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Regulation of Leydig Cell Steroidogenic Function During Aging¹

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION LEYDIG CELL AGING REFERENCES

 
This article summarizes a talk on Leydig cell aging presented at the 1999 Annual Meeting of the Society for the Study of Reproduction. In the Brown Norway rat, serum testosterone levels decrease with aging, accompanied by increases in serum FSH. The capacity of Leydig cells to produce testosterone is higher in young than in old rats. Binding studies with hCG revealed reduced receptor number in old vs. young Leydig cells. In response to incubation with LH, cAMP production was found to be reduced in old vs. young Leydig cells, indicating that signal tranduction mechanisms in the old cells are affected by aging. Steroidogenic acute regulatory protein and mRNA levels are reduced in old Leydig cells, suggesting that there may be deficits in the transport of cholesterol to the inner mitochondrial membrane of aged cells. The activity of P450 side-chain cleavage enzyme is reduced in old vs. young cells, as are the activities of each of 3ß-hydroxysteroid dehydrogenase, 17-hydroxylase/C17–20 lyase, and 17-ketosteroid reductase. Serum LH levels do not differ between young and old rats, and the administration of LH failed to induce old Leydig cells to produce high (young) testosterone levels, suggesting that the cause of age-related reductions in steroidogenesis is not LH deficits. We hypothesized that reactive oxygen, produced as a by-product of steroidogenesis itself, might be responsible for age-related reductions in testosterone production by the Leydig cells. Consistent with this, long-term suppression of steroidogenesis was found to prevent or delay the reduced steroidogenesis that accompanies Leydig cell aging. A possible explanation of this finding is that long-term suppression of steroidogenesis prevents free radical damage to the cells by suppressing the production of the reactive oxygen species that are a by-product of steroidogenesis itself.

LH, male reproductive tract, testes, testosterone

	INTRODUCTION

TOP ABSTRACT INTRODUCTION LEYDIG CELL AGING REFERENCES

 
This article summarizes a talk on Leydig cell aging presented by Dr. Zirkin at the 1999 Annual Meeting of the Society for the Study of Reproduction. The talk was part of a minisymposium, Neuroendocrinology of Aging, that was sponsored by the Mahesh Neuroendocrine Program Fund. The article, therefore, is not meant to be a comprehensive review of the literature on Leydig cell aging. Indeed, the literature citations are often to review articles rather than to the original literature.

Leydig cells are responsible for testosterone production in the mammalian testis. Testosterone production depends upon stimulation of these cells by LH that is secreted in pulses into the peripheral circulation by the pituitary gland in response to GnRH from the hypothalamus. Testosterone and its aromatized product, estradiol, then feed back to the hypothalamus and pituitary to suppress transiently LH and thus testosterone production. In response to reduced testosterone, GnRH and LH are again produced. This negative feedback cycle results in pulsatile secretion of LH followed by pulsatile production of testosterone [1, 2].

The administration of exogenous testosterone to rats similarly is able to suppress endogenous testosterone production by the Leydig cells via its suppression of LH [3]. If exogenous testosterone is administered continuously, as it is when its administration is via Silastic implants, LH remains suppressed and Leydig cell testosterone production is severely reduced [3, 4]. In many respects, the effects of experimental suppression of LH on Leydig cell structure and function are reminiscent of the effects of aging on these cells (please see below). A major difference, however, is that whereas experimental suppression of Leydig cell steroidogenesis in young rats is fully reversible by treating the rats or isolated Leydig cells with LH, the reduced steroidogenesis that characterizes aged Leydig cells is not reversible with LH. Indeed, as will be discussed below, it is unlikely that deficits of the hypothalamic-pituitary axis are primarily responsible for age-related changes in steroidogenesis.

