Электронный научный журнал

Introduction. Recent evidence implicated glucocorticoids in the mechanisms ofontogenetic bioregulation [16]. Therefore, the question emerged: is it possible to counteract adverse actions of glucocorticoids? Our work presented here aimed at considering somatolactogens and related peptides for this counteraction.

Since the seminal works of Walter Cannon and Hans Selye in the first half of 20^th century, glucocorticoids and catecholamines (noradrenaline and adrenaline) were considered as principal hormonal mediators of stress. Therefore, antistress hormones should be at least functional antagonists of glucocorticoids.

Basically, we need to discuss, as referred to stress and its mediators, the activities of principal somatolactogenic proteins: growth hormone (GH) and prolactin, as well as insulin-like growth factor of type I (IGF-I) and oxytocin, i.e. peptide regulators related to growth and lactation respectively.

Growth hormone and insulin-like growth factori.

Hans Selye was the first to demonstrate in 1952 that GH could counteract growth-inhibitory action of cortisone acetate in rats [37]. Since that moment, a lot of studies have confirmed and extended this data. For example, GH prevented prednisolone-induced increase in functional hepatic nitrogen clearance in humans [50]. In addition, IGF-I had a potential to counteract the decrease in nitrogen balance induced by dexamethasone in rats [25].

GH and IGF-I promoted protein deposition and body growth in dexamethasone-treated piglets [47]. In addition, GH or IGF-I prevented glucocorticoid-induced muscular atrophy in rats [20]. The GH secretagogue ipamorelin counteracted methylprednisolone-induced decrease in bone formation and muscle strength in rats [3]. On the other hand, IGF-I increased total gut weight in dexamethasone-treated rats [33].

However, not always GH was able to counteract glucocorticoid effects. For example, combined administration of GH with cortisone acetate could not prevent the decrease in somatomedin activity in glucocorticoid-treated rats [5]. Besides, IGF-I did not prevent dexamethasone-induced apoptosis of thymocytes, although it slightly reduced cell death in the spleen of rats [19].

These data indicated that it is important to evaluate also the effects of glucocorticoids on GH / IGF-I axis. In this sense, both stimulatory and inhibitory effects of glucocorticoids on GH secretion were demonstrated. In fact, dexamethasone enhanced GH release in male volunteers. Probably, glucocorticoids may initially enhance GH release by augmenting GH-releasing hormone (GHRH) receptor function. In addition, they may diminish the sensitivity of somatotropes to somatostatin and IGF-I [42].

However, high doses of glucocorticoids inhibit GH secretion in rats and humans, probably by stimulating somatostatin release from the hypothalamus [43]. Acute and sustained hypercortisolism decreased GH secretion induced by GHRH in acromegaly, probably by enhancing somatostatin tone also [14]. The response of GH secretion to GHRH and GH-releasing peptide-6 was significantly less in dexamethasone-treated rats [46].

In vitro low concentrations of corticosterone increased GHRH production by cultured fetal rat hypothalamic cells, whereas high concentrations decreased it; besides, corticosterone increased somatostatin production [11]. Cortisol inhibited GHRH-stimulated GH release in sheep pituitary cell culture [36].

The data concerning IGF-I and its binding proteins (IGFBP) are quite heterogeneous. For example, long-term prednisone treatment suppressed GH levels and increased IGF-I in humans [32]. In normal male volunteers dexamethasone enhanced serum immunoreactive IGF-I level, but it decreased IGFBP-1 and IGFBP-2 levels and IGF-I bioactivity [26]. In rats methylprednisolone dose-dependently decreased free serum IGF-I, what correlated with body weight changes [40].

Finally, there are some data involving glucocorticoid-induced changes of receptors and sensitivity to the action of GH and IGF-I. It seems that glucocorticoids diminish sensitivity of chondrocytes to GH and IGF-I [39]. In rats glucocorticoids decreased GH receptor expression and binding activity in the liver [35].

What for aging, Hertoghe [18] suggested that elderly persons are considerably more depleted in anabolic hormones, including GH, than in cortisol. The resulting imbalance with predominance of catabolism may trigger or accelerate pathological aging. Besides, it was proposed that age-related changes in body composition are the result of age-dependent decrease of GH / cortisol ratio at the level of adipose tissue [27].

In fact, GH is able to inhibit the activity of 11beta-hydroxysteroid dehydrogenase of type I, therefore GH deficiency in the elderly provokes local reactivation of glucocorticoids in target tissues (liver and adipose), what can be responsible, at least in part, for the pathogenesis of central obesity, adverse metabolic profile (increased body metabolic index and fat mass, decreased lean body mass, dyslipidemia, insulin resistance and glucose intolerance) and osteoporosis [41].

