Enhanced Proinflammatory Cytokine Response to Bacterial Lipopolysaccharide in the Adult Male Rat after either Neonatal or Prepubertal Ablation of Biological Testosterone Activity

Ongaro, Luisina; Castrogiovanni, Daniel; Giovambattista, Andrés; Gaillard, Rolf C.; Spinedi, Eduardo

doi:10.1159/000324125

Cited by 14 publications

(16 citation statements)

References 91 publications

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“…Conversely, Ongaro et al showed an elevated LPS-induced TNF-α secretion in plasma of adult male rats after androgen receptor antagonism or testosterone depletion with neonatal flutamide treatment or prepubertal orchidectomy, respectively 33 . In this regard, our studies have shown that flutamide administration following trauma increases aromatase activity which promotes the synthesis of 17β-estradiol from testosterone 34 - 36 .…”

Section: Gender-specific Immune Response After Sepsismentioning

confidence: 43%

Gender differences in sepsis

Angele¹,

Pratschke²,

et al. 2013

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During sepsis, a complex network of cytokine, immune, and endothelial cell interactions occur and disturbances in the microcirculation cause organ dysfunction or even failure leading to high mortality in those patients. In this respect, numerous experimental and clinical studies indicate sex-specific differences in infectious diseases and sepsis. Female gender has been demonstrated to be protective under such conditions, whereas male gender may be deleterious due to a diminished cell-mediated immune response and cardiovascular functions. Male sex hormones, i.e., androgens, have been shown to be suppressive on cell-mediated immune responses. In contrast, female sex hormones exhibit protective effects which may contribute to the natural advantages of females under septic conditions. Thus, the hormonal status has to be considered when treating septic patients. Therefore, potential therapies could be derived from this knowledge. In this respect, administration of female sex hormones (estrogens and their precursors) may exert beneficial effects. Alternatively, blockade of male sex hormone receptors could result in maintained immune responses under adverse circulatory conditions. Finally, administration of agents that influence enzymes synthesizing female sex hormones which attenuate the levels of pro-inflammatory agents might exert salutary effects in septic patients. Prospective patient studies are required for transferring those important experimental findings into the clinical arena.

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Section: Gender-specific Immune Response After Sepsismentioning

confidence: 43%

Gender differences in sepsis

Angele¹,

Pratschke²,

et al. 2013

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“…Indeed, several authors including our group have demonstrated the deleterious effects of neonatal androgen excess in the physiology of the adult female rat [8, 10, 19, 21]. On the other hand, early (pre-/postnatal) flutamide intervention has been used to test the long-term effect of lack of full AR function in adult rats [13, 22, 23]. We must mention that the efficacy of flutamide, a nonsteroidal pure anti-AR [12], has largely been proved through its therapeutic effect to mitigate androgen-dependent prostate cancer [12, 24].…”

Section: Discussionmentioning

confidence: 99%

“…On day 5 of age, female rats (Sprague-Dawley; n = 12/16 per group obtained from 3-4 different litters) were s.c. injected with either 50 μ L of sterile corn oil alone (control; CT) or 1.25 mg of testosterone propionate (TP) [8], 1.75 mg flutamide (F) [13], or both (TP + F). Rats were checked daily (between days 7 and 30 of age) for vaginal opening.…”

Section: Methodsmentioning

confidence: 99%

Impact of Neonatal Manipulation of Androgen Receptor Function on Endocrine-Metabolic Programming in the Juvenile Female Rat

2013

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The impact of neonatal androgen receptor (AR) stimulation/blockage, due to testosterone propionate (TP)/AR antagonist treatment, on individual anthropometry and neuroendocrine-metabolic function was evaluated in the juvenile female rat. Pups (age 5 days) were s.c. injected with TP (1.25 mg), flutamide (F; 1.75 mg), and TP + F or vehicle (control, CT) and studied on day 30 of age. Body weight (BW), parametrial adipose tissue (PMAT) mass, food intake, adipoinsular axis, and steroidogenic functions were examined. Opposite to TP-rats, F-treated rats developed hypophagia, grew slowly (BW and PMAT), and displayed heightened peripheral insulin sensitivity. These F effects were abrogated in TP + F animals. Accordingly, TP rats displayed hyperleptinemia, an effect fully prevented by F cotreatment. Finally, androgen-treated animals bore an irreversible ovarian dysfunction (reduced circulating levels of 17HOP4 and ovary 17HOP4 content and P450c17 mRNA abundance). These data indicate that early stimulation of AR enhanced energy store, blockage of AR activity resulted in some beneficial metabolic effects, and neonatally androgenized rats developed a severe ovarian dysfunction. Our study highlights the important role of AR in the early organizational programming of metabolic and neuroendocrine functions.

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“…We measured TNF-␣ and found that the levels were attenuated in testosterone-treated I/R rats compared with untreated rats with I/R injury. Androgens have been shown previously to be anti-inflammatory (9,19,35). For example, DHT, via the androgen receptor, inhibits IL-1␣ and TNF-␣-induced proinflammatory cytokine production in a rheumatoid cell line (35), and LPS treatment caused increased proinflammatory cytokines in a model of androgen ablation (19).…”

Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

“…Androgens have been shown previously to be anti-inflammatory (9,19,35). For example, DHT, via the androgen receptor, inhibits IL-1␣ and TNF-␣-induced proinflammatory cytokine production in a rheumatoid cell line (35), and LPS treatment caused increased proinflammatory cytokines in a model of androgen ablation (19). Because TNF-␣ is produced by nonimmune cells in the kidney, such as medullary thick ascending limb, the reduction in TNF-␣ may not be contributory to the protection caused by testosterone, but may simply be an indication of less injury to the medulla in the presence of testosterone.…”

Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Soljancic

Ruiz

Chandrashekar

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-␣ and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol. kidney injury molecule-1; sex; androgens; vascular endothelial growth factor ACUTE KIDNEY INJURY (AKI) is thought to affect ϳ2-5% of all hospitalized individuals in the United States (31a), and the mortality rates are as high as 80% (5, 11, 31). Aging increases both the incidence and the mortality rates due to AKI in both men and women. Despite the importance of the problem, the mechanisms responsible for AKI have not been completely elucidated.The incidence of acute renal failure in surgical patients is significantly higher in men than women (8,16,20). Animal studies have also reported sex differences in the adverse effects of ischemia reperfusion (I/R) of the kidney with males being more susceptible than females (18, 21). The mechanisms responsible for the sex differences in AKI in humans and the sex differences in animals are not clear.Reductions in serum testosterone in men have been shown in numerous studies to occur with chronic disease, such as heart disease, obesity, hypertension, and renal disease (2, 13, 15, 24). The association of reduction in testosterone with increased cardiovascular disease has lead investigators to suggest that it is the reduction in testosterone that may contribute to chronic disease states rather than that the chronic disease is the cause of the reduction in circulating testosterone levels (15). There is also evidence that acute conditions may reduce androgen levels. For example, Pugh et al. (23) and Tripathi and Hegde (30...

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Enhanced Proinflammatory Cytokine Response to Bacterial Lipopolysaccharide in the Adult Male Rat after either Neonatal or Prepubertal Ablation of Biological Testosterone Activity

Cited by 14 publications

References 91 publications

Gender differences in sepsis

Gender differences in sepsis

Impact of Neonatal Manipulation of Androgen Receptor Function on Endocrine-Metabolic Programming in the Juvenile Female Rat

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

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