A single intraperitoneal injection of lipopolysaccharide (LPS) causes a biphasic suppression of testicular steroidogenesis in adult rats, with inhibition at 6 h and 18-24 h after injection. The inhibition of steroidogenesis is independent of the reduction in circulating LH that also occurs after LPS treatment, indicating a direct effect of inflammation at the Leydig cell level. The relative contributions to this inhibition by intratesticular versus systemic responses to inflammation, including the adrenal glucocorticoids, was investigated in this study. Adult male Wistar rats (eight/group) received injections of LPS (0.1 mg/kg i.p.), dexamethasone (DEX; 50 microg/kg i.p.), LPS and DEX, or saline only (controls), and were killed 6 h, 18 h and 72 h later. Treatment with LPS stimulated body temperature and serum corticosterone levels measured 6 h later. Administration of DEX had no effect on body temperature, but suppressed serum corticosterone levels. At the dose used in this study, DEX alone had no effect on serum LH or testosterone at any time-point. Expression of mRNA for interleukin-1beta (IL-1beta), the principal inflammatory cytokine, was increased in both testis and liver of LPS-treated rats. Serum LH and testosterone levels were considerably reduced at 6 h and 18 h after LPS treatment, and had not completely recovered by 72 h. At 6 h after injection, DEX inhibited basal IL-1beta expression and the LPS-induced increase of IL-1beta mRNA levels in the liver, but had no effect on IL-1beta in the testis. The effects of DEX on IL-1beta levels in the liver were no longer evident by 18 h. In LPS-treated rats, DEX caused a significant reversal of the inhibition of serum LH and testosterone at 18 h, although not at 6 h or 72 h. Accordingly, DEX inhibited the systemic inflammatory response, but had no direct effect on either testicular steroidogenesis or intra-testicular inflammation, at the dose employed. These data suggest that the inhibition of Leydig cell steroidogenesis at 6 h after LPS injection, which was not prevented by co-administration of DEX, is most likely due to direct actions of LPS at the testicular level. In contrast, the later Leydig cell inhibition (at 18 h) may be attributable to extra-testicular effects of LPS, such as increased circulating inflammatory mediators or the release of endogenous glucocorticoids, that were inhibited by DEX treatment. These data indicate that the early and late phases of Leydig cell inhibition following LPS administration are due to separate mechanisms.

The insulin-like growth factors-I and -II (IGFs) are involved in a wide array of cellular processes such as proliferation, prevention of apoptosis, and differentiation. Most of these effects are mediated by the IGF-I receptor, although at higher IGF concentrations the insulin receptor can also be activated. As the expression of both the IGFs and their receptors is widespread, IGFs are thought to have autocrine/paracrine modes of actions also, particularly during foetal life. The endocrine component of the IGF system is recognised to be important after birth, with IGF-I mediating many of the effects of growth hormone (GH), and linking anabolic processes to nutrient availability. Consideration of ligands and receptors, however, is insufficient to provide a complete understanding of the biology of IGF. This is because IGFs are found in binary complexes of 40-50 kDa with members of a family of IGF-binding proteins (IGFBPs-1 to -6) in all biological fluids. In addition, in postnatal serum, most IGFs are sequestered into ternary complexes of 150 kDa consisting of one molecule each of IGF, IGFBP-3 or IGFBP-5, and acid-labile subunit (ALS). Despite evidence that ALS plays an important role in the biology of circulating IGFs, it has received only limited attention relative to the other components of the IGF system. This review provides an overview on the current knowledge of ALS protein and gene structure, organisation and regulation by hormones, and insights from novel animal models such as the ALS knockout mice.

The differential production of prostaglandin (PG) F(2 alpha) and PGE(2) within the uterine compartment may play a role in controlling myometrial contraction. We hypothesized that the enzymes downstream of PG endoperoxide synthase-2 (PGHS-2) determine the ratio of PGF(2 alpha) and PGE(2) in the utero-ovarian vein plasma and the time of normal and preterm labour onset. The aim of this study was to simultaneously determine the expression of PGF and PGE synthases (PGFS and PGES) in gestational tissues at spontaneous and induced-preterm labour in sheep. Myometrial, endometrial and placental tissue were obtained from ewes in dexamethasone-induced preterm labour, age-matched control ewes, and ewes in spontaneous term labour for analysis of mRNA expression by real-time PCR. PGFS mRNA expression was significantly increased following dexamethasone-induced and spontaneous labour onset in placentome (P<0.01) but was unchanged in the myometrium and endometrium. In contrast, PGES mRNA expression remained unchanged or decreased. PGHS-2 mRNA expression was increased in all tissues examined in both dexamethasone-induced and spontaneous labour (P<0.001). Plasma PGE(2) and PGF(2 alpha) concentrations rose in both dexamethasone-induced and spontaneous labour with the ratio of PGF(2 alpha):PGE(2) increased with labour onset (P<0.05). These results are consistent with the hypothesis that the increased expression, of PGFS is responsible for the increased PGF(2 alpha):PGE(2) ratio and this, together with increased PGHS-2 expression, accounts for myometrial activity at labour onset. The findings point to PGFS expression as a key factor in regulating the uterotonic process in the sheep.

Testosterone is metabolised to the more potent androgen, dihydrotestosterone, by the 5alpha-reductase (5alphaR) enzyme. We previously showed that 5alpha-reduced androgens are important for maintaining androgen action on rat spermatogenesis when testicular testosterone concentrations are reduced. This study investigated expression and activity of the 5alphaR isoforms, type 1 (5alphaR-1) and type 2 (5alphaR-2), in the rat during hormone manipulation in order to understand the factors that regulate the testicular concentration of 5alphaR and testicular 5alpha-reduced androgen biosynthesis. Testicular 5alphaR-1 and 5alphaR-2 mRNA and enzyme activity were measured by real-time PCR and specific enzyme assays respectively. Hormone levels were first suppressed using two models of gonadotrophin suppression: testosterone and oestradiol treatment (LH/testosterone deficiency) or GnRH immunisation (LH/testosterone and FSH deficiency). Hormones were then either restored or suppressed for 6 days by a variety of hormonal treatments. 5alphaR-1 mRNA and enzyme activity increased when testosterone was suppressed, yet restoration of testosterone decreased 5alphaR-1 mRNA and enzyme activity, suggesting that testosterone negatively regulates 5alphaR-1. suppression of FSH decreased 5alphaR-1 mRNA yet FSH administration increased 5alphaR-1 mRNA, but no changes in 5alphaR-1 activity were observed within the 6 day period. In contrast to 5alphaR-1, testosterone did not affect the testicular concentration of 5alphaR-2 mRNA or activity, but there was evidence for modulation of 5alphaR-2 activity by FSH. Measurement of testicular androgens revealed that 5alphaR-1 was primarily responsible for the production of 5alpha-reduced metabolites. It is concluded that the 5alphaR isoforms in rat testis are differentially regulated by testosterone and FSH: testosterone negatively regulated 5alphaR-1 mRNA and enzyme activity but had no affect on 5alphaR-2, whereas FSH positively regulated 5alphaR-1 mRNA and appeared to regulate 5alphaR-2.