Reproduction in Domestic Animals

Endotoxin and Neuroendocrinology 319the timely generation of nitric oxide (NO) as driven byTNF-a and accompanied by translocation of NFjb tothe nucleus which in turn attenuates transcription of theTNF-a gene. The result is a necessary turndown orsuppression of proinflammatory signalling elementsthat, if left unchecked, leads to free radical tissuedamage (Zeisberger and Roth 1998).Sites of Endotoxin Action on Growth Hormone(GH) and Luteinizing Hormone (LH)Both GH and LH are produced and secreted by thepituitary under the influence of releasing hormones fromthe hypothalamus. Thus, LPS may influence circulatingconcentrations of GH and LH directly by alteringproduction and secretion at the pituitary, or indirectlyby altering production and secretion of releasinghormones at the level of the hypothalamus.Endotoxin was reported to impair adenohypophysialLH release in rats (Rettori et al. 1994) and sheep(Coleman et al. 1993; Fig. 2). In cycling heifers receivingan experimental challenge 42 h after the PGF 2a (dinoprost)-inducedluteolysis (Suzuki et al. 2001), LPSreduced the pulse frequency of LH for 6 h, andincreased the mean concentration and pulse amplitudeof LH. Plasma concentrations of cortisol andLH (ng/ml)GH (ng/ml)87654321–1 0 1 2 3 4 5 6 7 8 9 10Hours after treatment18161412108642ControlEndotoxinEndotoxin (0.4 µg/kg BW)Control0–1 0 1 2 3 4 5 6 7 8 9Hours after treatmentFig. 2. Effects of LPS on pulsatile patterns of LH and GH in sheeptreated with LPS (Coleman et al. 1993)10progesterone were simultaneously and transientlyincreased due to the adrenocortical over-production ofthese hormones. Plasma oestradiol concentrations weredecreased and the preovulatory LH pulse was delayed orcompletely blocked. A similar disruption was demonstratedin the preovulatory rise of oestradiol and in thesecretory pattern of LH in ewes following endotoxinchallenge (Battaglia et al. 2000). Endotoxin absorbedfrom the uterine lumen was reported to suppress theformation of the preovulatory LH peak and to inducethe cystic degeneration of dominant follicles in postpartumcows (Peter et al. 1989). Also of particularimportance in farm animals is the finding that neonatalexposure to LPS actually programs long-term sensitivityof the GnRH regulatory system, such that post-natalresponses to LPS produce a greater inhibition of GnRHand LH (Li et al. 2007).Endotoxin suppresses circulating concentrations ofLH at the level of the hypothalamus (Coleman et al.1993). This is supported as follows by three primarypieces of evidence. Firstly, portal vein cannulationindicates that LPS results in reduced secretion of GnRHfrom the hypothalamus, thus suggesting endotoxininhibits circulating concentrations of LH by inhibitinghypothalamic stimulation of LH secretion (Battagliaet al. 1997). Secondly, the increased secretion of LH inresponse to LPS by dispersed pituitary cells (Colemanet al. 1993) further suggests that LPS acts at the level ofthe hypothalamus to inhibit circulating concentrationsof LH. Finally, LPS challenge reduces electrical activityin areas of the hypothalamus associated with thegeneration of GnRH and thus LH pulses (Takeuchiet al. 1997; Yoo et al. 1997).In contrast to the effects on LH, endotoxin’s effect oncirculating concentration of GH is more complicated. Inspecies where LPS decreases, the circulating concentrationof GH (cattle and rat), the effect is primarily at thelevel of the hypothalamus. However, in species whereLPS increases circulating concentrations of GH (sheepand human), the effect appears to occur primarily at thepituitary. In pigs, an acute increase in circulatingconcentrations of GH following an LPS challenge hasbeen reported (Parrott et al. 1995; Hevener et al. 1997).However, this effect was only short-lived, and subsequentLPS-induced uncoupling of the GH ⁄ IGF-I axispersisted. Pituitary production and secretion of GH isprimarily under the regulation of GH releasing hormone(GHRH) and somatostatin from the hypothalamus. Inspecies where GH concentration is decreased by LPS,the effect is likely mediated through cytokine-inducedstimulation of somatostatin production (Scarborough1990). Sheep injected with LPS secrete GH during thesame period when LH secretion is reduced (Fig. 2;Coleman et al. 1993). Challenge with LPS also results inan increase in somatostatin concentrations in hypophysialportal blood with no change in the concentrations ofGHRH in sheep (Briard et al. 1998). Under normalphysiological conditions, an increase in somatostatinaccompanied with no change in GHRH would beexpected to result in decreased circulating concentrationsof GH. However, Briard et al. (1998) observedincreased circulating concentrations of GH associatedwith increased hypophysial portal blood concentrationsÓ 2008 The Authors. Journal compilation Ó 2008 Blackwell Verlag