Abstract
It is well accepted that stress, measured by increased glucocorticoid secretion, leads to profound reproductive dysfunction. In times of stress, glucocorticoids activate many parts of the fight or flight response, mobilizing energy and enhancing survival, while inhibiting metabolic processes that are not necessary for survival in the moment. This includes reproduction, an energetically costly procedure that is very finely regulated. In the short term, this is meant to be beneficial, so that the organism does not waste precious energy needed for survival. However, long-term inhibition can lead to persistent reproductive dysfunction, even if no longer stressed. This response is mediated by the increased levels of circulating glucocorticoids, which orchestrate complex inhibition of the entire reproductive axis. Stress and glucocorticoids exhibits both central and peripheral inhibition of the reproductive hormonal axis. While this has long been recognized as an issue, understanding the complex signaling mechanism behind this inhibition remains somewhat of a mystery. What makes this especially difficult is attempting to differentiate the many parts of both of these hormonal axes, and new neuropeptide discoveries in the last decade in the reproductive field have added even more complexity to an already complicated system. Glucocorticoids (GCs) and other hormones within the hypothalamic-pituitary-adrenal (HPA) axis (as well as contributors in the sympathetic system) can modulate the hypothalamic-pituitary-gonadal (HPG) axis at all levels—GCs can inhibit release of GnRH from the hypothalamus, inhibit gonadotropin synthesis and release in the pituitary, and inhibit testosterone synthesis and release from the gonads, while also influencing gametogenesis and sexual behavior. This chapter is not an exhaustive review of all the known literature, however is aimed at giving a brief look at both the central and peripheral effects of glucocorticoids on the reproductive function.
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References
Handa RJ, Weiser MJ. Gonadal steroid hormones and the hypothalamo-pituitary-adrenal axis. Front Neuroendocrinol. 2014;35(2):197–220. doi:10.1016/j.yfrne.2013.11.001.
Jennes L, Conn PM. Gonadotropin-releasing hormone and its receptors in rat brain. Front Neuroendocrinol. 1994;15(1):51–77. doi:10.1006/frne.1994.1003.
King JC, Tobet SA, Snavely FL, Arimura AA. LHRH immunopositive cells and their projections to the median eminence and organum vasculosum of the lamina terminalis. J Comp Neurol. 1982;209(3):287–300. doi:10.1002/cne.902090307.
Levine JE, Bauer-Dantoin AC. Neuroendocrine regulation of the luteinizing hormone-releasing hormone pulse generator in the rat. Recent Prog Horm Res. 1991;47:97–151.
Moenter SM, Anthony DeFazio R, Pitts GR, Nunemaker CS. Mechanisms underlying episodic gonadotropin-releasing hormone secretion. Front Neuroendocrinol. 2003;24(2):79–93. doi:10.1016/S0091-3022(03)00013-X.
Haisenleder DJ, Dalkin AC, Ortolano GA, Marshall JC, Shupnik MA. A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: evidence for differential regulation of transcription by pulse frequency in vivo. Endocrinology. 1991;128(1):509–17. doi:10.1210/endo-128-1-509.
Sarkar DK, Chiappa SA, Fink G, Sherwood NM. Gonadotropin-releasing hormone surge in pro-oestrous rats. Nature. 1976;264(5585):461–3. doi:10.1038/264461a0.
Park O-K, Ramirez VD. Spontaneous changes in LHRH release during the rat estrous cycle, as measured with repetitive push-pull perfusions of the pituitary gland in the same female rats. Neuroendocrinology. 1989;50(1):66–72. doi:10.1159/10.1159/000125203.
Marshall JC, Griffin ML. The role of changing pulse frequency in the regulation of ovulation. Hum Reprod. 1993;8 Suppl 2:57–61. http://www.ncbi.nlm.nih.gov/pubmed/8276970. Accessed 27 May 2014.
Marshall JC, Dalkin AC, Haisenleder DJ, Griffin ML, Kelch RP. GnRH pulses—the regulators of human reproduction. Trans Am Clin Climatol Assoc. 1993;104:31–46. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2376610&tool=pmcentrez&rendertype=abstract. Accessed 27 May 2014.
Herbison AE. Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V). Brain Res Rev. 2008;57(2):277–87. doi:10.1016/j.brainresrev.2007.05.006.
Chazal G, Faudon M, Gogan F, Laplante E. Negative and positive effects of oestradiol upon luteinizing hormone secretion in the female rat. J Endocrinol. 1974;61(3):511–2. doi:10.1677/joe.0.0610511.
Shupnik MA. Gonadotropin gene modulation by steroids and gonadotropin-releasing hormone. Biol Reprod. 1996;54(2):279–86. doi:10.1095/biolreprod54.2.279.
Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53–88.
Baird DT, McNeilly AS. Gonadotrophic control of follicular development and function during the oestrous cycle of the ewe. J Reprod Fertil Suppl. 1981;30:119–33. http://europepmc.org/abstract/MED/6300383. Accessed 2 Sept 2014.
Legan SJ, Karsch FJ. A daily signal for the LH surge in the rat. Endocrinology. 1975;96(1):57–62. doi:10.1210/endo-96-1-57.
Ferin M, Tempone A, Zimmering PE, Van de Wiele RL. Effect of antibodies to 17beta-estradiol and progesterone on the estrous cycle of the rat. Endocrinology. 1969;85(6):1070–8. doi:10.1210/endo-85-6-1070.
Labhsetwar AP. Role of estrogens in ovulation: a study using the estrogen-antagonist, I.C.I. 46,474. Endocrinology. 1970;87(3):542–51. doi:10.1210/endo-87-3-542.
