The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Environmental and social stresses have deleterious effects on reproductive function in vertebrates. Global climate change, human disturbance and endocrine disruption from pollutants are increasingly likely to pose additional stresses that could have a major impact on human society. Nonetheless, some populations of vertebrates (from fish to mammals) are able to temporarily resist environmental and social stresses, and breed successfully. A classical trade-off of reproductive success for potential survival is involved. We define five examples. (i) Aged individuals with minimal future reproductive success that should attempt to breed despite potential acute stressors. (ii) Seasonal breeders when time for actual breeding is so short that acute stress should be resisted in favour of reproductive success. (iii) If both members of a breeding pair provide parental care, then loss of a mate should be compensated for by the remaining individual. (iv) Semelparous species in which there is only one breeding period followed by programmed death. (v) Species where, because of the transience of dominance status in a social group, individuals may only have a short window of opportunity for mating. We suggest four mechanisms underlying resistance of the gonadal axis to stress. (i) Blockade at the central nervous system level, i.e. an individual no longer perceives the perturbation as stressful. (ii) Blockade at the level of the hypothalamic-pituitary-adrenal axis (i.e. failure to increase secretion of glucocorticosteroids). (iii) Blockade at the level of the hypothalamic-pituitary-gonad axis (i.e. resistance of the reproductive system to the actions of glucocorticosteroids). (iv) Compensatory stimulation of the gonadal axis to counteract inhibitory glucocorticosteroid actions. Although these mechanisms are likely genetically determined, their expression may depend upon a complex interaction with environmental factors. Future research will provide valuable information on the biology of stress and how organisms cope. Such mechanisms would be particularly insightful as the spectre of global change continues to unfold.

Reproduction and resistance to stress: When and how

Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis.

The sublethal effects of high predation risk on both prey behavior and phys- iology may have long-term consequences for prey population dynamics. We tested the hypothesis that snowshoe hares during the population decline are chronically stressed be- cause of high predation risk whereas those during the population low are not, and that this has negative effects on both their physiology and demography. Snowshoe hares exhibit 10- yr population cycles; during declines, virtually every hare that dies is killed by a predator. We assessed the physiological responsiveness of the stress axis and of energy mobilization by subjecting hares during the population decline and low to a hormonal-challenge protocol. We monitored the population demography through live-trapping and assessed reproduction through a maternal-cage technique. During the 1990s' decline in the Yukon, Canada, hares were chronically stressed-as indicated by higher levels of free cortisol, reduced maximum corticosteroid-binding ca- pacity, reduced testosterone response, reduced index of body condition, reduced leucocyte counts, increased overwinter body-mass loss, and increased glucose mobilization, relative to hares during the population low. This evidence is consistent with the explanation that predation risk, not high hare density or poor nutritional condition, accounted for the chronic stress and for the marked deterioration of reproduction during the decline. Reproduction and indices of stress physiology did not improve until predation risk declined. These findings may also account for the lag in recovery of hare reproduction after predator densities have declined and thus may implicate the long-term consequences of predation risk on prey populations beyond the immediate effects of predators on prey behavior and physiology.

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The impact of predator-induced stress on the snowshoe hare cycle

In the adult castrated male rat, exposure to inescapable, intermittent electroshocks inhibited the pulsatile pattern of luteinizing hormone release and markedly lowered its plasma concentrations. The central administration of the corticotropin-releasing factor (CRF) antagonist alpha-helical ovine CRF residues 9 to 41 reversed the inhibitory action of stress. Neither its peripheral injection, nor the intraventricular injection of the inactive CRF analog des-Glu to Arg ovine CRF was effective. These results suggest that endogenous CRF may mediate some deleterious effects of noxious stimuli on reproduction.

https://science.sciencemag.org/content/sci/231/4738/607.full.pdf

Stress-induced inhibition of reproductive functions: role of endogenous corticotropin-releasing factor

