (n = 105)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*, \u003cem\u003eP\u003c/em\u003e-value \u0026lt; .05\u003c/p\u003e\n\u003cp\u003eGH, growth hormone; PitNET, pituitary neuroendocrine\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eGH/PRL-PitNETs have consistently been reported to have larger size [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and a greater tendency toward invasiveness [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] across multiple studies. However, recent large series have shown similar long-term remission rates between GH/PRL- and GH-PitNETs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], while other studies have reported markedly lower surgical remission in GH/PRL-PitNET [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Despite these discrepancies, these studies suggest shared biological features of PRL co-secretion in acromegaly patients, such as an immature PIT1 lineage and a propensity for invasive growth [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These variations are likely due to methodological differences, including heterogeneous diagnostic criteria, endpoint definitions, and adjustments for baseline tumor characteristics. Our study aimed to address these limitations by applying stringent group definitions and performing time-to-event analyses using multivariable Cox proportional hazards models, adjusting for key confounders.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe definition and prevalence of GH/PRL-PitNETs have not yet been firmly established, and the criteria used across studies remain heterogeneous [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In our cohort, we identified many patients who showed positive staining for PRL on IHC but no increased serum PRL level. We first grouped our patients based on the presence of PRL-positive tumor cells on IHC, although it did not demonstrate clinically meaningful differences in tumor behavior or treatment outcomes, consistent with the observations reported by Araujo-Castro et al [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Thus, for our endocrinologically and pathologically proven acromegalic patients, GH/PRL-PitNETs were defined as meeting one of two conditions; (1) dual positive staining for GH and PRL on IHC together with serum PRL concentrations above the ULN, or (2) PRL levels\u0026thinsp;\u0026gt;\u0026thinsp;150 ng/mL when PRL staining was not conclusive on IHC. Also, in all tumors of our cohort, PIT1 transcription factor expression was confirmed to be positive, as recommended in the WHO classification of pituitary tumors [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. By this definition, GH/PRL-PitNETs accounted for 24.5% of our cohort, a prevalence comparable to that reported in previous studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Based on this definition, further characterization of tumor biology revealed that GH/PRL-PitNETs exhibit more aggressive features compared with GH-PitNETs. Tumors in the GH/PRL-PitNET group were larger and more invasive. In addition to typical manifestations such as amenorrhea or galactorrhea caused by hyperprolactinemia, visual field defects, which reflect tumor size [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], were significantly more frequent in GH/PRL-PitNET patients. Cavernous sinus invasion was much more common in the GH/PRL-PitNET group. In addition, tumor invasion into other regions such as the suprasellar area and sphenoid sinus, was also more common in GH/PRL-PitNET patients. Taken together, these findings suggest that GH/PRL-PitNETs exhibit inherently invasive and biologically unfavorable characteristics. Consequently, in patients with GH/PRL-PitNETs, complete tumor removal and endocrinological remission was achieved less frequently. In these patients with sustained acromegalic condition, adjuvant GKS was more often required (\u003cem\u003eP\u003c/em\u003e = .002). Considering that the efficacy of GKS in patients with GH/PRL-PitNETs was not inferior to that in patients with GH-PitNETs, and that tumors were generally larger and more invasive in the GH/PRL-PitNET group, early adjuvant GKS may represent a rational strategy to counteract the adverse tumor biology of GH/PRL-PitNETs.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eNotably, despite their more aggressive tumor behavior, GH/PRL‑PitNETs exhibited significantly low prevalence of medical comorbidities such as hypertension and thyroid carcinoma, compared with GH‑PitNETs. One plausible explanation is that the more rapid tumor progression in GH/PRL‑PitNETs may result in a shorter duration of exposure to the acromegalic condition prior to diagnosis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, dopamine agonists and somatostatin analogues, which are more frequently prescribed in patients with GH/PRL‑PitNETs, are known to suppress TSH secretion through central mechanisms, leading to attenuation of hypothalamic\u0026ndash;pituitary\u0026ndash;thyroid axis activity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Although these agents rarely induce overt central hypothyroidism, even modest reductions in TSH may attenuate proliferative signaling in thyroid follicular cells that would otherwise act synergistically with GH/IGF‑1, thereby potentially contributing to the lower incidence of thyroid carcinoma observed in this group.