ever since the previous post on some of my hypothesis about the state of my skin, i’ve wanted to make more of those entries that are backed with scientific research, because.. who doesn’t like research, especially since you and i are so skeptical about everything ever since the entire topical steroid and eczema saga?
i’ll raise some of the interesting points i’ve read from the scientific journal (they’ll be in quotes), and i’ll add on the translation (in italics) as well as some of my personal thoughts and even more hypothesis on that point.
Andrea H. Marques, Marni N. Silverman, and Esther M. Sternberg
Section on Neuroendocrine Immunology and Behavior, Integrative Neural Immune Program,
National Institute of Mental Health, National Institutes of Health, Rockville, Maryland, USA
There is evidence to show that the regulation of glucocorticoid might have an effect on depression. Glucocorticoid regulation includes the HPA axis, glucocorticoid hormone levels, factors that regulate local glucocorticoid availability and the glucocorticoid receptor functions. It has also been found that immune molecules (cytokines and interleukins) activates the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines induces sickness behaviours, which resembles depressive symptoms.
POINT 1 ____________________________________________________
Cushing’s syndrome can also be triggered by prolonged and topical application of high doses of corticosteroids that can lead to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Conversely, major depressive disorder (MDD) itself is associated with dysregulation of the HPA axis, although it is not clear whether the altered HPA axis function is primary or secondary to depression. Both exogenous use of high-dose steroids and endogenous excess of these hormones are associated with mood disorders or depressive symptomatology in some individuals… indeed, successful antidepressant treatment with reduction of depressive symptomatology is associated with resolution of impaired HPA axis function.
By correcting impaired HPA axis function, the depressive symptoms have been reduced, hence, There is a link between HPA axis dysregulation and the state of the mood.
Previously, I have attributed the feeling of depression I experienced during TSW to the lack of self-esteem, overall sadness of feeling out of control of my skin, and the pain and sufferings I experienced both physically and mentally. But now, there might be an additional reason to add to the list!
What if, during TSW (at least in the very initial stages), my HPA axis is indeed dysregulated (most probably down regulated by the years of steroid use, and then rapidly upregulated due to the sudden cessation of topical steroids, which led to a stable oscillatory recovery to normalcy over time. I’ll talk more about system control next time :D), thus contributing to the depression? if that’s the case, then the state of the mind might be used to determine the state of the body! BUT, with that said, the HPA axis will normalize within a few months, which is way shorter than the entire duration of time when i felt depressed. so.. yeap, the depression that i felt is most probably a mixture of many reasons.
POINT 2 ____________________________________________________
At a molecular level, polymorphisms in the human glucocorticoid receptor gene may be associated either with receptor hypo- or hyperfunction, which could contribute to differential individual sensitivity to the effects of glucocorticoid treatment. … Morever, changes in expression and stability of different glucocorticoid isoforms can be triggered by inflammation and have also been associated with mutations or polymorphism in the receptor.
A glucocorticoid receptor in layman’s term is the light bulb socket. The lightbulb (glucocorticoid) will fit snugly into the socket and light up (glucocorticoid doing what it should, producing anti-inflammatory effects).
A polymorphism is like a foreign factory worker that creates these lamps based on a given set of instructions written in a language that he didn’t know better. there are three different correct interpretation to the gene if read in different ways. the optimal scenario is when he installs 2 sockets into the lamp. sometimes, he installs three sockets, sometimes just one. So one lamp is brighter (hyperfunction) while the other is dimmer (hypofunction). Get it? Some cells react better to glucocorticoids while some react less well.
Which got me thinking, what if the use of topical steroids
1) increased the cortisol level in my body so much, to counter it, the body try to blunts the sensitivity of the glucocorticoid receptors? To achieve that, they’ll have to change their protein structure by deliberate changing the expression of the DNA. i don’t think the DNA actually mutates, but the decryption of said DNA might have changed due to mutation, meaning, if the source code 123 will produce ABC initially, after mutation, 123 will now produce DEF.
2) changes it’s architecture by some salt/ionic influence (after all, it’s a protein, and the shape of protein will affect it’s affinity to its relevant molecule), therefore reducing its sensitivity towards glucocorticoids.
