Summary:
In adult rats, bacterial endotoxin (lipopolysaccharide or LPS) is known to diminish the activity of the reproductive axis, mainly by inhibiting luteinizing hormone-releasing hormone (LHRH) secretion; until now, this effect has not been studied in immature rats. The aim of the present study was to evaluate the effect of LPS 1) on LHRH output (and associated changes in the release of inhibitory amino acid neurotransmitters such as γ-aminobutyric acid (GABA) and taurine) by superfused hypothalamic fragments, and 2) on gonadotropin secretion by incubated hemipituitaries, obtained from young adult (60-day-old) and peripubertal (30-day-old) intact male rats.
In adult animals, LPS induced a significant inhibition (50% of basal values) of LHRH release, accompanied by an increase in GABA and taurine output. In juvenile rats the inhibition of LHRH secretion by LPS attained 90% of basal values (p < 0.0001 versus adult rats), and the concurrent increase in GABA release was significantly greater (p < 0.0001 versus adult rats). LPS did not affect in vitro gonadotropin secretion in adult animals. Conversely, the release of these hormones was significantly (p < 0.001 and < 0.02 for LH and FSH, respectively) reduced in 30-day-old rats.
Our results demonstrate the existence of age-related differences in the effect of LPS on LHRH and gonadotropin secretion. These differences might well be attributed to an increased activity of the hypothalamic GABAergic system. Furthermore, the participation of other factors known to play a role in immune-neuroendocrine relationships (e.g., corticotropin-releasing hormone, testosterone) is discussed.
Key words:
LPS - LHRH - gonadotropins - GABA - taurine - sexual maturation
References
1
Arias P, Feleder C, Rodriguez M, Ginzburg D, Refojo D, Szwarcfarb B, Moguilevsky J A.
Repeated intracerebroventricular administration of taurine lowers LH levels and postpones vaginal opening in peripubertal female rats.
Developmental Brain Res.
85
137-139
1995;
2
Arias P, Goroll D, Convertini V, Jarry H, Wuttke W.
Effects of taurine on basal and stimulated luteinizing hormone (LH) and LH-releasing hormone secretion in ovariectomized rats: in vitro studies.
Brain Research.
634
325-327
1994;
3
Besedovsky H O, Del Rey A.
Immune-neuroendocrine interactions: Facts and hypotheses.
Endocr Rev.
17
64-84
1996;
4
Clough R W, Hoffmann G E, Sladek C D.
Peripupertal development of noradrenergic stimulation of luteinizing hormone-releasing hormone neurosecretion in vitro.
Brain Research.
446
121-132
1988;
5
Coleman E S, Elsasser T H, Kemppainen R J, Coleman D A, Sartin J L.
Effect of endotoxin on pituitary hormone secretion in sheep.
Neuroendocrinology.
58
111-122
1993;
6
Ebisui O, Fukata J, Tominaga T, Murakami N, Kobayashi H, Segawa H, Muro S, Naito Y, Nakai Y, Masui Y. et al .
Role of interleukin-1 alpha and beta in endotoxin induced suppression of plasma gonadotropins levels in rats.
Endocrinology.
130
3307-3313
1992;
7
Feleder C, Jarry H, Leonhardt S, Moguilevsky J A, Wuttke W.
Effects of endotoxin on in vitro release of LHRH and amino acid neurotransmitters by preoptic mediobasal hypothalamic fragments.
Neuroimmunomodulationo.
3
76-81
1996a;
8
Feleder C, Refojo D, Jarry H, Wuttke W, Moguilevsky J A.
Bacterial endotoxin inhibits LHRH secretion following the increased release of hypothalamic GABA levels. Differents effects on amino acid neurotransmitter release.
Neuroimmunomodulation.
3
342-351
1996b;
9
Feleder C, Refojo D, Nacht S, Moguilevsky J A.
Interleukin-1 stimulates hypothalamic inhibitory amino acid neurotransmitter release.
Neuroimmunomodulation.
5
1-4
1998;
10
Gertner J M, Kaufmann F R, Donfield S M, Sleeper L A, Shapiro A D, Howard C, Gomperts E D, Hilgartner M W.
Delayed somatic growth and pubertal development in human immunodeficiency virus-infected hemophiliac boys: Hemophilia growth and development study.
J Pediatr.
124
896-902
1994;
11
Grossman C J.
Regulation of the immune system by sex steroids.
Endocrine Reviews.
5
435-455
1984;
12
Hagan P, Poole S, Bristow A F.
Endotoxin-stimulated production of rat hypothalamic interleukin-1ß in vivo and in vitro, measured by specific immunoradiometric assay.
J Endocrinology.
11
31-36
1993;
13
Ibrahim I I, Barakat R M, Bassiouny H K, Hanna L S, Aboul-Atta A M, Bayad M A, Ghaly I M, Abdalla M I, Hafez E S.
Effect of urinary bilharzial infection on male pubertal development and endocrine functions.
Arch Androl.
11
59-64
1983;
14
Jarry H, Hirsch B, Leonhardt S, Wuttke W.
Amino acid neurotransmitter release in the preoptic area of rats during the positive feedback action of estradiol on LH release.
Neuroendocrinology.
56
133-140
1992;
15
Kalra P S, Sahu A, Kalra S P.
Interleukin-1 inhibits the ovarian steroid-induced luteinizing hormone surge and the release of hypothalamic luteinizing hormone-releasing hormone in rats.
Endocrinology.
