Abstract
Estradiol (E2) has been documented to have anti-inflammatory effects on the immune system. Interleukin-6 (IL-6), is classified as a “myokine”, and has known metabolic consequences. Thus, the purpose of this study was to determine the effects of menstrual phase and exercise on the interaction of E2 and IL-6, and the role of IL-6 in substrate metabolism. Ten female subjects completed three separate testing sessions: baseline evaluation, and 1 h of treadmill exercise at 65% of peak \( \dot V {\text{O}}_{2} \) during both the midfollicular (MF) and midluteal (ML) menstrual phases. Saliva was collected prior to, during, and post-exercise for determination of E2 and IL-6. Expired gases and an additional saliva sample were collected 30 min post-exercise. No significant differences were observed in any of the measured variables across menstrual phase. Exercise resulted in an acute rise in estradiol and IL-6; however, E2 was not related to IL-6 at baseline or in response to exercise. IL-6 remained elevated at the end of exercise and was found to be related to energy expenditure from fat, and to total energy expenditure at 60 min, and 30 min post-exercise. No relationships were found between the anti-inflammatory estrogen E2 and the cytokine IL-6. However, relationships were found between IL-6 and indices of substrate metabolism. Based on the data from the current research, IL-6 likely plays a metabolic role in healthy individuals during exercise when released from the muscle as a result of reduced energy availability, acting as a “myokine”, in comparison to inflammation-induced IL-6 release.
Similar content being viewed by others
References
Belkien LD, Bordt J, Moller P, Hano R, Nieschlag E (1985) Estradiol in saliva for monitoring follicular stimulation in an in vitro fertilization program. Fertil Steril 44:322–327
Berthonneau J, Tanguy G, Janssens Y, Guichard A, Boyer P, Zorn JR, Cedard L (1989) Salivary oestradiol in spontaneous and stimulated menstrual cycles. Hum Reprod 4:625–628
Bonen A, Haynes F, Graham T (1991) Substrate and hormonal responses to exercise in women using oral contraceptives. J Appl Physiol 70:1917
Casa DJ, Armstrong LE, Hillman SK, Montain SJ, Reiff RV, Rich BS, Roberts WO, Stone JA (2000) National athletic trainers’ association position statement: fluid replacement for athletes. J Athl Train 35:212–224
Casazza G, Suh S, Miller B, Navazio F, Brooks G (2002) Effects of oral contraceptives on peak exercise capacity. J Appl Physiol 93:1698
Celec P, Ostanikova D, Skoknova M, Hodosy J, Putz Z, Kudela M (2009) Salivary sex hormones during the menstrual cycle. Endocr J 56:521–523
Chatterton RT Jr, Vogelsong KM, Lu YC, Ellman AB, Hudgens GA (1996) Salivary alpha-amylase as a measure of endogenous adrenergic activity. Clin Physiol 16:433–448
Chiappelli F, Iribarren FJ, Prolo P (2006) Salivary biomarkers in psychobiological medicine. Bioinformation 1:331–334
Choe JK, Khan-Dawood FS, Dawood MY (1983) Progesterone and estradiol in the saliva and plasma during the menstrual cycle. Am J Obstet Gynecol 147:557–562
Connolly P, Caiozzo V, Zaldivar F, Nemet D, Larson J, Hung S, Heck J, Hatfield G, Cooper D (2004) Effects of exercise on gene expression in human peripheral blood mononuclear cells. J Appl Physiol 97:1461
Davison G, Gleeson M, Phillips S (2007) Antioxidant supplementation and immunoendocrine responses to prolonged exercise. Med Sci Sports Exerc 39:645
de Jonge X (2003) Effects of the menstrual cycle on exercise performance. Sports Med 33:833–851
Febbraio M, Pedersen B (2005) Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33:114
Febbraio M, Steensberg A, Keller C, Starkie R, Nielsen H, Krustrup P, Ott P, Secher N, Pedersen B (2003) Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol 549:607
Febbraio M, Hiscock N, Sacchetti M, Fischer C, Pedersen B (2004) Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53:1643
Frayn KN (1983) Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 55(2):628
Gandara BK, Leresche L, Mancl L (2007) Patterns of salivary estradiol and progesterone across the menstrual cycle. Ann NY Acad Sci 1098:446–450
Gann P, Giovanazzi S, Van Horn L, Branning A, Chatterton R (2001) Saliva as a medium for investigating intra-and interindividual differences in sex hormone levels in premenopausal women. Cancer Epidemiol Biomark Prev 10:59
Gavrilova N, Lindau ST (2009) Salivary sex hormone measurement in a national, population-based study of older adults. J Gerontol Series B Psychol Sci Soc Sci 64B:i94–i105
