Rapid Glucocorticoid Mediation of Suppressed Testosterone Biosynthesis in Male Mice Subjected to Immobilization Stress

Dong, Qiang; Salva, Antonio José Ramis; Sottas, Chantal M.; Niu, En‐Mei; Holmes, Michael; Hardy, Matthew P.

doi:10.1002/j.1939-4640.2004.tb03170.x

Cited by 124 publications

(81 citation statements)

References 65 publications

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“…The decrese in testosterone likely reflects the increase in corticosterone during chronic stress. This may be mediated by non-genomic mechanisms [Dong et al 2004] or genetic mechanisms through the inhibition of genes encoding testosterone biosynthetic enzymes [Payne and Sha 1991], such as 3b-hydroxysteroid dehydrogenase and 17a-hydroxylase/17-20-lyase [Hales and Payne 1989;Orr et al 1994]. Corticosterone also induces Leydig cell apoptosis [Chen et al 2012], resulting in a significant reduction in the secretion of testosterone [Hardy et al 2005] as confirmed by TUNEL.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress

Juárez-Rojas

García-Lorenzana²,

Martínez

et al. 2015

Systems Biology in Reproductive Medicine

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Testicular apoptosis is activated by stress, but it is not clear which signaling pathway is activated in response to stress. The aim of this study was to investigate whether intrinsic, extrinsic, or both apoptotic signaling pathways are activated by acute and chronic stress. Adult male rats were subjected to cold water immersion-induced stress for 1, 20, 40, and 50 consecutive days. The seminiferous tubules:apoptotic cell ratio was assayed on acute (1 day) and chronic (20, 40, 50 days) stress. Apoptotic markers, including cleaved-caspase 3 and 8, the pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were also determined after acute and chronic stress induction. Additionally, epididymal sperm quality was evaluated, as well as corticosterone and testosterone levels. An increase in tubule apoptotic cell count percentage after an hour of acute stress and during chronic stress induction was observed. The apoptotic cells rate per tubule increment was only detected one hour after acute stress, but not with chronic stress. Accordingly, there was an increase in Bax, cleaved caspase-8 and caspase-3 proapoptotic proteins with a decrease of anti-apoptotic Bcl-2 in both acutely and chronically stressed male testes. In addition, sperm count, viability, as well as total and progressive motility were low in chronically stressed males. Finally, the levels of corticosterone increased whereas testosterone levels decreased in chronically stressed males. Activation of the extrinsic apoptotic pathway was shown by cleaved caspase-8 increase whereas the intrinsic apoptotic pathway activation was determined by the increase of Bax, along with Bcl-2 decrease, making evident a cross-talk between these two pathways with the activation of caspase-3. These results suggest that both acute and chronic stress can potentially activate the intrinsic/extrinsic apoptosis pathways in testes. Chronic stress also reduces the quality of epididymal spermatozoa, possibly due to a decrease in testosterone.

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Section: Discussionmentioning

confidence: 99%

Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress

Juárez-Rojas

García-Lorenzana²,

Martínez

et al. 2015

Systems Biology in Reproductive Medicine

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“…Leydig cells were isolated as described in ref. 41. Brief ly, testes from adult mice were decapsulated and dispersed in a shaking water bath at 34°C for 10 min in 10 ml of Medium 199 (M-199) with 0.25 mg/ml collagenase D, 35 mU/ml Dispase II, and 6 g/ml DNase I.…”

Section: Methodsmentioning

confidence: 99%

Modulation of Leydig cell function by cyclic nucleotide phosphodiesterase 8A

Vasta

Shimizu‐Albergine

Beavo

2006

Proc. Natl. Acad. Sci. U.S.A.

