Chronopharmacological effects of growth hormone on the executive function and oxidative stress response in rats

Document Type: Original Article


1 Federal University of Mato Grosso (UFMT), Mato Grosso, Brazil

2 São Paulo State University (UNESP), São Paulo, Brazil

3 University Center of Araxá (UNIARAXA), Minas Gerais, Brazil


Objective(s): to investigate the chronopharmacological effects of growth hormone on executive function and the oxidative stress response in rats.
Materials and Methods: Fifty male Wistar rats (36-40 weeks old) had ad libitum access to water and food and were separated into four groups: diurnal control, nocturnal control, diurnal GH-treated, and nocturnal GH-treated animals. Levels of Cu, Zn superoxide dismutase (Cu,Zn-SOD), and superoxide release by spleen macrophages were evaluated. For memory testing, adaptation and walking in an open field platform was used. GH-treated animals demonstrated better performance in exploratory and spatial open-field tests.
Results: The latency time in both GH-treated groups was significantly lower compared with the latency time of the control groups. The diurnal GH treatment did not stimulate superoxide release but increased the CuZn-SOD enzyme levels. The nocturnal GH treatment did not influence the superoxide release and CuZn-SOD concentration. GH treatment also resulted in heart atrophy and lung hypertrophy.
Conclusion: Growth hormone treatment improved the performance of executive functions at the cost of oxidative stress triggering, and this effect was dependent on the circadian period of hormone administration. However, GH treatment caused damaging effects such as lung hypertrophy and heart atrophy.


1.Aleman A, Vries WR, Haan EHF, Samson MM, Koppeschaar HP. Age-sensitive cognitive function, growth hormone and insulin-like growth factor I plasma levels in healthy older men. Neuropsychobiology 2000; 4:73-78.

2.Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR. Intracerebroventricular infusion of insulin-like growth hormone factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 2001; 107:603-613.

3.Maruff P, Falleti M. Cognitive function in growth hormone deficiency and growth hormone replacement. Hormone Res 2005; 64:100–108.

4.Landi F, Capoluongo E, Russo A, Onder G, Cesari M, Lulli P, et al. Free insulin-like growth factor-I and cognitive function in older persons living in community. Growth Horm IGF Res 2007; 17:58–66.

5.Sathiavageeswaran M, Burman P, Lawrence D, Harris AG, Falleti MG, Maruff P, et al. Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: a placebo-controlled 12-month study. Eur J Endocrinol 2007; 156:439–447.

6.Deijen JB, de Boer H, Blok GJ, van der Veen EA. Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendo-crinology 1996; 21:313-322.

7.Baum HB, Katznelson L, Sherman JC, Biller BMK, Hayden DL, Schoenfeld JC, et al. Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab 1998; 83:3184-3189.

8.Pavel ME, Lohman T, Hahn EG, Hoffman M. Impact of growth hormone on central nervoussystem activity, vigilance and tiredness after short term therapy in growth hormone-deficient adults. Horm Metab Res 2003; 35:114-119.

9.Oertel H, Schneider HJ, Stalla GK, Holsboer F, Zihl J. The effect of growth hormone substitution on cognitive performance in adult patients with hypopituitarism. Psychoneuroendocrinology 2004; 29:839–850.

10.Arwert LI, Deijenb JB, Mqllerb M, Drenta ML. Long-term growth hormone treatment preserves GH-induced memory and mood improvements: a 10-year follow-up study in GH-deficient adult men. Horm Behav 2005; 47:343–349.

11.van Dam PS. Neurocognitive function in adults with Growth Hormone deficiency. Horm Res 2005; 64:109-114.

12.Falleti MG, Maruff P, Burman P, Harris A. The effects of growth hormone (GH) deficiency and GH replacement on cognitive performance in adults: A meta-analysis of the current literature. Psychoneuroendocrinology 2006; 31:681-691.

13.Corpas E, Harman SM, Blackman S. Human growth hormone and human aging. Endocr Rev 1993; 14:20-39.

