Evaluation of the effects of estradiol on the hypothalamic-pitutary adrenal axis response during systemic and local inflammation

DOI: 10.4236/mri.2012.11001   PDF   HTML     5,900 Downloads   11,821 Views   Citations


The immune and nervous systems are closely interrelated through their messenger molecules: cytokines, hormones and nitric oxide. There are sex differences in the magnitude of the inflammatory response and one of the mechanism by which female sex steroids modulate the inflammatory response could be through the hypothalamo-pituitary-adrenal axe(HPA axes). In this study, we aimed to investigate the inter-relationship between the different levels of estradiol hormone and the different inflammatory stimuli on the HPA axis response, and the role of interleukin 6(IL6) and nitric oxide (NO). This was achieved by using 100 female albino rats divided in to 3 main groups: The first group was the sham group, which was used to test the effect of all sham procedures used in the study. The two other groups represented the two inflammatory states: local (induced by formaline injection) and systemic (cecal ligation and puncture: CLP). Under each inflammatory state, the effect of intact ovary, estradiol treated ovariectomy and placebo treated ovariectomy were studied. HPA responses were evaluated, 24 hours after the sham or the inflammatory procedure, through the measurement of the plasma levels of Corticotropin-releasing Hormone (CRH), adrenocorticotropes Hormone (ACTH) and cortisol. Both IL6 and nitrite were also measured.We found that high physiological levels of estradiol reduced the enhanced HPA response induced by different inflammatory mediators during systemic and local inflammation. With significant enhancement of the HPA response observed mainly during local inflammation. We conclude that both the levels of estradiol hormone and the type of inflammation seem to play an important determining role on HPA response. IL6 and NO play important roles that could explain the previous findings.

Share and Cite:

Sharawy, N., Hassan, M., Rashed, L., Shawky, W. and Rateb, M. (2012) Evaluation of the effects of estradiol on the hypothalamic-pitutary adrenal axis response during systemic and local inflammation. Modern Research in Inflammation, 1, 1-10. doi: 10.4236/mri.2012.11001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Bone, R.C. (1992) Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). The Journal of the American Medical Association, 268, 3452-3455. HUdoi:10.1001/jama.1992.03490240060037U
[2] Brun-Buisson, C. (2000) The epidemiology of the sys-temic inflammatory response. Intensive Care Medicine, 26, S64-S74. HUdoi:10.1007/s001340051121U
[3] Wade, S., Bussow, M. and Hanisch, E. (1998) Epidemiology of systemic inflammatory response syndrome, infection and septic shock in surgical intensive care patients. Der Chirurg, 69, 648-655. HUdoi:10.1007/s001040050470U
[4] Van den Berghe, G., de Zegher, F. and Bouillon, R. (1998) Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. The Journal of Clinical Endocrinology & Metabolism, 83, 1827-1834. HUdoi:10.1210/jc.83.6.1827U
[5] Mebis, L., Debaveye, Y., Ellger, B., Derde, S., Ververs, E.J., et al. (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Critical Care, 13, R147. HUdoi:10.1186/cc8043U
[6] Sriram, K., Rodriguez-Fernandez, M. and Doyle, F.J. III, (2012) Modeling cortisol dynamics in the neuro-endocrine axis distinguishes normal, depression, and post- traumatic stress disorder (PTSD) in humans. PLoS Computational Biology, 8, e1002379. HUdoi:10.1371/journal.pcbi.1002379U
[7] Tsigos, C. and Chrousos, G.P. (2002) Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of Psychosomatic Research, 53, 865-871. HUdoi:10.1016/S0022-3999(02)00429-4U
[8] Turnbull, A.V. and Rivier, C.L. (1999) Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: Actions and mechanisms of action. Physiological Reviews, 79, 1-71.
[9] Leon, L.R., White, A.A. and Kluger, M.J. (1998) Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 275, R269- R277.
