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Difficulty in establishing the diagnosis of Cushing disease is well known, given the impossibility of performing biopsy of the ACTH-secretory pituitary adenomas due to their extremely small size. This impediment can be overcome if we observe the results obtained by Oklu R and co [A] in his metabolomics study performed in 2013. Thus, he evaluated 8 patients with suspicion of Cushing disease, who presented clinical manifestations suggestive of hypercorticism (e.g. hypertension, osteoporosis, easy bruising, weight gain, fatigue, diabetes mellitus, hirsutism, moon face etc.), but with indeterminate imaging. In order to confirm the diagnosis, these patients underwent bilateral inferior petrosal sinus with dosage of central blood samples at 0’, 3’, 5’, 10’ and 15’ after intravenous injection of CRH. ACTH-secretory pituitary adenomas were confirmed in 7 patients, while in one patient the diagnosis was excluded. Plasma obtained after centrifugation of central blood samples from the ipsilateral inferior petrosal sinus to ACTH-secreting adenomas (7 samples) was compared to contralateral plasma samples and two samples from the patient to whom the ACTH secretion has not been documented (9 samples).
Postoperative follow-up showed an improvement in symptomatology in 4 patients and a remission of this in the remaining 3 patients. Using three LC-MS methods (hydrophilic interaction liquid chromatography method for analyses of polar metabolites in the positive and negative ion mode respectively and a reversed phase method to profile lipids in the positive ion mode) initially identified 12 significantly metabolites in ACTH-pituitary adenomas in comparison to control group (p<0.05). These are represented by 2-Hydroxybutyric acid, aminoadipic acid, L-Aspartic acid, 3-Hydroxyphenylacetic acid, hypoxanthine, 4-Pyridoxic acid, quinolinic acid, sucrose, xanthine, glucose 6-phosphate, deoxycholic acid and 3-Methyladipate.
After Bonferroni adjustment, only 3-Methyladipate, deoxycholic acid and pyridoxate are statistically significant. In addition, using KEGG pathway database, the aouthor identified 8 main pathways: alanine, aspartate and glutamate metabolism (the most affected), vitamin B metabolism, lysine biosynthesis, purine metabolism, amino sugar and nucleotide sugar metabolism, glycolysis or gluconeogenesis and starch and sucrose metabolism.
The first metabolomics study on pituitary adenomas was implemented by Oklu R and co [A] in 2013. He evaluated the metabolomic profile in seven patients with ACTH-secreting pituitary adenomas using plasma from the inferior petrosal sinus in comparison with nine contralateral plasma samples. Reference Biological sample analyzed from pituitry adenomas Analytical Technique Results Oklu R [A] 16 central blood samples (plasma) from 7 patients with ACTH-secreting pituitary adenomas who underwent bilateral inferior petrosal sinus versus 9 control plasma samples LC-MS/MS Metabolites: deoxycholic acid, 3-methyladipate, pyridoxate – significantly altered Pathways: alanine, aspartate and glutamate metabolism (the most affected), vitamin B metabolism, lysine biosynthesis, purine metabolism, amino sugar and nucleortide sugar metabolism, glycolysis or gluconeogenesis and starch and sucrose metabolism Calligaris D [B] MALDI mass spectrometry Ijare O [X] postoperative pituitary tissue from 3 FSH/LH-secreting pituitary adenomas and 3 PRL-secreting pituitary adenomas NMR spectometry Metabolites: phosphoethanolamine, glutamate, glutamine, N-acetyl aspartate, aspartate and myo-inositol – significantly altered in both types of adenomas (↓ phosphoethanolamine, N-acetyl aspartate and myo-inositol and ↑ aspartate, glutamate and glutamine in PRL-secreting pituitary adenomas compared to LH/FSH-secreting pituitary adenomas).
In 2017, Ijare O and co. [X] used NMR spectrometry to assess the metabolomic profile in FSH/LH and PRL-secreting adenomas in the postoperative pituitary tissue. He observed that both types of pituitary adenomas contain central nervous system metabolites such as phosphoethanolamine, glutamate, glutamine, N-acetyl aspartate, aspartate and myo-inositol. In addition, comparing these two types of pituitary adenomas, it was found that phosphoethanolamine, N-acetyl aspartate and myo-inositol are downregulated in PRL-secreting pituitary adenomas, while aspartate, glutamate and glutamine are upregulated. Ijare’s study is currently underway, so a large number of patients could provide additional insights into the evaluation of the metabolomic fingerprint in the FSH/LH and PRL-pituitary adenomas.
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