The direct effects of glucocorticoids on testicular LH receptor content and steroidogenesis were studied in vivo and in vitro. Immature hypophysectomized rats were treated with varying doses of dexamethasone, corticosterone, or a synthetic progestin, 17,21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione (R5020). Some animals were also treated concomitantly with FSH to prevent the hypophysectomy-induced decrease in testis functions. At the end of 5 days of treatment, testicular LH/hCG receptor content was measured by [125I]hCG binding assay while steroidogenic responsiveness was measured by in vitro incubation of testes. Dexamethasone decreased testicular LH receptor in control and FSH-treated hypophysectomized rats in doses as low as 10 microgram/day, whereas corticosterone (10 microgram/day) decreased testicular LH receptor in the FSH-treated rats but had no effect in rats not treated with FSH. In contrast, R5020 had no effect on testicular LH receptor content. In vivo treatment of hypophysectomized rats with FSH increased both basal and hCG-stimulated production of androstanediol in vitro. In contrast, concomitant treatment with dexamethasone, but not R5020, decreased both basal and hCG-stimulated testicular androstanediol production. The direct effect of glucocorticoids on testicular steroidogenic potentials was also studied in primary culture of testicular cells obtained from adult hypophysectomized rats. Treatment of cultured testicular cells wtih hCG increased testosterone production. The addition of various natural and synthetic glucocorticoids, but not R5020, to hCG-treated cells decreased testosterone production in a dose- and time-related manner (triamcinolone greater than or equal to dexamethasone greater than cortisol greater than or equal to corticosterone). A 40% decrease in testosterone production was apparent at 6 h after addition of 10(-7) M dexamethasone to hCG-treated cells. These results demonstrate the direct inhibitory effect of glucocorticoids on testicular LH receptor content and steroidogenesis, suggesting the adrenal glucocorticoids may regulate testis functions.

Direct inhibitory effect of glucocorticoids upon testicular luteinizing hormone receptor and steroidogenesis in vivo and in vitro.

The mechanism whereby glucocorticoids directly inhibit gonadotropin-stimulated testosterone production was studied by using primary cultures of testicular cells from adult hypophysectomized rats. Testicular cells were maintained in serum-free media with hormone treatments administered on Day 8 and media collected 48 h later for steroid and cAMP measurement. Highly purified human chorionic gonadotropin (hCG) increased testosterone production relative to controls. Concomitant administration of either natural (cortisone greater than deoxycorticosterone = aldosterone) or synthetic (dexamethasone greater than or equal to prednisolone) corticosteroids inhibited hCG-stimulated testosterone production in a dose-dependent manner. Dexamethasone at 10(-7) M decreased testosterone production by approximately 50-60% and this inhibitory effect was reversible upon removal of the glucocorticoid. In the presence or absence of a phosphodiesterase inhibitor, dexamethasone decreased hCG-stimulated cAMP production by approximately 60%. Dexamethasone also decreased testosterone production induced by cholera toxin and (Bu)2 cAMP by 43 and 63%, respectively. The dexamethasone suppression of testosterone production was accompanied by marked decreases in androstenedione (80% decrease) and 17 alpha-hydroxyprogesterone (57%) production, with a lesser effect on progesterone production (28% decrease) and no effect on pregnenolone production. Exogenous progesterone and 17 alpha-hydroxyprogesterone augmented hCG-stimulated testosterone production. Dexamethasone reduced the conversion of exogenous progesterone to testosterone by 33% but did not affect the conversion of 17 alpha-hydroxyprogesterone to androstenedione and testosterone, suggesting a specific inhibition of 17 alpha-hydroxylase. These results suggest that glucocorticoids directly suppress Leydig cell steroidogenesis by decreasing gonadotropin stimulation of cAMP production and the activity of 17 alpha-hydroxylase.

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Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro.

The direct effect of gonadotropin-releasing hormone (GnRH) and its agonist on testicular LH receptor and steroidogenesis was studied in hypophysectomized immature and adult rats. Hypophysectomized rats were treated daily with varying doses of GnRH or [des-Gly10,D-Leu6(N alpha Me)Leu7, Pro9-NHEt]GnRH(a potent agonist). Some animals were also treated concomitantly with FSH, PRL, GH and/or LH to prevent the hypophysectomy-induced loss of testicular LH receptor and steroidogenic capacity. At the end of 5 days of treatment, testicular LH/hCG receptor concentration was measured by a [125I]-hCG-binding assay and steroidogenic responsiveness was determinded by in vitro incubations. GnRH and the GnRH agonist reduced testicular LH receptor in control and FSH-treated hypophysectomized immature rats. As little as 0.5 microgram agonist/day induced a greater than 40% decrease in the LH receptor content, whereas GnRH was less potent, with 50 micrograms/day inducing about a 50% decrease. The inhibitory effect of GnRH was shown to be the result of decreases in the concentration of LH receptor rather than changes in the receptor affinity (Kd = 1.1 X 10(-10)M). GnRH did not interfere with the [125I]hCG receptor assay. Treatment with PRL, GH, and FSH, alone or in various combinations, increased the testicular LH receptor content. The stimulatory effect of these pituitary hormones was depressed by concomitant treatment with the GnRH agonist. Similar inhibitory effects of GnRH and the agonist on testicular LH receptor were demonstrated in adult hypophysectomized rats. In vitro studies demonstrated that treatment with the GnRH agonist in vivo inhibited both basal and hCG-stimulated androgen production in FSH-primed immature hypophysectomized rats. Associated with decreases in androgens (testosterone and androstenedione) and reduced androgens (dihydrotestosterone, androstanediol, and androsterone), there was marked suppression of 17 alpha-hydroxylated precursors and C-21 steroid intermediates in animals treated with the GnRH agonist, thus suggesting that the inhibitory effect of the GnRH agonist was associated with possible defects in 17 alpha-hydroxylase and side-chain cleavage enzymes. Likewise, treatment with the GnRH agonist inhibited in vitro testicular steroidogenic responses in adult hypopysectomized rats. These results demonstrate the extrapituitary inhibitory effect of GnRH on testicular LH receptor content and Leydig cell steroidogenesis in immature and adult hypophysectomized rats.

