Growth Hormone-secreting Pituitary Tumors Research Articles

Asynchronous, double, growth hormone-secreting pituitary neuroendocrine tumor of a variable proliferative potential.

Asynchronous, double, growth hormone-secreting pituitary neuroendocrine tumor of a variable proliferative potential.

Collision sellar lesion: coexistence of growth hormone-secreting pituitary neuroendocrine tumor and pituicytoma.

Collision sellar lesion: coexistence of growth hormone-secreting pituitary neuroendocrine tumor and pituicytoma.

Exploring the role of the tumor microenvironment in refractory pituitary tumor pathogenesis.

Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a dominant role in promoting aggressiveness and refractoriness. However, role of the TME in pituitary tumors is not well studied. Literature on the TME and development of refractory pituitary tumors was reviewed RESULTS: TME harbors tumorigenic immune cells, cancer-associated fibroblasts (CAF), extracellular matrix, and other factors that have been shown to affect behavior of tumor tissue. For example, tumor-associated macrophages and tumor-infiltrating lymphocytes correlate with aggressive and invasive tumor behavior in nonfunctioning and growth hormone-secreting (GH) pituitary tumors, while CAF release of TGFβ, FGF2, cytokines, chemokines, and growth factors may promote treatment resistance, tumor fibrosis, and inflammation in prolactinomas and GH-secreting tumors. In turn, Wnt pathway activation can further promote cell growth in dopamine-resistant prolactinomas. Finally, proteins secreted by extracellular matrix are associated with increased angiogenesis in invasive tumors. It is likely that multiple mechanisms, including TME, contribute to the development of aggressive refractory pituitary tumors. Given the increased morbidity and mortality associated with pituitary tumor refractoriness, more research on the role of TME is warranted.

The Prognostic-Based Approach in Growth Hormone-Secreting Pituitary Neuroendocrine Tumors (PitNET): Tertiary Reference Center, Single Senior Surgeon, and Long-Term Follow-Up

Postoperative deserved outcomes in acromegalic patients are to normalize serum insulin-like growth factor (IGF-1), reduce the tumoral mass effect, improve systemic comorbidities, and reverse metabolic alterations. Pituitary neuroendocrine tumors (PitNET) are characterized to present a heterogeneous behavior, and growth hormone (GH)-secreting PitNET is not an exception. Promptly determining which patients are affected by more aggressive tumors is essential to guide the optimal postoperative decision-making process [prognostic-based approach]. From 2006 to 2019, 394 patients affected by PitNET were intervened via endoscopic endonasal transsphenoidal approach by the same senior surgeon. A total of 44 patients that met the criteria to be diagnosed as acromegalic and were followed up at least for 24 months (median of 66 months (26-156) were included in the present study. Multiple predictive variables [age, gender, preoperative GH and IGF-1 levels, maximal tumor diameter, Hardy's and Knosp's grade, MRI. T2-weighted tumor intensity, cytokeratin expression pattern, and clinicopathological classification] were evaluated through uni- and multivariate statistical analysis. Sparse probability of long-term remission was related to younger age, higher preoperative GH and- or IGF-1, group 2b of the clinicopathological classification, and sparsely granulated cytokeratin expression pattern. Augmented recurrence risk was related to elevated preoperative GH levels, tumor MRI T2-weighted hyperintensity, and sparsely granulated cytokeratin expression pattern. Finally, elevated risk for reintervention was related to group 2b of the clinicopathological classification, Knosp's grade IV, and tumor MRI T2-weighted hyperintensity. In this study, the authors determined younger age, higher preoperative GH and- or IGF-1 levels, group 2b of the clinicopathological classification, Knosp's grade IV, MRI T2-weighted tumor hyperintensity and sparsely granulated cytokeratin expression pattern are related to worse postoperative outcomes in long-term follow-up patients affected with GH-secreting PitNET.

RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.

GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of G s and G q/11

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). We report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101mice. We also show that GPR101 promotes GH secretion through the activation of not only Gs, but also Gq/11, in a PKA and PKC-dependent manner, respectively. Interestingly, in stark contrast with other Gs-coupled receptors, GPR101 activation did not lead to the proliferation of somatotrope cells. These signatures of GPR101 signaling, notably PKC activation, are also present in human X-LAG pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.

Oncogene-induced DNA damage: cyclic AMP steps into the ring.

