Rodent Glucocorticoid-Testosterone Interaction

Cross references:  Rodent 5-HT1R         Rodent 5-HT3R     
Rodent Serotonin & Aggression      Rodent Testosterone   
Testosterone Serotonin Interaction
     Rodent Nonapeptides            Vasopressin, Serotonin & Aggression   
Rodent Hormone-Nerve Interaction         Rodent Dominance Hierarchies 
   
 

Role of glucocorticoids in the stress-induced suppression of testicular steroidogenesis in adult male rats. (Goog)     
Only abstract available online.  I got the PDF through the library.   
from the abstract 
    "Immobilization (3 hr) reduced plasma testosterone (T) levels to 24% of control values but did not affect plasma LH levels. This reduction was partially reversed by in vivo injections of the antiglucocorticoid, RU486, prior to the stress session"    
    "Stressed rats had eightfold higher plasma corticosterone levels than controls, and RU486 had no effect on control or stress levels of corticosterone."    
    "Our results suggest that during stress increases in plasma levels of glucocorticoids in male rats act via glucocorticoid receptors on testicular interstitial cells to suppress the testicular response to gonadotropins, and that the decline of testosterone production during immobilization stress is in part mediated by a direct action of glucocorticoids on the testis." 
from the PDF 
    "Exposure to various stressors lowers plasma testosterone (T) levels in primates and rodents and reduces LH-stimulated T secretion. Restraint stress (3 hr) appears to inhibit T secretion by a mechanism that does not involve a reduction of circulating levels of LH since stress did not depress circulating LH levels or affect the conversion of cholesterol to pregnenolone (the primary site of action of LH) by rat testicular cells in vitro.
    The stress-induced disruption of T production appears to occur at a postreceptor site since stress did not affect the binding or affinity of testicular LH receptors but reduced the amount of T produced in response to CAMP stimulation. Evidence suggests that the site of the lesion in T production occurs at the 17a-hydroxylase and 17,20-desmolase steps in the testicular steroidogenic pathway."  


Stress-induced suppression of testicular function in the wild baboon: role of glucocorticoids.
Only abstract available online.  
from the abstract 
    "In an ongoing study of endocrine function in wild olive baboons living freely in Kenya, sustained social stress was associated with suppressed testosterone (T) concentrations in males. In the present report, the acute stressor of rapid capture and immobilization caused profound and rapid suppression of T concentrations in these individuals. Elevation of cortisol concentrations preceded, and was at least partially responsible for, the declining T concentrations"
     "These studies demonstrate acute stress-induced suppression of gonadal function in a population of primates living in their natural habitat. Furthermore, they implicate glucocorticoid actions mostly at the testes as possible underlying endocrine mechanisms for such regulation."


Subordination stress: behavioral, brain, and neuroendocrine correlates
(PubMed) 
Only abstract available online.   
    "
In mixed-sex rat groups consistent asymmetries in offensive and defensive behaviors of male dyads are associated with the development of dominance hierarchies. Subordinate males can be differentiated from dominants on the basis of both agonistic and non-agonistic behaviors, wound patterns, weight changes. Their behavior changes suggest chronic defensiveness and are also broadly isomorphic to many of the symptoms of depression

    "
Basal corticosterone (CORT) levels were sharply higher, and plasma testosterone (T) sharply lower, in subordinates compared to both dominants and controls

    "
Subordinates also appear to show widespread changes in serotonin systems, with increased 5-HIAA/5-HT ratios in a number of brain areas, and alterations of 5-HT1A receptor binding at some sites.

My comments
1.  This 1993 article is of particular interest because it records that high CORT levels are accompanied by both low T and high 5-HIAA/5-HT levels.  The implied opposite of this would be low CORT accompanied by high T and low 5-HIAA/5-HT levels, which is the endocrine profile found in adult humans labeled: 
"personality disordered", "criminal" and "impulsively aggressive".    See:  Human Cortisol, etc.   
2.  The other papers cited in this page provide an explanation for the relationship between CORT and T.  I have not yet found an explanation for the relationship between CORT and the 5-HIAA/5-HT ratio.  The page: 
  Testosterone Serotonin Interaction  was an attempt use T to explain the relationship between CORT and the 5-HIAA/5-HT ratio, but the attempt wasn't very successful.    


Rapid mechanisms of glucocorticoid signaling in the Leydig cell
(PubMed)
Full length HTML and PDF available online for free.  
    "
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 ... exclusively localized in Leydig cells where it is abundantly expressed and may catalyze the oxidative inactivation of glucocorticoids.