Chappell PE, Levine JE. Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology. 2000;141(4):1477–85. doi:10.1210/endo.141.4.7428.
Micevych P, Sinchak K, Mills RH, Tao L, LaPolt P, Lu JKH. The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats. Neuroendocrinology. 2003;78(1):29–35. doi:10.1159/000071703.
Kuo J, Hamid N, Bondar G, Prossnitz ER, Micevych P. Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes. J Neurosci. 2010;30(39):12950–7. doi:10.1523/JNEUROSCI.1158-10.2010.
Micevych P, Soma KK, Sinchak K. Neuroprogesterone: key to estrogen positive feedback? Brain Res Rev. 2008;57(2):470–80. doi:10.1016/j.brainresrev.2007.06.009.
Micevych PE, Chaban V, Ogi J, Dewing P, Lu JKH, Sinchak K. Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology. 2007;148(2):782–9. doi:10.1210/en.2006-0774.
Micevych P, Sinchak K. The neurosteroid progesterone underlies estrogen positive feedback of the LH surge. Front Endocrinol (Lausanne). 2011;2:90. doi:10.3389/fendo.2011.00090.
Chaban VV, Lakhter AJ, Micevych P. A membrane estrogen receptor mediates intracellular calcium release in astrocytes. Endocrinology. 2004;145(8):3788–95. doi:10.1210/en.2004-0149.
Ubuka T, Inoue K, Fukuda Y, et al. Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone. Endocrinology. 2012;153(1):373–85. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1434.
Ubuka T, Morgan K, Pawson A, et al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS One. 2009;4(12):1334–9. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1233.
Ubuka T, Lai H, Kitani M, et al. Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain. J Comp Neurol. 2009;517:841–55. doi:10.1002/cne.22191.
Ukena K, Iwakoshi E, Minakata H, Tsutsui K. A novel rat hypothalamic RFamide-related peptide identified by immunoaffinity chromatography and mass spectrometry. FEBS Lett. 2002;512(1–3):255–8. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1299.
Tsutsui K, Saigoh E, Ukena K, et al. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun. 2000;275(2):661–7. doi:10.1006/bbrc.2000.3350.
De Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972–6. doi:10.1073/pnas.1834399100.
Thompson EL, Patterson M, Murphy KG, et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004;16(10):850–8. doi:10.1111/j.1365-2826.2004.01240.x.
Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145(9):4073–7. doi:10.1210/en.2004-0431.
Navarro VM, Castellano JM, Fernández-Fernández R, et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology. 2005;146(4):1689–97. doi:10.1210/en.2004-1353.
Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90(12):6609–15. doi:10.1210/jc.2005-1468.
Li X-F, Kinsey-Jones JS, Cheng Y, et al. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. Tena-Sempere M, ed. PLoS One. 2009;4(12):e8334. doi:10.1371/journal.pone.0008334.
Maeda K-I, Ohkura S, Uenoyama Y, et al. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res. 2010;1364:103–15. doi:10.1016/j.brainres.2010.10.026.
Roseweir AK, Kauffman AS, Smith JT, et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;29(12):3920–9. doi:10.1523/JNEUROSCI.5740-08.2009.
Messager S, Chatzidaki EE, Ma D, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005;102(5):1761–6. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1232.
Millar RP, Roseweir AK, Tello JA, et al. Kisspeptin antagonists: unraveling the role of kisspeptin in reproductive physiology. Brain Res. 2010;1364:81–9. doi:10.1016/j.brainres.2010.09.044.
Pineda R, Garcia-Galiano D, Sanchez-Garrido MA, et al. Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies. Am J Physiol Endocrinol Metab. 2010;299(1):E39–46. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1269.
Khan AR, Kauffman AS. The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian-timed preovulatory luteinising hormone surge. J Neuroendocrinol. 2012;24(1):131–43. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1435.
Clarke I, Smith J, Henry B, et al. Gonadotropin-inhibitory hormone is a hypothalamic peptide that provides a molecular switch between reproduction and feeding. Neuroendocrinology. 2012;95(4):305–16. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1596.
Wu M, Dumalska I, Morozova E, van den Pol AN, Alreja M. Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism. J Physiol. 2009;587(7):1401. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1234.
Kriegsfeld LJ, Gibson EM, Williams WP, et al. The roles of RFamide-related peptide-3 in mammalian reproductive function and behaviour. J Neuroendocrinol. 2010;22(7):692–700. doi:10.1111/j.1365-2826.2010.02031.x.
Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci. 2008;28(35):8691–7. doi:10.1523/JNEUROSCI.1775-08.2008.
Sinchak K, Wagner EJ. Estradiol signaling in the regulation of reproduction and energy balance. Front Neuroendocrinol. 2012;33(4):342–63. doi:10.1016/j.yfrne.2012.08.004.
Christensen A, Bentley GE, Cabrera R, et al. Hormonal regulation of female reproduction. Horm Metab Res. 2012;44(8):587–91. doi:10.1055/s-0032-1306301.
Giuliani FA, Yunes R, Mohn CE, Laconi M, Rettori V, Cabrera R. Allopregnanolone induces LHRH and glutamate release through NMDA receptor modulation. Endocrine. 2011;40(1):21–6. doi:10.1007/s12020-011-9451-8.