Prolactin and oxytocin.

Oxytocin is considered as antistress hormone having anxiolytic and relaxing effects [15].      Prolactin can reduce the activity of HPA axis, whereas oxytocin can inhibit adrenocorticotropic hormone (ACTH) and cortisol release in both men and women, following corticotropin-releasing hormone (CRH) or exercise [6].

According to Arumugam et al. [4], prolactin and glucocorticoids have opposing effects on a number of pancreatic beta-cell genes. Besides, prolactin induces beta-cell replication and inhibits beta-cell apoptosis, whereas glucocorticoids provoke the opposite. In addition, lactogens appear to preserve beta-cell function during fasting, stress or states of glucocorticoid excess.

There are several studies confirming oxytocin and prolactin actions on HPA axis activity. For example, central oxytocin administration decreased stress-induced corticosterone release in rats [48]. Besides, central oxytocin attenuated the activation of specific forebrain regions associated with modulation of HPA activity during the stress reaction [49]. This oxytocin action is considered as manifestation of its antistress influence.

Elevated prolactin antagonized apoptosis in murine thymocytes exposed to glucocorticoids in vivo [23]. It was suggested that prolactin may function as antistress mediator under conditions of elevated glucocorticoid levels in vivo. Prolactin prevented restraint stress-induced gastric erosions and ulcers, as well as hypocalcemia in rats [12].

Centrally administered prolactin decreased stress-induced ACTH secretion and therefore, was considered as antistress factor [44]. In vivo prolactin protected neurogenesis in the dentate gyrus of chronically stressed mice from adverse glucocorticoid action [45].

Oxytocin reduced salivary cortisol during the couple conflict in humans [7]. This neuropeptide appears to have an important mediating role in stress-buffering effects of positive social interactions. Besides, human volunteers treated with a combination of oxytocin and social support, exhibited the lowest salivary cortisol during the stress reaction [17].

If prolactin and oxytocin affect HPA axis activity, then stress and its mediators like glucocorticoids may influence their secretion. In fact, acute stress increases a release of prolactin which in turn can augment glucocorticoid secretion [34]. Serum prolactin increased after ether stress and decreased following dexamethasone treatment in rats [31]. Corticosterone inhibited prolactin release from rat pituitaries incubated in vitro. Moreover, corticosterone decreased prolactin levels in hypophysectomized rats with pituitary grafts [24]. For evaluation of the role of glucocorticoid interactions with lactogens in late postnatal ontogeny and aging, it is important to mention that prolactin, together with GH, IGF-I and thyroid hormones, is considered as antistress and immunoprotective factor, since primary role of these hormones appears to counteract the effects of negative immunoregulatory factors, such as glucocorticoids, especially during the stress situations [9].

Important advances in this sense were obtained principally in hypopituitary dwarf mice. In fact, earlier works have already demonstrated that immunodeficiency of these animals and precocious aging-like alterations could be overcome by GH and thyroxine [10, 30]. In subsequent studies it was shown that a combination of thyroxine with GH and prolactin corrected the defects in numbers of various types of splenocytes in dwarf mice [13]. Besides, GH3 pituitary adenoma cells, producing GH and prolactin, could reverse thymic aging, when transplanted into rats [22]. Nevertheless, the role of glucocorticoid interactions with prolactin and GH in aging is all far from clear.

Although GH / IGF-I axis and insulin were implicated by genetic studies in negative influences on life expectancy [1, 21], caution is suggested against the tendency to translate results in simple postmitotic organisms like worms and flies to large mammals in which somatic organs are regulated by stem cell compartment. In fact, restoration of IGF-I levels in the elderly may have significant health benefits due to preventive IGF-I effects against skeletal muscle atrophy and cardiomyocyte loss as a function of age [2].

On the other hand, data in rodents indicate that there is an optimal level of GH / IGF-I axis activity to maximize survival in mammals [38]. Strains of mice and rats used as controls may have increased frequency of some tumors in advanced age, for example, those of pituitary gland [21]. However, the severly attenuated GH / IGF-I axis in dwarf mice might also promote tumorigenesis by reducing immune function, particularly NK cell activity [38].

Finally, the retardation or apparent acceleration of aging induced by changes of GH levels in mutant mice may be a consequence of compensatory changes in insulin levels [8]. In any case, the GH / insulin ratio should be considered for evaluating the effects of anti-aging procedures like caloric restriction [29].

Concluding remarks.