Girasole G, Jilka R, Passeri G, Boswell S, Boder G, Williams D, Manolagas S (1992) 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
Goebel M, Mills P, Irwin M, Ziegler M (2000) Interleukin-6 and tumor necrosis factor-{alpha} production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways. Psychosom Med 62:591
Groschl M (2008) Current status of salivary hormone analysis. Clin Chem 54:1759–1769
Hofman LF (2001) Human saliva as a diagnostic specimen. J Nutr 131:1621S–1625S
Horton T, Miller E, Glueck D, Tench K (2002) No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate-intensity exercise. Am J Physiol Endocrinol Metab 282:E752
Jackson AS, Pollock ML, Ward A (1980) Generalized equations for predicting body density of women. Med Sci Sports Exerc 12:175–182
Jankord R, Turk J, Schadt J, Casati J, Ganjam V, Price E, Keisler D, Laughlin M (2007) Sex difference in link between interleukin-6 and stress. Endocrinology 148:3758
Kendall B, Eston R (2002) Exercise-induced muscle damage and the potential protective role of estrogen. Sports Med 32:103–123
Kirschbaum C, Kudielka B, Gaab J, Schommer N, Hellhammer D (1999) Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus–pituitary–adrenal axis. Psychosom Med 61:154
Kivlighan KT, Granger DA, Schwartz EB (2005) Blood contamination and the measurement of salivary progesterone and estradiol. Horm Behav 47:367–370
Kovacs E, Plackett T, Witte P (2004) Estrogen replacement, aging, and cell-mediated immunity after injury. J Leukoc Biol 76:36
Lu Y, Bentley GR, Gann PH, Hodges KR, Chatterton RT (1999) Salivary estradiol and progesterone levels in conception and nonconception cycles in women: evaluation of a new assay for salivary estradiol. Fertil Steril 71:863–868
Lyngsø D, Simonsen L, Bülow J (2002) Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise. J Physiol 543:373
Margeli A, Skenderi K, Tsironi M, Hantzi E, Matalas A, Vrettou C, Kanavakis E, Chrousos G, Papassotiriou I (2005) Dramatic elevations of interleukin-6 and acute-phase reactants in athletes participating in the ultradistance foot race spartathlon: severe systemic inflammation and lipid and lipoprotein changes in protracted exercise. J Clin Endocrinol Metab 90:3914
McConnell T, Clark B (1988) Treadmill protocols for determination of maximum oxygen uptake in runners. Br J Sports Med 22:3
Mentes JC, Wakefield B, Culp K (2006) Use of a urine color chart to monitor hydration status in nursing home residents. Biol Res Nurs 7:197–203
Mohamed-Ali V, Goodrick S, Rawesh A, Katz D, Miles J, Yudkin J, Klein S, Coppack S (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-{alpha}, in vivo. J Clin Endocrinol Metab 82:4196
Mounib N, Sultan C, Bringer J, Hedon B, Nicolas JC, Cristol P, Bressot N, Descomps B (1988) Correlations between free plasma estradiol and estrogens determined by bioluminescence in saliva, plasma, and urine during spontaneous and FSH stimulated cycles in women. J Steroid Biochem 31:861–865
Noble B, Borg G, Jacobs I, Ceci R, Kaiser P (1983) A category-ratio perceived exertion scale: relationship to blood and muscle lactates and heart rate. Med Sci Sports Exerc 15:523
O’Connor M, Motivala S, Valladares E, Olmstead R, Irwin M (2007) Sex differences in monocyte expression of IL-6: role of autonomic mechanisms. Am J Physiol Regul Integr Comp Physiol 293:R145
Papanicolaou D, Wilder R, Manolagas S, Chrousos G (1998) The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 128:127
Pedersen B, Edward F (2009) Adolph Distinguished Lecture: muscle as an endocrine organ: IL-6 and other myokines. J Appl Physiol 107:1006
Pedersen B, Febbraio M (2005) Muscle-derived interleukin-6—a possible link between skeletal muscle, adipose tissue, liver, and brain. Brain Behav Immun 19:371–376
Pedersen B, Steensberg A, Keller P, Keller C, Fischer C, Hiscock N, van Hall G, Plomgaard P, Febbraio M (2003) Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects. Pflügers Arch Eur J Physiol 446:9–16
Pedersen B, Akerstrom T, Nielsen A, Fischer C (2007a) Role of myokines in exercise and metabolism. J Appl Physiol 103:1093
Pedersen B, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Wolsk-Petersen E, Febbraio M (2007b) The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? Proc Nutr Soc 63:263–267
Pottratz S, Bellido T, Mocharla H, Crabb D, Manolagas S (1994) 17 beta-Estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest 93:944
Puder J, Freda P, Goland R, Wardlaw S (2001) Estrogen modulates the hypothalamic–pituitary–adrenal and inflammatory cytokine responses to endotoxin in women. J Clin Endocrinol Metab 86:2403