	LEYDIG CELL AGING

TOP ABSTRACT INTRODUCTION LEYDIG CELL AGING REFERENCES

 
Background

During the life of the human male, decreases in serum testosterone typically begin in the fifth decade [5] (for review please see Chen et al. [6]). In the human, such decreases are accompanied by increased serum levels of FSH and either increased or unchanging levels of LH [7]. These observations, though they do not rule out age-related deficits of the hypothalamic-pituitary axis during human aging, suggest a primary testicular deficit. Our interest has been in understanding the mechanisms by which deficits in serum testosterone occur in the human. To this end, we chose to study aging of Leydig cells in the Brown Norway rat as a model for the human [6, 8, 9]. In this strain, as in the human and also other rat strains, serum testosterone levels decrease with age (Fig. 1). In contrast to most other rat strains, however, age-related decreases in serum testosterone are accompanied by increases in serum FSH (Fig. 2) and unchanged serum LH [10, 11], suggesting that, as in humans, reduced testosterone results at least in part from a primary testicular deficit. Moreover, the Brown Norway strain is particularly long-lived and healthy [12]; the rats typically die of heart disease at about 40 mo of age, gain little weight as they age, and rarely incur testicular, pituitary, or other tumors. Consequently, it is possible with this strain to distinguish between age- and health-related deficits.

View larger version (39K): [in this window] [in a new window]   FIG. 1. Testosterone concentration in the serum of young (3- to 5-mo-old) and old (18- to 21-mo-old) Brown Norway rats. A significant, age-related decrease in serum testosterone level is seen

View larger version (44K): [in this window] [in a new window]   FIG. 2. Follicle-stimulating hormone concentration in the serum of young and old Brown Norway rats. Age-related increase in serum FSH is seen

In initial studies, we demonstrated age-related reductions in the capacity of the testes of Brown Norway rats to produce testosterone [12]. An obvious possible explanation for such reductions was decreased numbers of Leydig cells with age. We examined this possibility by conducting stereological analyses to assess Leydig cell number in the testes of young and old rats [10]. No differences were observed, suggesting that there must be deficits in the capacity of individual old Leydig cells to produce testosterone. To test this, Leydig cells were isolated by centrifugal elutriation and Percoll density gradient centrifugation and incubated in vitro with maximally stimulating LH [10, 11]. As illustrated in Figure 3, we found that the capacity of young Leydig cells to produce testosterone indeed was higher than that of the old cells.

View larger version (41K): [in this window] [in a new window]   FIG. 3. Testosterone production by Leydig cells isolated from young and old Brown Norway rats. The cells were incubated with maximally stimulating LH for 3 h. The capacity of the young cells to produce testosterone was significantly higher than that of the old cells

With this information as background, we have pursued two major questions: 1) What changes occur in the Leydig cells with aging that explain the reduced ability of old cells to produce testosterone? 2) By what mechanisms do Leydig cells lose their ability to produce testosterone over time?

What Changes Occur in the Leydig Cells with Aging?

In its acute actions on Leydig cells, LH binds to receptors on the Leydig cell plasma membrane, thereby initiating a cascade of events that includes activation of adenylate cyclase, increased intracellular cAMP formation, translocation of cholesterol into the mitochondria, association of cholesterol with the P450 side-chain cleavage enzyme (P450_scc), production of pregnenolone from cholesterol in the mitochondria, translocation of pregnenolone from the mitochondria to the smooth endoplasmic reticulum, and conversion of pregnenolone to testosterone via a series of reactions in the smooth endoplasmic reticulum (Fig. 4). The rate-limiting step in this process is now considered to be the translocation of cholesterol from the outer to the inner mitochondrial membrane [13, 14]. Although controversy remains about how this translocation is accomplished, it is clear that steroidogenic acute regulatory protein (StAR), a cycloheximide-sensitive 30-kDa mitochondrial protein that is synthesized acutely in response to LH or cAMP, is integrally involved [13, 14]. Other molecules also have been implicated in cholesterol transport from intracellular stores to the inner mitochondrial membrane and with loading of P450_scc with cholesterol, most notably mitochondrial peripheral benzodiazepine receptor (PBR) [15, 16]. Alteration in the mitochondrial and/or smooth endoplasmic reticulum membranes of the Leydig cell or indeed perturbation of any step in the sequence from LH binding to its receptor through the steroidogenic reactions in the smooth endoplasmic reticulum could potentially account for the observed age-related reductions in steroidogenesis.

