ENDOCRINE EFFECT OF GHRELIN ON HISTOLOGICAL, HORMONAL AND MORPHOMETRIC PARAMETERS OF THE PITUITARY GLAND AND THE POSSIBILITY OF ITS CLINICAL APPLICATION
Keywords:
ghrelin, pituitary cells, hormonal status, morphometry, clinical application
Abstract
Background: Ghrelin, a brain-intestinal hormone, is a growth hormone (GH) secretagogue. As it regulates appetite and is most secreted before meals, it is often described as a "hunger hormone". It consists of 28 amino acids. Given the connection between nutritional status and energy metabolism, it suggests that disorders in these areas can lead to anorexia, especially during aging. The aim of this review article is to demonstrate the influence of ghrelin on the histological, hormonal, and stereological characteristics of pituitary cells, as well as its potential clinical applications.
Methods: To write this review, we performed an electronic literature search through Google Scholar and PubMed databases with the terms ghrelin, structure, pituitary cells, metabolism, and aging, with reference to the authors and co-authors of published works related to this topic, as well as the option "related articles", which were related to the content of this publication.
Results: The topic of this review article relates to the structure, morphometric and hormonal characteristics of adrenocorticotropic (ACTH), somatotropic (GH), and gonadotropic (FSH and LH) pituitary cells in control and ghrelin-treated rats.
Conclusion: This review showed that central administration of nanomolar doses of ghrelin to rats has a modulatory role on the immunohistomorphometric and hormonal characteristics of pituitary hormone-producing cells. The changes are particularly significant in the volume of corticotropes, somatotropes and luteinizing hormone (LH) producing cells, their volume density, and the levels of hormones they secrete compared to the control group.
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9. Grönberg M, Tsolakis AV, Magnusson L, Janson ET, Saras J. Distribution of obestatin and ghrelin in human tissues: immunoreactive cells in the gastrointestinal tract, pancreas, and mammary glands. J Histochem Cytochem 2008; 56(9): 793-801.
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10. Delporte C. Structure and physiological actions of ghrelin. Scientifica 2013; 518909. DOI:10.1155/2013/518909
11. Nishi Y, Yoh J, Hiejima H, Kojima M. Structures and molecular forms of the ghrelin-family peptides. Peptides 2011; 32(11): 2175-82. DOI: 10.1016/j.peptides.2011.07.024
12. Bukhari SNA. An insight into the multifunctional role of ghrelin and structure activity relationship studies of ghrelin receptor ligands with clinical trials. Eur J Med Chem 2022; 235: 114308. DOI:10.1016/j.ejmech.2022.114308
13. Nampoothiri VM. Ghrelin and its role in animals. International Journal of Veterinary Sciences and Animal Husbandry 2021; 6(1): 19-22. DOI: 10.22271/veterinary.2021
14. Otero M, Nogueiras R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O. Chronic inflammation modulates ghrelin levels in humans and rats. Rheumatology (Oxford) 2004; 43(3): 306-10. DOI: 10.1093/rheumatology/keh055
15. Dornonville de la Cour C, Björkqvist M, Sandvik AK, Bakke I, Zhao CM, Chen D, Håkanson R. A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 2001; 99(2-3): 141-50. DOI: 10.1016/s0167-0115(01)00243-9
16. Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin hormone with multiple functions. Front Neuroendocrinol 2004; 25: 27-68. DOI: 10.1016/j.yfrne.2004.03.002