\u003c/p\u003e \u003cp\u003eThe unfavorable outcomes associated with GH/PRL-PitNETs may reflect a shift toward a less differentiated state along the PIT1 lineage spectrum, with PRL co-secreting tumors representing a more aggressive phenotype. While the precise mechanism by how tumor cells benefit from PRL co-secretion remains unclear, one plausible hypothesis is that these cells undergo transdifferentiation between somatotrophs and lactotrophs. Physiological and experimental data suggest that such transdifferentiation can occur in specific contexts, such as pregnancy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and epithelial-mesenchymal transition‑related pathways may play a role in facilitating these processes [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, it remains uncertain whether PRL co-secretion directly drives these unfavorable behaviors or simply reflects an already aggressive cellular state. Therefore, future studies involving human pituitary tumor tissues and cell models are needed to better elucidate the role of PRL co-secretion. Ultimately, these investigations will be essential for determining the position of PRL co-secreting tumors within the spectrum of immature PIT1 lineage neoplasms and for providing a molecular basis for their distinct clinical behaviors.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, serum PRL elevation could be caused not only by PRL secretion from the tumors, but also by the stalk effect in cases with large enough tumors to compress the pituitary stalk. As it is not clear whether the unfavorable clinical outcomes of GH/PRL-PitNETs are based on their intrinsic tumor biology or hyperprolactinemia itself, GH/PRL-PitNETs may not represent a single disease entity but possibly a rather heterogeneous group. Second, the retrospective and single-center design inherently reduces generalizability, and the limited subgroup events further lower the statistical power, which may be overcome by future multicenter prospective studies. Third, the analyses involving adjuvant GKS were subject to structural and statistical limitations. Patients receiving GKS represent a conditional subset defined by surgical non-remission, introducing selection (collider) bias. In addition, the small number of post-GKS events and correlations between key covariates (tumor size and cavernous sinus invasion) limit the statistical power and preclude definitive conclusions regarding time-dependent treatment effects or treatment sequencing strategies. Lastly, although the proportional hazards assumption was not violated globally, a mild non-proportionality signal was observed for cavernous-sinus invasion, for which HRs should be interpreted as time-averaged effects. These analytic and design-related limitations highlight the need for standardized remission criteria and confirmatory evidence from larger, multicenter, prospective studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDisclosure statement:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\n\u003ch2\u003eEthics approval\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of Severance hospital (approval No 4-2025-1720), and the requirement for informed consent was waived.\u003c/p\u003e\n\u003ch2\u003eCompeting interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis research was supported by the Bio/Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2023-00261820) and the Technology Innovation Program (RS-2025-02308375) funded by the Ministry of Trade, Industry / Energy (MOTIE, Korea).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eWon Kyu Lee: data curation, formal analysis, writing - original draft, formal analysis; Hyeong-Cheol Oh: conceptualization, writing - review \u0026amp; editing; Jin-Kyung Shim: conceptualization; Hyeyeon Oh: conceptualization; So Young Won: data curation; Seonah Choi: data curation; Yoon-a Hwang: data curation; Ju Hyung Moon: data curation; Cheol Ryong Ku: data curation; Eun Jig Lee: data curation; Sun Ho Kim: writing - review \u0026amp; editing; Eui Hyun Kim: conceptualization, Formal Analysis, Writing - Review \u0026amp; Editing, Funding Acquisition, Resources, Project Administration\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eSome or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFleseriu M, Langlois F, Lim DST, Varlamov EV, Melmed S (2022) Acromegaly: Pathogenesis, diagnosis, and