126
2145-2152
1990;
16
Katsuura G, Gottschall P E, Arimura A.
Identification of a high-affinity receptor for interleukin-1 beta in rat brain.
Biochem Biophys Res Comm.
156
61-67
1988;
17
Kontro P, Oja S S.
Release of taurine, GABA and dopamine from rat striatal slices: mutual interactions and developmental aspects.
Neuroscience.
24
49-58
1988;
18 Kordon C, Drouva S V, Martinez de la Escalera G, Weiner R I. Role of classic and peptide neuromediators in the neuroendocrine regulation of LH and prolactin. In: Knobil E, Neill J, et al (Eds.): The Physiology of Reproduction Raven Press, Ltd.; New York 1621-1682 1994
19
Lechan R M, Toni R, Clarck B D, Cannon J G, Shaw A R, Dinarello C A, Reichlin S.
Immunoreactive interleukin-1ß localization in the rat forebrain.
Brain Res.
514
135-140
1990;
20
Li Z, Inenaga K, Yamashita H.
GABAergic inputs modulate effects of interleukin-1β on supraoptic neurons in vitro.
Neuroreport.
5
181-183
1993;
21
MacDonald M C, Wilkinson M.
Peripubertal treatment with N-methyl-D-aspartic acid or neonatally with monosodium glutamate accelerates sexual maturation in female rats, an effect reversed by MK-801.
Neuroendocrinology.
52
143-149
1990;
22
Meister B, Hokfelt T, Geffart M, Oertel W.
Glutamic acid decarboxylase- and gamma-aminobutyric acid-like immunoreactivities in corticotropin-releasing factor-containing parvocellular neurons of the hypothalamic paraventricular nucleus.
Neuroendocrinology.
48
516-526
1988;
23
Miller L G, Fahey J.
Interleukin-1 modulates GABAergic and glutamatergic function in brain.
Ann NY Acad Sci.
739
293-298
1994;
24
Mitsushima D, Hei D L, Terasawa E.
γ-aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty.
Proc Natl Acad Sci USA.
91
395-399
1994;
25
Moguilevsky J A, Carbone S, Szwarcfarb B, Rondina D.
Sexual maturation modifies the GABAergic control of gonadotrophin secretion in female rats.
Brain Research.
563
12-16
1991;
26
Refojo D, Arias P, Moguilevsky J A, Feleder C.
Effect of bacterial endotoxin on in vivo pulsatile gonadotropin secretion in adult male rats.
Neuroendocrinology.
67
275-281
1998;
27
Rettori V, Gimeno M F, Karara A, Gonzalez M C, McCann S M.
Interleukin-1α inhibits prostaglandin E2 release to suppress pulsatile release of luteinizing hormone but not follicle-stimulating hormone.
Proc Natl Acad Sci USA.
88
2763-2768
1991;
28
Rivest S, Rivier C.
Centrally injected interleukin-1ß inhibits the hypothalamic GnRH secretion and circulating LH levels via prostaglandins in rats.
J Neuroendocrinol.
5
445-450
1993;
29
Rivest S, Rivier C.
Influence of the paraventricular nucleus of the hypothalamus in the alteration of neuroendocrine functions induced by intermittent footshock or interleukin.
Endocrinology.
129
2049-2057
1991;
30 Rivier C. Role of endotoxin and interleukin-1 in modulating ACTH, LH and sex steroid secretion. In: Porter JC, Jezová D (eds.): Circulating regulatory factors and neuroendocrine function. Plenum Press, New York 195-301 1990
31
Rivier C, Rivier J, Vale W.
Stress-induced inhibition of reproductive functions: role of endogenous corticotropin-releasing factor.
Science.
231
607-609
1986;
32
Rivier C, Vale W.
In the rat, interleukin-1α acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion.
Endocrinology.
124
2105-2109
1989;
33
Spangelo B L, Gorospe W C.
Role of the cytokines in the neuroendocrine-immune system axis.
Front Neuroendocrinology.
16
1-22
1995;
34
Spinedi E, Chisari A, Pralong F, Gaillard R C.
Sexual dimorphism in the mouse hypothalamic-pituitary-arenal axis function after endotoxin and insulin stresses during development.
Neuroimmunomodulation.
4
77-83
1997;
35
Spinedi E, Suescun M O, Hadid R, Daneva T, Gaillard R C.
Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological sexual dimorphism.
Endocrinology.
131
2430-2436
1992;
36
Thomas L.
Physiologic and pathologic alterations produced by endotoxins of Gram-negative bacteria.
AMA Arch Intern Med.
101
452-459
1958;
37
Tukey J W.
Comparing individual means in the analysis of variance.
Biometrics.
5
99-114
1949;
38
Warner B A, Dufau M L, Santen R J.
Effects of aging and illness on the pituitary testicular axis in men: qualitative as well as quantitative changes in luteinizing hormone.
J Clin Endocrinol Metab.
60
263-268
1985;
39
Yoo M J, Nishihara M, Takahashi M.
Tumor necrosis factor-alpha mediates endotoxin induced supression of gonadotropin-releasing hormone pulse generator activity in the rat.
Endocr J.
44
141-148
1997;
Prof. Dr. Jaime A. Moguilevsky
Departamento de Fisiología
Facultad de Medicina, U.B.A.
Paraguay 2155
ARG-1121 Buenos Aires
Argentina
Fax: + 5411 4963 6287
Email: feleder@ciudad.com.ar