Sim JA, Skynner MJ, Herbison AE. Direct regulation of postnatal GnRH neurons by the progesterone derivative allopregnanolone in the mouse. Endocrinology. 2001;142(10):4448–53. doi:10.1210/endo.142.10.8451.
el-Etr M, Akwa Y, Fiddes RJ, Robel P, Baulieu EE. A progesterone metabolite stimulates the release of gonadotropin-releasing hormone from GT1-1 hypothalamic neurons via the gamma-aminobutyric acid type A receptor. Proc Natl Acad Sci U S A. 1995;92(9):3769–73. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=42043&tool=pmcentrez&rendertype=abstract. Accessed 27 May 2014.
Breen KM, Karsch FJ. New insights regarding glucocorticoids, stress and gonadotropin suppression. Front Neuroendocrinol. 2006;27(2):233–45. doi:10.1016/j.yfrne.2006.03.335.
Li XF, Knox AMI, O’Byrne KT. Corticotrophin-releasing factor and stress-induced inhibition of the gonadotrophin-releasing hormone pulse generator in the female. Brain Res. 2010;1364:153–63. doi:10.1016/j.brainres.2010.08.036.
Rivier C, Vale W. Influence of corticotropin-releasing factor on reproductive functions in the rat. Endocrinology. 1984;114(3):914–21. doi:10.1210/endo-114-3-914.
Cates PS, Li XF, O’Byrne KT. The influence of 17beta-oestradiol on corticotrophin-releasing hormone induced suppression of luteinising hormone pulses and the role of CRH in hypoglycaemic stress-induced suppression of pulsatile LH secretion in the female rat. Stress. 2004;7(2):113–8. doi:10.1080/1025389042000218988.
Bowe JE, Li XF, Kinsey-Jones JS, Brain SD, Lightman SL, O’Byrne KT. The role of corticotrophin-releasing hormone receptors in the calcitonin gene-related peptide-induced suppression of pulsatile luteinising hormone secretion in the female rat. Stress. 2008;11(4):312–9. doi:10.1080/10253890701801448.
Li XF, Bowe JE, Kinsey-Jones JS, Brain SD, Lightman SL, O’Byrne KT. Differential role of corticotrophin-releasing factor receptor types 1 and 2 in stress-induced suppression of pulsatile luteinising hormone secretion in the female rat. J Neuroendocrinol. 2006;18(8):602–10. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p701.
Li XF, Bowe JE, Lightman SL, O’Byrne KT. Role of corticotropin-releasing factor receptor-2 in stress-induced suppression of pulsatile luteinizing hormone secretion in the rat. Endocrinology. 2005;146(1):318–22. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p710.
Kinsey‐Jones J, Li X, Knox A, et al. Corticotrophin‐releasing factor alters the timing of puberty in the female rat. J Neuroendocrinol. 2010;22(2):102–109. file:///Users/annageraghty/Documents/Papers/2010/Kinsey‐Jones/Journal of Neuroendocrinology 2010 Kinsey‐Jones.pdf.
Rivier C, Rivest S. Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis: peripheral and central mechanisms. Biol Reprod. 1991;45(4):523–32. http://www.ncbi.nlm.nih.gov/pubmed/1661182. Accessed 9 Sept 2013.
Rivest S, Rivier C. Central mechanisms and sites of action involved in the inhibitory effects of CRF and cytokines on LHRH neuronal activity. Ann N Y Acad Sci. 1993;697(1 Corticotropin):117–41. doi:10.1111/j.1749-6632.1993.tb49928.x.
Oakley AE, Breen KM, Clarke IJ, Karsch FJ, Wagenmaker ER, Tilbrook AJ. Cortisol reduces gonadotropin-releasing hormone pulse frequency in follicular phase ewes: influence of ovarian steroids. Endocrinology. 2009;150(1):341–9. doi:10.1210/en.2008-0587.
Calogero AE, Burrello N, Bosboom AM, Garofalo MR, Weber RF, D’Agata R. Glucocorticoids inhibit gonadotropin-releasing hormone by acting directly at the hypothalamic level. J Endocrinol Invest. 1999;22(9):666–70. http://www.ncbi.nlm.nih.gov/pubmed/10595829. Accessed 28 May 2014.
Jasoni CL, Todman MG, Han S-K, Herbison AE. Expression of mRNAs encoding receptors that mediate stress signals in gonadotropin-releasing hormone neurons of the mouse. Neuroendocrinology. 2005;82(5–6):320–8. doi:10.1159/000093155.
Ahima RS, Harlan RE. Glucocorticoid receptors in LHRH neurons. Neuroendocrinology. 1992;56(6):845–50. http://www.ncbi.nlm.nih.gov/pubmed/1369593. Accessed 27 May 2014.
Dondi D, Piccolella M, Messi E, et al. Expression and differential effects of the activation of glucocorticoid receptors in mouse gonadotropin-releasing hormone neurons. Neuroendocrinology. 2005;82(3–4):151–63. doi:10.1159/000091693.
DeFranco DB, Attardi B, Chandran UR. Glucocorticoid receptor-mediated repression of GnRH gene expression in a hypothalamic GnRH-secreting neuronal cell line. Ann N Y Acad Sci. 1994;746:473–5. http://www.ncbi.nlm.nih.gov/pubmed/7825918. Accessed 28 May 2014.
Tellam DJ, Perone MJ, Dunn IC, et al. Direct regulation of GnRH transcription by CRF-like peptides in an immortalized neuronal cell line. Neuroreport. 1998;9(14):3135–40. doi:10.1097/00001756-199810050-00003.