View larger version (51K): [in this window] [in a new window]   FIG. 4. Illustration of the molecular events involved in testosterone production by Leydig cells. Luteinizing hormone binds to receptors on the Leydig cell plasma membrane, thereby initiating a cascade of events that includes increased intracellular cAMP formation, translocation of cholesterol into the mitochondria (with the involvement of steroidogenic acute regulatory protein and peripheral benzodiazepine receptor), association of cholesterol with P450scc, production of pregnenolone from cholesterol in the mitochondria, translocation of pregnenolone from the mitochondria to the smooth endoplasmic reticulum, and conversion of pregnenolone to testosterone via a series of reactions in the smooth endoplasmic reticulum

LH binding to its receptor Binding studies with hCG have revealed reduced receptor number in old vs. young Leydig cells (our unpublished observations). Whether or not the occurrence of fewer binding sites has functional significance, however, is uncertain.

cAMP production We reported previously that cAMP production by young and old Leydig cells did not differ when cAMP production was measured 3 h after the cells were incubated with maximally stimulating LH [8]. However, in response to incubation with maximally stimulating LH for 0–20 min, a time period that is relevant to testosterone production, cAMP production was found to be reduced in old vs. young Leydig cells (our unpublished observations). Thus, signal tranduction mechanisms in the old cells are affected by aging. This may or may not result from reduced LH receptor numbers.

Cholesterol transport The StAR protein and mRNA levels are reduced in old Leydig cells (our unpublished observations). This suggests, but it does not prove, that there may be deficits in the transport of cholesterol to the inner mitochondrial membrane of aged cells.

Cholesterol side-chain cleavage enzyme (P450_scc) The activity, protein level, and mRNA level of this crticial mitochondrial enzyme are reduced in old vs. young cells [17]. The deficit in P450_scc, by itself, could account for the reduced steroidogenesis that characterizes the old cells.

Steroidogenic enzymes of the smooth endoplasmic reticulum Once formed in the mitochondria, pregnenolone moves to the smooth endoplasmic reticulum where, after binding to 3ß-hydroxysteroid dehydrogenase, it is converted to progesterone. Progesterone is then acted on by 17-hydroxylase/C17–20 lyase to produce 17-hydroxyprogesterone and then androstenedione. Androstenedione then is converted to testosterone by 17-ketosteroid reductase. We have shown that the activities of each of these enzymatic reactions is reduced in old vs. young Leydig cells [17].

In sum, we have found that each of the steps in the sequence from LH binding to its receptor through the steroidogenic reactions in the smooth endoplasmic reticulum is altered with the aging of the Leydig cell. It seems likely that, among these changes, there must be a critical, initiating event that ultimately leads to the rest. At this juncture, we do not know whether this is true, and if it is, which of the changes in fact is the initiator.

By What Mechanisms Do Leydig Cells Lose Steroidogenic Function with Aging?

The reduced ability of aging Leydig cells to produce testosterone might be caused by events occurring outside these cells that impinge upon them or by events that occur over time within the Leydig cells themselves. If the former pertained, the most likely suspect would be age-related changes in LH.

LH and aging Serum LH levels do not differ between young and old rats [10, 11]. However, age-related changes in GnRH gene expression and content in the hypothalamus, and in the amplitude of LH pulses, have been shown to occur [18–22]. Such changes could have consequences for Leydig cell function. Therefore, the observation that there are no age-related differences in average LH concentration in the serum is not sufficient to rule out a primary role for the hypothalamus-pituitary axis in Leydig cell aging. With this in mind, we reasoned that if, indeed, LH deficits of one kind or another caused reduced Leydig cell testosterone production, long-term exposure of young and old Leydig cells to equivalent concentrations of LH, delivered in the same way, might increase the ability of old Leydig cells to produce testosterone to the high levels of young cells. To test this, we [23] suppressed endogenous testosterone production in young and old rats by administering LH-suppressive testosterone- and estradiol-filled Silastic capsules for 5 days, and, at the same time, we administered LH to these rats via miniosmotic pumps programmed to provide LH in equivalent concentrations and pulses. As shown in Figure 5, when LH was administered at 24–36 µg/day, testosterone production by the young Leydig cells was maintained at or above control levels. In contrast, old Leydig cells could not be induced to produce high (young) testosterone levels at any LH dose.