management. Lancet Diabetes Endocrinol 10(11):804\u0026ndash;826. https://doi.org/10.1016/S2213-8587(22)00244-3\u003c/li\u003e\n\u003cli\u003eLv L, Jiang Y, Yin S et al (2019) Mammosomatotroph and mixed somatotroph-lactotroph adenoma in acromegaly: A retrospective study with long-term follow-up. Endocrine 66(2):310\u0026ndash;318. https://doi.org/10.1007/s12020-019-02029-1\u003c/li\u003e\n\u003cli\u003eGadelha MR, Kasuki L, Lim DST, Fleseriu M (2019) Systemic complications of acromegaly and the impact of the current treatment landscape: An update. Endocr Rev 40(1):268\u0026ndash;332. https://doi.org/10.1210/er.2018-00115\u003c/li\u003e\n\u003cli\u003eFleseriu M, Barkan A, Del Pilar Schneider M et al (2022) Prevalence of comorbidities and concomitant medication use in acromegaly: Analysis of real-world data from the united states. Pituitary 25(2):296\u0026ndash;307. https://doi.org/10.1007/s11102-021-01198-5\u003c/li\u003e\n\u003cli\u003eOrme SM, McNally RJ, Cartwright RA, Belchetz PE (1998) Mortality and cancer incidence in acromegaly: A retrospective cohort study. United kingdom acromegaly study group. J Clin Endocrinol Metab 83(8):2730\u0026ndash;2734. https://doi.org/10.1210/jcem.83.8.5007\u003c/li\u003e\n\u003cli\u003eMaione L, Brue T, Beckers A et al (2017) Changes in the management and comorbidities of acromegaly over three decades: The french acromegaly registry. Eur J Endocrinol 176(5):645\u0026ndash;655. https://doi.org/10.1530/EJE-16-1064\u003c/li\u003e\n\u003cli\u003eTerzolo M, Reimondo G, Berchialla P et al (2017) Acromegaly is associated with increased cancer risk: A survey in italy. Endocr Relat Cancer 24(9):495\u0026ndash;504. https://doi.org/10.1530/ERC-16-0553\u003c/li\u003e\n\u003cli\u003eRahman M, Jusue-Torres I, Alkabbani A, Salvatori R, Rodriguez FJ, Quinones-Hinojosa A (2014) Synchronous gh- and prolactin-secreting pituitary adenomas. Endocrinol Diabetes Metab Case Rep 2014:140052. https://doi.org/10.1530/EDM-14-0052\u003c/li\u003e\n\u003cli\u003eRick J, Jahangiri A, Flanigan PM et al (2019) Growth hormone and prolactin-staining tumors causing acromegaly: A retrospective review of clinical presentations and surgical outcomes. J Neurosurg 131(1):147\u0026ndash;153. https://doi.org/10.3171/2018.4.JNS18230\u003c/li\u003e\n\u003cli\u003eVan Laethem D, Michotte A, Cools W et al (2020) Hyperprolactinemia in acromegaly is related to prolactin secretion by somatolactotroph tumours. Horm Metab Res 52(9):647\u0026ndash;653. https://doi.org/10.1055/a-1207-1132\u003c/li\u003e\n\u003cli\u003eWildemberg LE, Gadelha MR (2024) Gh and prolactin co-secreting adenomas: It is time for a definition. J Clin Endocrinol Metab 110(1):e192\u0026ndash;e193. https://doi.org/10.1210/clinem/dgae262\u003c/li\u003e\n\u003cli\u003eWebb SM, Rigla M, W\u0026auml;gner A, Oliver B, Bartumeus F (1999) Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas. J Clin Endocrinol Metab 84(10):3696\u0026ndash;3700. https://doi.org/10.1210/jcem.84.10.6019\u003c/li\u003e\n\u003cli\u003ede Vries F, Lobatto DJ, Bakker LEH, van Furth WR, Biermasz NR, Pereira AM (2020) Early postoperative hpa-axis testing after pituitary tumor surgery: Reliability and safety of basal cortisol and crh test. Endocrine 67(1):161\u0026ndash;171. https://doi.org/10.1007/s12020-019-02094-6\u003c/li\u003e\n\u003cli\u003eKim EH, Ku CR, Lee EJ, Kim SH (2015) Extracapsular en bloc resection in pituitary adenoma surgery. Pituitary 18(3):397\u0026ndash;404. https://doi.org/10.1007/s11102-014-0587-4\u003c/li\u003e\n\u003cli\u003eWang M, Mou C, Jiang M et al (2012) The characteristics of acromegalic patients with hyperprolactinemia and the differences in patients with merely gh-secreting adenomas: Clinical analysis of 279 cases. Eur J Endocrinol 166(5):797\u0026ndash;802. https://doi.org/10.1530/eje-11-1119\u003c/li\u003e\n\u003cli\u003eAraujo-Castro M, Biagetti B, Menendez Torre E et al (2024) Differences between gh- and prl-cosecreting and gh-secreting pituitary adenomas: A series of 604 cases. J Clin Endocrinol Metab 109(12):e2178\u0026ndash;e2187. https://doi.org/10.1210/clinem/dgae126\u003c/li\u003e\n\u003cli\u003eGuo X, Zhang R, Zhang D et al (2021) Hyperprolactinemia and hypopituitarism in acromegaly and effect of pituitary surgery: Long-term follow-up on 529 patients. Front Endocrinol (Lausanne) 12:807054. https://doi.org/10.3389/fendo.2021.807054\u003c/li\u003e\n\u003cli\u003eMelmed S, Kaiser UB, Lopes MB et al (2022) Clinical biology of the pituitary adenoma. Endocr Rev 43(6):1003\u0026ndash;1037. https://doi.org/10.1210/endrev/bnac010\u003c/li\u003e\n\u003cli\u003eAsa SL, Ezzat S, Mete O (2025) Clinical integration and application of the 2022 who pituitary tumor classification. Neurooncol Adv 7(Suppl 1):i10\u0026ndash;i16. https://doi.org/10.1093/noajnl/vdae145\u003c/li\u003e\n\u003cli\u003eChong L, Lou Y, Chen X et al (2025) Comparison of the clinical and