Although stress peptide hormones may be subdivided into 3 subgroups: stress-, euphoria- and coping-related peptides [28], and it seems that at least, coping and perhaps, euphoria peptides could be considered as antistress factors, nevertheless, the overlapping nature of hormonal proteins and peptides complicates such subdivision, therefore, even CRH and glucocorticoids may paradoxically have antistress activity inhibiting gastric ulcers in rats [12]. The picture tends to become even more complicated, if to consider multiple hormonal interactions. Here we tried to create stress- and principally glucocorticoid-centered schemes involving somatolactogenic hormones and related peptides. However, many future research efforts are necessary yet (probably, with the use of systems biology and medicine), in order to make these schemes and integral picture more clear. 

Список литературы.

1. Anisimov V.N. Insulin / IGF-I signaling pathway driving aging and cancer as a target for pharmacological intervention / V.N. Anisimov // Exp. Gerontol. – 2003. - Vol. 38, №. 10. - P. 1041 - 1049.
2. Anversa P. Aging and longevity: the IGF-1 enigma / P. Anversa // Circ. Res. – 2005. - Vol. 97, №. 5. - P. 411 - 414.
3. Andersen N.B. The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats / N.B. Andersen, K. Malmlof, P.B. Johansen [et al.]. // Growth Hormone IGF Res. – 2001. - Vol. 11, № 5. - P. 266 - 272.
4. Arumugam R. The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy / R. Arumugam, E. Horowitz, D. Lu [et al.]. // Endocrinology. – 2008. - Vol. 149, № 11. - P. 5401 - 5414.
5. Asakawa K. Effects of glucocorticoid on body growth and serum levels of somatomedin A in the rat / K. Asakawa, K. Takano, M. Kogawa [et al.]. // Acta Endocr. (Kopenh.) . – 1982. - Vol. 100, № 2. - P. 206 - 210.
6. Carter C.S. Integrative functions of lactational hormones in social behavior and stress management / C.S. Carter, M. Altemus //Ann. N.Y. Acad. Sci. – 1997. – №. 807. - P. 164 - 174.
7. Ditzen B. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict / B. Ditzen, M. Schaer, B. Gabriel [et al.]. // Biol. Psychiatry. – 2009. - Vol. 65, № 9. - P. 728 - 731.
8. Dominici F.P. Growth hormone-induced alterations in the insulin-signaling system / F.P. Dominici, D. Turyn // Exp. Biol. Med. – 2002. - Vol. 227, № 3. - P. 149 - 157.
9. Dorshkind K. Anterior pituitary hormones, stress, and immune system homeostasis / Dorshkind, N.D. Horseman // Bioessays. – 2001. - Vol.23, № 3. - P. 288 - 294.
10. Fabris N. Neuroendocrine – immune interactions: a theoretical approach to aging / N. Fabris // Arch. Gerontol. Geriatr. – 1991. - Vol. 12, № 2 - 3. - P. 219 - 230.
11. Fernandez-Vazquez G. Corticosterone modulates growth hormone-releasing factor and somatostatin in fetal rat hypothalamic cultures / G. Fernandez-Vazquez, L. Cacicedo, M.J. Lorenzo [et al.]. // Neuroendocrinology. – 1995. - Vol. 61, № 1. - 31 - 35.
12. Fujikawa T. Prolactin prevents acute stress-induced hypocalcemia and ulcerogenesis by acting in the brain of rat / T. Fujikawa, H. Soya, K.L. Tamashiro [et al.]. // Endocrinology. – 2004. - Vol. 145, № 4. - P. 2006 - 2013.
13. Gala R.R. Influence of thyroxine and thyroxine with growth hormone and prolactin on splenocyte subsets and on the expression of interleukin-2 and prolactin receptors on splenocyte subsets of Snell dwarf mice / R.R. Gala // Proc. Soc. Exp. Biol. Med. – 1995. - Vol. 210, № 2. - P. 117 - 125.
14. Giustina A. Effect of hydrocortisone on the growth hormone response to growth hormone-releasing hormone in acromegaly / A. Giustina, A.R. Bussi, M. Doga [et al.]. // Horm. Res. – 1994. - Vol . 41, № 1. - P. 33 - 37.
15. Gordon I. Oxytocin, cortisol, and triadic family interactions / I. Gordon, O. Zagoory-Sharon, J.F. Leckman [et al.]. // Physiol. Behav. – 2010. - Vol. 101, № 5. - P. 679 - 684.
