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Cyclooxygenase-2 and Reduced Steroidogenesis in the Aging Male

Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Barry R. Zirkin, Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, Maryland 21205.

In rodents, as in men, there is age-related decline in serum levels of testosterone. Cohort studies in men have dissociated decline in testosterone from disease (1). Age-related changes in testosterone have significant potential public implications, including decline in sexual and muscle function and bone density (2, 3). As yet, testosterone hormonal therapy is not available for men.

Among the many rodent strains that have been studied, Brown Norway rats have proven to be particularly advantageous because of their long life span and because they rarely develop the tumors and excessive fat that typify other strains. Thus, in the Brown Norway rat strain as in men, aging effects can be disassociated from disease. Previous studies of these rats have shown that reduced testosterone biosynthesis by the Leydig cells, rather than loss of Leydig cells, explains age-related reductions in testosterone production (4). It has been shown that LH, the primary trophic stimulator of testosterone production by Leydig cells, does not decline significantly with age, although as in men there is diminished LH pulse amplitude (5). As yet, the molecular mechanism(s) by which reductions in testosterone occur largely are uncertain. Recent studies suggest the integral involvement of reduced cAMP in this process (6), but how cAMP is reduced is not known.

LH and cAMP have been shown to stimulate arachidonic acid release from Leydig cells; cyclooxygenase is an enzyme involved in metabolizing arachidonic acid. Cyclooxygenase-2 (COX2) has been suggested to inhibit Leydig cell steroidogenesis, although only through correlational studies (7). Previous studies using cDNA analysis had demonstrated that COX2 mRNA levels were increased and testosterone production decreased in aged Leydig cells (8), but a cause-and-effect relationship between COX2 and aging had not been shown.

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, overexpression 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 overexpression or inhibition of COX2 on steroidogenesis both in vitro and in vivo.

Although the mechanism by which COX2 functions is not established, the data suggest that the overexpression of COX2 may result in a decreased sensitivity to cAMP stimulation and thus in reduced testosterone. In vivo, dietary supplementation with a selective COX2 inhibitor was shown to increase serum testosterone concentrations. The authors suggest that this might be due to increased cholesterol supply. Whatever the mechanism, the in vivo study suggests the possibility of delaying or overcoming the decrease in testosterone biosynthesis that typically accompanies male aging. This is a particularly exciting finding.

	Footnotes

 
Abbreviations: COX-2, Cyclooxygenase-2; StAR, steroidogenic acute regulatory protein.

Received August 2, 2005.

Accepted for publication August 3, 2005.

	References

Top References

 

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