下垂体性PRL分泌亢進症

Prolactinomas are the most common neuroendocrine tumors of the pituitary and the leading cause of hyperprolactinemia. Dopamine Receptor Agonists (DAs), particularly cabergoline (CAB), effectively reduce prolactin levels and tumor volume, and are therefore the first-line therapy for prolactinomas. With long-term cabergoline use, adverse effects may become more consequential for some patients. Cabergoline-Associated Valvulopathy (CAV) primarily affects the mitral, tricuspid, and aortic valves, although its underlying mechanisms remain unclear. The potential link between CAB use and Valvular Heart Disease (VHD) in patients with prolactinomas remains controversial. This review summarizes current understanding of CAV and explores potential molecular mechanisms, including CAB's modulation of catecholaminergic, serotonergic, and Transforming Growth Factor-beta (TGF-β) related signaling pathways, along with inflammatory pathways. By integrating clinical patterns with mechanistic plausibility, we aim to support practical surveillance decisions and improve the long-term safety of CAB therapy in patients with prolactinomas.

We report a woman in her 50s with a giant co-secreting pituitary macroadenoma producing both prolactin and growth hormone. She presented with headache, proptosis, chemosis and secondary amenorrhoea since her 20s. Workup showed hyperprolactinaemia (251 μg/L; normal ≤23 μg/L). A brain MRI showed a giant mass at the base of the skull. Repeat prolactin assay after serum dilution showed marked hyperprolactinaemia (386 020 μg/L), consistent with a giant prolactin-secreting tumour. Additional tests established the presence of growth hormone excess. She was treated with cabergoline, leading to substantial clinical improvement and progressive decrease in tumour size and prolactin. Additionally, she was initially treated with lanreotide which was ineffective. She was switched to pegvisomant therapy, resulting in insulin-like growth factor I normalisation. This case emphasises the critical importance of recognising the hook effect artefact in patients with large sellar masses. Slow uptitration of dopamine agonist therapy is advisable in patients with large tumours to minimise the risks of cerebrospinal fluid leak, apoplexy and herniation.

Male lactotroph pituitary neuroendocrine tumors (PitNETs) are often considered more aggressive than those in women, but surgically treated cohorts are highly selected and may reflect differences in presentation and indication for surgery. We examined whether advanced clinical presentation in surgically treated lactotroph PitNETs is accompanied by distinct pathologic features. We reviewed 43 patients who underwent surgery for lactotroph PitNETs between 2018 and 2023 at a high-volume referral center. Cases were classified by surgical indication as preference for surgery/intolerance to dopamine agonists (P/I, n=26), resistance with hormonal symptoms (R/H, n=10), and resistance with mass effect (R/M, n=7). Clinical, radiologic, and pathologic parameters, including Ki-67, cytokeratin (CAM5.2), estrogen receptor, somatostatin receptor 2/5, and O6-methylguanine-DNA methyltransferase, were compared. Postoperative endocrinological remission was assessed at the last follow-up (median: 34 mo). All tumors were prolactin-immunoreactive, confirming lactotroph differentiation. Patients in the R/M group were older (median: 56 y), predominantly male (71.4%), and had larger tumors (median: 26 mm) with more frequent cavernous sinus invasion (Knosp grade 4, 85.7%) than those in the other groups. Long-term endocrinological remission differed significantly by indication (P/I, 88.5%; R/H, 80.0%; and R/M, 0%). In contrast, Ki-67 labeling index did not differ significantly across groups (P/I, 1.3%; R/H, 1.5%; and R/M, 2.6%; P=0.598), and no clear between-group differences were identified in CAM5.2 pattern, estrogen receptor, somatostatin receptor 2/5, or O6-methylguanine-DNA methyltransferase status. These findings suggest that the clinically most advanced surgical cases are not matched by distinct pathologic differences in the markers assessed and that the apparent aggressiveness of male-predominant mass-effect cases should not be interpreted solely as reflecting intrinsically aggressive tumor biology.

CONTEXT: Prolactinomas are the most common functional pituitary adenomas. While altered gut microbiota has been observed in prolactinomas, whether these changes influence tumor behavior remains unclear. Our study integrated multi-omics data to investigate potential associations between gut microbiota composition and tumor characteristics in prolactinomas, as well as to explore potential molecular mechanisms and therapeutic pathway targets. METHODS: Through 16S rRNA and mRNA sequencing of 10 paired patients, we identified Blautia-invasiveness associations and PTGS1 involvement in invasive heterogeneity of prolactinomas. We validated findings using large-cohort multi-omics datasets and evaluated PTGS1 as a therapeutic target in patient-derived organoids. RESULTS: Blautia abundance in the gut microbiota of patients with prolactinomas correlated with tumor invasiveness. Integrating tumor transcriptomic data, we observed a positive correlation between Blautia abundance and PTGS1 expression. We leveraged previously published large-cohort multi-omics datasets and confirmed that PTGS1 is markedly upregulated in prolactinomas, with higher expression in highly invasive tumors. Differential expression analysis of tumor mRNA-seq revealed that PTGS1-high tumors showed enrichment of extracellular matrix remodeling and immune-related pathways associated with tumor invasiveness. Finally, targeting PTGS1 with the selective inhibitor Tenidap in patient-derived prolactinoma organoids suppressed organoid proliferation and prolactin secretion. CONCLUSION: We identified a correlation between Blautia abundance and PTGS1 expression in prolactinomas, with PTGS1-high tumors showing enrichment of tumor microenvironment remodeling and immune-related pathways. These findings suggest a potential Blautia-PTGS1-tumor microenvironment association in prolactinomas that requires further mechanistic investigation to establish causality. Keywords Prolactinoma, Multi-omics, Blautia, Prostaglandin endoperoxide synthase 1, Tumor environment.