Tellam DJ, Mohammad YN, Lovejoy DA. Molecular integration of hypothalamo-pituitary-adrenal axis-related neurohormones on the GnRH neuron. 2011. http://www.nrcresearchpress.com/doi/abs/10.1139/o00-060#.U4Z5rlhdX-Y. Accessed 29 May 2014.
Mellon PL, Windle JJ, Goldsmith PC, Padula CA, Roberts JL, Weiner RI. Immortalization of hypothalamic GnRH by genetically targeted tumorigenesis. Neuron. 1990;5(1):1–10. doi:10.1016/0896-6273(90)90028-E.
Wetsel WC, Mellon PL, Weiner RI, Negro-Vilar A. Metabolism of pro-luteinizing hormone-releasing hormone in immortalized hypothalamic neurons. Endocrinology. 1991;129(3):1584–95. doi:10.1210/endo-129-3-1584.
Chandran UR, Attardi B, Friedman R, Dong KW, Roberts JL, DeFranco DB. Glucocorticoid receptor-mediated repression of gonadotropin-releasing hormone promoter activity in GT1 hypothalamic cell lines. Endocrinology. 1994;134(3):1467–74. doi:10.1210/endo.134.3.8119188.
Attardi B, Tsujii T, Friedman R, et al. Glucocorticoid repression of gonadotropin-releasing hormone gene expression and secretion in morphologically distinct subpopulations of GT1-7 cells. Mol Cell Endocrinol. 1997;131(2):241–55. http://www.ncbi.nlm.nih.gov/pubmed/9296383. Accessed 28 May 2014.
Gore A, Attardi B, DeFranco D. Glucocorticoid repression of the reproductive axis: effects on GnRH and gonadotropin subunit mRNA levels. Mol Cell Endocrinol. 2006;256(1-2):40–8. Papers
Kinsey‐Jones J, Li X, Knox A, et al. Down‐regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress‐induced suppression of luteinising hormone secretion in the female rat. J Neuroendocrinol. 2009;21(1):20–29. file:///Users/annageraghty/Documents/Papers/2009/Kinsey‐Jones/Journal of Neuroendocrinology 2009 Kinsey‐Jones-1.pdf.
Iwasa T, Matsuzaki T, Murakami M, et al. Decreased expression of kisspeptin mediates acute immune/inflammatory stress-induced suppression of gonadotropin secretion in female rat. J Endocrinol Invest. 2008;31(7):656–9. http://europepmc.org/abstract/MED/18787387. Accessed 28 May 2014.
Grachev P, Li XF, O’Byrne K. Stress regulation of kisspeptin in the modulation of reproductive function. Adv Exp Med Biol. 2013;784:431–54. doi:10.1007/978-1-4614-6199-9_20.
Takumi K, Iijima N, Higo S, Ozawa H. Immunohistochemical analysis of the colocalization of corticotropin-releasing hormone receptor and glucocorticoid receptor in kisspeptin neurons in the hypothalamus of female rats. Neurosci Lett. 2012;531(1):40–5. doi:10.1016/j.neulet.2012.10.010.
Grachev P, Li XF, Hu MH, et al. Neurokinin B signaling in the female rat: a novel link between stress and reproduction. Endocrinology. 2014;155(7):2589–601. doi:10.1210/en.2013-2038.
Goodman RL, Hileman SM, Nestor CC, et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology. 2013;154(11):4259–69. doi:10.1210/en.2013-1331.
Okamura H, Tsukamura H, Ohkura S, Uenoyama Y, Wakabayashi Y, Maeda K. Kisspeptin and GnRH pulse generation. Adv Exp Med Biol. 2013;784:297–323. doi:10.1007/978-1-4614-6199-9_14.
Wakabayashi Y, Yamamura T, Sakamoto K, Mori Y, Okamura H. Electrophysiological and morphological evidence for synchronized GnRH pulse generator activity among Kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in goats. J Reprod Dev. 2013;59(1):40–8. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3943231&tool=pmcentrez&rendertype=abstract. Accessed 28 May 2014.
Bowe JE, Li XF, Kinsey-Jones JS, et al. Calcitonin gene-related peptide-induced suppression of luteinizing hormone pulses in the rat: the role of endogenous opioid peptides. J Physiol. 2005;566(Pt 3):921–8. doi:10.1113/jphysiol.2005.085662.
Nabeshima T, Katoh A, Wada M, Kameyama T. Stress-induced changes in brain Met-enkephalin, Leu-enkephalin and dynorphin concentrations. Life Sci. 1992;51(3):211–7. http://www.ncbi.nlm.nih.gov/pubmed/1352028. Accessed 28 May 2014.
Petraglia F, Vale W, Rivier C. Opioids act centrally to modulate stress-induced decrease in luteinizing hormone in the rat. Endocrinology. 1986;119(6):2445–50. doi:10.1210/endo-119-6-2445.
Ukena K, Iwakoshi E, Minakata H, Tsutsui K. A novel rat hypothalamic RFamide-related peptide identified by immunoaffinity chromatography and mass spectrometry. FEBS Lett. 2002;512(1–3):255–8. http://www.ncbi.nlm.nih.gov/pubmed/11852091. Accessed 9 Sept 2013.
Sari IP, Rao A, Smith JT, Tilbrook AJ, Clarke IJ. Effect of RF-amide-related peptide-3 on luteinizing hormone and follicle-stimulating hormone synthesis and secretion in ovine pituitary gonadotropes. Endocrinology. 2009;150(12):5549–56. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1243.
Kirby ED, Geraghty AC, Ubuka T, Bentley GE, Kaufer D. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc Natl Acad Sci U S A. 2009;106(27):11324–9. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1273.