prognostic characteristics of patients with different pathological types in acromegaly. Front Endocrinol (Lausanne) 16:1571598. https://doi.org/10.3389/fendo.2025.1571598\u003c/li\u003e\n\u003cli\u003eAsa SL, Mete O, Perry A, Osamura RY (2022) Overview of the 2022 who classification of pituitary tumors. Endocr Pathol 33(1):6\u0026ndash;26. https://doi.org/10.1007/s12022-022-09703-7\u003c/li\u003e\n\u003cli\u003eYang F, Bi Y, Zhou Q et al (2023) Pituitary adenoma with cavernous sinus compartment penetration and intracranial extension: Surgical anatomy, approach, and outcomes. Front Oncol 13:1169224. https://doi.org/10.3389/fonc.2023.1169224\u003c/li\u003e\n\u003cli\u003eWang MTM, Meyer JA, Danesh-Meyer HV (2024) Neuro-ophthalmic evaluation and management of pituitary disease. Eye (Lond) 38(12):2279\u0026ndash;2288. https://doi.org/10.1038/s41433-024-03187-x\u003c/li\u003e\n\u003cli\u003eHaugen BR (2009) Drugs that suppress tsh or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab 23(6):793\u0026ndash;800. https://doi.org/10.1016/j.beem.2009.08.003\u003c/li\u003e\n\u003cli\u003eMelmed S (2003) Mechanisms for pituitary tumorigenesis: The plastic pituitary. J Clin Invest 112(11):1603\u0026ndash;1618. https://doi.org/10.1172/jci20401\u003c/li\u003e\n\u003cli\u003eKiesslich T, Pichler M, Neureiter D (2013) Epigenetic control of epithelial-mesenchymal-transition in human cancer. Mol Clin Oncol 1(1):3\u0026ndash;11. https://doi.org/10.3892/mco.2012.28\u003c/li\u003e\n\u003c/ol\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":"Growth hormone, Pituitary neuroendocrine tumor, Prolactin, Remission","lastPublishedDoi":"10.21203/rs.3.rs-9255559/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9255559/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eData on GH and prolactin (PRL) co-secreting pituitary neuroendocrine tumors (GH/PRL-PitNETs), a subtype of acromegaly, remain limited. In particular, comparative analyses of clinical outcomes, including remission rates, between GH/PRL-PitNETs and GH-secreting pituitary neuroendocrine tumors (GH-PitNETs) are scarce.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to characterize and compare the clinical course and remission outcomes of GH/PRL-PitNETs and GH-PitNETs.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 188 patients with acromegaly who underwent surgery between 2018 and 2024. GH/PRL-PitNETs (n\u0026thinsp;=\u0026thinsp;46) were compared with GH-PitNETs (n\u0026thinsp;=\u0026thinsp;142) in terms of their clinical, biochemical, and radiological features. Kaplan\u0026ndash;Meier analysis was used to assess differences in biochemical remission between the groups, after which Cox proportional hazards modeling\u0026mdash;including a time-dependent treatment variable\u0026mdash;was used to identify covariates independently associated with remission.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eGH/PRL-PitNETs were significantly larger and more invasive than GH-PitNETs. The surgical remission rate was lower in the GH/PRL-PitNET group (\u003cem\u003eP\u003c/em\u003e = .023). In multivariable Cox analysis, tumor size and cavernous sinus invasion independently predicted inferior outcome in biochemical remission. GH-PitNETs showed a higher incidence of medical comorbidities such as hypertension and thyroid carcinoma.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eGH/PRL-PitNETs demonstrated greater tumor burden and more pronounced structural invasiveness, resulting in a significantly lower likelihood of endocrinological remission.\u003c/p\u003e","manuscriptTitle":"Co-secretion of growth hormone and prolactin defines a high-risk acromegaly phenotype","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 06:40:40","doi":"10.21203/rs.3.rs-9255559/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-20T20:15:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T19:25:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-09T21:09:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"265382778285957333101303187546012805788","date":"2026-04-06T09:01:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224378775747693232205544519539919854716","date":"2026-04-03T12:42:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-03T10:22:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-31T06:53:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-31T06:53:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pituitary","date":"2026-03-28T23:27:17+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":"50982677-f06f-446b-acbd-0ee530418235","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T10:07:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 06:40:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9255559","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9255559","identity":"rs-9255559","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}