Growth hormone-secreting (GH-secreting) pituitary tumors are driven by oncogenes that induce cAMP signaling. In this issue of the JCI, Ben-Shlomo et al. performed a whole-exome study of pituitary adenomas. GH-secreting tumors had a high frequency of whole chromosome or chromosome arm copy number alterations and were associated with an increase in the tumor protein p53 and the cyclin-dependent kinase inhibitor p21WAF1/CIP1, which are findings consistent with induction of a response to DNA damage. Further, treatment of mouse pituitary cells with cAMP pathway agonists in vitro and in vivo elicited biomarkers of DNA replication stress or double-strand breaks. The findings of Ben Shlomo et al. indicate that oncoproteins that drive constitutively high cAMP signaling pathway output in susceptible cell types can elicit DNA replication stress and may promote genomic instability.

Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors

Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory Gα protein (Gαs encoded by GNAS) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone-secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were GNAS mutation negative (Gsp- ). The chromosome stable (CS) -group contained Gsp+ somatotropinomas and two totally aneuploidy-free Gsp- tumors. Genes related to the mitotic G1-S-checkpoint transition were differentially expressed in CA- and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct Gsp genotype-specific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Gα (Gαi) signaling is activated in Gsp+ tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp- somatotropinomas, whereas Gsp+ tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Gαi signaling. IMPLICATIONS: These findings provide valuable new information about subtype-specific pituitary tumorigenesis and may help to elucidate the mechanisms of aneuploidy also in other tumor types.

Sparsely and densely granulated growth hormone-secreting pituitary tumours (somatotropinomas): from histopathology to epigenomics

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Distinct methylation patterns in sparsely and densely granulated growth hormone-secreting pituitary tumours provide clues to different underlying tumorigenic mechanisms

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Propofol Requirement in Patients with Growth Hormone-Secreting Pituitary Tumors Undergoing Transsphenoidal Surgery.

Growth hormone (GH) secretion is regulated by various hormones or neurotransmitters, including gamma-aminobutyric acid. The aim of this study was to determine the propofol requirement in patients with GH-secreting pituitary tumors undergoing transsphenoidal surgery. General anesthesia was induced in 60 patients with GH-secreting tumors (GH group, n = 30) or nonfunctioning pituitary tumors (NF group, n = 30) using an effect-site target-controlled intravenous propofol infusion. The effect-site concentrations were recorded at both a loss of consciousness and a bispectral index (BIS) of 40, along with the effect-site concentration after extubation, during emergence from the anesthesia. The effect-site concentration of propofol was higher in the GH group than in the NF group at a loss of consciousness and a BIS of 40 (4.09 ± 0.81 vs. 3.58 ± 0.67, p = 0.009 and 6.23 ± 1.29 vs. 5.50 ± 1.13, p = 0.025, respectively) and immediately after extubation (1.60 ± 0.27 vs. 1.40 ± 0.41, p = 0.046). The total doses of propofol and remifentanil during anesthesia were comparable between the groups (127.56 ± 29.25 vs. 108.64 ± 43.16 µg/kg/min, p = 0.052 and 6.67 ± 2.89 vs. 7.05 ± 1.96 µg/kg/h, p = 0.550, respectively). The propofol requirement for the induction of a loss of consciousness and the achievement of a BIS of 40 is increased during the induction of general anesthesia in patients with GH-secreting tumors.

SUN-LB056 The Pharmacological Blockade of the Splicing Factor SF3B1 Exerts Antitumor Actions in Different Endocrine-Related Cancers

The intrinsic heterogeneity of endocrine-related cancers (ERCs) hampers the identification and development of global and effective therapeutic treatments for these pathologies. However, the dysregulation of the splicing process has been postulated as a new common hallmark shared by most cancer types, since it is associated with the appearance of splicing variants with oncogenic potential (e.g. CD44v6, BCL-xs, AR-v7, SST5TMD4, In1-ghrelin). Yet, the putative alteration, pathophysiological role and potential therapeutic utility of the elements involved in the control of the splicing process [i.e. spliceosome components (SCs) and splicing factors (SFs)] remain still unknown. For this reason, we have analysed the expression levels of a representative set of SCs (n=18) and SFs (n=27) in different cohorts of ERCs [i.e. growth hormone secreting pituitary tumors (n=96); non-functioning pituitary tumors (n=23); pancreatic neuroendocrine tumors (n=20); prostate cancer (n=126); and in four in silico cohorts of liver cancer (HCC; n=445, n=115, n=75, n=45)]. Our results showed that the SF3b subunit 1 (SF3B1) gene, which encodes a protein necessary for spliceosome assembly, was consistently overexpressed in all the ERCs evaluated in this study. Interestingly, SF3B1 expression was positively correlated and associated with clinical and molecular aggressiveness features (e.g. histopathological grade, presence of metastasis, expression of oncogenic splicing variants, etc.) in these ERCs. In vitro analyses revealed that the specific blockade of SF3B1 activity, using the pladienolide-B compound, exhibited potent and relevant antitumor effects (reducing cell proliferation, migration, tumorospheres and colonies formation, hormone release and inducing apoptosis) in the vast majority of representative models of ERC cells tested herein (primary ERCs cell cultures and cell lines such as BON-1, QGP-1, LNCaP, 22Rv1, PC-3, HepG2, Hep3b or SNU-387). Remarkably, the antitumor effects of pladienolide-B treatment were further validated in vivo in that we found a significant reduction of tumor volume after 9-days of local treatment of pladienolide-B in a xenograft model of ERC. Moreover, we found that pladienolide-B treatment modulated an ample repertoire of molecular events, such as inhibition of major oncogenic signalling pathways (e.g. PI3K/AKT and JNK), modulation of the expression of key tumour markers (e.g. MKI67/CDK6/CDKN2A) and oncogenic splicing variants (e.g. AR-v7/In1-ghrelin), and regulation of the expression pattern of key components of mRNA homeostasis-associated machineries (spliceosome and SURF/EJC). In conclusion, these results indicate that SF3B1 is consistently overexpressed in different ERCs and associated to malignant features and that its pharmacological blockade with pladienolide-B could represent a novel, global and effective therapeutic approach for ERCs Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein (AIP) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP-mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip-knockout (AipFlox/Flox;Hesx1Cre/+) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the “epithelial-to-mesenchymal transition (EMT) pathway” as one of the most significantly altered pathways in AIPpos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip-knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP-mutation-positive human adenomas. Aip-knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP-mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.