17. Skoracka K, Hryhorowicz S, Schulz P, Zawada A, Ratajczak-Pawłowska AE, Rychter AM, Słomski R, Dobrowolska A, Krela-Kaźmierczak I. The role of leptin and ghrelin in the regulation of appetite in obesity. Peptides 2025; 186: 171367. DOI: 10.1016/j.peptides.2025.171367
18. Nešić D, Stevanović D, Stanković S, Milošević V, Trajković V, Starčević V, Severs W, Age-dependent modulation of central ghrelin effects on food intake and lipid metabolism in rats. Eur J Pharmacol 2013; 710: 85-91. DOI:10.1016/j.ejphar.2013.03.052
19. Chapman IM, MacIntosh CG, Morley JE, Horowitz M. The anorexia of ageing. Biogerontology 2002; 3(1-2): 67-71. [DOI: 10.1023/a:1015211530695]
20. Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, Sisto A, Marzetti E. Anorexia of Aging: Risk Factors, Consequences, and Potential Treatments. Nutrients 2016; 8(2): 69. DOI:10.3390/nu8020069
21. Yanagi S, Sato T, Kangawa K, Nakazato M. The Homeostatic force of ghrelin. Cell Metab 2018; 27(4): 786-804. DOI:10.1016/j.cmet.2018.02.008
22. Stevanović D, Milosević V, Starčević VP, Severs WB. The effect of centrally administered ghrelin on pituitary ACTH cells and circulating ACTH and corticosterone in rats. Life Sci 2007; 80(9): 867-72. DOI: 10.1016/j.lfs.2006.11.018
23. Čukuranović-Kokoris J, Ajdžanović V, Pendovski L, Ristić N, Milošević V, Dovenska M, et al. The effects of long-term exposure to moderate heat on rat pituitary ACTH cells: histological and hormonal study. Acta Vet 2022a; 72(1):1-15. [DOI: 10.2478/acve-2022-0001]
24. Pavlović M, Jovanović I, Ugrenović S, Stojanović V, Živković V, Kundalić B, et al; Human anterior pituitary's ACTH cells during the aging process: immunohistochemic and morphometric study. Anat Sci Int 2021; 96(2): 250-7. [DOI: 10.1007/s12565-020-00583-7]
25. Čukuranović-Kokoris J, Kundalić B, Pavlović M, Ugrenović S. Pituitary cells in man during aging: an immunohistological and morphometric study. J Med Biochem 2025a; 44(2): 203-10. [DOI: 10.5937/jomb0-54605]
26. Milošević V, Ajdžanović V, Nešić D, Starčević V, Filipović B, Rakočević R, et al. Central ghrelin treatment stimulates ACTH cells in normal-fed, food-restricted and high-fed rats: An immunohistomorphometric and hormonal study. Acta Histochem 2013; 115:858-64. DOI:10.1016/j.acthis.2013.04.003
27. Stevanović D, Milošević V, Nešić D, Ajdžanović V, Starčević V, Severs W. Central effects of ghrelin on serum growth hormone and morphology of pituitary somatotropes in rats. Exp Biol Med (Maywood), 2006; 231(10): 1610-5. DOI: 10.1177/153537020623101005
28. Čukuranović-Kokoris J, Đorđević M, Jovanović I, Kundalić B, Pavlović M, Graovac I, et al: Morphometric analysis of somatotropic and folliculostellate cells of human anterior pituitary during ageing. Srp Arh Celok Lek 2022b; 50(5-6): 274-81.
[DOI:10.2298/SARH211214044C]
29. Čukuranović Kokoris, Dovenska M, Parapid B, Pendovski L, Nikolovski M, Kundalić B, et al. Immunohistomorphometric response of pituitary growth hormone producing cells in rats to prolonged exposure to moderately elevated ambient temperature. Srp Arh Celok Lek 2025b; 153(5-6): 243-7. [DOI:10.2298/SARH250515041C]
30. Čukuranović-Kokoris J, Marković-Filipović J, Đorđević M, Kundalić B, Stojanović V, Trandafilović M, et al. Correlation analysis of pituitary lutheinizing and somatotropic cells in male cadavers during aging. Acta Medica Medianae 2024; 63(1): 90-6. [DOI: 10.5633/amm.2024.0110]
31. Šošić-Jurjević B, Stevanović D, Milošević V, Sekulić M, Starčević V. Central ghrelin affects pituitary-thyroid axis: histomorphological and hormonal study in rats. Neuroendocrinology 2009; 89: 327-36. [DOI:10.1159/000188603]
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