Lee Son Y, Ubuka T, Narihiro M, et al. Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone. Endocrinology. 2014;155(5):1817–26. doi:10.1210/en.2013-2076.
Gojska NM, Belsham DD. Glucocorticoid receptor-mediated regulation of Rfrp (GnIH) and Gpr147 (GnIH-R) synthesis in immortalized hypothalamic neurons. Mol Cell Endocrinol. 2014;384(1–2):23–31. doi:10.1016/j.mce.2013.12.015.
Geraghty A, Muroy S, Zhao S, Bentley G, Kriegsfeld L, Kaufer D. Chronic stress causes an increase in RFRP expression and leads to reproductive dysfunction in the adult female rat. [abstract]. In: 2013 Neuroscience Meet Plan, Society for Neuroscience; 2013.
Kaiser UB, Jakubowiak A, Steinberger A, Chin WW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology. 1997;138(3):1224–31. doi:10.1210/endo.138.3.4968.
Vale W, Rivier C, Brown M. Regulatory peptides of the hypothalamus. Annu Rev Physiol. 1977;39:473–527. doi:10.1146/annurev.ph.39.030177.002353.
Pierce JG, Parsons TF. Glycoprotein hormones: structure and function. Annu Rev Biochem. 1981;50:465–95. doi:10.1146/annurev.bi.50.070181.002341.
Kononen J, Honkaniemi J, Gustafsson JA, Pelto-Huikko M. Glucocorticoid receptor colocalization with pituitary hormones in the rat pituitary gland. Mol Cell Endocrinol. 1993;93(1):97–103. http://www.ncbi.nlm.nih.gov/pubmed/8319836. Accessed 28 May 2014.
Breen KM, Thackray VG, Hsu T, Mak-McCully RA, Coss D, Mellon PL. Stress levels of glucocorticoids inhibit LHβ-subunit gene expression in gonadotrope cells. Mol Endocrinol. 2012;26(10):1716–31. doi:10.1210/me.2011-1327.
Armario A, Lopez-Calderon A, Jolin T, Balasch J. Response of anterior pituitary hormones to chronic stress. The specificity of adaptation. Neurosci Biobehav Rev. 1986;10(3):245–50. doi:10.1016/0149-7634(86)90011-4.
Lopez-Calderon A, Gonzalez-Quijano MI, Tresguerres JAF, Ariznavarreta C. Role of LHRH in the gonadotrophin response to restraint stress in intact male rats. J Endocrinol. 1990;124(2):241–6. doi:10.1677/joe.0.1240241.
Blake CA. Effects of “stress” on pulsatile luteinizing hormone release in ovariectomized rats. Proc Soc Exp Biol Med. 1975;148(3):813–5. http://www.ncbi.nlm.nih.gov/pubmed/165534. Accessed 29 May 2014.
Kamel F, Kubajak CL. Modulation of gonadotropin secretion by corticosterone: interaction with gonadal steroids and mechanism of action. Endocrinology. 1987;121(2):561–8. doi:10.1210/endo-121-2-561.
Baldwin DM, Sawyer CH. Effects of dexamethasone on LH release and ovulation in the cyclic rat. Endocrinology. 1974;94(5):1397–403. doi:10.1210/endo-94-5-1397.
Collu R, Taché Y, Ducharme J. Hormonal modifications induced by chronic stress in rats. J Steroid Biochem. 1979;11(1):989–1000. doi:10.1016/0022-4731(79)90042-6.
Vreeburg JT, de Greef WJ, Ooms MP, van Wouw P, Weber RF. Effects of adrenocorticotropin and corticosterone on the negative feedback action of testosterone in the adult male rat. Endocrinology. 1984;115(3):977–83. doi:10.1210/endo-115-3-977.
Taché Y, Ducharme JR, Charpenet G, Haour F, Saez J, Collu R. Effect of chronic intermittent immobilization stress on hypophyso-gonadal function of rats. Acta Endocrinol (Copenh). 1980;93(2):168–74. http://www.ncbi.nlm.nih.gov/pubmed/7376788. Accessed 28 May 2014.
Briski KP, Sylvester PW. Differential impact of naltrexone on luteinizing hormone release during single versus repetitive exposure to restraint stress. Psychoneuroendocrinology. 1992;17(2–3):125–33. http://www.ncbi.nlm.nih.gov/pubmed/1332097. Accessed 28 May 2014.
Li XF, Edward J, Mitchell JC, et al. Differential effects of repeated restraint stress on pulsatile lutenizing hormone secretion in female Fischer, Lewis and Wistar rats. J Neuroendocrinol. 2004;16(7):620–7. doi:10.1111/j.1365-2826.2004.01209.x.
Briski KP, Sylvester PW. Effects of repetitive daily acute stress on pituitary LH and prolactin release during exposure to the same stressor or a second novel stress. Psychoneuroendocrinology. 1987;12(6):429–37. http://www.ncbi.nlm.nih.gov/pubmed/3441582. Accessed 28 May 2014.
Sakakura M, Takebe K, Nakagawa S. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long-term treatment with glucocorticoids in human subjects. J Clin Endocrinol Metab. 1975;40(5):774–9. doi:10.1210/jcem-40-5-774.
Du Ruisseau P, Taché Y, Brazeau P, Collu R. Effects of chronic immobilization stress on pituitary hormone secretion, on hypothalamic factor levels, and on pituitary responsiveness to LHRH and TRH in female rats. Neuroendocrinology. 1979;29(2):90–9. http://www.ncbi.nlm.nih.gov/pubmed/116141. Accessed 9 Sept 2013.
