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Molecular Biology of the Pituitary 3.0
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Molecular Biology of the Pituitary 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 8941

Special Issue Editors

Dr. Rosa Maria Paragliola

E-Mail Website
Guest Editor
Department of Translational Medicine and Surgery, Unit of Endocrinology, Università Cattolica del Sacro Cuore—Fondazione Policlinico “Gemelli” IRCCS, Largo Gemelli 8, I-00168 Rome, Italy
Interests: pituitary; acromegaly; Cushing’s syndrome; hyperprolactinemia; TSH-secreting pituitary adenoma; syndrome of reduced sensitivity to thyroid hormones; thyroid; adrenal gland
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Salvatore Maria Corsello

E-Mail Website
Guest Editor
Department of Translational Medicine and Surgery, Unit of Endocrinology, Università Cattolica del Sacro Cuore—Fondazione Policlinico “Gemelli” IRCCS, Largo Gemelli 8, I-00168 Rome, Italy
Interests: pituitary; acromegaly; Cushing’s syndrome; hyperprolactinemia; TSH-secreting pituitary adenoma; syndrome of reduced sensitivity to thyroid hormones; thyroid; adrenal gland
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue, “Molecular Biology of the Pituitary 2.0”.

This Special Issue aims to present recent research on the molecular biology of pituitary diseases. Pituitary adenoma is a common disease, present in about 10% of the general population, which generally presents as benign tumors. However, rarely, tumors can become malignant and metastasize. Pituitary adenomas are also associated with specific syndromes (e.g., acromegaly, Cushing’s syndrome, prolactinoma, inappropriate TSH secretion syndrome) due to inappropriate hormonal secretion. The continuous development of molecular biology techniques has improved the understanding of both the pathogenesis and the biology of these tumors and this knowledge can be applied for the development of diagnostic approaches and therapeutic options. Interestingly, molecular biology techniques have led to the discovery of the pathophysiological mechanisms at the basis of non-neoplastic pituitary diseases, such as thyroid hormone resistance syndrome or inappropriate non-neoplastic TSH secretion. Regarding syndromes of reduced sensitivity to thyroid hormones, an important topic is the discovery of polymorphisms in genes which code for type 2 deiodinase. Finally, genetic analyses can identify mutations of genes coding for transcription factors involved in pituitary development, which can be involved in the pathogenesis of combined pituitary hormone deficiency.

Dr. Rosa Maria Paragliola
Prof. Dr. Salvatore Maria Corsello
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acromegaly
  • somatostatin receptor ligands
  • prolactinoma
  • Cushing’s syndrome
  • TSH-secreting adenomas
  • syndromes of reduced sensitivity to thyroid hormones
  • pituitary adenomas
  • pituitary carcinomas
  • hypopituitarism

Published Papers (6 papers)

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Research

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18 pages, 8348 KiB  
Article
The Value of ER∝ in the Prognosis of GH- and PRL-Secreting PitNETs: Clinicopathological Correlations
by Roxana-Ioana Dumitriu-Stan, Iulia-Florentina Burcea, Valeria Nicoleta Nastase, Raluca Amalia Ceaușu, Anda Dumitrascu, Laurentiu Catalin Cocosila, Alexandra Bastian, Sabina Zurac, Marius Raica and Catalina Poiana
Int. J. Mol. Sci. 2023, 24(22), 16162; https://doi.org/10.3390/ijms242216162 - 10 Nov 2023
Viewed by 745
Abstract
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 [...] Read more.
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∝, 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∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, p < 0.01) and postoperative PRL levels (rho = 0.58, p < 0.001). In our study, the ER∝ 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 < 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 < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter (p = 0.63, p < 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∝ can be used as a prognostic marker and loss of ER∝ 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. Full article
(This article belongs to the Special Issue Molecular Biology of the Pituitary 3.0)
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11 pages, 2576 KiB  
Article
The Methylation Analysis of the Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Locus in GH-Secreting Pituitary Adenomas
by Mattia Dalle Nogare, Sarah D’Annunzio, Giovanni Vazza, Daniela Regazzo, Luna Picello, Luca Denaro, Giacomo Voltan, Carla Scaroni, Filippo Ceccato and Gianluca Occhi
Int. J. Mol. Sci. 2023, 24(11), 9264; https://doi.org/10.3390/ijms24119264 - 25 May 2023
Cited by 1 | Viewed by 1248
Abstract
The glucose-dependent insulinotropic polypeptide receptor (GIPR) is aberrantly expressed in about one-third of GH-secreting pituitary adenomas (GH-PAs) and has been associated with a paradoxical increase of GH after a glucose load. The reason for such an overexpression has not yet been clarified. In [...] Read more.
The glucose-dependent insulinotropic polypeptide receptor (GIPR) is aberrantly expressed in about one-third of GH-secreting pituitary adenomas (GH-PAs) and has been associated with a paradoxical increase of GH after a glucose load. The reason for such an overexpression has not yet been clarified. In this work, we aimed to evaluate whether locus-specific changes in DNA methylation patterns could contribute to this phenomenon. By cloning bisulfite-sequencing PCR, we compared the methylation pattern of the GIPR locus in GIPR-positive (GIPR+) and GIPR-negative (GIPR−) GH-PAs. Then, to assess the correlation between Gipr expression and locus methylation, we induced global DNA methylation changes by treating the lactosomatotroph GH3 cells with 5-aza-2′-deoxycytidine. Differences in methylation levels were observed between GIPR+ and GIPR− GH-PAs, both within the promoter (31.9% vs. 68.2%, p < 0.05) and at two gene body regions (GB_1 20.7% vs. 9.1%; GB_2 51.2% vs. 65.8%, p < 0.05). GH3 cells treated with 5-aza-2′-deoxycytidine showed a ~75% reduction in Gipr steady-state level, possibly associated with the observed decrease in CpGs methylation. These results indicate that epigenetic regulation affects GIPR expression in GH-PAs, even though this possibly represents only a part of a much more complex regulatory mechanism. Full article
(This article belongs to the Special Issue Molecular Biology of the Pituitary 3.0)
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15 pages, 4711 KiB  
Article
The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas
by Zhenye Li, Yiyuan Chen, Xiaohui Yao, Qian Liu, Haibo Zhu, Yazhuo Zhang, Jie Feng and Hua Gao
Int. J. Mol. Sci. 2022, 23(21), 13067; https://doi.org/10.3390/ijms232113067 - 28 Oct 2022
Viewed by 1360
Abstract
Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of [...] Read more.
Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2β (EIF2β) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2β in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2β was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p < 0.001) for EIF2β and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p < 0.001) for GCN2, and r = 0.732 (p < 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2β was greater than that in patients with a low EIF2β (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p < 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p < 0.001). In in vitro experiments, the knockdown of EIF2β changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies. Full article
(This article belongs to the Special Issue Molecular Biology of the Pituitary 3.0)
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Review

