11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2, metabolises cortisol.

11-beta HSD1 utilizes the cofactor NADPH to convert inert cortisone to active cortisol. Thereby, it increases the local concentrations of cortisol in a given tissue.

On the other hand, 11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone. Decreasing the local concentration of cortisol in a given tissue.

When a person is stressed, cortisol is released to restore homeostasis. However, prolonged cortisol secretion results in significant physiological changes.

Cortisol counteracts insulin, by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane. However, cortisol increases glycogen synthesis (glycogenesis) in the liver.

Cortisol stimulates gastric-acid secretion. Cortisol stimulates the excretion of ammonium ions by deactivating the renal glutaminase enzyme of the kidneys. Therefore,  the net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).

Cortisol prevents sodium loss through the small intestine of mammals. However, cortisol cannot be used to regulate serum sodium as sodium depletion does not affect cortisol levels.

In order for potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell. This makes pH regulation much easier as compared to the normal potassium-deficiency situation. A decline in cortisol also helps block potassium from being lost in the kidneys.

Cortisol acts as a diuretic hormone, controlling one-half of intestinal diuresis.

Cortisol stimulates many copper enzymes to increase copper availability for immune purposes. This includes lysyl oxidase, an enzyme which is used to cross-link collagen and elastin. Particularly valuable for immune response is cortisol's stimulation of the superoxide dismutase, since this copper enzyme is used by the body to permit superoxides to poison bacteria.

Cortisol weakens the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1). Cortisol also has a negative-feedback effect on interleukin-1. IL-1 must be especially useful in combating some diseases; however, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of CRH hormone, thus antagonizing IL-1).

Cortisol reduces bone formation, favouring long-term development of osteoporosis. As mentioned earlier, it transports potassium out of cells in exchange for an equal number of sodium ions. This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.

Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events. However, long-term exposure to cortisol damages cells in the hippocampus; this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.