Rivier C, Vale W. Effect of the long-term administration of corticotropin-releasing factor on the pituitary-adrenal and pituitary-gonadal axis in the male rat. J Clin Invest. 1985;75(2):689–94. doi:10.1172/JCI111748.
Suter DE, Schwartz NB, Ringstrom SJ. Dual role of glucocorticoids in regulation of pituitary content and secretion of gonadotropins. Am J Physiol. 1988;254(5 Pt 1):E595–600. http://ajpendo.physiology.org/content/254/5/E595.abstract. Accessed 20 May 2014.
Baldwin DM. The effect of glucocorticoids on estrogen-dependent luteinizing hormone release in the ovariectomized rat and on gonadotropin secretin in the intact female rat. Endocrinology. 1979;105(1):120–8. doi:10.1210/endo-105-1-120.
Maya-Núñez G, Conn PM. Transcriptional regulation of the GnRH receptor gene by glucocorticoids. Mol Cell Endocrinol. 2003;200(1–2):89–98. doi:10.1016/S0303-7207(02)00419-7.
Kotitschke A, Sadie-Van Gijsen H, Avenant C, Fernandes S, Hapgood JP. Genomic and nongenomic cross talk between the gonadotropin-releasing hormone receptor and glucocorticoid receptor signaling pathways. Mol Endocrinol. 2009;23(11):1726–45. doi:10.1210/me.2008-0462.
Bronson FH. Establishment of social rank among grouped male mice: relative effects on circulating FSH, LH, and corticosterone. Physiol Behav. 1973;10(5):947–51. doi:10.1016/0031-9384(73)90065-6.
Du Ruisseau P, Taché Y, Brazeau P, Colin R. Effects of chronic immobilization stress on pituitary hormone secretion, on hypothalamic factor levels, and on pituitary responsiveness to LHRH and TRH in female rats. Neuroendocrinology. 1979;29(2):90–9. doi:10.1159/000122910.
Ringstrom SJ, Schwartz NB. Differential effect of glucocorticoids on synthesis and secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). J Steroid Biochem. 1987;27(1–3):625–30. doi:10.1016/0022-4731(87)90362-1.
Ringstrom SJ, McAndrews JM, Rahal JO, Schwartz NB. Cortisol in vivo increases FSH beta mRNA selectively in pituitaries of male rats. Endocrinology. 1991;129(5):2793–5. doi:10.1210/endo-129-5-2793.
Thackray VG, McGillivray SM, Mellon PL. Androgens, progestins, and glucocorticoids induce follicle-stimulating hormone beta-subunit gene expression at the level of the gonadotrope. Mol Endocrinol. 2006;20(9):2062–79. doi:10.1210/me.2005-0316.
Smals AG, Kloppenborg PW, Benraad TJ. Plasma testosterone profiles in Cushing’s syndrome. J Clin Endocrinol Metab. 1977;45(2):240–5. doi:10.1210/jcem-45-2-240.
Whirledge S, Cidlowski JA. Glucocorticoids, stress, and fertility. Minerva Endocrinol. 2010;35(2):109–25. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3547681&tool=pmcentrez&rendertype=abstract. Accessed 20 May 2014.
Schultz R, Isola J, Parvinen M, et al. Localization of the glucocorticoid receptor in testis and accessory sexual organs of male rat. Mol Cell Endocrinol. 1993;95(1–2):115–20. doi:10.1016/0303-7207(93)90036-J.
Silva EJR, Queiróz DBC, Honda L, Avellar MCW. Glucocorticoid receptor in the rat epididymis: expression, cellular distribution and regulation by steroid hormones. Mol Cell Endocrinol. 2010;325(1–2):64–77. doi:10.1016/j.mce.2010.05.013.
Bernier M, Gibb W, Collu R, Ducharme JR. Effect of glucocorticoids on testosterone production by porcine Leydig cells in primary culture. Can J Physiol Pharmacol. 1984;62(9):1166–9. doi:10.1139/y84-195.
Orr T. Effects of restraint stress on plasma LH and testosterone concentrations, Leydig cell LH/HCG receptors, and in vitro testicular steroidogenesis in adult rats. Horm Behav. 1990;24(3):324–41. doi:10.1016/0018-506X(90)90013-N.
Orr T. Role of glucocorticoids in the stress-induced suppression of testicular steroidogenesis in adult male rats. Horm Behav. 1992;26(3):350–63. doi:10.1016/0018-506X(92)90005-G.
Cumming DC, Quigley ME, Yen SS. Acute suppression of circulating testosterone levels by cortisol in men. J Clin Endocrinol Metab. 1983;57(3):671–3. doi:10.1210/jcem-57-3-671.
Marić D, Kostić T, Kovačević R. Effects of acute and chronic immobilization stress on rat Leydig cell steroidogenesis. J Steroid Biochem Mol Biol. 1996;58(3):351–5.
Saez JM, Morera AM, Haour F, Evain D. Effects of in vivo administration of dexamethasone, corticotropin and human chorionic gonadotropin on steroidogenesis and protein and DNA synthesis of testicular interstitial cells in prepuberal rats. Endocrinology. 1977;101(4):1256–63. doi:10.1210/endo-101-4-1256.
Bambino TH, Hsueh AJ. Direct inhibitory effect of glucocorticoids upon testicular luteinizing hormone receptor and steroidogenesis in vivo and in vitro. Endocrinology. 1981;108(6):2142–8. doi:10.1210/endo-108-6-2142.