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Leydig cells produce testosterone in the testes under the pulsatile control of pituitary luteinizing hormone (LH). cAMP is the intracellular messenger for LH action on steroidogenesis, and pharmacological evidence indicates that the response to LH can be modulated by cyclic nucleotide phosphodiesterases (PDEs). However the types and roles of the PDEs present in Leydig cells have not been fully defined. We report here that PDE8A is expressed in Leydig cells, and using PDE8A knockout mice we provide evidence that PDE8A is a key regulator of LH signaling and steroidogenesis. A 4-fold increase in the sensitivity to LH for testosterone production was detected in Leydig cells isolated from PDE8A knockout mice. In Leydig cells from wild-type mice, 3-isobutyl-1-methylxanthine, a compound that inhibits all cAMP PDEs except PDE8A, elicited only a small increase in the sensitivity of testosterone production to LH. However, in the PDE8-null mice, the effect of this inhibitor is much more pronounced. These observations indicate that PDE8A and at least one other PDE control the same or a complementary pool of cAMP that mediates LH-regulated steroidogenesis. Overall, these results suggest that pharmacological manipulation of PDE8A, alone or in combination with other PDEs present in Leydig cells, may be exploited to modulate testosterone synthesis and possibly to treat various conditions where the local levels of this androgen need to be altered.cAMP ͉ testosterone ͉ PDE8A ͉ testis ͉ steroidogenesis T he second messenger cAMP plays important roles in mediating the biological effects of a wide variety of first messengers. Increases in intracellular cAMP lead to activation of cAMP-dependent protein kinases, guanine nucleotide exchange factors, and cyclic nucleotide-gated channels, which in turn can regulate the activity of other signaling and metabolic pathways (1). cAMP signaling pathways are controlled through regulation of the synthesis of cAMP by adenylyl cyclases and degradation by phosphodiesterases (PDEs) (1, 2). The cyclic nucleotidePDEs are now recognized to form a superfamily of 11 different, but homologous, gene-families that all contain highly homologous catalytic domains near their C termini (3). PDE-catalyzed cyclic nucleotide degradation provides an important mechanism for regulating signaling. Indeed, the PDE component of cAMP pathways ensures the proper intensity and spatiotemporal distribution of the signal (4, 5), as illustrated by many studies on different endocrine tissues (6-8).Leydig cells are interstitial cells located adjacent to the seminiferous tubules in the testes. The best-established function of Leydig cells is to produce the androgen, testosterone, under the pulsatile control of pituitary luteinizing hormone (LH) (9). It has been demonstrated that cAMP is the major intracellular messenger for LH action on steroidogenesis and that most, if not all, of the signaling action of cAMP is due to cAMP-dependent protein kinase (PKA)-mediated effects on proteins regulating the steroid biosynthetic pathway (9...

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“…A rapid action of glucocorticoids on Leydig cell function was also demonstrated. A rapid (30-min) decline of testosterone production was seen in mouse Leydig cells when these cells were exposed to 1.44 µM corticosterone (CORT), indicating that a non-genomic mechanism of glucocorticoids in Leydig cells [28], since the genomic mechanism of glucocorticoids requires hours to register at the protein level [29]. CORT can inhibit cAMP formation in mouse Leydig cells within 15 min [28].…”

Section: Rapid Glucocorticoid Actions Via Membrane Receptorsmentioning

confidence: 99%

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Lian

Lin

et al. 2008

Steroids

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Stress-mediated elevations in circulating glucocorticoid levels lead to corresponding rapid declines in testosterone production by Leydig cells in the testis. In previous studies we have established that glucocorticoids act on Leydig cells directly, through the classic glucocorticoid receptor (GR), and that access to the GR is controlled prior to the GR by a metabolizing pathway mediated by the type 1 isoform of 11β-hydroxysteroid dehydrogenase (11βHSD1). This enzyme is bidirectional (with both oxidase and reductase activities) and in the rat testis is exclusively localized in Leydig cells where it is abundantly expressed and may catalyze the oxidative inactivation of glucocorticoids. The predominant reductase direction of 11βHSD1 activity in liver cells is determined by an enzyme, hexose-6-phosphate dehydrogenase (H6PDH), on the luminal side of the smooth endoplasmic reticulum (SER). Generation of the pyridine nucleotide cofactor NADPH by H6PDH stimulates the reductase direction of 11βHSD1 resulting in increased levels of active glucocorticoids in liver cells. Unlike liver cells, steroidogenic enzymes including 17β-hydroxysteroid dehydrogenase 3 (17βHSD3) forms the coupling with 11βHSD1. Thus the physiological concentrations of androstenedione serve as a substrate for 17βHSD3 utilizing NADPH to generate NADP+, which drives 11βHSD1 in Leydig cells primarily as an oxidase; thus eliminating the adverse effects of glucocorticoids on testosterone production. At the same time 11βHSD1 generates NADPH which promotes testosterone biosynthesis by stimulating 17βHSD3 in a cooperative cycle. This enzymatic coupling constitutes a rapid mechanism for modulating glucocorticoid control of testosterone biosynthesis. Under stress conditions, glucocorticoids also have rapid actions to suppress cAMP formation thus to lower testosterone production.

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Rapid Glucocorticoid Mediation of Suppressed Testosterone Biosynthesis in Male Mice Subjected to Immobilization Stress

Cited by 124 publications

References 65 publications

Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress

Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress

Modulation of Leydig cell function by cyclic nucleotide phosphodiesterase 8A

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

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