Randle P (1999) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283
Roepstorff C, Donsmark M, Thiele M, Vistisen B, Stewart G, Vissing K, Schjerling P, Hardie D, Galbo H, Kiens B (2006a) Sex differences in hormone-sensitive lipase expression, activity, and phosphorylation in skeletal muscle at rest and during exercise. Am J Physiol Endocrinol Metab 291:E1106
Roepstorff C, Thiele M, Hillig T, Pilegaard H, Richter E, Wojtaszewski J, Kiens B (2006b) Higher skeletal muscle 2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise. J Physiol 574:125
Sandoval D, Matt K (2002) Gender differences in the endocrine and metabolic responses to hypoxic exercise. J Appl Physiol 92:504
Shirtcliff E, Granger D, Schwartz E, Curran M, Booth A, Overman W (2000) Assessing estradiol in biobehavioral studies using saliva and blood spots: simple radioimmunoassay protocols, reliability, and comparative validity. Horm Behav 38:137–147
Shirtcliff E, Granger D, Schwartz E, Curran M (2001) Use of salivary biomarkers in biobehavioral research: cotton-based sample collection methods can interfere with salivary immunoassay results. Psychoneuroendocrinology 26:165–173
Soo-Quee Koh D, Choon-Huat Koh G (2007) The use of salivary biomarkers in occupational and environmental medicine. Occup Environ Med 64:202–210
Starkie R, Rolland J, Angus D, Anderson M, Febbraio M (2001) Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-{alpha} levels after prolonged running. Am J Physiol Cell Physiol 280:C769
Steensberg A, Febbraio M, Osada T, Schjerling P, Van Hall G, Saltin B, Pedersen B (2001a) Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 537:633
Steensberg A, Toft A, Schjerling P, Halkjar-Kristensen J, Pedersen B (2001b) Plasma interleukin-6 during strenuous exercise: role of epinephrine. Am J Physiol Cell Physiol 281:C1001
Steensberg A, Keller C, Starkie R, Osada T, Febbraio M, Pedersen B (2002) IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283:E1272
Steinberg J, Ba A, Brégeon F, Delliaux S, Jammes Y (2007) Cytokine and oxidative responses to maximal cycling exercise in sedentary subjects. Med Sci Sports Exerc 39:964
Stellingwerff T, Boon H, Gijsen AP, Stegen JHCH, Kuipers H, van Loon LJC (2007) Carbohydrate supplementation during prolonged cycling exercise spares muscle glycogen but does not affect intramyocellular lipid use. Pflügers Arch Eur J Physiol 454(4):635–647
Suh S, Casazza G, Horning M, Miller B, Brooks G (2003) Effects of oral contraceptives on glucose flux and substrate oxidation rates during rest and exercise. J Appl Physiol 94:285
Tamate K, Charleton M, Gosling JP, Egan D, Ishikawa M, Fottrell PF, Kane MM (1997) Direct colorimetric monoclonal antibody enzyme immunoassay for estradiol-17{beta} in saliva. Clin Chem 43:1159–1164
Tara JC, Gordon GG (1998) Variation in risk taking behavior among female college students as a function of the menstrual cycle. 19:27–32
Tarnopolsky M (2008) Sex differences in exercise metabolism and the role of 17-beta estradiol. Med Sci Sports Exerc 40:648
Timmons B, Hamadeh M, Devries M, Tarnopolsky M (2005) Influence of gender, menstrual phase, and oral contraceptive use on immunological changes in response to prolonged cycling. J Appl Physiol 99:979
van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio M (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88:3005
Weigert C, Dufer M, Simon P, Debre E, Runge H, Brodbeck K, Haring H, Schleicher E (2007) Upregulation of IL-6 mRNA by IL-6 in skeletal muscle cells: role of IL-6 mRNA stabilization and Ca2+-dependent mechanisms. Am J Physiol Cell Physiol 293:C1139
Wong YF, Mao K, Panesar NS, Loong EPL, Chang AMZ, Mi ZJ (1990) Salivary estradiol and progesterone during the normal ovulatory menstrual cycle in Chinese women. Eur J Obstet Gynecol Reprod Biol 34:129–135
Worthman C, Stallings J, Hofman L (1990) Sensitive salivary estradiol assay for monitoring ovarian function. Clin Chem 36:1769–1773
Acknowledgments
The authors would like to thank the subjects for their participation as well as, the Springfield College Graduate Research Fund for financial support of this project.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by William J. Kraemer.
Rights and permissions
About this article
Cite this article
Ives, S.J., Blegen, M., Coughlin, M.A. et al. Salivary estradiol, interleukin-6 production, and the relationship to substrate metabolism during exercise in females. Eur J Appl Physiol 111, 1649–1658 (2011). https://doi.org/10.1007/s00421-010-1789-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00421-010-1789-8