Hales DB, Payne AH. Glucocorticoid-mediated repression of P450scc mRNA and de novo synthesis in cultured Leydig cells. Endocrinology. 1989;124(5):2099–104. doi:10.1210/endo-124-5-2099.
Payne AH, Sha LL. Multiple mechanisms for regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5––delta 4-isomerase, 17 alpha-hydroxylase/C17-20 lyase cytochrome P450, and cholesterol side-chain cleavage cytochrome P450 messenger ribonucleic acid levels in primary cultures of mouse Leydig cells. Endocrinology. 1991;129(3):1429–35. doi:10.1210/endo-129-3-1429.
Martin LJ, Tremblay JJ. Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1. J Mol Endocrinol. 2008;41(3):165–75. doi:10.1677/JME-07-0145.
Sasagawa I, Yazawa H, Suzuki Y, Nakada T. Stress and testicular germ cell apoptosis. 2009. http://informahealthcare.com/doi/abs/10.1080/014850101753145924. Accessed 20 May 2014.
Yazawa H. Apoptosis of testicular germ cells induced by exogenous glucocorticoid in rats. Hum Reprod. 2000;15(9):1917–20. doi:10.1093/humrep/15.9.1917.
Gao H-B, Tong M-H, Hu Y-Q, Guo Q-S, Ge R, Hardy MP. Glucocorticoid induces apoptosis in rat Leydig cells. 2013. http://press.endocrine.org/doi/abs/10.1210/endo.143.1.8604?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed. Accessed 20 May 2014.
Almeida SA, Petenusci SO, Anselmo-Franci JA, Rosa-e-Silva AAM, Lamano-Carvalho TL. Decreased spermatogenic and androgenic testicular functions in adult rats submitted to immobilization-induced stress from prepuberty. Braz J Med Biol Res. 1998;31(11):1443–8. doi:10.1590/S0100-879X1998001100013.
Zorn B, Auger J, Velikonja V, Kolbezen M, Meden-Vrtovec H. Psychological factors in male partners of infertile couples: relationship with semen quality and early miscarriage. Int J Androl. 2008;31(6):557–64. doi:10.1111/j.1365-2605.2007.00806.x.
Seckl JR. 11Beta-hydroxysteroid dehydrogenase in the brain: a novel regulator of glucocorticoid action? Front Neuroendocrinol. 1997;18(1):49–99. doi:10.1006/frne.1996.0143.
Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1—a tissue-specific amplifier of glucocorticoid action. Endocrinology. 2001;142(4):1371–6. doi:10.1210/endo.142.4.8114.
Tetsuka M. Expression of 11 beta-hydroxysteroid dehydrogenase, glucocorticoid receptor, and mineralocorticoid receptor genes in rat ovary. Biol Reprod. 1999;60(2):330–5. doi:10.1095/biolreprod60.2.330.
Benediktsson R, Yau JLW, Brett LP, Cooke BE, Edwards CRW, Seckl JR. 11β-Hydroxysteroid dehydrogenase in the rat ovary: high expression in the oocyte. J Endocrinol. 1992;135(1):53–58. http://www.scopus.com/inward/record.url?eid=2-s2.0-0026757114&partnerID=tZOtx3y1.
McDonald SE, Henderson TA, Gomez-Sanchez CE, Critchley HOD, Mason JI. 11Beta-hydroxysteroid dehydrogenases in human endometrium. Mol Cell Endocrinol. 2006;248(1–2):72–8. doi:10.1016/j.mce.2005.12.010.
Michael AE, Evagelatou M, Norgate DP, et al. Isoforms of 11β-hydroxysteroid dehydrogenase in human granulosa-lutein cells. Mol Cell Endocrinol. 1997;132(1–2):43–52. doi:10.1016/S0303-7207(97)00118-4.
Schreiber JR, Nakamura K, Erickson GF. Rat ovary glucocorticoid receptor: identification and characterization. Steroids. 1982;39(5):569–84. doi:10.1016/0039-128X(82)90057-5.
Michael A, Cooke B. A working hypothesis for the regulation of steroidogenesis and germ cell development in the gonads by glucocorticoids and 11β-hydroxysteroid dehydrogenase (11βHSD). Mol Cell Endocrinol. 1994;100(1–2):55–63. doi:10.1016/0303-7207(94)90279-8.
Albiston AL, Smith RE, Krozowski ZS. Changes in the levels of 11β-hydroxysteroid dehydrogenase mRNA over the oestrous cycle in the rat. J Steroid Biochem Mol Biol. 1995;52(1):45–8. doi:10.1016/0960-0760(94)00154-E.
Hillier SG. Molecular biology of the female reproductive system. Amsterdam: Elsevier; 1994. p. 1–37. doi:10.1016/B978-0-08-091819-8.50005-9.
Hillier S, Tetsuka M. An anti-inflammatory role for glucocorticoids in the ovaries? J Reprod Immunol. 1998;39(1–2):21–7. doi:10.1016/S0165-0378(98)00011-4.
Michael AE, Pester LA, Curtis P, Shaw RW, Edwards CR, Cooke BA. Direct inhibition of ovarian steroidogenesis by cortisol and the modulatory role of 11 beta-hydroxysteroid dehydrogenase. Clin Endocrinol (Oxf). 1993;38(6):641–4. http://www.ncbi.nlm.nih.gov/pubmed/8334750. Accessed 29 May 2014.
