{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:27:01Z","timestamp":1792805221240,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T00:00:00Z","timestamp":1699574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cCarol Davila\u201d University of Medicine and Pharmacy Bucharest","award":["33PFE\/30.12.2021"],"award-info":[{"award-number":["33PFE\/30.12.2021"]}],"id":[{"id":"https:\/\/ror.org\/04fm87419","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER\u221d, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER\u221d; ER\u221d expression was correlated with basal PRL levels at diagnosis (rho = 0.60, p &lt; 0.01) and postoperative PRL levels (rho = 0.58, p &lt; 0.001). In our study, the ER\u221d intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade (p = 0.02); CAM 5.2 pattern (densely\/sparsely granulated\/mixed densely and sparsely granulated) was correlated with postoperative PRL level (p = 0.002), and with ki-67 (p &lt; 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, p &lt; 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter (p = 0.63, p &lt; 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER\u221d can be used as a prognostic marker and loss of ER\u221d expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.<\/jats:p>","DOI":"10.3390\/ijms242216162","type":"journal-article","created":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T05:04:56Z","timestamp":1699592696000},"page":"16162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Value of ER\u221d in the Prognosis of GH- and PRL-Secreting PitNETs: Clinicopathological Correlations"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4568-2714","authenticated-orcid":false,"given":"Roxana-Ioana","family":"Dumitriu-Stan","sequence":"first","affiliation":[{"name":"Department of Endocrinology, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iulia-Florentina","family":"Burcea","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u2018C. I. Parhon\u2019 National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria Nicoleta","family":"Nastase","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u2018Victor Babes\u2019 University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u2018Victor Babes\u2019 University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0067-8247","authenticated-orcid":false,"given":"Raluca Amalia","family":"Ceau\u0219u","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u2018Victor Babes\u2019 University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u2018Victor Babes\u2019 University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anda","family":"Dumitrascu","sequence":"additional","affiliation":[{"name":"\u2018C. I. Parhon\u2019 National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurentiu Catalin","family":"Cocosila","sequence":"additional","affiliation":[{"name":"\u2018Bagdasar-Arseni\u2019 Emergency Hospital, 041915 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bastian","sequence":"additional","affiliation":[{"name":"Department of Pathology, Colentina Clinical Hospital, 020125 Bucharest, Romania"},{"name":"Department of Pathology, Faculty of Dental Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Zurac","sequence":"additional","affiliation":[{"name":"Department of Pathology, Colentina Clinical Hospital, 020125 Bucharest, Romania"},{"name":"Department of Pathology, Faculty of Dental Medicine, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Raica","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology\/Histology, \u2018Victor Babes\u2019 University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"Angiogenesis Research Centre, \u2018Victor Babes\u2019 University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Poiana","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, \u2018Carol Davila\u2019 University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u2018C. I. Parhon\u2019 National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.beem.2019.101290","article-title":"The epidemiology, diagnosis and treatment of Prolactinomas: The old and the new","volume":"33","author":"Chanson","year":"2019","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_2","first-page":"27","article-title":"Criteria for medical as opposed to surgical treatment of prolactinomas","volume":"129","author":"Besser","year":"1993","journal-title":"Acta Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1111\/cen.12242","article-title":"Giant prolactinomas: The therapeutic approach","volume":"79","author":"Moraes","year":"2013","journal-title":"Clin. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.2174\/1871530323666230511104045","article-title":"Italian Guidelines for the Management of Prolactinomas","volume":"23","author":"Cozzi","year":"2023","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1007\/s12020-019-02029-1","article-title":"Mammosomatotroph and mixed somatotroph-lactotroph adenoma in acromegaly: A retrospective study with long-term follow-up","volume":"66","author":"Jiang","year":"2019","journal-title":"Endocrine"},{"key":"ref_6","first-page":"2897","article-title":"Estrogen receptors alpha and beta immunohistochemical expression: Clinicopathological correlations in pituitary adenomas","volume":"30","author":"Manoranjan","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"\u0160o\u0161i\u0107-Jurjevi\u0107, B., Ajd\u017eanovi\u0107, V., Milji\u0107, D., Trifunovi\u0107, S., Filipovi\u0107, B., Stankovi\u0107, S., Bolevich, S., Jakovljevi\u0107, V., and Milo\u0161evi\u0107, V. (2020). Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens\u2014An Insight from Translational Studies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062024"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"706","DOI":"10.3389\/fendo.2018.00706","article-title":"Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated with a Specific Gene-Expression Signature and Genome Instability","volume":"9","author":"Wierinckx","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1172\/JCI0214264","article-title":"Functional role of estrogen in pituitary tumor pathogenesis","volume":"109","author":"Heaney","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Haydar Ali Tajuddin, A., Kamaruddin, N., Sukor, N., Azizan, E.A., and Omar, A.M. (2020). Estrogen Receptors in Nonfunctioning Pituitary Neuroendocrine Tumors: Review on Expression and Gonadotroph Functions. J. Endocr. Soc., 12.","DOI":"10.1210\/jendso\/bvaa157"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"684055","DOI":"10.3389\/fendo.2021.684055","article-title":"Galectin-3 and Estrogen Receptor Alpha as Prognostic Markers in Prolactinoma: Preliminary Results from a Pilot Study","volume":"12","author":"Bima","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_12","unstructured":"Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., and Hofland, J. (2000). Endotext, MDText.com, Inc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/s41574-018-0058-5","article-title":"A Consensus Statement on acromegaly therapeutic outcomes","volume":"14","author":"Melmed","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1186\/s13063-021-05604-y","article-title":"The PRolaCT