Cyclooxygenase-2 Regulation of the Age-Related Decline in Testosterone Biosynthesis

Wang, XingJia; Shen, Chwan Li; Dyson, Matthew T.; Eimerl, Sarah; Orly, Joseph; Hutson, James C.; Stocco, Douglas M.

doi:10.1210/en.2005-0298

Cited by 89 publications

(97 citation statements)

References 36 publications

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“…Previous studies have reported that StAR protein expression and testosterone production were decreased in aged Leydig cells. [9][10][11]33 No studies on the linkage between autophagy and testosterone production have been reported, although Taneike et al 34 reported decreased autophagic activity in aged heart tissue, and Zhang et al 29 reported low autophagic activity in aged smooth muscles of the corpus cavernosum. Our study showed that the autophagic activity could affect StAR protein We attributed the linkage between lower testosterone levels and autophagic deficiency in aged Leydig cells to intracellular ROS accumulation generated from dysfunctional or aged mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Li¹,

Chen²,

Chen³

et al. 2011

Asian J Androl

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Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males, but the mechanism remains unclear. In this study, we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity. Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production. In Leydig cells from young and aged rats, treatment with wortmannin, an autophagy inhibitor, inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production. In contrast, treatment with rapamycin, an autophagy activator, enhanced LH-stimulated steroidogenesis in Leydig cells from aged, but not young, rats. Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin. Furthermore, an increased level of ROS, induced by H 2 O 2 , resulted in LH-stimulated steroidogenic inhibition. Finally, knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells, which were associated with increased intracellular ROS level. These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells, which might be influenced by intracellular ROS levels.

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Section: Discussionmentioning

confidence: 99%

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Li¹,

Chen²,

Chen³

et al. 2011

Asian J Androl

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“…In regard to the apparent critical function of an "acute" regulatory protein in steroidogenesis, it is of interest that expression of both StarD1/StAR and PBR/TSPO is downregulated in the adrenal and Leydig cells of aging rats [422][423][424][425][426]. For example, studies from this laboratory have shown an 80% reduction in StarD1/StAR protein expression of nonstimulated Leydig cells prepared from old Sprague-Dawley rats suggesting that the impaired testosterone production that occurs during aging may involve attenuated StAR expression [422].…”

Section: Aging and P38 Subfamily Of Map Kinasesmentioning

confidence: 99%

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Zaidi¹

2013

TOLSJ

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Steroid hormones are lipophilic, low-molecular weight organic compounds all of which are derived from cholesterol. They are primarily synthesized by steroidogenic glands such as gonads (ovary and testis), the adrenal gland and, during pregnancy, by the placental trophoblasts. Limited steroid synthesis also takes place in the brain. Steroid hormones are crucial for the proper functioning of the body. They mediate a wide variety of vital physiological functions, ranging from maintaining normal reproductive function and secondary sexual characteristics, to regulating virtually every metabolic process in the body. Like many age-related endocrine disorders, aging also progressively impacts the tissue-specific synthesis and secretion of steroid hormones. The goal of this review is to summarize the effects of aging on steroid hormone synthesis and secretion by the adrenal gland and gonads of both human and experimental animal models, to describe the potential involvement of excessive oxidative stress in mediating age-related alterations in steroidogenesis, and to discuss the possible underlying mechanisms involved.

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“…By immunohistochemistry, we found only positive PTGS2 immunostaining in Leydig cells of the reproductively active seasonal breeder Syrian hamster (Frungieri et al 2006). However, other authors have been able to detect PTGS2 expression in testes and Leydig cells from rats, mice and even humans using different experimental techniques such as RT-PCR, real-time RT-PCR and western blot (O'Neill & Ford-Hutchinson 1993, Neeraja et al 2003, Wang et al 2005, Balaji et al 2007, Chen et al 2007, Winnall et al 2007. One plausible explanation for these discrepancies is that the levels of PTGS2 expression in normal testes of most species, including the men, may be too low to be detected by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 75%

“…Thus, these early studies suggest that PGs may not be important for the functioning of the testis. However, several reports have shown that PTGS is up-regulated in testicular cancer (Hase et al 2003) and aging (Wang et al 2005), and that some PGs (i.e. PGD 2 , PGE 2 , PGF 2a ) participate in the regulation of testicular testosterone production (Saksena et al 1973, Kimball et al 1979, Didolkar et al 1981, Sawada et al 1994, Romanelli et al 1995, Gunnarsson et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells

Matzkin¹,

González-Calvar²,

Mayerhofer³

et al. 2009

Reproduction

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We have previously observed expression of prostaglandin-endoperoxide synthase 2 (PTGS2), the key enzyme in the biosynthesis of prostaglandins (PGs), in reproductively active Syrian hamster Leydig cells, and reported an inhibitory role of PGF 2a on hamster testicular steroidogenesis. In this study, we further investigated PTGS2 expression in hamster Leydig cells during sexual development and photoperiodic gonadal regression. Since PTGS2 is mostly expressed in pubertal and reproductively active adult hamsters with high circulating levels of LH and androgens, we studied the role of these hormones in the regulation/maintenance of testicular PTGS2/PGF 2a . In active hamster Leydig cells, LH/hCG and testosterone induced PTGS2 and PGF 2a production, and their actions were abolished by the antiandrogen bicalutamide (Bi). These results indicate that LH does not exert a direct effect on PG synthesis. Testosterone also stimulated phosphorylation of the mitogen-activated protein kinase isoforms 3/1 (MAPK3/1) within minutes and hours, but the testosterone metabolite dihydrotestosterone had no effect on PTGS2 and MAPK3/1. Because Bi and U0126, an inhibitor of the MAP kinase kinases 1 and 2 (MAP2K1/2), abolished testosterone actions on MAPK3/1 and PTGS2, our studies suggest that testosterone directly induces PTGS2/PGF 2a in hamster Leydig cells via androgen receptors and a non-classical mechanism that involves MAPK3/1 activation. Since PGF 2a inhibits testosterone production, it might imply the existence of a regulatory loop that is setting a brake on steroidogenesis. Thus, the androgen environment might be crucial for the regulation of testicular PG production at least during sexual development and photoperiodic variations in hamsters.

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Cyclooxygenase-2 Regulation of the Age-Related Decline in Testosterone Biosynthesis

Cited by 89 publications

References 36 publications

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells

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