Diagnosis and Treatment of Pituitary Apoplexy, A True Endocrine Emergency.

Pituitary apoplexy (PA) is a clinical syndrome resulting from a hemorrhagic infarction of the pituitary gland. It is characterized by the sudden onset of visual disturbances, nausea, vomiting, headache and occasionally, signs of meningeal irritation and an altered mental status. The exact pathogenesis of PA remains to be elucidated, although tumor overgrowth of its blood supply remains the most popular theory. Main risk factors for the development of PA include systemic, iatrogenic, and external factors as well as the presence of an underlying pituitary tumor. The diagnostic approach of PA includes both neuroimaging and evaluation of pituitary secretory function. PA is a potentially life-threatening condition which should be managed with hemodynamic stabilization, correction of electrolyte abnormalities and replacement of hormonal deficiencies. PA treatment should be individualized based on the severity of the clinical picture which may vary widely. Treatment options include conservative management with periodic follow-up or neurosurgical intervention, which should be decided by a multidisciplinary team. We conducted a systematic review of the literature to unveil the frequency of PA predisposing factors, clinical and biochemical presentations, management strategies and outcomes.

The molecular biology of sporadic acromegaly.

GH-secreting tumors represent 15 % to 20 % of all pituitary neuroendocrine tumors (pitNETs), of which 95 % occur in a sporadic context, without an identifiable inherited cause. Recent multi-omic approaches have characterized the epigenomic, genomic, transcriptomic, proteomic and kynomic landscape of pituitary tumors. Transcriptomic analysis has allowed us to discover specific transcription factors driving the differentiation of pituitary tumors and gene expression patterns. GH-secreting, along with PRL- and TSH-secreting pitNETs are driven by POU1F1; ACTH-secreting tumors are determined by TBX19; and non-functioning tumors, which are predominantly of gonadotrope differentiation are conditioned by NR5A1. Upregulation of certain miRNAs, such as miR-107, is associated with tumor progression, while downregulation of others, like miR-15a and miR-16-1, correlates with tumor size reduction. Additionally, miRNA expression profiles are linked to treatment resistance and clinical outcomes, providing insights into potential therapeutic targets. Specific somatic mutations in GNAS, PTTG1, GIPR, HGMA2, MAST and somatic variants associated with cAMP, calcium signaling, and ATP pathways have also been associated with the development of acromegaly. This review focuses on the oncogenic mechanisms by which sporadic acromegaly can develop, covering a complex series of molecular alterations that ultimately alter the balance between proliferation and apoptosis, and dysregulated hormonal secretion.

Mesenchymal stem cells induce an immunosuppressive microenvironment in pituitary tumors.

BACKGROUND: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells among others. MSC have been isolated from different tumors and they favor tumor cell growth, however, their role in pituitary tumors (PT) remains unknown. Herein we report the presence of MSCs in 2 ACTH-secreting PT causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF) and 2 non tumoral pituitary glands (MS). METHODS: We have analyzed their transcriptomic profiles by RNAseq and compared MSC in terms of their immunosuppressive effects against lymphoid T cell and macrophage populations by means of co-cultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSC derived from non-tumoral pituitaries and MSC derived from PT. Two distinct subpopulations of MSC, one displaying immunosuppressive properties and the other with increased pro-proliferative capabilities, regardless of their origin. MSC derived from ACTH- and nonfunctioning PT, but not those derived from non-tumoral glands significantly inhibited the proliferation of activated T cells, favored the generation of Tregs and promote M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony stimulating factor (M-CSF) and IL-10. Importantly, MSC derived from ACTH-PT showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least two MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSC may have important implications in PT growth.

Genomics, Transcriptomics, and Epigenetics of Sporadic Pituitary Tumors.

Pituitary tumors (PT) are highly heterogeneous neoplasms, comprising functioning and nonfunctioning lesions. Functioning PT include prolactinomas, causing amenorrhea-galactorrhea in women and sexual dysfunction in men; GH-secreting adenomas causing acromegaly-gigantism; ACTH-secreting corticotrophinomas causing Cushing disease (CD); and the rare TSH-secreting thyrotrophinomas that result in central hyperthyroidism. Nonfunctioning PT do not result in a hormonal hypersecretion syndrome and most of them are of gonadotrope differentiation; other non-functioning PT include null cell adenomas and silent ACTH-, GH- and PRL-adenomas. Less than 5% of PT occur in a familial or syndromic context whereby germline mutations of specific genes account for their molecular pathogenesis. In contrast, the more common sporadic PT do not result from a single molecular abnormality but rather emerge from several oncogenic events that culminate in an increased proliferation of pituitary cells, and in the case of functioning tumors, in a non-regulated hormonal hypersecretion. In recent years, important advances in the understanding of the molecular pathogenesis of PT have been made, including the genomic, transcriptomic, epigenetic, and proteomic characterization of these neoplasms. In this review, we summarize the available molecular information pertaining the oncogenesis of PT.