Functional Pituitary Tumors Masquerading as Primary Glaucoma and Effect of Hypophysectomy on Intraocular Tension

We report 2 bilateral cases that presented as primary ocular hypertension and primary angle-closure glaucoma, respectively; however, they were subsequently discovered to be harboring secretory pituitary tumors. After transsphenoidal tumor resection, intraocular pressures (IOPs) in all 4 eyes returned to normal levels. Sudden rise in IOP then again served as a primary manifestation of relapse in the second patient with growth hormone secreting pituitary tumor. It was not found feasible for resurgery; thus, patient needed trabeculectomy in both eyes to achieve an optimum control of intraocular tension. We conclude that pituitary adenomas may mimic primary glaucoma without producing vertical hemianopia and cause a reversible rise in IOP. Furthermore, a careful ongoing expert ophthalmologic assessment may serve as a useful clinical marker for early relapse in these tumors.

Влияние иммуногистохимических маркеров Ki-67 и p53 на отдаленные результаты лечения опухолей гипофиза, секретирующих гормон роста: когортное исследование

Влияние иммуногистохимических маркеров Ki-67 и p53 на отдаленные результаты лечения опухолей гипофиза, секретирующих гормон роста: когортное исследование

Should all patients with acromegaly receive somatostatin analogue therapy before surgery and, if so, for how long?

Current guidelines do not recommend the routine use of somatostatin analogue pretreatment prior to surgery in patients with growth hormone-secreting pituitary tumours. In theory, presurgical use of somatostatin analogues should improve metabolic control and reduce soft tissue swelling, leading to improved anaesthetic outcomes. Shrinkage of tumours prior to surgery might also improve surgical remission rates. Hence, this article addresses the question: Should all patients with acromegaly receive a somatostatin analogue prior to surgery? Clinical trials published before December 2013 were reviewed, although literature in this area remains relatively deficient. We conclude: (i) On the basis of limited data available, somatostatin analogue pretreatment does not improve anaesthetic or immediate postoperative outcomes (i.e. hospital stay, rates of surgical complications and postoperative pituitary dysfunction). (ii) Somatostatin analogues should be considered in all patients with growth hormone-secreting macroadenomas, including invasive macroadenomas, when the overall surgical remission rate for macroadenomas at the treating centre is below 50%. Four recent RCTs have demonstrated increased rates of surgical remission using such an approach. (iii) When deemed appropriate, patients should be treated with somatostatin analogues for at least 3months before surgery; there is currently no evidence that treatment beyond 6months provides any additional benefit. Patients with minimally invasive macroadenomas are those most likely to benefit in terms of improved surgical remission.

