The concentration of cortisol in the skin tissue is kept lower than in the blood.
According to the following article about thermal injured patients, for example, plasma total cortisol took the value of 8.8μg/dl, free (protein unbound) cortisol 1.7μg/dl and tissue (skin) cortisol 0.74μg/dl.
Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation.Cohen J et al, Crit Care. 2009;13(6):R189. Epub 2009 Nov 27.
In healthy subjects as a control, the tissue cortisol was 0.20μg/dl. Only a fraction of the concentration in the blood is detected in the normal skin tissue outside the blood vessels and the value increases once inflammation such as burn occurs.
By the way, epidermal cells, hair follicular cells and fibroblasts in the dermis can produce cortisol by themselves. What is more interesting is that the production of cortisol by those cells is amplified by the skin tissue cortisol. There is a positive feedback mechanism.
On the other hand, there is also an enzyme that inactivates cortisol in the sweat gland. The concentration of cortisol in the skin tissue is controlled by those factors. The following figure is what is summarized.
11βHSD1 is an enzyme that converts cortisone (inactive steroid) to cortisol (active steroid) while 11βHSD2 is an enzyme that converts the latter to the former.
What is the meaning of the positive feedback mechanism of cortisol production? It must be for the purpose of increasing the skin tissue concentration of cortisol rapidly in case of any inflammation such as burn occurs.
If topical steroids are applied to the skin, epidermal cells or fibroblasts react to TS and produce cortisol. The increased cortisol effects to the cells themselves and suppress their own proliferation. In case of systemic steroids such as oral steroids, the effect to the skin tissue concentration is not so much because blood vessels regulate cortisol not to transfer too much to the skin tissue.
Now you can understand how abnormal the situation of continuous use of topical steroids to the skin is. Physiologically the concentration of cortisol in the skin tissue is kept considerably low. Topical steroids violate the controlled situation.
After stopping topical steroids, the epidermis becomes thicker than before TS application temporarily. It means the skin tissue lacks enough steroids temporarily.
1A:Before application of TS, 1B: thin epidermis after TS application, 1C 1D 1E: temporarily thickened epidermis after discontinuance of TS
（Morphologic Investigations on the Rebound Phenomenon After Corticosteroid Induced Atrophy in Human Skin. Zheng P, et al. J Invest Dermatol 82: 345-352, 1984）
The fact that epidermis becomes thick means that the steroid deficiency has occurred. But what is the mechanism of the deficiency? There must have been too much steroids.
One of the possible mechanism is as the following.
After discontinuance of TS, the skin tissue cortisol becomes low temporarily. Inactive form of steroid (cortisone ) is accumulated within the cell. After 11βHSD1 reactivation, skin tissue cortisol will be produced but from the accumulated cortisone. It never is a normal condition. The gene coding cortisol will not be up-regulated under such a condition and various proteins which are related to the gene will not also be produced. So the skin remains fragile and the barrier dysfunction continues.
It is only a hypothesis. However the temporarily deficiency of steroids after discontinuance must be explained in any way.
The below figure shows 11βHSD1/2 expression of the normal skin (brown means 11βHSD) . 11βHSD1 is expressed on the whole cells of epidermis while 11βHSD2 is expressed only on the outer layer. Obviously there is a regulated balance of 11βHSD1/2 in the normal conditions.
The concentration of cortisol in the skin tissue is kept low basically and the constituent cells produce or inactivate cortisol according to the inflammatory status. Topical steroids application violates its harmony and constituent cells become instable after TS application. I consider it might be the essence of TSA existing as the ground of the barrier dysfunction caused by TS.
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