In 2014, Dr. George Habib who has authored many studies trying to find out if, how, and when a cortisone injection into the knee has side-effects throughout the body, found that injection of the glucosteroid methylprednisolone acetate disrupted the hypothalamic-pituitary-adrenal axis in 25% of subject patients receiving the injection for knee osteoarthritis. These were patients who first failed to respond to nonsteroidal anti-inflammatory medications and physical therapy. The disruption was transient, lasting 2 – 4 weeks after the injection.

When activated macrophages start to secrete IL-1, which synergistically with CRH increases ACTH, [10] T-cells also secrete glucosteroid response modifying factor (GRMF), as well as IL-1; both increase the amount of cortisol required to inhibit almost all the immune cells. [11] Immune cells then assume their own regulation, but at a higher cortisol setpoint. The increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time. [58] The cells do not lose all their fight-or-flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1 [10] —especially useful to treat diseases that force the hypothalamus to secrete too much CRH, such as those caused by endotoxic bacteria. The suppressor immune cells are not affected by GRMF, [11] so the immune cells' effective setpoint may be even higher than the setpoint for physiological processes. GRMF affects primarily the liver (rather than the kidneys) for some physiological processes. [59]