Aging-Related Adaptations in the Corticotropic Axis: Modulation by Gender

Growth hormone secretagogues (GHSs) are a family of synthetic peptidyl and nonpeptidyl molecules that bind specific receptors (GHS-Rs) in the hypothalamus and pituitary with stimulatory effect on somatotrope secretion. Over the last 40 years, many nonnatural GHSs, with different oral bioavailability, have been synthesized in order to treat GH deficiency. Although GHS-R had been designated as an orphan receptor specific for synthetic GHSs, in 1999 Kojima et al. isolated, from the enteroendocrine cells in the stomach, the first natural bioactive ligand for this receptor, named ghrelin.Ghrelin, a 28-amino acid peptide, is multifunctional and it exerts several endocrine and nonendocrine activities. It has a strong GH-releasing effect through which it has been used as a provocative test for the diagnosis of GH deficiency and as an anabolic treatment of cachexia. The stimulatory effect of ghrelin on ACTH and PRL secretion is even more pronounced than other GHSs, and it has been studied in healthy individuals and in pathological conditions (Cushing׳s disease and prolactinoma). Ghrelin also regulates the hypothalamus–pituitary–gonadal (HPG) axis acting both at the central and at the peripheral level in a gender-different manner: it has an inhibitory effect on LH, but not on FSH, pulsatility in men while it suppresses gonadotropin secretion in women.Besides these endocrine effects, ghrelin is also endowed with metabolic functions: it is the first known peripheral hormone to display strong orexigenic effects through its action on the hypothalamic appetite-regulating pathways. Moreover, a ghrelin infusion has been shown to increase glucose levels in healthy subjects and to inhibit insulin secretion. Thus, it has been hypothesized a potential therapeutic role of ghrelin blockade in glucose intolerance/diabetes and in obesity. Furthermore, some bariatric surgery procedures could decrease ghrelin secretion resulting in inhibition of appetite and improvement of glycemic metabolism and remission of diabetes.Finally, emerging evidences have revealed ghrelin function on the cardiovascular system and in regulating several processes related to cancer progression, especially in tumor cell proliferation.