3) down regulates the gene that makes glucocorticoid receptor proteins by some unknown mechanism.
4) inflammation causing mutation to the glucocorticoid receptor!?
The direct implication of the modification of glucocorticoid receptor (in our case, it’s most probably the hypofunction, meaning it’s not binding to glucocorticoids correctly) is increased inflammation, resulting in a loss of effect of glucocorticoids because it’s not binding appropriately to inflamed areas. Makes sense?
It has been shown over in research that prolonged usage of topical steroids will lead to systemic absorption of said steroids. Only god knows if such excessive quantities will result in changes in the sensitivity of our glucocorticoid receptors. By which method do the steroids change the receptors? I do not know.
I’m not ready to join professor X and his school yet. My special power to shed skin like a snake is already gone.
POINT 3 ____________________________________________________
Immune molecules, such as interleukins and cytokines, activate the HPA axis, with the resultant release of glucocorticoids, which in turn modulates the immune response. In addition, cytokines can alter local glucocorticoid availability and glucocorticoid receptor function, therefore affecting an individual’s glucocorticoid sensitivity.
In order for glucocorticoids to exert their effects, they diffuse across the cell membrane and bind to cytosolic receptors. Only unbound glucocorticoids are capable of diffusing across the membrane. However, 90% of circulating glucocorticoids are bound to CBG. … reduced level of plasma CBG have also been found during various inflammatory conditions.
In addition, the enzyme 11β-HSD regulates glucocorticoid availability by acting as a shuttle in the conversion of glucocorticoids between its active and inactive forms. There are two isoforms of this enzyme. 11β-HSD-1 acts mainly as a reductase, converting inactive glucocorticoids (cortisone) to active glucocorticoids (cortisol), whereas 11β-HSD-2 acts as an oxidase/dehydrogenase to convert glucocorticoids from an active (cortisol) to inactive form (cortisone). Pro-inflammatory cytokines…have been shown to upregulate 11β-HSD-1 or downregulate 11β-HSD-2 expression/activity, favouring the formation of active glucocorticoids and counterbalancing inflammation. However, enhanced expression of 11β-HSD-2 or reduced expression of 11β-HSD-1 in immune cells would lead to reduced local levels of glucocorticoid, thereby favouring a pro-inflammatory cytokine profile. This condition has been demonstrated in autoimmune patients and could be another possible mechanism underlying glucocorticoid resistance in such diseases.
The body senses inflammation -> hypothalamus in the brain sends a signal to the pituitary gland that sends another signal to the adrenal gland to produce some cortisol to tame inflammation. This is the gist of the HPA axis.
Cortisol up regulates anti-inflammatory cytokines and/or inhibits pro-inflammatory cytokines.
Moving on to the availability of glucocorticoids, what is produced does not equate to the amount of cortisol that reaches the target cell. For the glucocorticoids to have an effect, it must first pass through the cell membrane, and only single cortisol can pass through. It’s as though the bouncer of a club will screen the cortisol for a partner before he allows it into the area to bind with the receptor. HAHAHAHA what an analogy.
If the cortisol is already bound to something else, it can’t reach the target cell! During inflammation, CBG levels are lowered -> lesser cortisol is bound -> more cortisol is able to enter target cell.
So, if inflammatory conditions promote the entrance of corticorticoids into the cell, why is it not having the expected anti-inflammatory effect?
I can only say .. One does not simply walk to Mordor.
It appears there are enzymes that will devour the glucocorticoids. If you read the above excerpt from the paper and got confused (like I did), I’ll make your life easier by just calling them 1 and 2. 1 activates cortisone to cortisol, while 2 deactivates cortisol to cortisone. Under normal circumstances, inflammation markers will increase the amount of 1 (mostly residing in the liver, lung, adipose tissue and brain), while decreasing the amount of 2 (expressed in kidney, colon, and sweat glands) to favour the formation of cortisol to reduce inflammation.
But due to some strange event, the expression of 2 seems to be enhanced in immune patients (and most likely in us too, if you were to read this entry written by dr Fukaya, explaining a possible mechanism of such tendencies). When enzyme 2 is at work, it converts cortisol to its inactive form, leading to a lower LOCAL level of active cortisol, which favours the production of pro inflammatory cytokines (since cortisol inhibits them, the lack of cortisol would mean there is nothing to stop its increase). This is the only logical reason that I could use to explain why does the skin continues to be inflamed despite a normal serum cortisol level.
I have always wondered the relationship between adrenal functions and the state of the skin. Many people have reported about adrenal fatigue, but I remember reading somewhere that blood cortisol levels and adrenal readings of TSW patients are normal (did I see someone report his test result in the ITSAN forum? I really can’t remember. If you happen to know, do correct me, for my memory is faulty, and this piece of memory went against my hypothesis that we’re all having too low a cortisol level, that’s why our skin is constantly inflamed).
However, I believe I can now construct a new hypothesis. The action of glucocorticoid have on a cell is determined by 2 factors – whether or not it reaches the final destination, and whether it is able to fit into the socket appropriately. For all I know, our adrenal gland is diligently producing enough cortisol, but some of the cortisol could not resist CBG, so they can’t enter the cell. While those who managed to remain single gets devoured by enzyme 2. If there are still any remaining cortisol left by that, it will realize that the socket no longer fits perfectly, or the number of sockets are way lesser than usual.
This is such a sad story.
POINT 4 ____________________________________________________
Cytokines have been shown to induce a constellation of symptoms referred to as the “sickness behaviour”, which has many overlapping features with depression (lethargy, somnolence, fatigue, anhedonia, decreased appetite and locomotion, and cognitive deficits). … Conversely, cytokine antagonists or knockout mice have been found to block these behavioural changes in rodents and reduce depression and fatigue in patients with autoimmune or inflammatory disorders.
… only a percentage of patients with depression exhibit increased levels of pro-inflammatory cytokines. The presence of inflammation and elevated cytokines could be a risk factor contributing to the development of depressive symptomatology in patients treated with high doses of glucocorticoids.
Continuing from the sad story of the cortisol not being able to fit into the socket to exert its power to inhibit pro-inflammatory cytokines and promote the production of anti-inflammatory cytokines, the result is obvious: INFLAMMATION.
The excessive cytokines that are present will then induce some behaviours that you and I are all very familiar with.
Lethargy, excessive sleeping, tiredness despite sleeping excessively (or normally), inability to enjoy activities that used to be pleasurable, decreased appetite and movement.. and.. retardation in the mental processes.
I guess I can blame my bad results on TSW. And you guys can blame your lethargy and crazy sleeping on TSW too. OK, if not TSW, just blame it on the inflammation, that’s a more general statement that will apply to more people. ;P
The last bullet point is saying, if one is already treated with high doses of glucocorticoids, there is a higher possibility that the cytokines levels are elevated (due to factors mentioned earlier), and it may lead to the development of depressive behaviours.
as this paper is talking most about the relationship between HPA axis dysregulation and clinical depression, it appears to me that the paper try to make it sound like inflammation will cause depression. i’m not in any stand to refute that, but i just want to inform you guys that i’m merely drawing the points that are relevant to our skin condition and presenting them to you. there are a lot more information in the paper, you can read it by clicking on the link!
my original plan was to digest all 20 papers (i admit i bloated that figure up :X) that i’ve downloaded before coming up with something coherent, but i realize that by the time i went on to the second paper, i already forgot what i noted down for the first paper and could hardly follow that train of thought. plus, that would have taken me a few more months before i can present to you my findings, which would have felt like another final year project to me.
instead, presenting these papers in bite size chunks seems more beneficial for everyone! i wouldn’t want you to get indigestion like i did 😛
as i share more papers with you all, you’ll see how everything ties in together to show you the complexity of our immune system and our skin. it is seriously so difficult to try to pin point specific causes or factors because everything is so inter-related. the cause of a problem might be the result of another problem, it’s almost never-ending.
the best thing to do is to actually.. stop thinking.
but for those of you who would like to have an answer to help explain certain things, i hope this helped in some way or another.