16. Goudochnikov V.I. The role of glucocorticoids in aging and age-related pharmacotherapy / V.I. Goudochnikov // Adv. Gerontol. – 2011. - Vol.24, № 1. - P. 48 -  53.
17. Heinrichs M. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol / M. Heinrichs, T. Baumgartner, C. Kirschbaum [et al.]. // Psychiatry. – 2003. - Vol. 54, № 12. - P. 1389 - 1398.
18. Hertoghe T. The “multiple hormone deficiency” theory of aging: is human senescence caused mainly by multiple hormone deficiencies?/ T. Hertoghe //Ann. N.Y. Acad. Sci. – 2004. - № 1057. - P. 448 - 465.
19. Hinton P.S. IGF-I alters lymphocyte survival and regeneration in thymus and spleen after dexamethasone treatment / P.S. Hinton, C.A. Peterson, E.M. Dahly [et al.]. // Am. J. Physiol. – 1998. - Vol. 274, № 4, Pt 2. - P. R912 - R920.
20. Kanda F. Steroid myopathy: pathogenesis and effects of growth hormone and insulin-like growth factor-I administration / F. Kanda, S. Okuda, T. Matsushita [et al.]. // Horm. Res. – 2001. – № 56, Suppl. 1. - P. 24 - 28.
21. Kappeler L. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism / L. Kappeler, C. de Magalhaes Filho, J. Dupont [et al.]. // PLoS Biol. – 2008. - Vol.6, № 10. doi: 10.1371/journal.pbio.0060254.
22. Kelley K.W. GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc. Nat / K.W. Kelley, S. Brief, H.J. Westly [et al.]. // Acad. Sci. USA. – 1986. - Vol. 83, № 15. -  P. 5663 - 5667.
23. Krishnan N. Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo / N. Krishnan, O. Thellin, D.J. Buckley[et al.]. // Endocrinology. – 2003. - Vol. 144, № 5. - P. 2102 -2110.
24. Leung F.C. Mechanism(s) by which adrenalectomy and corticosterone influence prolactin release in the rat / F.C. Leung, H.T. Chen, S.J. Verkaik [et al.]. // J. Endocrinol. – 1980. - Vol. 87, № 1. - P. 131 - 140.
25. Malmlof K. The role of insulin, insulin-like growth factor-I and growth hormone in counteracting dexamethasone induced nitrogen wasting in rats / K. Malmlof, V. Arrhenius-Nyberg, H. Saxerholt [et al.]. // Horm. Metab. Res. – 1997. - Vol. 29, № 1. -  P. 20 - 24.
26. Miell J.P. The effects of dexamethasone treatment on immunoreactive and bioactive insulin-like   growth   factors       (IGFs)   and  IGF-binding   proteins   in   normal    male volunteers / J.P. Miell, A.M. Taylor, J. Jones [et al.]. // J. Endocrinol. – 1993. - Vol. 136, № 3. - P. 525 - 533.
27. Nass R. Impact of the GH-cortisol ratio on the age-dependent changes in body composition / R. Nass, M.O. Thorner // Growth Hormone IGF Res. – 2002. - Vol. 12, №.  3. - P. 147 - 161.
28. Papathanassoglou E.D. Potential effects of stress in critical illness through the the role of stress neuropeptides / E.D. Papathanassoglou, M. Giannakopoulou, M. Mpouzika [et al.] // Nursing Crit. Care. – 2010. - Vol. 15, №. 4. - P. 204 - 216.
29. Parr T. Insulin exposure and aging theory / T. Parr // Gerontology. – 1997. - Vol. 43, №.  3. - P. 182 - 200.
30. Pierpaoli W. Hormones and immunological capacity. II. Reconstitution of antibody production in hormonally deficient mice by somatotropic hormone, thyrotropic hormone and thyroxin / W. Pierpaoli, C. Baroni, N. Fabris, E. Sorkin // Immunology. – 1969. - Vol. 16, №. 2. - P. 217 - 230.
31. Piroli G. Glucocorticoid receptors and inhibition of serum prolactin by dexamethasone are reduced in rats with estrogen-induced pituitary tumors / G. Piroli, C. Grillo, V. Luz de Lantos [et al.]. // Neuroendocrinol. Lett. – 1991. - Vol.13, №. 2. - P. 75 - 81.
32. Prummel M.F. The effect of long-term prednisone treatment on growth hormone and insulin-like growth factor-I / M.F. Prummel, W.M. Wiersinga, H. Oosting [et al.]. // J. Endocrinol. Invest. – 1996. - Vol. 19, №. 9. - P. 620 - 623.
