Objective: high IGF-1 and unsuppressed GH levels after glucose load confirm the diagnosis of acromegaly. Management of patients with conflicting results could be challenging. Our aim was to evaluate the clinical and hormonal evolution over a long follow-up in patients with high IGF-1 but normal GH nadir (GHn<0.4 μg/L according to the latest guidelines). Design: retrospective cohort study. Methods: we enrolled 53 patients presenting high IGF-1 and GHn<0.4 μg/L, assessed because of clinical suspicion of acromegaly or in other endocrinological contexts (e.g., pituitary incidentaloma). Clinical and hormonal data collected at the first and last visit were analyzed. Results: at the first evaluation, the mean age was 54.1±15.4 years, 34/53 were females, median IGF-1 and GHn were +3.1 SDS and 0.06 μg/L, respectively. In the whole group, over a median time of 6 years, IGF-1 and GHn levels did not significantly change (IGF-1 mean of differences -0.58, p=0.15; GHn +0.03, p=0.29). In patients with clinical features of acromegaly, the prevalence of acromegalic comorbidities was higher than in the others (median of 3 vs 1 comorbidities per patient, p=0.005), especially malignancies (36% vs 6%, p=0.03), and the clinical worsening overtime was more pronounced (4 vs 1 comorbidities at the last visit). Conclusions: in patients presenting high IGF-1 but GHn<0.4 μg/L, a hormonal progression is improbable, likely excluding classical acromegaly on its early stage. However, despite persistently low GH nadir values, patients with acromegalic features present more acromegalic comorbidities whose rate increases over time. Close clinical surveillance in this group is advised.
The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.