Pro‐opiocortin Related Peptides in Human Pituitary and Ectopic Acth Secreting Tumours

Abstract

Basal and stimulated secretion of N-terminal pro-opiocortin (Pro-gamma-MSH), ACTH and LPH from seven pituitary and three ectopic ACTH secreting tumours have been studied in vitro using a perfused isolated cell system. The peptides were shown to be released concomitantly and in equimolar amounts. The pituitary tumours responded to stimulation with rat stalk median eminence extracts (SME) and synthetic AVP. However, peptide release from the ectopic tumours, although pulsatile, remained autonomous. Prior to surgery, gel-chromatographic profiles of plasma immunoreactive ACTH showed only one peak, which eluted in the position of 1-39 ACTH, in patients with the pituitary tumours, but there was a second peak of large molecular weight ACTH present in the plasma from those with the ectopic ACTH syndrome. This second form of ACTH could not be detected in any of the tumour cell column effluents. An eighth pituitary tumour was atypical, in its unusually large size, clinically aggressive nature and spectrum of peptide release. Although peptide release in response to stimulation with SME was similar to that observed with the other pituitary tumours, the chromatography of the plasma ACTH resembled the ectopic plasma pattern, showing two peaks of immunoreactivity.

Malignant Gastric Carcinoid Causing Ectopic ACTH Syndrome: Discrepancy of Plasma ACTH Levels Measured by Different Immunoradiometric Assays

“…For example, 'big ACTH' has been reported to be undetectable by in vivo bioassay [25] or only 3-5% of ACTH(1-39) by in vitro assay [26]. By contrast, pro-ACTH has been reported to be equipotent with ACTH(1-39) by rat adrenal cell [13] or 8-33% of ACTH(1-39) by cytochemical assay [10]. The predominant HMW form of ACTH in plasma associated with profound hypercortisolemia as in the present case is very similar to that of our previous case of 'big ACTH'-producing gastric carcinoid causing clinically overt Cushing's syndrome [27].…”

“…In contrast to high ACTH levels determined by Allegro ® assay kit, those determined by Yuka ® assay kit in the same patient's plasma samples were almost normal. Two-site IRMA kit by Allegro ® employs 125 I-labeled antibody against Nterminal fragment (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) and antibody against Cterminal fragment(34-39) of ACTH, while that by Yuka ® employs 125 I-labeled antibody against Nterminal fragment (20)(21)(22)(23) and antibody against Cterminal fragment(35-39) of ACTH, respectively. These data strongly suggest that various circulating forms of ACTH molecule in patient's plasma could be differentially recognized by these two different IRMA kits.…”

“…However, the complexity of chromatographic methods limited the identification of ectopic ACTH syndrome [10][11][12]. By using an IRMA that recognizes different sites of the POMC molecule, White et al reported that plasma levels of HMW form of ACTH in patients with ectopic ACTH syndrome were greater than those in patients with Cushing's disease, suggesting the impaired processing of POMC by the tumors [13].…”

Defective Expression of Prohormone Convertase 1/3 in Silent Corticotroph Adenoma

“…Biological activities of ACTH precursors still remain undetermined; big ACTH is undetectable by in vivo bioassay [18], but its biologically activity corresponds to only 3-5% of ACTH(1-39) by in vitro assay [19], whereas proACTH has been shown to only 8-33% of ACTH(1-39) by cytochemical assay [20]. Therefore, it is possible to speculate that biologically inactive HMW form of ACTH may be generated from the impaired processing of POMC and/or ACTH precursor by the defective PC1/3 expression in SCA.…”

Paraneoplazi kavramı

“…Normal periferik hücrelerde P3'ün kontrolü altında az miktarda ACTH-ilişkili moleküller üretilirken, tümör dokusunda artmış upstream promoter P1'in etkisiyle kontrolsüz üretim gerçekleşmektedir 9-11 . Tümör hücrelerinde POMC'in sentez sürecindeki bu farklılık nedeniyle yüksek oranlarda üretilse dahi molekülde genetik instabilite ve işlevsel yetersizlik ortaya çıkmaktadır ki, yapılan çalışmalarda tümör hücreleri tarafından üretilen ve kana salınan bu ACTH-like materyalin düşük biyoaktiviteye sahip POMC fragmanları olduğu gösterilmiştir [12][13][14] . KHAK'larının küçük bir kısmı (muhtemelen yüksek endoproteaz aktivitesine sahip olanlar) bu yüksek miktarda sentezlenen ancak düşük biyolojik aktiviteye sahip POMC'i biyolojik olarak aktif ACTH molekülüne dönüştürmekte ve özellikle bu hastalarda ektopik ACTH sendromuna bağlı Cushing sendromu ortaya çıkmaktadır 10,15 .…”