[10] Zellweger, R., Wichmann, M.W., Ayala, A., Stein, S., DeMaso, C.M., et al. (1997) Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Critical Care Medicine, 25, 106-110. HUdoi:10.1097/00003246-199701000-00021U
[11] Jankord, R., Turk, J.R., Schadt, J.C., Casati, J., Ganjam, V.K., et al. (2007) Sex difference in link between inter-leukin-6 and stress. Endocrinology, 148, 3758-3764. HUdoi:10.1210/en.2006-1650U
[12] Serova, L.I., Harris, H.A., Maharjan, S. and Sabban, E.L. (2010) Modulation of responses to stress by estradiol benzoate and selective estrogen receptor agonists. Journal of Endocrinology, 205, 253-262. HUdoi:10.1677/JOE-10-0029U
[13] Evuarherhe, O., Leggett, J., Waite, E., Kershaw, Y. and Lightman, S. (2009) Reversal of the hypothalamo-pituitary-adrenal response to oestrogens around puberty. Journal of Endocrinology, 202, 279-285. HUdoi:10.1677/JOE-09-0175U
[14] Weiser, M.J. and Handa, R.J. (2009) Estrogen impairs glucocorticoid dependent negative feedback on the hypo-thalamic-pituitary-adrenal axis via estrogen receptor alpha within the hypothalamus. Neuroscience, 159, 883- 895. HUdoi:10.1016/j.neuroscience.2008.12.058U
[15] Kumsta, R., Entringer, S., Koper, J.W., Van Rossum, E.F., Hellhammer, D.H., et al. (2007) Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress. Biological Psychiatry, 62, 863-869. HUdoi:10.1016/j.biopsych.2007.04.013U
[16] Windle, R.J., Gamble, L.E., Kershaw, Y.M., Wood, S.A., Lightman, S.L., et al. (2006) Gonadal steroid modulation of stress-induced hypothalamo-pituitary-adrenal activity and anxiety behavior: Role of central oxytocin. Endocrinology, 147, 2423-2431. HUdoi:10.1210/en.2005-1079U
[17] Seale, J.V., Wood, S.A., Atkinson, H.C., Harbuz, M.S. and Lightman, S.L. (2004) Gonadal steroid replacement reverses gonadectomy-induced changes in the corticosterone pulse profile and stress-induced hypothalamic-pituitary-adrenal axis activity of male and female rats. Journal of Neuroendocrinology, 16, 989-998. HUdoi:10.1111/j.1365-2826.2004.01258.xU
[18] Isgor, C., Cecchi, M., Kabbaj, M., Akil, H. and Watson, S.J. (2003) Estrogen receptor beta in the paraventricular nucleus of hypothalamus regulates the neuroendocrine response to stress and is regulated by corticosterone. Neuroscience, 121, 837-845. HUdoi:10.1016/S0306-4522(03)00561-XU
[19] McCormick, C.M., Linkroum, W., Sallinen, B.J. and Miller, N.W. (2002) Peripheral and central sex steroids have differential effects on the HPA axis of male and fe-male rats. Stress, 5, 235-247. HUdoi:10.1080/1025389021000061165U
[20] Kirschbaum, C., Kudielka, B.M., Gaab, J., Schommer, N.C. and Hellhammer, D.H. (1999) Impact of gender, menstrual cycle phase, and oral contraceptives on the ac-tivity of the hypothalamus-pituitary-adrenal axis. Psycho-somatic Medicine, 61, 154-162.
[21] Suzuki, S. and Handa, R.J. (2004) Regulation of estrogen receptorbeta expression in the female rat hypothalamus: differential effects of dexamethasone and estradiol. Endocrinology, 145, 3658-3670. HUdoi:10.1210/en.2003-1688U
[22] Deng, J., Muthu, K., Gamelli, R., Shankar, R. and Jones, S.B. (2004) Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis. American journal of physiology. Cell physiology, 287, C730-C736. HUdoi:10.1152/ajpcell.00562.2003U
[23] Green, P.G., Dahlqvist, S.R., Isenberg, W.M., Strausbaugh, H.J., Miao, F.J., et al. (1999) Sex steroid regulation of the inflammatory response: Sympathoadrenal dependence in the female rat. The Journal of Neuroscience, 19, 4082- 4089.