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20 pages, 2272 KiB  
Review
Prolactin and Growth Hormone Signaling and Interlink Focused on the Mammosomatotroph Paradigm: A Comprehensive Review of the Literature
by Marta Araujo-Castro, Mónica Marazuela, Manel Puig-Domingo and Betina Biagetti
Int. J. Mol. Sci. 2023, 24(18), 14002; https://doi.org/10.3390/ijms241814002 - 12 Sep 2023
Cited by 2 | Viewed by 1952
Abstract
Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or [...] Read more.
Prolactin (PRL) and growth hormone (GH) are peptide hormones that bind to the class 1 cytokine receptor superfamily, a highly conserved cell surface class of receptors. Both hormones control their own secretion via a negative autocrine loop in their own mammosomatotroph, lactotroph or somatotroph. In this regard, GH and PRL are regulated by similar signaling pathways involving cell growth and hormone secretion. Thus, GH and PRL dysregulation and pituitary neuroendocrine tumor (PitNET) development may have common pathogenic pathways. Based on cell linage, lactotroph and somatotroph PitNETs come from pituitary-specific POU-class homeodomain transcription factor (Pit-1). Mammosomatotroph and plurihormonal PitNETs are a unique subtype of PitNETs that arise from a single-cell population of Pit-1 lineage. In contrast, mixed somatotroph–lactotroph PitNETs are composed of two distinct cell populations: somatotrophs and lactotrophs. Morphologic features that distinguish indolent PitNETs from locally aggressive ones are still unidentified, and no single prognostic parameter can predict tumor aggressiveness or treatment response. In this review, we aim to explore the latest research on lactotroph and somatotroph PitNETs, the molecular mechanisms involved in PRL and GH axis regulation and the signaling pathways involved in their aggressiveness, particularly focused on mammosomatotroph and mixed subtypes. Finally, we summarize epidemiological, clinical, and radiological features of these exceptional tumors. We aim to shed light, from basic to clinical settings, on new perspectives and scientific gaps in this field. Full article
(This article belongs to the Special Issue Molecular Biology of the Pituitary 3.0)
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18 pages, 1793 KiB  
Review
Role of Estrogen and Estrogen Receptor in GH-Secreting Adenomas
by Giacomo Voltan, Pierluigi Mazzeo, Daniela Regazzo, Carla Scaroni and Filippo Ceccato
Int. J. Mol. Sci. 2023, 24(12), 9920; https://doi.org/10.3390/ijms24129920 - 08 Jun 2023
Viewed by 1035
Abstract
Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some [...] Read more.
Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some decades ago, estrogens were first used to treat acromegaly, resulting in a significant decrease in IGF1 levels. However, due to the consequent side effects of the high dose utilized, this treatment was later abandoned. The evidence that estrogens are able to blunt GH activity also derives from the evidence that women with GH deficiency taking oral estro-progestins pills need higher doses of GH replacement therapy. In recent years, the role of estrogens and Selective Estrogens Receptor Modulators (SERMs) in acromegaly treatment has been re-evaluated, especially considering poor control of the disease under first- and second-line medical treatment. In this review, we analyze the state of the art concerning the impact of estrogen and SERMs on the GH/IGF1 axis, focusing on molecular pathways and the possible implications for acromegaly treatment. Full article
(This article belongs to the Special Issue Molecular Biology of the Pituitary 3.0)
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15 pages, 2852 KiB  
Review
Hypophysitis: Defining Histopathologic Variants and a Review of Emerging Clinical Causative Entities
by Cameron A. Rawanduzy, Alexander Winkler-Schwartz and William T. Couldwell
Int. J. Mol. Sci. 2023, 24(6), 5917; https://doi.org/10.3390/ijms24065917 - 21 Mar 2023
Cited by 1 | Viewed by 2080
Abstract
Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis is variable and diverse. Hypophysitis can be primary and idiopathic or autoimmune related, or secondary to local lesions, systemic disease, [...] Read more.
Inflammatory disease of the pituitary gland is known as hypophysitis. There are multiple histological subtypes, the most common being lymphocytic, and the pathogenesis is variable and diverse. Hypophysitis can be primary and idiopathic or autoimmune related, or secondary to local lesions, systemic disease, medications, and more. Although hypophysitis was previously accepted as an exceedingly rare diagnosis, a greater understanding of the disease process and new insights into possible etiologic sources have contributed to an increased frequency of recognition. This review provides an overview of hypophysitis, its causes, and detection strategies and management. Full article
(This article belongs to the Special Issue Molecular Biology of the Pituitary 3.0)
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