From PMID 16166231: The importance of the study by Wang et al. (9) is that it convincingly demonstrates a cause-effect relationship between COX2 and steroidogenesis. First, in correlational studies, COX2 protein was shown to increase dramatically in Leydig cells from aged rats in comparison to cells from young rats. Increased COX2 was accompanied by significant reductions in serum testosterone concentration, testosterone biosynthesis by Leydig cells, and steroidogenic acute regulatory protein (StAR) _expression_. With respect to the latter, the rate-limiting step in testosterone biosynthesis is the transport of the substrate cholesterol to the mitochondrial inner membrane. It is well established that StAR plays a significant role in this transport (10), as does peripheral benzodiazapine receptor (11). Importantly, over_expression_ of COX2 in MA-10 Leydig cells was shown to inhibit both steroidogenesis and StAR _expression_, and this effect was prevented by blocking COX2 activity. In the case of aged Leydig cells, their incubation with a COX2 inhibitor for as little as 30 min resulted in significantly increased testosterone biosynthesis. Finally, aged rats, when fed a COX2 inhibitor for about a month, had increased serum testosterone levels. These results, taken together, suggest that COX2 plays a significant role in age-related decline in testosterone biosynthesis. Thus, this paper takes the apparent relationship between COX2 and steroidogenesis that is suggested by correlational studies to a mechanistic level, showing the effects of experimental over_expression_ or inhibition of COX2 on steroidogenesis both in vitro and in vivo. Endocrinology. 2005 Oct;146(10):4202-8. Epub 2005 Jul 7. Cyclooxygenase-2 regulation of the age-related decline in testosterone biosynthesis. Wang X, Shen CL, Dyson MT, Eimerl S, Orly J, Hutson JC, Stocco DM. Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA. The age-related decline in testosterone biosynthesis in testicular Leydig cells has been well documented, but the mechanisms involved in the decline are not clear. Recent studies have described a cyclooxygenase-2 (COX2)-dependent tonic inhibition of Leydig cell steroidogenesis and _expression_ of the steroidogenic acute regulatory protein (StAR). The present study was conducted to determine whether COX2 protein increases with age in rat Leydig cells and whether COX2 plays a role in the age-related decline in testosterone biosynthesis. Our results indicate that from 3 months of age to 30 months, COX2 protein in aged rat Leydig cells increased by 346% over that of young Leydig cells, StAR protein decreased to 33%, and blood testosterone concentration and testosterone biosynthesis in Leydig cells decreased to 41 and 33%, respectively. Further experiments demonstrated that overexpressing COX2 in MA-10 mouse Leydig cells inhibited StAR gene _expression_ and steroidogenesis and that the inhibitory effects of COX2 could be reversed by blocking COX2 activity. Notably, incubation of aged Leydig cells with the COX2 inhibitor NS398 enhanced their testosterone biosynthesis. Blood testosterone concentrations in aged rats fed the COX2 inhibitor DFU, at doses of 5, 10, 15, and 20 mg/kg body weight per day were increased by 15, 23, 56, and 120%, respectively, over the levels in the rats receiving no DFU. The present study suggests a novel mechanism in male aging involving COX2 and a potential application of the mechanism to delay the age-related decline in testosterone biosynthesis. PMID: 16002525 Fertil Steril. 2007 Jul;88(1):233-6. Epub 2007 Feb 20. A prostaglandin D2 system in the human testis. Schell C, Frungieri MB, Albrecht M, Gonzalez-Calvar SI, Köhn FM, Calandra RS, Mayerhofer A. Anatomisches Institut am Biederstein, Ludwig-Maximilians-Universität, Munich, Germany. As shown recently, cyclooxygenase 2 (COX2), the inducible key enzyme for the prostaglandin (PG) biosynthetic pathway, is abundantly present in interstitial cells of testes of men suffering from different forms of impaired spermatogenesis and sub- or infertility, but it is absent in human testes with normal spermatogenesis. Although the spectrum of the downstream products of COX2 action in testis, namely PGs, and their effects are not known, our results show that Prostaglandin D2 (PGD2) likely plays a role. We describe (a) PGD2 synthetases, as well as receptors for PGD2 (DP) in testicular interstitial cells of men suffering from spermatogenic damage and infertility, and report that (b) PGD2 is produced by and can affect Leydig cells of an animal model, which expresses testicular COX2 and DP. PMID: 17307169 Anim. Reprod., v.4, n.3/4, p.63-69, Jul./Dec. 2007 Prostaglandins (PGs) are derived from arachidonic acid by action of the cyclooxygenase (COX) isoenzymes COX1 and COX2. The development of mice deficient in COX1 and/or COX2 has shown that COX2–null female mice are infertile. In contrast, male fertility is not affected in COX1- or COX2-mutant mice from knock-out experiments, suggesting that PGs may not be important for the functioning of the testis. This early general view is being challenged by recent observations. We have reported that whereas COX2 is not detected in normal human testes, it is expressed in testicular biopsies of men with impaired spermatogenesis and male infertility. Moreover, COX is up-regulated in testicular cancer, and COX2 _expression_ is induced in Brown-Norway rat Leydig cells during aging. Several reports describe actions of COX and PGs on steroid hormone production, _expression_ of PGs and their receptors in Sertoli cells, and inhibitory effects of some PGs on spermatogenesis and sperm counts. In brief, this review summarizes the results obtained in the last decades by our laboratory and other groups that point out the impact of COX and PGs in the regulation of testicular function and male fertility. FULL TEXT: http://www.cbra.org.br/pages/publicacoes/animalreproduction/issues/do...