Hsueh A. Glucocorticoid inhibition of FSH-induced estrogen production in cultured rat granulosa cells. Steroids. 1978;32(5):639–48. doi:10.1016/0039-128X(78)90074-0.
Schoonmaker JN, Erickson GF. Glucocorticoid modulation of follicle-stimulating hormone-mediated granulosa cell differentiation. Endocrinology. 1983;113(4):1356–63. doi:10.1210/endo-113-4-1356.
Yang J-G. Effects of glucocorticoids on maturation of pig oocytes and their subsequent fertilizing capacity in vitro. Biol Reprod. 1999;60(4):929–36. doi:10.1095/biolreprod60.4.929.
Jimena P, Castilla JA, Peran F, et al. Adrenal hormones in human follicular fluid. Eur J Endocrinol. 1992;127(5):403–6. doi:10.1530/acta.0.1270403.
González R, Ruiz-León Y, Gomendio M, Roldan ERS. The effect of glucocorticoids on ERK-1/2 phosphorylation during maturation of lamb oocytes and their subsequent fertilization and cleavage ability in vitro. Reprod Toxicol. 2010;29(2):198–205. doi:10.1016/j.reprotox.2009.10.009.
Andersen CY. Effect of glucocorticoids on spontaneous and follicle-stimulating hormone induced oocyte maturation in mouse oocytes during culture. J Steroid Biochem Mol Biol. 2003;85(2–5):423–7. doi:10.1016/S0960-0760(03)00190-0.
Liang B, Wei D-L, Cheng Y-N, et al. Restraint stress impairs oocyte developmental potential in mice: role of CRH-induced apoptosis of ovarian cells. Biol Reprod. 2013;89(3):64. doi:10.1095/biolreprod.113.110619.
Liu Y-X, Cheng Y-N, Miao Y-L, et al. Psychological stress on female mice diminishes the developmental potential of oocytes: a study using the predatory stress model. PLoS One. 2012;7(10), e48083. doi:10.1371/journal.pone.0048083.
Rabin DS. Glucocorticoids inhibit estradiol-mediated uterine growth: possible role of the uterine estradiol receptor. Biol Reprod. 1990;42(1):74–80. doi:10.1095/biolreprod42.1.74.
Bever AT, Hisaw FL, Velardo JT. Inhibitory action of desoxycorticosterone acetate, cortisone acetate, and testosterone on uterine growth induced by estradiol-17beta. Endocrinology. 1956;59(2):165–9. doi:10.1210/endo-59-2-165.
Johnson DC, Dey SK. Role of Histamine in implantation: dexamethasone inhibits estradiol-induced implantation in the rat. Biol Reprod. 1980;22(5):1136–1141. http://www.biolreprod.org/content/22/5/1136.abstract. Accessed 26 May 2014.
Zhao L-H, Cui X-Z, Yuan H-J, et al. Restraint stress inhibits mouse implantation: temporal window and the involvement of HB-EGF, estrogen and progesterone. PLoS One. 2013;8(11), e80472. doi:10.1371/journal.pone.0080472.
Chien EJ, Liao C-F, Chang C-P, et al. The non-genomic effects on Na+/H+-exchange 1 by progesterone and 20alpha-hydroxyprogesterone in human T cells. J Cell Physiol. 2007;211(2):544–50. doi:10.1002/jcp.20962.
Szekeres-Bartho J, Barakonyi A, Miko E, Polgar B, Palkovics T. The role of gamma/delta T cells in the feto-maternal relationship. Semin Immunol. 2001;13(4):229–33. doi:10.1006/smim.2000.0318.
Arck P, Hansen PJ, Mulac Jericevic B, Piccinni MP, Szekeres-Bartho J. Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol (New York, NY 1989). 2007;58(3):268–279. papers://cf7c60b8-94a1-4c79-88e4-6c57345fd583/Paper/p1437.
Szekeres-Bartho J, Wegmann TG. A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J Reprod Immunol. 1996;31(1–2):81–95. http://www.ncbi.nlm.nih.gov/pubmed/8887124. Accessed 29 May 2014.
Polgar B, Kispal G, Lachmann M, et al. Molecular cloning and immunologic characterization of a novel cDNA coding for progesterone-induced blocking factor. J Immunol. 2003;171(11):5956–63. http://www.ncbi.nlm.nih.gov/pubmed/14634107. Accessed 29 May 2014.
Wiebold JL, Stanfield PH, Becker WC, Hillers JK. The effect of restraint stress in early pregnancy in mice. Reproduction. 1986;78(1):185–92. doi:10.1530/jrf.0.0780185.
Joachim R, Zenclussen AC, Polgar B, et al. The progesterone derivative dydrogesterone abrogates murine stress-triggered abortion by inducing a Th2 biased local immune response. Steroids. 2003;68(10–13):931–40. doi:10.1016/j.steroids.2003.08.010.
Blois SM, Joachim R, Kandil J, et al. Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile. J Immunol. 2004;172(10):5893–9. doi:10.4049/jimmunol.172.10.5893.
Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am J Reprod Immunol. 2005;53(4):166–71. doi:10.1111/j.1600-0897.2005.00261.x.
Raghupathy R, Al Mutawa E, Makhseed M, Azizieh F, Szekeres-Bartho J. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. BJOG. 2005;112(8):1096–101. doi:10.1111/j.1471-0528.2005.00633.x.
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Geraghty, A.C., Kaufer, D. (2015). Glucocorticoid Regulation of Reproduction. In: Wang, JC., Harris, C. (eds) Glucocorticoid Signaling. Advances in Experimental Medicine and Biology, vol 872. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2895-8_11
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