Metformin Inhibits Pituitary Tumor Cell Growth Even When GHRH Receptor Signaling Is Overactive | Research

The takeaway

Metformin activates AMPK and suppresses pituitary tumor cell growth through the mTOR pathway, and this effect persists even when GHRH receptor signaling is hyperactivated.

Growth inhibition maintained despite GHRH stimulation
Metformin suppressed pituitary tumor growth through AMPK activation even when the GHRH peptide receptor pathway was overactivated

What the researchers found

Metformin inhibited rat pituitary tumor cell growth through AMPK activation and suppression of the mTOR-p70S6 kinase pathway. Crucially, metformin maintained its ability to activate AMPK and inhibit cell growth even in cells treated with forskolin (an adenylyl cyclase activator) and in cells overexpressing the GHRH receptor stimulated with GHRH. This demonstrates that adenylyl cyclase over-activation — a hallmark of some pituitary tumors — does not prevent metformin from working, contradicting concerns that hyperactive cAMP signaling might negate AMPK-based therapies.

Why it matters

Growth hormone-secreting pituitary adenomas cause acromegaly, a serious condition with cardiovascular and metabolic complications. Current treatments include surgery and somatostatin analog drugs, but many patients don't respond adequately. Metformin is already widely used, safe, and inexpensive. Showing that it can suppress pituitary tumor growth — even when the GHRH peptide signaling pathway is hyperactive — supports investigating metformin as an adjunctive therapy for these tumors.

How the study worked

Researchers used rat pituitary adenoma cell cultures and tested metformin's effects on cell growth, AMPK activation, and downstream signaling pathways (mTOR-p70S6K, ERK). They used MTT assays for cell viability, Western blotting for protein signaling, and tested interactions with forskolin (adenylyl cyclase activator) and GHRH in cells transfected to overexpress the GHRH receptor. Energetic stress conditions were also examined.

What this study cannot tell us

This study used rat pituitary adenoma cell lines in vitro, not human tumors. The abstract notes that some human pituitary tumors don't respond to AMPK-activating compounds, suggesting species-specific or tumor-specific differences. No in vivo tumor models or clinical data were included. The specific metformin concentrations achieving these effects may not be achievable in the pituitary in humans at standard oral doses.

How to read the evidence

This is a preclinical in vitro study using rat pituitary adenoma cells. While it provides mechanistic insight into metformin's effects on AMPK and mTOR signaling in pituitary tumors, the findings need validation in human tumor cells and clinical settings.

When this study was published

Published in 2018, this study is part of ongoing research into metformin repurposing for pituitary tumors. Subsequent clinical investigations may have advanced these findings.

The bigger picture

Drug repurposing — finding new uses for existing medications — is an increasingly important strategy in oncology. Metformin has shown anticancer effects in multiple tumor types, and this study extends those findings to pituitary adenomas. The GHRH receptor is a peptide receptor that drives pituitary tumor growth, and showing that metformin works even when this pathway is hyperactive removes a theoretical concern that could have limited its clinical exploration. Combined with GHRH antagonists or somatostatin analogs, metformin could become part of a multi-drug approach to difficult pituitary tumors.

Questions still open

Could metformin be used as an adjunctive therapy alongside somatostatin analogs for GH-secreting pituitary adenomas in patients?
Do human pituitary adenoma cells show the same AMPK-mediated growth suppression as rat cells?
Would combining metformin with GHRH receptor antagonists produce synergistic antitumor effects?

Common questions

Could the diabetes drug metformin help treat pituitary tumors?

This study suggests it might. Metformin activated AMPK (an energy-sensing enzyme) in pituitary tumor cells, which suppressed the mTOR growth pathway and inhibited cell proliferation. Impressively, it worked even when the GHRH receptor — a key driver of pituitary tumor growth — was hyperactivated. While these are early in vitro results, metformin's established safety record and low cost make it a promising candidate for clinical investigation in pituitary adenomas.

What is the GHRH receptor and why does it matter for pituitary tumors?

GHRH (growth hormone-releasing hormone) is a peptide that signals the pituitary gland to produce growth hormone. Its receptor (GHRH-R) activates adenylyl cyclase, which drives cell growth in pituitary tumors. Some researchers worried that this hyperactive signaling might override AMPK-based drugs like metformin, but this study showed that's not the case — metformin maintained its antitumor effects regardless of GHRH stimulation.

Read the original research

Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals.

Molecular and cellular endocrinology, 470, 60-74

View on PubMed ↗Publisher’s paper ↗

Citation

Faggi, Lara; Giustina, Andrea; Tulipano, Giovanni. (2018). Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals.. Molecular and cellular endocrinology, 470, 60-74. https://doi.org/10.1016/j.mce.2017.09.030