14.Zadik Z, Chalew SA, McCarter RJ, Meistas M, Kowarski AA. The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab 1995; 60:513-516.

15.Xu X, Bennett SA, Ingram RL, Sonntag WE. Decreases in growth hormone receptor signal transduction contribute to the decline in insulin- like growth factor I gene expression with age. Endocrinology 1995; 136:4551-4557.

16.Rosen CJ, Conover C. Growth hormone/insulin-like growth factor-1 axis in aging: a summary of a National Institutes of Aging-Sponsored Symposium. J Clin Endocrinol Metab 1997; 82:3919-3922.

17.Rudman D, Feller AG, Nagraj H, Gergans GA, Lalitha PY, Goldberg AF, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323:1-6.

18.Attanasio AF, Mo D, Erfurth EM, Tan M, Ho KY, Kleinberg D, et al. Prevalence of metabolic syndrome in adult hypopituitary growth-hormone (GH)-deficient patients before and after GH replacement. J Clin Endocrinol Metab 2010; 95:74-81.

19.Kinneya BA, Coschiganob KT, Kopchickb JJ, Stegera RW. Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 2001; 72:653-660.

20.Santos LOM, Simões MLPB, Machado APB, Matioski Filho GR, Endo PC, Gruen GR, Cipriani VR, Mesquita LD. Effect of somatotropin on skin wound healing in rats.. Acta Cir Bras2002; 17:220-224.

21.Honorio-França AC, Carvalho MP, Isaac L, Trabulsi LR, Carneiro-Sampaio MM. Colostral mononuclear phagocytes are able to kill enteropathogenic escherichia coli (EPEC) opsonized by colostral IgA. Scand J Immunol 1997; 46:59-66.

22.França EL, Feliciano ND, Silva KA, Ferrari CK, Honorio-França AC. Modulatory role of melatonin on superoxide release by spleen macrophages isolated from alloxan-induced diabetic rats. Bratisl Lek Listy 2009; 110: 517-522.

23.Pick E, Mizel D. Rapid microassays for the measurement of superoxide and hydrogen peroxide production by macrophages in culture using an automatic enzyme immunoassay reader. J Immunol Methods 1981; 46:211-26.

24.Novelli EL, Rodríguez NL, França EL, Gebra LMN, Ribas BO. High Dietary Carbohydrate and Panceatic lesion. Braz J Med Biol Res 1993; 26:31-36.

25.Ledig MM, Paria JR, Mandel P. Superoxide dismutase activity in rat brain during acute and chronic alcohol intoxication. Neurochem Res 1981; 6:385-390.

26.Endo H, Nito C, Kamada H, Yu F, Chan PH. Reduction in oxidative stress by superoxide dismutase over expression attenuates acute brain injury after subarachnoid hemorrhage via activation of Akt/glycogen synthase kinase-3beta survival signaling. J Cereb Blood Flow Metab 2007; 27:975-982.

27.Barros D, Amaral O, Izquierdo I, Geracitano L, do Carmo Bassols Raseira M, Henriques AT, et al. Behavioral and genoprotective effects of vaccinium berries intake in mice. Pharmacol Biochem Behav 2006; 84:229-334.

28.Mello PB, Benetti, F, Cammarota M, Izquierdo I. Effects of acute and chronic physical exercise and stress on different types of memory in rats. An Acad Bras Ciênc 2008; 80:301-309.

29.Zar JH. Bioestatical Analysis. Englewood cliffs:  Prentice-Hall International Editions, 1984.

30.Rotnem D, Genel M, Hintz RL, Cohen DJ. Personality development in children with growth hormone deficiency. J Am Acad Child Psychiatr 1977; 16:412-426.

31.Hayashi M, Shimohira M, Saisho S, Shimozawa K, Iwakawa Y. Sleep disturbance in children with growth hormone deficiency. Brain Dev 1992; 14:170-174.

