Endocrinology, Vol 127, 849-856, Copyright © 1990 by Endocrine Society

ARTICLES

Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat

C Rivier and W Vale
Clayton Foundation, Laboratories for Peptide Biology, La Jolla, California.

Alterations of immune activity are often accompanied by reproductive disorders. Because interleukins mediate the host's response to immune activation, we first examined the effect of the central injection of several lymphokines on LH secretion by gonadectomized rats. We then studied the ability of the most potent lymphokine in this system, interleukin-1 beta (Il-1 beta), to interfere with the proestrous LH surge and ovulation in the intact female rat as well as the dependence of this effect on the activation of opiate receptors. Finally, we investigated the possibility that increased brain levels of Ils, as induced by the central administration of a bacterial endotoxin, might also alter the normal ovulatory process. After intracerebroventricular (icv) injection, Il-1 beta, Il-6, and tumor necrosis factor all lowered plasma LH levels in castrated rats. On a molar basis, Il-1 beta was the most potent inhibitor of LH secretion. In gonadectomized animals, 2.5 and 10 ng Il-1 beta administered icv significantly (P less than or equal to 0.01) decreased plasma LH levels for 6 h, while the effect of 40 ng lasted up to 12 h. By contrast, FSH secretion was only measurably altered by 40 ng Il-1 beta 8 and 12 h posttreatment. In intact cycling female rats, icv injection of 40 ng Il-1 beta or 400 ng Il-1 alpha at 0830 h on the morning of proestrus significantly (P less than 0.01 and P less than 0.05, respectively) interfered with the proestrous surge of LH. In contrast, the peripheral administration of either lymphokine was without measurable effect. Centrally injected Il-1 beta (40 ng at 0830 h on proestrus) also blocked ovulation in most animals, while a dose of 25 ng injected iv was ineffective. Finally, we observed that the icv injection of endotoxin (a lipopolysaccharide), also interfered with ovulation. The possible involvement of opiate-dependent pathways in mediating the inhibitory action of Il-1 beta on reproductive processes was tested by implanting naloxone pellets 16-24 h before lymphokine treatment. The pellets, which released 200, 400, or 800 micrograms naloxone/h (corresponding to approximately 0.6, 1.32, or 2.64 mg/kg BW.h), had no effect on ovulation by themselves. When given before icv Il-1 beta, all naloxone regimens countered the effect of the cytokine, with the 800-micrograms/h dose restoring ovulation in eight of nine rats.(ABSTRACT TRUNCATED AT 400 WORDS)

This article has been cited by other articles:

				A. Jain, A. J. Polotsky, D. Rochester, S. L. Berga, T. Loucks, G. Zeitlian, K. Gibbs, H. N. Polotsky, S. Feng, B. Isaac, et al. Pulsatile Luteinizing Hormone Amplitude and Progesterone Metabolite Excretion Are Reduced in Obese Women J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2468 - 2473. [Abstract] [Full Text] [PDF]

				G. G. Gosman, H. I. Katcher, and R. S. Legro Obesity and the role of gut and adipose hormones in female reproduction Hum. Reprod. Update, September 1, 2006; 12(5): 585 - 601. [Abstract] [Full Text] [PDF]

				H. N. Richardson, E. P. Zorrilla, C. D. Mandyam, and C. L. Rivier Exposure to Repetitive Versus Varied Stress during Prenatal Development Generates Two Distinct Anxiogenic and Neuroendocrine Profiles in Adulthood Endocrinology, May 1, 2006; 147(5): 2506 - 2517. [Abstract] [Full Text] [PDF]

				P. Igaz, R. Salvi, J.-P. Rey, M. Glauser, F. P. Pralong, and R. C. Gaillard Effects of Cytokines on Gonadotropin-Releasing Hormone (GnRH) Gene Expression in Primary Hypothalamic Neurons and in GnRH Neurons Immortalized Conditionally Endocrinology, February 1, 2006; 147(2): 1037 - 1043. [Abstract] [Full Text] [PDF]

				H. Watanobe and Y. Hayakawa Hypothalamic Interleukin-1{beta} and Tumor Necrosis Factor-{alpha}, But Not Interleukin-6, Mediate the Endotoxin-Induced Suppression of the Reproductive Axis in Rats Endocrinology, November 1, 2003; 144(11): 4868 - 4875. [Abstract] [Full Text] [PDF]

				B. J. Arey, D. C. Deecher, E. S. Shen, P. E. Stevis, E. H. Meade Jr, J. Wrobel, D. E. Frail, and F. J. Lopez Identification and Characterization of a Selective, Nonpeptide Follicle-Stimulating Hormone Receptor Antagonist Endocrinology, October 1, 2002; 143(10): 3822 - 3829. [Abstract] [Full Text] [PDF]

				K. Held Hales, T. Diemer, S. Ginde, B. K. Shankar, M. Roberts, H. B. Bosmann, and D. B. Hales Diametric Effects of Bacterial Endotoxin Lipopolysaccharide on Adrenal and Leydig Cell Steroidogenic Acute Regulatory Protein Endocrinology, November 1, 2000; 141(11): 4000 - 4012. [Abstract] [Full Text] [PDF]

				J. J. Puder, P. U. Freda, R. S. Goland, M. Ferin, and S. L. Wardlaw Stimulatory Effects of Stress on Gonadotropin Secretion in Estrogen-Treated Women J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2184 - 2188. [Abstract] [Full Text]

				M. A. Sortino, F. Condorelli, C. Vancheri, and P. L. Canonico Tumor Necrosis Factor-{alpha} Induces Apoptosis in Immortalized Hypothalamic Neurons: Involvement of Ceramide-Generating Pathways Endocrinology, October 1, 1999; 140(10): 4841 - 4849. [Abstract] [Full Text]

				M. Ferin Stress and the Reproductive Cycle J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1768 - 1774. [Full Text]

				E. Xiao, L. Xia-Zhang, and M. Ferin Stress and the Menstrual Cycle: Short- and Long-Term Response to a Five-Day Endotoxin Challenge during the Luteal Phase in the Rhesus Monkey J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 623 - 626. [Abstract] [Full Text]

				K. M. Ogilvie, K. Held Hales, M. E. Roberts, D. Buchanan Hales, and C. Rivier The Inhibitory Effect of Intracerebroventricularly Injected Interleukin 1ß on Testosterone Secretion in the Rat: Role of Steroidogenic Acute Regulatory Protein Biol Reprod, February 1, 1999; 60(2): 527 - 533. [Abstract] [Full Text] [PDF]

				E. Xiao, L. Xia-Zhang, A. Barth, J. Zhu, and M. Ferin Stress and the Menstrual Cycle: Relevance of Cycle Quality in the Short- and Long-Term Response to a 5-Day Endotoxin Challenge during the Follicular Phase in the Rhesus Monkey J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2454 - 2460. [Abstract] [Full Text]

				N. Briard, V. Guillaume, C. Frachebois, M. Rico-Gomez, N. Sauze, C. Oliver, and A. Dutour Endotoxin Injection Increases Growth Hormone and Somatostatin Secretion in Sheep Endocrinology, June 1, 1998; 139(6): 2662 - 2669. [Abstract] [Full Text] [PDF]

				A. V. Turnbull and C. Rivier Inhibition of Gonadotropin-Induced Testosterone Secretion by the Intracerebroventricular Injection of Interleukin-1{beta} in the Male Rat Endocrinology, March 1, 1997; 138(3): 1008 - 1013. [Abstract] [Full Text] [PDF]