View larger version (31K): [in this window] [in a new window]   FIG. 5. Testosterone production by Leydig cells isolated from testes of young (light cross-hatched bars) and old (dark cross-hatched bars) rats and incubated with maximally stimulating LH. Five days before the cells were isolated, rats received LH-suppressive testosterone/estradiol-containing Silastic capsules plus miniosmotic pumps programmed to deliver 0, 12, 24, or 35 µg LH/day in pulses; control rats received empty Silastic capsules plus miniosmotic pumps containing vehicle. When LH was administered at 24–36 µg/day, testosterone production by the young Leydig cells was maintained at or above control levels. In contrast, old Leydig cells could not be induced to produce high (young) testosterone levels at any LH dose

Even this approach has caveats, however. Although the young and old rats received equivalent subcutaneous doses of LH, the LH concentration within the testes of these rats, and thus the LH concentration to which Leydig cells were exposed, might have differed. This issue is receiving further attention at present by two approaches: First, we are determining whether the administration of LH directly to the testes will increase the ability of old Leydig cells to produce testosterone to the level of the young; and second, we are determining whether long-term, in vitro culture of young and old Leydig cells with LH will restore the testosterone-producing ability of the old cells. Taken together, the results of these studies will determine whether or not the reduced testosterone production that characterizes old Leydig cells can be explained by age-related changes, of one kind or another, in LH. Our prediction is that this will not prove to be the case.

Steroidogenesis, reactive oxygen, and aging Numerous studies have examined the deterioration of cell function during aging in relationship to damage to protein, DNA, and/or phospholipid that results from the exposure of cells to reactive oxygen. Accumulated free radical damage seemed to us to be a plausible explanation for age-related functional deficits in Leydig cells for two reasons: first, reactive oxygen species have been shown to be produced during steroidogenesis; and second, reactive oxygen has been shown to damage critical components of the steroidogenic pathway [24, 25]. We hypothesized that reactive oxygen, produced as a by-product of steroidogenesis itself, might be responsible for age-related reductions in testosterone production by the Leydig cells. We predicted that if this were the case, the chronic suppression of steroidogenesis should diminish or prevent age-related reductions in steroidogenesis. How might this prediction be tested? As indicated earlier, we knew from previous studies that the administration of contraceptive doses of testosterone to rats via Silastic implants, functioning through a negative feedback mechanism on the hypothalamus and pituitary, suppresses LH; that this, in turn suppresses Leydig cell testosterone production; and that removal of the implants restores Leydig cell steroidogenesis [3]. This provided an experimental means by which to suppress Leydig cell steroidogenesis reversibly, in effect placing the cells in a state of steroidogenic hibernation until removal of the implants. Using this approach, we examined the possibility that long-term suppression of steroidogenesis might prevent or delay the reduced steroidogenesis that accompanies Leydig cell aging [26]. Rats of 3 (young) or 13 (middle-aged) mo of age received the LH-suppressive implants. Eight months later, when the rats were 11 and 21 mo of age, respectively, the implants were removed, thus restoring LH. Two months after that, when the rats were 13 and 23 mo of age, respectively, Leydig cells were isolated from the testes and examined for their ability to produce testosterone (Fig. 6). Leydig cells from 3- and 13-mo-old rats produce equivalent, high levels of testosterone. As expected, the testosterone implants resulted in suppression of steroidogenesis. Two months after the implants were removed, the Leydig cells from both the middle-aged (13-mo-old) and old (23-mo-old) rats were found to produce testosterone at the high levels of young Leydig cells. Thus, by suppressing steroidogenesis long term, the reductions in Leydig cell testosterone production that invariably accompany aging did not occur.