[24] Malmberg, A.B. and Yaksh, T.L. (1995) Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: A micro-dialysis study in unanesthetized rats. The Journal of Neuroscience, 15, 2768-2776.
[25] Roy, B.N., Reid, R.L. and Van Vugt, D.A. (1999) The effects of estrogen and progesterone on corticotropin-releasing hormone and arginine vasopressin messenger ribonucleic acid levels in the paraventricular nucleus and supraoptic nucleus of the rhesus monkey. Endocrinology, 140, 2191-2198. HUdoi:10.1210/en.140.5.2191U
[26] Berkenbosch, F., van Oers, J., Del Rey, A., Tilders, F. and Besedovsky, H. (1987) Corticotropin-releasing factor- producing neurons in the rat activated by interleukin-1. Science, 238, 524-526. HUdoi:10.1126/science.2443979U
[27] Turnbull, A.V. and Rivier, C. (1996) Corticotropin-releasing factor, vasopressin, and prostaglandins me-diate, and nitric oxide restrains, the hypothalamic-pituitary-adrenal response to acute local inflammation in the rat. Endocrinology, 137, 455-463. HUdoi:10.1210/en.137.2.455U
[28] Rivier, C. (1994) Stimulatory effect of interleukin-1 beta on the hypothalamic-pituitary-adrenal axis of the rat: Influence of age, gender and circulating sex steroids. Journal of Endocrinology, 140, 365-372. HUdoi:10.1677/joe.0.1400365U
[29] Lee, S. and Rivier, C. (1995) Altered ACTH and corticosterone responses to interleukin-1 beta in male rats exposed to an alcohol diet: Possible role of vasopressin and testosterone. Alcoholism: Clinical and Experimental Re-search, 19, 200-208. HUdoi:10.1111/j.1530-0277.1995.tb01493.xU
[30] Xiao, E.N., Xia-Zhang, L., Ferin, M. and Wardlaw, S.L. (2001) Differential effects of estradiol on the adrenocor-ticotropin responses to interleukin-6 and interleukin-1 in the monkey. Endocrinology, 142, 2736-2741. HUdoi:10.1210/en.142.7.2736U
[31] Spinedi, E., Suescun, M.O., Hadid, R., Daneva, T. and Gaillard, R.C. (1992) Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypotha-lamo-pituitary-adrenal axis: Evidence for a neuroendo-crine-immunological sexual dimorphism. Endocrinology, 131, 2430-2436. HUdoi:10.1210/en.131.5.2430U
[32] Hubbard, W.J., Choudhry, M., Schwacha, M.G., Kerby, J.D., Rue, L.W. III, et al. (2005) Cecal ligation and punc-ture. Shock, 24, 52-57. HUdoi:10.1097/01.shk.0000191414.94461.7eU
[33] Maier, S., Traeger, T., Entleutner, M., Westerholt, A., Kleist, B., et al. (2004) Cecal ligation and puncture versus colon ascendens stent peritonitis: Two distinct animal models for polymicrobial sepsis. Shock, 21, 505-511. HUdoi:10.1097/01.shk.0000126906.52367.ddU
[34] Hopkins, S.J. (2007) Central nervous system recognition of peripheral inflammation: A neural, hormonal collaboration. Acta Bio-Medica: Atenei Parmensis, 78, 231-247.
[35] Watanobe, H. and Yoneda, M. (2003) A mechanism underlying the sexually dimorphic ACTH response to lipo- polysaccharide in rats: Sex steroid modulation of cytokine binding sites in the hypothalamus. The Journal of Physiology, 547, 221-232. HUdoi:10.1113/jphysiol.2002.032169U
[36] Watanobe, H., Anzai, J., Nigawara, T., Habu, S. and Ta-kebe, K. (1996) Effects of gender and gonadectomy on ACTH response to interleukin-1beta in the rat: Comparison with the modulation of ACTH response to immobilization stress. Neuroimmunomodulation, 3, 254-258.
