Endocrine Abstracts

Antidiabetic biguanides, such as metformin (the most commonly prescribed drug to treat type 2 diabetes) and phenformin, are synthetic insulin-sensitizing agents. In addition to their well-known anti-hyperglycemic actions, biguanides are being also studied in other medical disorders due to the beneficial effects that they exert in important pathologies, including cardiovascular disease or different types of cancer. Although some scattered studies have suggested that metformin could modulate the production of pituitary hormones in certain pathological conditions, there are no previous reports describing the direct role that biguanides may play in the regulation of anterior pituitary cell types in the normal gland, especially in humans or primates. It is widely known that the pituitary gland is a master player in the control of body homeostasis and metabolism, owing to its ability to integrate multiple signals to modulate hormonal secretions that are involved in the control of key peripheral organs/tissues. Accordingly, this study was aimed to elucidate the direct effects of two biguanides (metformin and phenformin) on the expression and secretion of all pituitary hormones in two primate species (Papio anubis and Macaca fascicularis), which closely model human physiology. Moreover, to better understand the mechanisms behind the putative actions of these biguanides, we used pharmacological inhibitors of various intracellular signalling-pathways. Metformin and phenformin inhibited basal GH, ACTH and FSH secretion in a dose-and time-dependent fashion, but did not alter PRL, LH or TSH secretion or ghrelin/GHRH-stimulated hormonal release. Moreover, metformin and phenformin also reduced GH and ACTH expression without altering that of other pituitary hormones (PRL/LH/FSH/TSH). Treatment with these biguanides did not affect normal pituitary cell viability. Interestingly, metformin and phenformin increased the expression of sst2, sst5, IGF1R, Ins-R and leptin-R in baboon primary pituitary cell cultures. Finally, we demonstrated that metformin requires PI3K, mTOR and intracellular Ca²⁺ pathways to exert its actions on the modulation of GH/ACTH/FSH secretion, but also MAPK-signalling in the case of GH modulation. Altogether, our results provide strong, primary evidence for the direct actions of biguanides in the control of normal pituitary cell function in two primate models. This information could be relevant for the current understanding of normal human pituitary function in patients treated with metformin, given the likely translation of the findings in primate models into human pathophysiology. Furthermore our results invite to explore potential therapeutic effects of these compounds in pituitary dysfunctions (i.e. somatotropinomas, corticotropinomas and gonadotropinomas).