View larger version (48K): [in this window] [in a new window]   FIG. 6. Testosterone production by Leydig cells isolated from the testes of 13-mo-old (light cross-hatched bars) and 23-mo-old (dark cross-hatched bars) rats. In this study, 3- or 13-mo-old rats received LH-suppressive implants. Eight months later, when the rats were 11 and 21 mo of age, respectively, the implants were removed, thus restoring LH. Two months after that, when the rats were 13 and 23 mo of age, respectively, Leydig cells were isolated from the testes and examined for their ability to produce testosterone (+T/-T). Control rats received empty implants. Testosterone production was significantly greater in Leydig cells from 13-mo-old than the 23-mo-old control rats. In rats that had received steroid-filled implants, 2 mo after the implants were removed, when the rats were 13 and 23 mo of age, the Leydig cells produced equivalent amounts of testosterone, in both cases at the high levels of young Leydig cells. Thus, by suppressing steroidogenesis long term, the reductions in Leydig cell testosterone production that invariably accompany aging did not occur

The mechanism by which suppression of steroidogenesis results in the delay or prevention of age-related reductions in the ability of Leydig cells to produce testosterone remains uncertain. An attractive possibility, of course, is that long-term suppression of steroidogenesis prevents free radical damage to the cells by suppressing the production of the reactive oxygen species that are a by-product of steroidogenesis itself. However, as yet there is no direct evidence showing that reactive oxygen, whether derived from steroidogenesis or elsewhere, causes damage to Leydig cells, and whether such damage, if it occurs, might be involved in Leydig cell aging. These issues are under active investigation at present.

	FOOTNOTES

 
First decision: 22 March 2000.

¹ This work was supported by a grant from the National Institute on Aging (AG08321).

² Correspondence. FAX: 410 614 2356; brzirkin{at}jhsph.edu

Accepted: March 22, 2000.

Received: February 29, 2000.

	REFERENCES

TOP ABSTRACT INTRODUCTION LEYDIG CELL AGING REFERENCES

 