33. Read L.C. Insulin-like growth factor-I and its N-terminal modified analogues induce marked gut growth in dexamethasone-treated rats / L.C. Read, F.M. Tomas, G.S. Howarth [et al.]. // J. Endocrinol. – 1992. - Vol. 133, №. 3. - P. 421 - 431.
34. Reis F.M. Plasma prolactin and glucose alterations induced by surgical stress: a single or dual response? / F.M. Reis, Jr. A. Ribeiro de Oliveira, J.C. Machado [et al.]. // Exp. Physiol. –1998. - Vol. 83, №. 1. - P. 1 - 10.
35. Robinson I.C. Glucocorticoids and growth problems / I.C. Robinson, B. Gabrielsson, G. Klaus [et al.]. // Acta Paediatr. Suppl. – 1995. - №. 411. - P. 81 - 86.
36. Sartin J.L. Cortisol inhibition of growth hormone-releasing hormone-stimulated growth hormone release from cultured sheep pituitary cells / J.L. Sartin, R.J. Kemppainen, E.S. Coleman [et al.]. // J. Endocrinol. – 1994. - Vol. 141, №. 3. - P. 517 - 525.
37. Selye H. Prevention of cortisone overdosage: effects with the somatotropic hormone (STH) / H. Selye //Am. J. Physiol. – 1952. - Vol. 171, №. 2. - P. 381 - 384.
38. Shimokawa I. Life span extension by reduction in growth hormone – insulin-like growth factor-1 axis in a transgenic rat model / I. Shimokawa, Y. Higami, M. Utsuyama [et al.]. // Am. J. Pathol. – 2002. - Vol. 160, №. 6. - P. 2259 - 2265.
39. Siebler T. Glucocorticoids, thyroid hormone and growth hormone interactions: implications for the growth plate / T. Siebler, H. Robson, S.M. Shalet, Williams G.R. // Horm. Res. – 2001. - Vol. 56, Suppl.1. - P. 7 - 12.
40. Skjaerbaek C. Serum free insulin-like growth factor-I is dose-dependently decreased by methylprednisolone and related to body weight changes in rats / C. Skjaerbaek, J. Frystyk, T. Grofte [et al.]. // Growth Hormone IGF Res. – 1999. - Vol. 9, №. 1. - P. 74 - 80.
41. Stewart P.M. Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle / P.M. Stewart, A.A. Toogood, J.W. Tomlinson // Horm.Res. – 2001. - Vol. 56, Suppl.1. - P. 1 - 6.
42. Thakore J.H. Growth hormone secretion: the role of glucocorticoids / J.H. Thakore, T.G. Dinan // Life Sci. – 1994. - Vol.55, № 14. - P. 1083 - 1099.
43. Tonshoff B. Interaction between glucocorticoids and the somatotrophic axis / B. Tonshoff, O. Mehls // Acta Paediatr. Suppl. – 1996. - № 417. - P. 72 - 75.
44. Torner L. Anxiolytic and antistress effects of brain prolactin: improved efficacy of antisense targeting of the prolactin receptor by molecular modeling / L. Torner, N. Toschi, A. Pohlinger [et al.]. // J. Neurosci. – 2001. - Vol.21, № 9. - P. 3207 - 3214.
45. Torner L. Prolactin prevents chronic stress-induced decrease of adult hippocampal neurogenesis and promotes neuronal fate / L. Torner, S. Karg, A. Blume [et al.]. // J. Neurosci. – 2009. - Vol. 29, № 6. - P. 1826 - 1833.
46. Voltz D.M. Effect of GHRP-6 and GHRH on GH secretion in rats following chronic glucocorticoid treatment / D.M. Voltz, A.W. Piering, M. Magestro [et al.]. // Life Sci. – 1995. - Vol. 56, № 7. - P. 491 - 497.
47. Ward W.E. Growth hormone and insulin-like growth factor-I therapy promote protein deposition and growth in dexamethasone-treated piglets / W.E. Ward, S.A. Atkinson // J. Pediat. Gastroenterol. Nutr. – 1999. - Vol.28, № 4. - P. 404 - 410.
48. Windle R.J. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats / R.J. Windle, N. Shanks, S.L. Lightman, C.D. Ingram // Endocrinology. – 1997. - Vol. 138, № 7. - P. 2829 - 2834.
49. Windle R.J. Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity/ R.J. Windle, Y.M. Kershaw, N. Shanks [et al.]. // J. Neurosci. – 2004. - Vol. 24, № 12. - P. 2974 - 2982.
50. Wolthers T. Growth hormone prevents prednisolone-induced increase in functional hepatic nitrogen clearance in normal man / T. Wolthers, T. Grofte, J.O. Jorgensen [et al.]. // J. Hepatol. – 1997. - Vol. 27, № 5. - P. 789 - 795.