studies\u2014A study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma","volume":"1","author":"Zandbergen","year":"2021","journal-title":"Trials"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1210\/jcem.86.2.7226","article-title":"Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma","volume":"86","author":"Klein","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3933","DOI":"10.1210\/jc.2014-2700","article-title":"Acromegaly: An endocrine society clinical practice guideline","volume":"11","author":"Katznelson","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1210\/jc.2010-1692","article-title":"Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline","volume":"2","author":"Melmed","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1159\/000499382","article-title":"Clinical, Pathological, and Molecular Factors of Aggressiveness in Lactotroph Tumours","volume":"1","author":"Trouillas","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1530\/EJE-14-0990","article-title":"Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth","volume":"172","author":"Delgrange","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_20","first-page":"31","article-title":"Giant prolactinomas in women","volume":"1","author":"Delgrange","year":"2013","journal-title":"Eur. J. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s11102-016-0723-4","article-title":"Giant prolactinomas larger than 60 mm in size: A cohort of massive and aggressive prolactin-secreting pituitary adenomas","volume":"4","author":"Shimon","year":"2016","journal-title":"Pituitary"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/s00234-015-1519-3","article-title":"Intensity of prolactinoma on T2-weighted magnetic resonance imaging: Towards another gender difference","volume":"7","author":"Kreutz","year":"2015","journal-title":"Neuroradiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1210\/jc.2009-1191","article-title":"Prognostic factors in prolactin pituitary tumors: Clinical, histological, and molecular data from a series of 94 patients with a long postoperative follow-up","volume":"4","author":"Raverot","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fmed.2015.00054","article-title":"Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors","volume":"2","author":"Roche","year":"2015","journal-title":"Front. Med."},{"key":"ref_25","first-page":"e35171","article-title":"Effect of Tamoxifen on the Management of Dopamine Agonist-Resistant Prolactinomas: A Systematic Review","volume":"15","author":"Bazuhair","year":"2023","journal-title":"Cureus."},{"key":"ref_26","first-page":"143","article-title":"What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics","volume":"2","author":"Karavitaki","year":"2007","journal-title":"Eur. J. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mce.2005.04.008","article-title":"Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release","volume":"1\u20132","author":"Kansra","year":"2005","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1046\/j.0007-1331.2001.00744.x","article-title":"Oestrogen receptors, receptor variants and oestrogen actions in the hypothalamic-pituitary axis","volume":"2","author":"Shupnik","year":"2002","journal-title":"J. Neuroendocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0010-7824(83)90057-4","article-title":"Oral contraceptive steroids do not promote the development or growth of prolactinomas","volume":"1","author":"Hulting","year":"1983","journal-title":"Contraception"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s00701-005-0498-2","article-title":"Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance","volume":"7","author":"Delgrange","year":"2005","journal-title":"Acta Neurochir."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1023\/A:1011412028660","article-title":"Rapid re-expansion of a macroprolactinoma after early discontinuation of bromocriptine","volume":"3","author":"Orrego","year":"2000","journal-title":"Pituitary"},{"key":"ref_32","first-page":"3268","article-title":"Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas","volume":"9","author":"Jaquet","year":"1999","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1530\/EJE-07-0806","article-title":"Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas","volume":"5","author":"Fusco","year":"2008","journal-title":"Eur. J. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101337","DOI":"10.1016\/j.ghir.2020.101337","article-title":"The significance of estrogen receptors in acromegaly: Are they useful as predictors of prognosis and therapy regimen?","volume":"55","author":"Ozturk","year":"2020","journal-title":"Growth Horm. IGF Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15409","DOI":"10.1038\/s41598-023-42157-3","article-title":"Supervised machine learning to validate a novel scoring system for the prediction of disease remission of functional pituitary adenomas following transsphenoidal surgery","volume":"13","author":"McKevitt","year":"2023","journal-title":"Sci Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/BF01833337","article-title":"Tamoxifen reduces serum insulin-like growth factor I (IGF-I)","volume":"22","author":"Pollak","year":"1992","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s11102-012-0426-4","article-title":"Estrogen treatment for acromegaly","volume":"15","author":"Shimon","year":"2012","journal-title":"Pituitary"},{"key":"ref_38","first-page":"119","article-title":"Immunohistochemical detection of estrogen receptor alpha in pituitary adenomas and its correlation with cellular replication","volume":"3","author":"Marroni","year":"2004","journal-title":"Neuroendocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1007\/s11102-019-00982-8","article-title":"Predictive modeling for pituitary adenomas: Single center experience in 501 consecutive patients","volume":"22","author":"Pappy","year":"2019","journal-title":"Pituitary"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"793337","DOI":"10.3389\/fendo.2021.793337","article-title":"Analysis of Related Factors of Tumor Recurrence or Progression After Transnasal Sphenoidal Surgical Treatment of Large and Giant Pituitary Adenomas and Establish a Nomogram to Predict Tumor Prognosis","volume":"12","author":"Chen","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1210\/jc.2013-3054","article-title":"Growth Patterns of Pituitary Adenomas and Histopathological Correlates","volume":"99","author":"Monsalves","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"419","DOI":"10.4132\/jptm.2016.06.30","article-title":"The Predictive Value of Pathologic Features in Pituitary Adenoma and Correlation with Pituitary Adenoma Recurrence","volume":"6","author":"Kim","year":"2016","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","article-title":"Overview of the 2022 WHO Classification of Pituitary Tumors","volume":"33","author":"Asa","year":"2022","journal-title":"Endocr. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:20:58Z","timestamp":1760131258000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,10]]},"references-count":43,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216162"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,10]]}}}