[37] Nappi, R.E., Bonneau, M.J. and Rivest, S. (1997) Influ-ence of the estrous cycle on c-fos and CRH gene tran-scription in the brain of endotoxin-challenged female rats. Neuroendocrinology, 65, 29-46. HUdoi:10.1159/000127162U
[38] Lunga, P. and Herbert, J. (2004) 17Beta-oestradiol modulates glucocorticoid, neural and behavioural adaptations to repeated restraint stress in female rats. Journal of Endocrinology, 16, 776-785. HUdoi:10.1111/j.1365-2826.2004.01234.xU
[39] Mannino, C.A., South, S.M., Quinones-Jenab, V. and Inturrisi, C.E. (2007) Estradiol replacement in ovariecto-mized rats is antihyperalgesic in the formalin test. The Journal of Pain, 8, 334-342. HUdoi:10.1016/j.jpain.2006.10.002U
[40] Kasckow, J.W., Regmi, A., Gill, P.S., Parkes, D.G. and Geracioti, T.D. (1997) Regulation of corticotropin-releasing factor (CRF) messenger ribonucleic acid and CRF peptide in the amygdala: Studies in primary amygdalar cultures. Endocrinology, 138, 4774-4782. HUdoi:10.1210/en.138.11.4774U
[41] Langlais, D., Couture, C., Balsalobre, A. and Drouin, J. (2008) Regulatory network analyses reveal genome-wide potentiation of LIF signaling by glucocorticoids and define an innate cell defense response. PLoS Genetics, 4, e1000224. HUdoi:10.1371/journal.pgen.1000224U
[42] Raber, J., O'Shea, R.D., Bloom, F.E. and Campbell, I.L. (1997) Modulation of hypothalamic-pituitary-adrenal function by transgenic expression of interleukin-6 in the CNS of mice. The Journal of Neuroscience, 17, 9473- 9480.
[43] Chiu, K.M., Arnaud, C.D., Ju, J., Mayes, D., Bacchetti, P., et al. (2000) Correlation of estradiol, parathyroid hormone, interleukin-6, and soluble interleukin-6 receptor during the normal menstrual cycle. Bone, 26, 79-85. HUdoi:10.1016/S8756-3282(99)00243-4U
[44] Puder, J.J., Freda, P.U., Goland, R.S. and Wardlaw, S.L. (2001) Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. The Journal of Clinical Endocrinology & Metabolism, 86, 2403-2408. HUdoi:10.1210/jc.86.6.2403U
[45] Pfeilschifter, J., Koditz, R., Pfohl, M. and Schatz, H. (2002) Changes in proinflammatory cytokine activity after menopause. Endocrine Reviews, 23, 90-119. HUdoi:10.1210/er.23.1.90U
[46] Bondeson, J., Foxwell, B., Brennan, F. and Feldmann, M. (1999) Defining therapeutic targets by using adenovirus: Blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proceedings of the National Academy of Sciences of the United States of America, 96, 5668-5673. HUdoi:10.1073/pnas.96.10.5668U
[47] Uribe, R.M., Lee, S. and Rivier, C. (1999) Endotoxin stimulates nitric oxide production in the paraventricular nucleus of the hypothalamus through nitric oxide synthase I: Correlation with hypothalamic-pituitary-adrenal axis activation. Endocrinology, 140, 5971-5981. HUdoi:10.1210/en.140.12.5971U
[48] Vegeto, E., Bonincontro, C., Pollio, G., Sala, A., Viappiani, S., et al. (2001) Estrogen prevents the lipopolysaccha-ride-induced inflammatory response in microglia. The Journal of Neuroscience, 21, 1809-1818.
[49] Turgeon, J.L., Carr, M.C., Maki, P.M., Mendelsohn, M.E. and Wise, P.M. (2006) Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocrine Reviews, 27, 575-605. HUdoi:10.1210/er.2005-0020U

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.