32.Dean HJ, McTaggart TL, Fish DG, Friesen HG. The educational, vocational, and marital status of growth hormone-deficient adults treated with growth hormone during childhood. Am J Dis Child 1985; 139:1105-1110.

33.Mitchell CM, Joyce S, Johanson AJ, Libber S, Plotnick L, Migeon CJ, et al. A retrospective evaluation of psychological impact of long-term growth hormone therapy. Clin Pediatr 1986; 25:17-23.

34.McGauley GA, Cuneo RC, Salomon F, Sonksen PH. Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency. Horm Res 1990; 33:52–54.

35.Libera LD, Ravara B, Volterrani M, Gobbo V, Barbera MD, Angelini A, et al. Beneficial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure. Am J Physiol Cell Physiol 2004; 286:C138-C144. 

36.Isgaard J, Arcopinto M, Karason K, Cittadini A. GH and the cardiovascular system: an update on a topic at heart. Endocrine 2015; 48:25-35.

37.Seiva FR, Evadí GM, Castro AV, Okoshi K, Nascimento A, Rocha KK, et al. Growth hormone and heart failure: Oxidative stress and energetic metabolism in rats. Growth Horm IGF Res 2008; 18:275-283.

38.Brown-Borg H, Bode AM, Bartke A. Antioxidative mechanisms and plasma growth hormone levels: potential relationship in the aging process. Endocrine 1999; 11:41-48.   

39.Brown-Borg H, Johnson WT, Rakoczy S, Romanick M. Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice. J Am Aging Assoc 2001; 24:85-96.

40.Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchik JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor 1 levels and increased life span. Endocrinology 2003; 144:3799-3810.   

41.Ferrari CKB. Total Antioxidant Capacity: a biomarker in biomedical and nutritional studies. J Cell Mol Biol 2008; 7:1-15.

42.Ferrari CKB., França EL, Honorio-França AC. Nitric Oxide, Health and Disease. J Appl Biomed 2009; 7:163-173.

43.Coschigano KT, Wetzel AN, Obichere N, Sharma A, Lee S, Rasch R, et al. Identification of differentially expressed genes in the kidneys of growth hormone transgenic mice. Growth Horm IGF Res 2010; 20:345-355.

44.Bogazzi F, Russo D, Raggi F, Bohlooly-Y M, Tornell J, Sardella C, et al. Cardiac extrinsic apoptotic pathway is silent in young but activated in elderly mice overexpressing bovine GH: interplay with the intrinsic pathway. J Endocrinol 2011; 210:231-238.

45.Masternak MM, Bartke A. Growth hormone, inflammation and aging. Pathobiol Aging Age Relate Dis 2012; 2:17293.   

46.Varadhan L, Reulen RC, Brown M, Clayton RN. The role of cumulative growth hormone exposure in determining mortality and morbidity in acromegaly: a single centre study. Pituitary 2016; 19:251-261.

47.Colao A, Spinelli L, Cuocolo A, Spiezia S, Pivonello R, di Somma C, et al. Cardiovascular consequences of early-onset growth hormone excess. J Clin Endocrinol Metab 2002; 87:3097-3104.

48.França EL, Bitencourt RV, Fujimori M, Morais TC, Calderon IMP, Honorio-França AC. Human colostral phagocytes eliminate enterotoxigenic Eschechia coli opsonized by colostrums supernatant. J Microbiol Immunol Infec  2011; 44:1-7

49.Morceli G, França EL. Magalhães VB, Damasceno DC, Calderon IMP, Honorio-França AC. Diabetes-induced immunobiochemical changes in human colostrum Acta Paediat 2011; 100:550-556.

50.van Dam PS, Aleman A,  de Vries WR, Deijen EA, van der Ven EA, de Haan EH,  et al. Growth hormone, insulin-like growth factor I and cognitive function in adults. Growth Horm IGF Res 2000; 10:69S–73S.

51.Glisky EL, Kong LL. Do young and older adults rely on different processes in source memory tasks? A neuropsychological study. J Exp Psychol 2008; 34:809–822.