1. Bremner WJ, Bagatell CJ, Christensen RB, Matsumoto AM. Neuroendocrine aspects of the control of gonadotropin secretion in men. In: Whitcomb RW, Zirkin BR (eds.), Understanding Male Infertility: Basic and Clinical Aspects. New York: Raven Press; 1993: 29–41
2. Ellis GB, Desjardins C, Fraser HM. Control of pulsatile LH release in male rats. Neuroendocrinology 1983; 37:177–183[Medline]
3. Ewing LL, Zirkin BR. Leydig cell structure and steroidogenic function. Recent Prog Horm Res 1983; 39:599–635
4. Keeney DS, Mendis-Handagama SMLC, Zirkin BR, Ewing LL. Effect of long term deprivation of luteinizing hormone on Leydig cell volume, Leydig cell number, and steroidogenic capacity of the rat testis. Endocrinology 1988; 123:2906–2915[Abstract/Free Full Text]
5. Belanger A, Candas B, Dupont A, Cusan L, Diamond P, Gomez L, Labrie F. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J Clin Endocrinol Metab 1994; 79:1086–1090[Abstract]
6. Chen H, Luo L, Zirkin BR. Leydig cell structure and function during aging. In: Payne AH, Hardy MP, Russell LD (eds.), The Leydig Cell. Illinois: Cache River Press; 1996: 222–230
7. Zwart AD, Urban RJ, Odell WD, Veldhuis JD. Contrasts in the gonadotropin-releasing hormone dose-response relationships for luteinizing hormone, follicle-stimulating hormone and alpha-subunit release in young versus older men: appraisal with high-specificity immuno-radiometric assay and deconvolution analysis. Eur J Endocrinol 1996; 135:399–406[Abstract/Free Full Text]
8. Zirkin BR, Chen H, Luo L. Leydig cell steroidogenesis in aging rats. Exp Gerontol 1997; 32:529–537[CrossRef][Medline]
9. Chen H, Luo L, Zirkin BR. Testicular aging: Leydig cells and spermatogenesis. In: Zirkin BR (ed.), Germ Cell Development, Division, Disruption and Death. New York: Springer-Verlag; 1998: 130–139
10. Chen H, Hardy MP, Huhtaniemi I, Zirkin BR. Age-related decreased Leydig cell testosterone production in the Brown Norway rat. J Androl 1994; 15:551–557[Abstract/Free Full Text]
11. Chen H, Huhtaniemi I, Zirkin BR. Depletion and repopulation of Leydig cells in the testes of aging Brown Norway rats. Endocrinology 1996; 137:3447–3452[Abstract]
12. Zirkin BR, Santulli R, Strandberg JD, Wright WW, Ewing LL. Testicular steroidogenesis in the aging Brown Norway rat. J Androl 1993; 14:119–124
13. Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996; 17:221–244[Abstract/Free Full Text]
14. Stocco DM. Acute regulation of Leydig cell steroidogenesis. In: Payne AH, Hardy MP, Russell LD (eds.), The Leydig Cell. Illinois: Cache River Press; 1996: 241–257
15. Papadopoulos V, Mukhin AG, Costa E, Krueger KE. The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis. J Biol Chem 1990; 265:3772–3779[Abstract/Free Full Text]
16. Culty M, Li H, Boujrad N, Amri H, Vidic B, Bernassau JM, Reversat JL, Papadopoulos V. In vitro studies on the role of the peripheral-type benzodiazepine receptor in steroidogenesis. J Steroid Biochem Mol Biol 1999; 69:123–130[CrossRef][Medline]
17. Luo L, Chen H, Zirkin BR. Are Leydig cell steroidogenic enzymes differentially regulated with aging? J Androl 1996; 17:509–515
18. Wang C, Leung A, Sinha Hikim AP. Reproductive aging in the male Brown-Norway rat: a model for the human. Endocrinology 1993; 133:2773–2781[Abstract/Free Full Text]
19. Bonavera JJ, Swerdloff RS, Leung A, Lue YH, Baravarian S, Superlano L, Sinha Hikim AP, Wang C. In the Brown-Norway male rat, reproductive aging is associated with decreased LH pulse amplitude and area. J Androl 1997; 18:359–365[Abstract/Free Full Text]
20. Bonavera JJ, Swerdloff RS, Sinha Hikim AP, Yan HL, Wang C. Aging results in attenuated gonadotropin releasing hormone-luteinizing hormone axis responsiveness to glutamate receptor agonist N-methyl-D-aspartate. J Neuroendocrinol 1998; 10:93–99[CrossRef][Medline]
21. Gruenwald DA, Naai MA, Hess DL, Matsumoto AM. The Brown Norway rat as a model for male reproductive aging: evidence for both primary and secondary testicular failure. J Gerontol Biol Sci 1994; 49:B42–B50
22. Gruenewald DA, Naai MA, Marck BT, Matsumoto AM. Age-related decrease in hypothalamic gonadotropin-releasing hormone (GnRH) gene expression, but not pituitary responsiveness to GnRH, in the male Brown Norway rat. J Androl 2000; 21:72–84[Abstract]
23. Grzywacz FW, Chen H, Allegretti J, Zirkin BR. Does age-associated reduced Leydig cell testosterone production in Brown Norway rats result from under-stimulation by luteinizing hormone? J Androl 1998; 19:625–630
24. Quinn PG, Payne AH. Steroid product-induced, oxygen-mediated damage of microsomal cytochrome P-450 enzymes in Leydig cell cultures. Relationship to desensitization. J Biol Chem 1985; 260:2092–2099[Abstract/Free Full Text]
25. Peltola V, Huhtaniemi I, Metsa-Ketela T, Ahotupa M. Induction of lipid peroxidation during steroidogenesis in the rat testis. Endocrinology 1996; 137:105–112[Abstract]
26. Chen H, Zirkin BR. Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging. Proc Natl Acad Sci U S A 1999; 96:14877–14881[Abstract/Free Full Text]

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