Acromegaly: A single centre’s experience of stereotactic radiosurgery and radiotherapy for growth hormone secreting pituitary tumours with the linear accelerator

Primary treatment for growth-hormone secreting pituitary adenomas usually involves surgery, with treatment options for recurrent and persistent disease including repeat surgery, medication and radiation therapy. The majority of previously published series for radiation therapy in acromegaly in the past 20years have been based on Gamma-Knife (Elekta, Stockholm, Sweden) surgery. To our knowledge, we present the largest series of linear accelerator-based treatment for this disease, with a review of 121 patients treated at our institution; since 1990, 86 patients underwent stereotactic radiosurgery (SRS), 10 patients underwent fractionated stereotactic radiotherapy (FSRT), and for the purposes of comparison we also reviewed 25 patients who underwent conventional radiotherapy prior to 1990. Tumour volume control in all three groups was excellent and consistent with previously reported literature – only three of 86 (4%) patients undergoing SRS had a documented increase in tumour size, and none of the patients undergoing FSRT had a documented increase in size following a median follow-up of 5.5 and 5.1years for SRS and FSRT, respectively. Target growth hormone levels of <2.5ng/mL were met by 12 of 86 (14%) of the SRS group, and by two of 10 (20%) in the FSRT group. Target insulin-like growth factor-1 levels of age and sex matched controls were achieved in 16 of 86 patients (18.6%) post-SRS and five of 10 patients (50%) post-FSRT. New hormonal deficits requiring replacement therapy were identified in 17 of 86 (19.8%) patients post-SRS which is consistent with previously published radiosurgical series. Identified non-hormonal morbidity was low (<5%).

Long-term treatment of somatostatin analog-refractory growth hormone-secreting pituitary tumors with pegvisomant alone or combined with long-acting somatostatin analogs: a retrospective analysis of clinical practice and outcomes

BackgroundPegvisomant (PEGV) is widely used, alone or with somatostatin analogs (SSA), for GH-secreting pituitary tumors poorly controlled by SSAs alone. No information is available on specific indications for or relative efficacies of PEGV?+?SSA versus PEGV monotherapy. Aim of our study was to characterize real-life clinical use of PEGV vs. PEGV?+?SSA for SSA-resistant acromegaly (patient selection, long-term outcomes, adverse event rates, doses required to achieve control).MethodsA retrospective analysis of data collected in 2005–2010 in five hospital-based endocrinology centers in Rome was performed. Sixty-two adult acromegaly patients treated ≥6 months with PEGV (Group 1, n?=?35) or PEGV?+?SSA (Group 2, n?=?27) after unsuccessful maximal-dose SSA monotherapy (≥12 months) were enroled. Groups were compared in terms of clinical/biochemical characteristics at diagnosis and before PEGV or PEGV?+?SSA was started (baseline) and end-of-follow-up outcomes (IGF-I levels, adverse event rates, final PEGV doses).ResultsGroup 2 showed higher IGF-I and GH levels and sleep apnea rates, higher rates residual tumor tissue at baseline, more substantial responses to SSA monotherapy and worse outcomes (IGF-I normalization rates, final IGF-I levels). Tumor growth and hepatotoxicity events were rare in both groups. Final daily PEGV doses were similar and significantly increased with treatment duration in both groups.ConclusionsPEGV and PEGV?+?SSA are safe, effective solutions for managing SSA-refractory acromegaly. PEGV?+?SSA tends to be used for more aggressive disease associated with detectable tumor tissue. With both regimens, ongoing monitoring of responses is important since PEGV doses needed to maintain IGF-I control are likely to increase over time.

Characteristics of Acromegaly in Korea with a Literature Review

Acromegaly is a slowly progressive disease caused by excessive growth hormone (GH), which is related to a GH secreting pituitary tumor in most cases. Herein, we describe the epidemiology, clinical characteristics, and treatment of acromegaly in Korea with a literature review. The average annual incidence of acromegaly in Korea was 3.9 cases per million people, which was within the range of previous Western studies. The primary treatment for acromegaly was also transsphenoidal adenomectomy, which accounted for 90.4% of patients whose primary therapeutic options were known. The overall surgical remission rates were 89%, 87%, 64%, 70%, and 50% for modified Hardy classification I, II, IIIA, IIIB, and IV, respectively. An updated and larger study regarding the treatment outcome of medical/radiotherapy in Korean acromegalic patients is needed.

A Case of Latent Autoimmune Diabetes in Adults Developed after Surgical Cure of Growth Hormone Secreting Pituitary Tumor

Wonjin Kim1, Jung Ho Kim1, Youngsook Kim1, Ji Hye Huh1, Su Jin Lee1, Mi Sung Park1, Eun Yeong Choe1, Jeong Kyung Park2, Myung Won Lee3, Jae Won Hong, Byung Wan Lee14, Eun Seok Kang14, Bong Soo Cha14, Eun Jig Lee14, Hyun Chul Lee14 Department of Internal Medicine, Yonsei University College of Medicine, Seoul; Institute of Endocrinology, Goodmorning Hospital, Pyeongtaek; Institute of Endocrinology, Gwangmyung Sungae Hospital, Gwangmyeong; Institute of Endocrine Research, Yonsei University College of Medicine, Seoul; Diabetes Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea