Differential age-related changes of hypothalamus - pituitary - adrenal axis hormones in healthy women and men Role of interleukin 6

Summary:

Aging is accompanied by marked changes of steroid hormone levels which vary among women and men. The age-related increase of cytokines such as interleukin (IL)- 6 may modulate the endocrine system. We aimed to investigate the role of IL-6 for the gender-specific changes of acrophase steroid hormone secretion in healthy subjects during aging. Out of 120 healthy subjects, 60 men and 48 women (non luteal phase) were recruited (age: 18 to 75 years). Age was positively correlated with IL-6 (female and male: p < 0.001) and adrenocorticotropic hormone (ACTH) in women only (p < 0.001). Age was negatively correlated with progesterone (female and male: p < 0.001), cortisol (only female: p = 0.003), androstenedione (female and male: p < 0.001), but not 17OH progesterone. After correction for IL-6, the age-related decrease of steroid hormones was blunted in both gender groups except for androstenedione (female and male: p < 0.005). Furthermore, the ratio of serum cortisol to plasma ACTH decreased with age only in women but not in men (female: p < 0.001). Correction for IL-6 did not markedly change the negative interrelationship between age and the mentioned ratio in these women. However, a linear regression analysis revealed that the increase of ACTH in relation to cortisol depends on serum free testosterone in men (p = 0.042) and on serum free 17β-estradiol (p < 0.001) together with serum IL-6 in women (p = 0.021). In conclusion, IL-6 plays an important role for acrophase pituitary and peripheral hormone secretion in women only. The gender-specific changes of cortisol in relation to ACTH depend on the age-related decrease of the respective sex hormone in both gender groups and the increase of IL-6 in women. This study underlines the hormone-like role of IL-6 in the aging process of the endocrine system in women.

Key words:

IL-6 - aging - hypothalamic-pituitary-adrenal axis - steroid hormones

References

• 1 Andus T, Geiger T, Hirano T, Kishimoto T, Heinrich P C. Action of recombinant human interleukin 6, interleukin 1 beta and tumor necrosis factor alpha on the mRNA induction of acute-phase proteins.  Eur J Immunol. 18 739-746 1988; 
• 2 Baker H W, Burger H G, de Kretser D M, Hudson B, O'Connor S, Wang C, Mirovics A, Court J, Dunlop M, Rennie G C. Changes in the pituitary-testicular system with age.  Clin Endocrinol (Oxf). 5 349-372 1976; 
• 3 Belanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez J L, Labrie F. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men.  J Clin Endocrinol Metab. 79 1086-1090 1994; 
• 4 Bellido T, Jilka R L, Boyce B F, Girasole G, Broxmeyer H, Dalrymple S A, Murray R, Manolagas S C. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor.  J Clin Invest. 95 2886-2895 1995; 
• 5 Besedovsky H O, Del Rey A. Immune-neuro-endocrine interactions.  Endocr Rev. 17 64-102 1996; 
• 6 Carroll B J, Curtis G C, Mendels J. Cerebrospinal fluid and plasma free cortisol concentrations in depression.  Psychol Med. 6 235-244 1976; 
• 7 da Silva J A. Sex hormones, glucocorticoids and autoimmunity: facts and hypotheses.  Ann Rheum Dis. 54 6-16 1995; 
• 8 Dasgupta B, Corkill M, Kirkham B, Gibson T, Panayi G. Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis.  J Rheumatol. 19 22-25 1992; 
• 9 Daynes R A, Araneo B A, Ershler W B, Maloney C, Li G Z, Ryu S Y. Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative.  J Immunol. 150 5219-5230 1993; 
• 10 Deshpande R, Khalili H, Pergolizzi R G, Michael S D, Chang M D. Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages.  Am J Reprod Immunol. 38 46-54 1997; 
• 11 Devasagayam T P, Pushpendran C K, Eapen J. Changes in enzymes of hepatic rough and smooth microsomes during postnatal development and ageing of rats.  Mech Ageing Dev. 21 365-375 1983; 
• 12 Dodt C, Theine K J, Uthgenannt D, Born J, Fehm H L. Basal secretory activity of the hypothalamo-pituitary-adrenocortical axis is enhanced in healthy elderly. An assessment during undisturbed night-time sleep.  Eur J Endocrinol. 131 443-450 1994; 
• 13 Ershler W B, Sun W H, Binkley N, Gravenstein S, Volk M J, Kamoske G, Klopp R G, Roecker E B, Daynes R A, Weindruch R. Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction.  Lymphokine Cytokine Res. 12 225-230 1993; 
• 14 Fried S K, Bunkin D A, Greenberg A S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.  J Clin Endocrinol Metab. 83 847-850 1998; 
• 15 Girasole G, Jilka R L, Passeri G, Boswell S, Boder G, Williams D C, Manolagas S C. 17 beta-estradiol inhibits interleukin-6 production by bone marrow- derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens.  J Clin Invest. 89 883-891 1992; 
• 16 Hager K, Machein U, Krieger S, Platt D, Seefried G, Bauer J. Interleukin-6 and selected plasma proteins in healthy persons of different ages.  Neurobiol Aging. 15 771-772 1994; 
• 17 Hammar M, Petersson F, Berg A A. In vitro conversion of progesterone in the human testis at different ages, pathophysiological conditions, and during treatment with estrogens or gonadotrophic hormones.  Arch Androl. 14 143-149 1985; 
• 18 Ikeda U, Ikeda M, Seino Y, Takahashi M, Kano S, Shimada K. Interleukin 6 gene transcripts are expressed in atherosclerotic lesions of genetically hyperlipidemic rabbits.  Atherosclerosis. 92 213-218 1992; 
• 19 Kassem M, Harris S A, Spelsberg T C, Riggs B L. Estrogen inhibits interleukin-6 production and gene expression in a human osteoblastic cell line with high levels of estrogen receptors.  J Bone Miner Res. 11 193-199 1996; 
• 20 Kau M M, Chen J J, Wang S W, Cho W L, Wang P S. Age-related impairment of aldosterone secretion in zona glomerulosa cells of ovariectomized rats.  J Investig Med. 47 425-432 1999; 
• 21 Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.  Nature. 332 83-85 1988; 
• 22 Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J, Pirke K M, Hellhammer D H. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men.  J Clin Endocrinol Metab. 81 3639-3643 1996; 
• 23 Kominami S, Ogawa N, Morimune R, De Ying H, Takemori S. The role of cytochrome b5 in adrenal microsomal steroidogenesis.  J Steroid Biochem Mol Biol. 42 57-64 1992; 
• 24 Kornel L, Miyabo S, Saito Z, Cha R-W, Wu F-T. Corticosteroids in human blood. VIII. Cortisol metabolites in plasma of normotensive subjects and patients with essential hypertension.  J Clin Endocrinol Metab. 40 949-958 1975; 
• 25 Lamberts S W, van den Beld A W, van der Lely A J. The endocrinology of aging.  Science. 278 419-424 1997; 
• 26 Leers-Sucheta S, Stocco D M, Azhar S. Down-regulation of steroidogenic acute regulatory (StAR) protein in rat Leydig cells: implications for regulation of testosterone production during aging.  Mech Ageing Dev. 107 197-203 1999; 
• 27 Ligthart G J, Corberand J X, Fournier C, Galanaud P, Hijmans W, Kennes B, Muller-Hermelink H K, Steinmann G G. Admission criteria for immunogerontological studies in man: the SENIEUR protocol.  Mech Ageing Dev. 28 47-55 1984; 
• 28 Luo L, Chen H, Zirkin B R. Are Leydig cell steroidogenic enzymes differentially regulated with aging?.  J Androl. 17 509-515 1996; 
• 29 Manolagas S C, Jilka R L. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis.  N Engl J Med. 332 305-311 1995; 
• 30 Mastorakos G, Chrousos G P, Weber J S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.  J Clin Endocrinol Metab. 77 1690-1694 1993; 
• 31 Michl P, Beikler T, Engelhardt D, Weber M M. Interleukin-3 and Interleukin-6 Stimulate Bovine Adrenal Cortisol Secretion Through Different Pathways.  J Neuroendocrinol. 12 23-28 2000; 
• 32 Miller W L, Auchus R J, Geller D H. The regulation of 17,20 lyase activity.  Steroids. 62 133-142 1997; 
• 33 Mohamed-Ali V, Goodrick S, Rawesh A, Katz D R, Miles J M, Yudkin J S, Klein S, Coppack S W. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.  J Clin Endocrinol Metab. 82 4196-4200 1997; 
• 34 Mysliwska J, Bryl E, Foerster J, Mysliwski A. Increase of interleukin 6 and decrease of interleukin 2 production during the ageing process are influenced by the health status.  Mech Ageing Dev. 100 313-328 1998; 
• 35 Nikolaus S, Raedler A, Fölsch U R, Schreiber S. Aging of the gastrointestinal immune system: Increased secretion of proinflammatory cytokines by LpMNC and increased mucosal activation of NFkappaB-p65.  Gut 45 ((Suppl V)) A344 1999; 
• 36 Orban Z, Remaley A T, Sampson M, Trajanoski Z, Chrousos G P. The differential effect of food intake and beta-adrenergic stimulation on adipose-derived hormones and cytokines in man.  J Clin Endocrinol Metab. 84 2126-2133 1999; 
• 37 Path G, Bornstein S R, Ehrhart-Bornstein M, Scherbaum W A. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis.  J Clin Endocrinol Metab. 82 2343-2349 1997; 
• 38 Poynter M E, Daynes R A. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging.  J Biol Chem. 273 32833-32841 1998; 
• 39 Ralston S H, Russell R G, Gowen M. Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women.  J Bone Miner Res. 5 983-988 1990; 
• 40 Roche N E, Fulbright J W, Wagner A D, Hunder G G, Goronzy J J, Weyand C M. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis.  Arthritis Rheum. 36 1286-1294 1993; 
• 41 Salas M A, Evans S W, Levell M J, Whicher J T. Interleukin-6 and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland cells.  Clin Exp Immunol. 79 470-473 1990; 
• 42 Schmidt M, Kreutz M, Löffler G, Schölmerich J, Straub R H. Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages.  J Endocrinol. 164 161-169 2000; 
• 43 Späth-Schwalbe E, Born J, Schrezenmeier H, Bornstein S R, Stromeyer P, Drechsler S, Fehm H L, Porzsolt F. Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man.  J Clin Endocrinol Metab. 79 1212-1214 1994; 
• 44 Straub R H, Hense H W, Andus T, Schölmerich J, Riegger G A, Schunkert H. Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study.  J Clin Endocrinol Metab. 85 1340-1344 2000; 
• 45 Straub R H, Konecna L, Hrach S, Rothe G, Kreutz M, Schölmerich J, Falk W, Lang B. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence.  J Clin Endocrinol Metab. 83 2012-2017 1998; 
• 46 Tsigos C, Papanicolaou D A, Defensor R, Mitsiadis C S, Kyrou I, Chrousos G P. Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure.  Neuroendocrinology. 66 54-62, 1997; 
• 47 Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men.  JAMA. 284 861-868 2000; 
• 48 Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome.  J Exp Med. 169 333-338 1989; 
• 49 Weber M M, Michl P, Auernhammer C J, Engelhardt D. Interleukin-3 and interleukin-6 stimulate cortisol secretion from adult human adrenocortical cells.  Endocrinology. 138 2207-2210 1997; 
• 50 Wei J, Xu H, Davies J L, Hemmings G P. Increase of plasma IL-6 concentration with age in healthy subjects.  Life Sci. 51 1953-1956 1992; 
• 51 Xia-Zhang L, Xiao E, Ferin M. A 5-day estradiol therapy, in amounts reproducing concentrations of the early-mid follicular phase, prevents the activation of the hypothalamo-pituitary-adrenal axis by interleukin-1 alpha in the ovariectomized rhesus monkey.  J Neuroendocrinol. 7 387-392 1995; 
• 52 Young D G, Skibinski G, Mason J I, James K. The influence of age and gender on serum dehydroepiandrosterone sulphate (DHEA-S), IL-6, IL-6 soluble receptor (IL-6 sR) and transforming growth factor beta 1 (TGF-beta1) levels in normal healthy blood donors.  Clin Exp Immunol. 117 476-481 1999;