Gonadotropin-releasing hormone and its agonist inhibit testicular luteinizing hormone receptor and steroidogenesis in immature and adult hypophysectomized rats

The direct effects of GnRH and its agonistic and antagonistic analogs upon testicular androgen biosynthesis were studied in primary cultures of testicular cells obtained from adult hypophysectomized rats. Treatment of cultured cells with hCG (10 ng/ml) substantially increased testosterone production, while concomitant addition of GnRH or its agonist [des-Gly10, D-Ser(TBu)6,Pro9NHEt-GnRH] decreased hCG-stimulated testosterone production in a dose-related manner with ED50 values of 1.2 × 10-9 and 4.5 × 10-11 M, respectively. Treatment with 10-6 M of either a GnRH partial peptide or a cyclic GnRH analog did not affect hCG action; however, the addition of a GnRH antagonist ([Ac-D-Phe1,D-p-Cl-Phe2,D-Trp3,6]GnRH) together with hCG and GnRH blocked the GnRH-induced decrease in testosterone production, with a half-maximal inhibitory dose ratio (antagonist to GnRH) of 0.15. The stimulatory effect of hCG became apparent by 8 h of incubation; no hCG effect was seen at this time in the presence of GnRH. Treatment wit...

Mechanism of the Direct Action of Gonadotropin-Releasing Hormone and Its Antagonist on Androgen Biosynthesis by Cultured Rat Testicular Cells*

The mechanism whereby glucocorticoids directly inhibit gonadotropin-stimulated testosterone production was studied by using primary cultures of testicular cells from adult hypophysectomized rats. Testicular cells were maintained in serum-free media with hormone treatments administered on Day 8 and media collected 48 h later for steroid and cAMP measurement. Highly purified human chorionic gonadotropin (hCG) increased testosterone production relative to controls. Concomitant administration of either natural (cortisone > deoxycorticosterone=aldosterone) or synthetic (dexamethasone �. prednisolone) corticosteroids inhibited hCG-stimulated testosterone production in a dose-dependent manner. Dexarnethasone at 10’M decreased testosterone production by approximately 50-60% and this inhibitory effect was reversible upon removal of the glucocorticoid. In the presence or absence of a phosphodiesterase inhibitor, dexamethasone decreased hCG-stimulated cAMP production by approximately 60%. Dexamethasone also decreased testosterone production induced by cholera toxin and (Bu), cAMP by 43 and 63%, respectively. The dexamethasone suppression of testosterone production was accompanied by marked decreases in androstenedione (80% decrease) and 17a-hydroxyprogesterone (57%) production, with a lesser effect on progesterone production (28% decrease) and no effect on pregnenolone production. Exogenous progesterone and 1 7a-hydroxyprogesterone augmented hCG-stimulated testosterone production. Dexamethasone reduced the conversion of exogenous progesterone to testosterone by 33% but did not affect the conversion of 17a-hydroxyprogesterone to androstenedione and testosterone, suggesting a specific inhibition of 17n-hydroxylase. These results suggest that glucocorticoids directly suppress Leydig cell steroidogenesis by decreasing gonadotropin stimulation of cAMP production and the activity of 17o-hydroxylase.

Thomas H. Bambino

Papers

Direct inhibitory effect of glucocorticoids upon testicular luteinizing hormone receptor and steroidogenesis in vivo and in vitro.

Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro.

Gonadotropin-releasing hormone and its agonist inhibit testicular luteinizing hormone receptor and steroidogenesis in immature and adult hypophysectomized rats

Mechanism of the Direct Action of Gonadotropin-Releasing Hormone and Its Antagonist on Androgen Biosynthesis by Cultured Rat Testicular Cells*

of Testicular Androgen Biosynthesis In Vitro