Glucocorticoids

Cross references: 
Hormones in General      Steroids        Intracellular Receptors    
Steroid Actions         Lamprey Cortisol, etc.           Shark Hormones          
Teleost Cortisol, etc.      Human Endocrinology in General           
Human Cortisol, etc.      


Glucocorticoid (Wiki) 
    "Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure."     
    "
Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, corticosteroid refers to both glucocorticoids and mineralocorticoids...

   
"Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Glucocorticoid receptors are found in the cells of almost all vertebrate tissues.


Cortisol (Wiki) 
    "Cortisol (hydrocortisone) is a steroid hormone, or glucocorticoid, produced by the adrenal gland.[1] It is released in response to stress and a low level of blood glucocorticoids.  Its primary functions are to increase blood sugar through gluconeogenesis, suppress the immune system, and aid in fat, protein and carbohydrate metabolism.
    "
Cortisol is produced by the adrenal gland in the zona fasciculata, the second of three layers comprising the outer adrenal cortex. This release is controlled by the hypothalamus, a part of the brain. The secretion of corticotropin-releasing hormone (CRH) by the hypothalamus triggers pituitary secretion of adrenocorticotropic hormone (ACTH). ACTH is carried by the blood to the adrenal cortex, where it triggers glucocorticoid secretion.

    "
Cortisol ... activates anti-stress and anti-inflammatory pathways.[3]

    "
Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, ...

    "
Cortisol is released in response to stress, acting to restore homeostasis. However, prolonged cortisol secretion (which may be due to chronic stress or the excessive secretion seen in Cushing's syndrome) results in significant physiological changes.[7]

    "
The decline in water excretion following a decline in cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), which is not overridden by water loading
.[25]
    "
Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future.

    Cortisol "
Inhibits secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH (Adrenocorticotropic hormone or corticotropin) secretion. Some researchers believe that this normal feedback system may become dysregulated when animals are exposed to chronic stress

   
Cortisol "Shuts down the reproductive system, resulting in an increased chance of miscarriage and (in some cases) temporary infertility. Fertility returns after cortisol levels return to normal[39]"  
    "
In addition to cortisol's effects in binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone it also binds to the mineralocorticoid receptor. Aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids and allow selective mineralocorticoid action. This enzyme—11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2)—catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites



Corticosterone  (Wiki)   
    "Corticosterone (CORT) is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands In many species, including amphibians, reptiles, rodents and birds, corticosterone is a main glucocorticoid,[1] involved in regulation of fuel, immune reactions, and stress responses."   
    "
However, in humans, corticosterone ... has only weak glucocorticoid and mineralocorticoid potencies ... and is important mainly as an intermediate in the steroidogenic pathway ...
"   
 

The adrenal gland - Endocrinology - NCBI Bookshelf 
    From the above.  Click on the "Box" links to see the diagrams. 
Cortisol Receptors
Box 4.8
The glucocorticoid receptor and activation by cortisol. Unbound, lipophilic cortisol readily crosses cell membranes and in target tissues will combine with the glucorticoid receptor (GR). Like the androgen and progesterone receptors, but unlike thyroid (more...) 
Cortisol Metabolic Effects 
Cortisol, like the thyroid hormone T3, has potent metabolic effects on many tissues (Box 4.9). These are essentially anabolic in the liver and catabolic in muscle and fat; the overall effect is to increase blood glucose concentrations. 


The Endocrine System (Goog)
    Glucocorticoids  From the above. 
Control of Cortisol Secretion    

Cortisol and other glucocorticoids are secreted in response to a single stimulator: adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH is itself secreted under control of the hypothalamic peptide corticotropin-releasing hormone (CRH). The central nervous system is thus the commander and chief of glucocorticoid responses, providing an excellent example of close integration between the nervous and endocrine systems.

Virtually any type of physical or mental stress results in elevation of cortisol concentrations in blood due to enhanced secretion of CRH in the hypothalamus. This fact sometimes makes it very difficult to assess glucocorticoid levels, particularly in animals. Observing the approach of a phlebotomist, and especially being restrained for blood sampling, is enough stress to artificially elevate cortisol levels several fold!

Cortisol secretion is suppressed by classical negative feedback loops. When blood concentrations rise above a certain theshold, cortisol inhibits CRH secretion from the hypothalamus, which turns off ACTH secretion, which leads to a turning off of cortisol secretion from the adrenal. The combination of positive and negative control on CRH secretion results in pulsatile secretion of cortisol. Typically, pulse amplitude and frequency are highest in the morning and lowest at night.

ACTH binds to receptors in the plasma membrane of cells in the zona fasiculata and reticularis of the adrenal. Hormone-receptor engagement activates adenyl cyclase, leading to elevated intracellular levels of cyclic AMP which leads ultimately to activation of the enzyme systems involved in biosynthesis of cortisol from cholesterol."    



Sex, seasonal, and stress-related variations in elasmobranch corticosterone concentrations (Goog)  Full length PDF available online for free. 
This is excerpted in  
Shark Hormones .  It was #31 of the "Related articles" provided by Google for "Serum levels...", on that page.  Below are two references from that article with relevance beyond just sharks.  In order to keep track of them more easily, I've numbered them 31a and 31b. 

31a,  How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.
    Abstract and citations: 
    Full length HTML and PDF available online for free. 
    "The onset of a stressor initiates inhibition of reproductive physiology and behavior. This involves a decline in portal GnRH (  gonadotropin-releasing hormone ) concentrations and pituitary release of gonadotropins (gonadotropins ) within minutes
    "
The first wave of hormonal mediators of the stress response are central to this reproductive suppression.  CRH ( corticotropin-releasing hormone
) inhibits reproductive physiology and behavior (257, 258), and administration of CRH antagonists partially reverses stress-induced suppression of LH  (luteinizing hormone ) release (259).  
    The effect on the pituitary is secondary to inhibition of GnRH release, since intracerebroventricular rather than peripheral administration of CRH or its antagonists is effective (259, 260, 261), CRH does not directly blunt pituitary responsiveness to GnRH (262), and CRH can directly inhibit hypothalamic release of GnRH in vitro (263). 
    Opiate release during stress is also reproductively suppressive and, like CRH, involves inhibition of hypothalamic GnRH release (264, 265, 266, 267, 268, 269, 270, 271, 272, 273). The opiate inhibition of GnRH appears to be the proximal mechanism by which CRH exerts its antireproductive actions (262, 274).  
    Finally, the sympathetic nervous system has antireproductive properties. For example, sympathetic activation blocks the parasympathetically mediated initiation of erections (275). Within the humoral realm, adrenomedullectomy or administration of sympathetic ß-blockers attenuates the suppression of LH and FSH (
follicle-stimulating hormone
) by stress (276).
    "
The effects of GCs in this realm are well understood. GCs potently disrupt reproductive physiology through a number of mechanisms. They decrease hypothalamic GnRH release (277, 278) and basal or GnRH-stimulated release of LH from the pituitary (Refs. 279, 280, 281, 282, 283, 284, 285, 286, 287 ; this effect predominately occurs in females). In addition, GCs reduce gonadal responsiveness to LH and concentrations of LH receptors (Refs. 286, 288, 289, 290, 291, 292 ; this effect predominately occurs in males). These patterns occur in both in vivo and in vitro systems and in rodents, humans, and other primates.

   
"Stress (and perhaps basal) GC levels inhibit reproduction in most species. ... These antireproductive effects can be rationalized as a logical contributor to the stress response, insofar as they triage an expensive physiological process until a more auspicious time."
    "
Like other hormones of the steroid-thyroid-retinoid family, GCs initiate primary molecular interactions in their target cells through binding to their nuclear receptors. The known GC receptors, GR (
glucocorticoid receptor ) and MR ( mineralocorticoid receptor ), function as ligand-activated transcription factors to regulate transcription of target genes.
My comment
The above is somewhat confusing, but it clearly makes the point that stress inhibits reproductive physiology.  I am particularly interested in the statement that:   "
In addition, GCs reduce gonadal responsiveness to LH and concentrations of LH receptors (Refs. 286, 288, 289, 290, 291, 292 ; this effect predominately occurs in males).", since this supports my references 28 and 29 in Boys without Fathers .    So the next step seems to be to check these references: 

286 
See: 
Primate Dominance Hierarchies

288 
Not helpful. 

289 
See:  
  Rodent Dominance Hierarchies  

290 
Acute Suppression of Circulating Testosterone Levels by Cortisol in Men (Goog) 
Full length HTML and PDF available online for free. 

291 
Direct Inhibitory Effect of Glucocorticoids upon Testicular Luteinizing Hormone Receptor and Steroidogenesis in Vivo and in Vitro (Goog) 
Full length PDF available online for free. 
This appears to be the same as reference 28 in
Boys without Fathers   even though I thought that reference was not available online.    

292 
Suppression of luteinizing hormone and testosterone secretion in bulls following adrenocorticotropin hormone treatment.
     
Only abstract available online. 


31b.  Seasonal and daily plasma corticosterone rhythms in American toads Bufo americanus.
Only abstract available online. 
    "
Under a natural photoperiod toads demonstrated a rhythm consisting of a spring peak and a fall peak in corticosterone concentration. Toads maintained under a 12L:12D photoperiod all year round demonstrated a similar rhythm with peaks in the spring and fall. This suggests that an endogenous (circannual) rhythm of corticosterone may be playing an important role in the seasonal change of overt behavior and physiology of Bufo americanus. A daily rhythm of corticosterone was also detected in toads when blood samples were taken every 4 hr. When compared to a previously published circadian rhythm study of locomotor activity, the surge in corticosterone concentration for the day occurred at 1730 just prior to the peak in locomotor activity.




Does cortisol acting via the type II glucocorticoid receptor mediate suppression of pulsatile luteinizing hormone secretion in response to psychosocial stress?
(PubMed) 
Full length PDF and HTML available online for free.    


Psychosocial stress inhibits amplitude of gonadotropin-releasing hormone pulses independent of cortisol action on the type II glucocorticoid receptor
(PubMed) 
Full length PDF and HTML available online for free.       



Insight into the neuroendocrine site and cellular mechanism by which cortisol suppresses pituitary responsiveness to gonadotropin-releasing hormone
(PubMed) 
Full length PDF and HTML available online for free.           


New insights regarding glucocorticoids, stress and gonadotropin suppression
(PubMed)   
Only abstract available online. 


Regulation of gonadotrophin-releasing hormone secretion by testosterone in male sheep
(PubMed) 
Only abstract available online.  


Role of glucocorticoids in the stress-induced suppression of testicular steroidogenesis in adult male rats
(PubMed) 
Only abstract available online.   



Direct inhibitory effect of glucocorticoids upon testicular luteinizing hormone receptor and steroidogenesis in vivo and in vitro
(PubMed) 
Only abstract available online.     


Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro
(PubMed) 
Only abstract available online.  


Dexamethasone (Wiki)  

    "Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant. It is 20 to 30 times more potent than the naturally
occurring hormone cortisol and 4 to 5 times more potent than prednisone.
"       

Asymmetric frontal brain activity, cortisol, and behavior associated with fearful temperament in rhesus monkeys 
http://www.ncbi.nlm.nih.gov/pubmed/9588478   
Only abstract available online.  I got the PDF through the library.  


For proteins (cortisol receptor), evolution can't go backwards 
http://www.newscientist.com/article/dn17841-for-proteins-evolution-cant-go-backwards.html   
Short but informative plain English article available online. 
"...
AncGR1, existed in its ancestral form from about 450 million years ago. As well as binding cortisol, it could respond to other hormones such as aldosterone and deoxycorticosterone.
"  "After a further 40 million years of evolution involving 37 mutations, a second ancient receptor emerged, called AncGR2. This, like the same protein in modern humans, could be activated only by cortisol.








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