.  Besides - if testosterone is so important - why not risk direct supplementation or indirect supplementation (e.g., carnitine) instead? can you please expand this? and would carnitine increase only free testosterone or DHT too? Testosterone is a carnitine *transporter*.  It increases tissue levels of carnitine.  I think it's a compensation for the damage men are prone to because we have only one X chromosome.  Possibly it's an adaptation to compensate for the lower estrogen levels and the loss of antioxidant capacity this brings.

I think it's a compensation for the damage men are prone to because we have only one X chromosome.  Possibly it's an adaptation to compensate for the lower estrogen levels and the loss of antioxidant capacity this brings. So Kofi you are saying that higher estrogen levels boost antioxidant capacity?  Should I be happy with my adipose tissue producing higher levels of estrogen? Anyway in my original post I showed that there was a causal relationship between COX induction in testis and low T production. The benefits of COX-2 you were citing are unrelated to this topic. Can you tell what raises the COX in testis during aging?  If you like to keep the arachidonic acid in your body during aging it may be beneficial to inhibit COX or prevent its induction in this organ.  If we knew what causes its induction we could specifically and locally target it to prevent the youthful hormone decline with aging.  My best guess is the accumulating glycation damage triggers the immune response a part of which is COX-2 ... Taka

to keep the arachidonic acid in your body during aging it may be beneficial to inhibit COX or prevent its induction in this organ.  If we knew what causes its induction we could specifically and locally target it to prevent the youthful hormone decline with aging.  My best guess is the accumulating glycation damage triggers the immune response a part of which is COX-2 ... What happens if it's a compensation for an age-related breakdown in the blood-testis barrier and suddenly there's all these immune cells flooding in and no COX-2 around to deactivate them?  COX-2 does too many things to target. This seems like another variation on the let's take testosterone for life extension debate.  There's evidence for carnitine affecting lifespan but the data on testosterone is mixed at best.

 COX-2 does too many things to target. This seems like another variation on the let's take testosterone for life extension debate.  There's evidence for carnitine affecting lifespan but the data on testosterone is mixed at best. I guess this is because of its aromatization especially in older individuals, but wait, you said estrogen was protective ...  BTW there are synthetic T analogues resembling DHT which cannot aromatize and these may be safe replacement especially when applied in injectable form to spare the liver. Taka