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Center for Biomedical Research, Population Council and Department of Urology, Weill Medical College of Cornell University, New York, New York 10021
Address all correspondence and requests for reprints to: Matthew Hardy, Center for Biomedical Research, 1230 York Avenue, New York, New York 10021. E-mail: m-hardy{at}popcbr.rockefeller.edu.
It has been established that circulating levels of testosterone (T) decrease with age in both male rodents and men. Demonstration that declines in androgen levels result from specific age-related changes in the male reproductive system, and not secondarily from increased disease frequency associated with the aging process, was achieved by analyzing cohorts of healthy older men (1). Among rodents, the Brown Norway (BN) rat has proved to be an advantageous model for male reproductive aging because, compared with other strains, they are largely free of age-related ailments that adversely affect reproduction, such as pituitary adenomas and the excessive accumulation of body fat. As is the case with humans, BN males display a pronounced decline in Leydig cell steroidogenesis and reproductive function with increasing age. LH is the main tropic stimulus of T secretion in Leydig cells, and considerable attention has been given to determining whether diminished LH signaling is the proximate cause of the age-related decline in T production. Serum levels of LH do not decline significantly in older males, nor would this be expected, given that the negative feedback of androgen on the hypothalamus and pituitary is diminished (2). There is evidence of diminished LH pulse amplitude caused by lowered output of GnRH from hypothalamic neurons (3), but the primary site of the aging effect appears to be the Leydig cell’s ability to respond to LH with increased T production (4).
Chen et al. (5) have investigated LH signal transduction in BN Leydig cells previously (6) and report in this issue that LH-stimulated adenylate cyclase activity declines with aging. Administration of the diffusible cAMP analog dibutyryl cAMP restored levels of T production in BN Leydig cell cultured for 3 d in vitro, whereas treatment with LH was ineffective. These results demonstrate that the site at which aging causes decrements in LH signaling must be the LH receptor, the adenylate cyclase, or one of the guanine nucleotide binding (G) proteins, the inhibitory Gi or stimulatory Gs, that modulate adenylate cyclase activity. The involvement of G proteins was examined further by incubating Leydig cells with pertussis toxin, to inhibit Gi, or with cholera toxin, which stimulates Gs. Inhibition of Gi activity did not restore T production in old Leydig cells, whereas stimulation of Gs did. Interestingly, the amount of Gs protein in Leydig cell membrane fractions as measured by Western blot was unchanged during aging. This led the authors to propose that age-dependent changes in the cell membrane environment affect the conformation of the LH receptor, adenylate cyclase, and/or Gs such that decreased cAMP is formed subsequent to LH binding. Thus, it may be that the aging effect on Leydig cell steroidogenesis is not precipitated by a reduced abundance of the proteins involved in LH signal transduction but rather by diminished functional activity of these proteins. Although these results do not identify the underlying causes of the decreased functionality of the cAMP generation system in the aging Leydig cell, they provide the best guide to date on where the brake on steroidogenesis is applied.
The authors have proposed that cumulative damage to proteins mediated by oxygen free radicals may mediate the physical declines of aging (7). Enzymes that scavenge oxygen free radicals are not as highly expressed in aging Leydig cells (8), which are, therefore, increasingly vulnerable to oxidative damage. The authors propose that the damage may disrupt LH signaling in particular by changing the fluidity of the Leydig cell membrane, an effect seen in membranes of aged vascular endothelial cells (9). All of the atrophic responses in the steroidogenic machinery of aging Leydig cells downstream to LH signaling appear to conform to expectations for deficient gonadotropic stimulation, with one notable exception presented in Fig. 2B in Ref.5 . Treatment of aged Leydig cells with dibutyryl cAMP in vitro did not restore protein levels of the 17
-hydroxylase enzyme as it did in the case of the cholesterol side-chain cleavage enzyme.
Studies of the aging Leydig cell have focused on declines in T biosynthesis, but this may be only one side of the equation: it is possible that some of the decline in T levels is attributable to increased degradation of T (from aromatization) rather than a decrease in T production. This alternative hypothesis should be considered. In aging human males, a dramatic increase in the ratio of serum T to estradiol has been observed. The relative increase in estrogen levels could be directly affecting Leydig cells during aging. Expression levels of 17-hydroxylase are sharply suppressed by exposure to estrogen (10) and the levels of estradiol in circulation tend to be disproportionately higher in aging men (11). Whether the decline in the ratio of T to estradiol is as involved in male reproductive aging as the decline in T itself is another topic worthy of investigation.
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Received July 12, 2004.
Accepted for publication July 12, 2004.
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-hydroxylase/C17-20 lyase in the fetal rat testis is reduced by maternal exposure to exogenous estrogens. Endocrinology 137:1063–1070[Abstract]
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  E. Colon, F. Zaman, M. Axelson, O. Larsson, C. Carlsson-Skwirut, K. V. Svechnikov, and O. Soder Insulin-Like Growth Factor-I Is an Important Antiapoptotic Factor for Rat Leydig Cells during Postnatal Development Endocrinology, January 1, 2007; 148(1): 128 - 139. [Abstract] [Full Text] [PDF]
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