Model approach for stress induced steroidal hormone cascade changes in severe mental diseases
Authors: Volko Claus D. , Regidor Pedro A. , Rohr Uwe D. 
Published: January 2016

Introduction: Stress was described by Cushing and Selye as an adaptation to a foreign stressor by the anterior pituitary increasing ACTH, which stimulates the release of glucocorticoid and mineralocorticoid hormones. The question is raised whether stress can induce additional steroidal hormone cascade changes in severe mental diseases (SMD), since stress is the common denominator.

Methods: A systematic literature review was conducted in PubMed, where the steroidal hormone cascade of patients with SMD was compared to the impact of increasing stress on the steroidal hormone cascade (a) in healthy amateur marathon runners with no overtraining; (b) in healthy well-trained elite soldiers of a ranger training unit in North Norway, who were under extreme physical and mental stress, sleep deprivation, and insufficient calories for 1 week; and, (c) in soldiers suffering from post traumatic stress disorder (PTSD), schizophrenia (SI), and bipolar disorders (BD).

Results: (a) When physical stress is exposed moderately to healthy men and women for 3–5 days, as in the case of amateur marathon runners, only few steroidal hormones are altered. A mild reduction in testosterone, cholesterol and triglycerides is detected in blood and in saliva, but there was no decrease in estradiol. Conversely, there is an increase of the glucocorticoids, aldosterone and cortisol. Cellular immunity, but not specific immunity, is reduced for a short time in these subjects. (b) These changes are also seen in healthy elite soldiers exposed to extreme physical and mental stress but to a somewhat greater extent. For instance, the aldosterone is increased by a factor of three. (c) In SMD, an irreversible effect on the entire steroidal hormone cascade is detected. Hormones at the top of the cascade, such as cholesterol, dehydroepiandrosterone (DHEA), aldosterone and other glucocorticoids, are increased. However, testosterone and estradiol and their metabolites, and other hormones at the lower end of the cascade, seem to be reduced. 1) The rate and extent of reduction of the androgen metabolites may cause a decrease of cellular and specific immunity which can lead to viral and bacterial infections; joint and stomach inflammation; general pain; and allergic reactions. 2) The decrease in testosterone, and estradiol in SMD may have detrimental effects in cell repair as the estradiol metabolite, 2-methoxy-estradiol (2ME2), helps to transforms stem cells into functional cells. As dopamine and 2ME2 are inversely metabolized via various forms of catechol-O-methyl transferase (COMT), well-being and hypertension may be related. 2ME2 is related to vascular endothelial growth factor (VEGF), which regulates blood capillary growth and O2 supply. As reduced O2 is a key marker of stress, the increase of glucocorticoids in all forms of mental and physical stress cannot counterbalance the reduced 2ME2 in cellular and mental stress. The increased cholesterol and triglycerides are related to stroke and infarction, contributing to a reduced life expectancy in SMD between 14 and 20 years. The increase of aldosterone leads to increases in anxiety, edema, and lung infections.

Discussion: Increasing mental and physical stress is related to systematic deviations in the steroidal hormone cascade in the non-psychotic state, which then may cause life threatening co-morbidities in PTSD, SI, and BD.