    "...
steroidogenic enzymes including 17β-hydroxysteroid dehydrogenase 3 (17βHSD3) form 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.
"   
My summary

1.  The enzyme
11βHSD1 is capable of oxidizing glucocorticoids and thus reducing their inhibition of testosterone production. 
2.  The enzyme
17βHSD3 both activates 11βHSD1 and promotes testosterone production. 
3.  In addition to their interaction with the GR, glucocorticoids also suppress T by another mechanism.  They suppress cAMP.  Presumably this is also moderated by
11βHSD1.  


Trends of Reproductive Hormones in Male Rats During Psychosocial Stress: Role of Glucocorticoid Metabolism in Behavioral Dominance
(PubMed) 
Full length HTML and PDF available online for free. 
    "I
t has been established that subordinate males have reduced serum testosterone (T) and higher corticosterone (CORT) relative to dominant and singly housed control males. ...
    We hypothesize that Leydig cells are protected from inhibition by CORT at basal concentrations through oxidative inactivation of glucocorticoid by 11β-hydroxysteroid dehydrogenase (11βHSD). However, Leydig cell steroidogenesis is inhibited when 11βHSD metabolizing capacity is exceeded. ...
    Serum CORT levels were higher in subordinate males compared to control at all three time points. In contrast, oxidative 11βHSD activity in Leydig cells of dominant males was higher relative to control and unchanged in subordinates. These results suggest the following:
    1) failure of Leydig cells of subordinate males to compensate for increased glucocorticoid action during stress, by increasing 11βHSD oxidative activity, potentiates stress-mediated reductions in T secretion; and
    2) an inhibition of the reproductive axis in subordinate males at the level of the pituitary.

My comment
It's a minor point, but  the article,  "
Rapid mechanisms ...", above, says that "11βHSD1 ... is ... exclusively localized in Leydig cells."  So what does the pituitary have to do with it?  


Stress hormone and male reproductive function. (PubMed) 
Only abstract available online.   
    "
Stress-induced increases in serum glucocorticoid concentrations inhibit testosterone-biosynthetic enzyme activity, leading to decreased rates of testosterone secretion. ...
    Access to glucocorticoid receptors in Leydig cells is modulated by oxidative inactivation of glucocorticoid by 11 beta-hydroxysteroid dehydrogenase (11 betaHSD). Under basal levels of glucocorticoid, sufficient levels of glucocorticoid metabolism occur and there is likely to be minimal binding of the glucocorticoid receptor.
    We have established that Leydig cells express type 1 11 betaHSD, an oxidoreductase, and type 2, a unidirectional oxidase. Generation of redox potential through synthesis of the enzyme cofactor NADPH, a byproduct of glucocorticoid metabolism by 11 betaHSD-1, may potentiate testosterone biosynthesis, as NADPH is the cofactor used by steroidogenic enzymes such as type 3 17beta-hydroxysteroid dehydrogenase.
    In this scenario, inhibition of steroidogenesis will only occur under stressful conditions when high input amounts of CORT exceed the capacity of oxidative inaction by 11 betaHSD.

 

Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro
(PubMed) 
Full length PDF available online for free.  
    "The glucocorticoid suppression of androgen biosynthesis in cultured
testicular cells is associated with decreases in cAMP formation, probably through interference with the gonadotropin stimulation of adenyl cyclase activity. Furthermore, glucocorticoids also affect androgen biosynthesis distal to cAMP formation by selectively inhibiting the reaction catalyzed by 1 7a-hydroxylase." 


Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system
(PubMed) 
Only abstract available online. 
    "
In a unique communal environment, the visible burrow system, male Long-Evans rats spontaneously segregated into unstressed dominant and stressed subordinate social relationships. Subordinate animals had elevated plasma corticosterone and diminished circulating testosterone levels relative to the dominant animals.


 
Role of cortisol in the ACTH-induced suppression of testicular steroidogenesis in guinea pigs. 
http://joe.endocrinology-journals.org/cgi/reprint/154/3/407 
Full length PDF available online for free.    Must download webpage to copy-and-paste. 
    "ACTH treatment of guinea pigs results in considerably elevated cortisol and strongly reduced testosterone plasma concentrations. The mechanism of cortisol action is independent of the LH plasma concentrations.  The in vitro experiments indicate that cortisol directly interacts with the Leydig cells"  

 
Direct inhibitory effect of glucocorticoids upon testicular luteinizing hormone receptor and steroidogenesis in vivo and in vitro. (PubMed) 
http://www.ncbi.nlm.nih.gov/pubmed/6262050 
Only abstract available online. 
    "
These results demonstrate the direct inhibitory effect of glucocorticoids on testicular LH receptor content and steroidogenesis, suggesting the adrenal glucocorticoids may regulate testis functions.

My comment
Since this article was published in 1981, the researchers did not have the benefit of more recently developed techniques.  The techniques they used were fairly indirect and open to question in that regard.   



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