Model approach for stress induced steroidal hormone cascade changes in severe mental diseases

Recreational marathon runners

The effect of physical stress on steroidal hormones in recreational, not over-trained, marathon runners, was investigated frequently over the last 20 years [10, 12]. Before starting a marathon race the subjects experience higher levels of anxiety and worrying, and it was found a decline in testosterone detected in saliva or blood was correlated to the length of the endurance run (Figure 3) [10, 12]. Cholesterol is reduced in these subjects shortly after the stress event (Figure 6). Although no change was seen in estradiol in men, women runners, including ultra-marathon female runners, did show an increase in estradiol during the race. These levels returned to pre-race levels immediately after the event and is consistent with the quick recovery of several days seen in these recreational runners [10].

Figure 6:

Schematic depiction if steroidal hormone cascade and the influence of a marathon run in healthy runners.

Dashed line represents increase (red) or dashed decrease (black) line.

However, when marathon training is both physically and psychologically stressful, immunity is impaired [10]. It is reported that marathon running reduces cellular immunity by altering the T-helper cells Th1 to Th2 cytokine ratio, but no change was reported in the specific immunity system. The immunity response involving Th1 and Th2 is not fully understood, because the source of the cytokines may be difficult to estimate, and cellular and systemic reactions may be different [13]. It is suggested, however, that these cytokine kinetics, which increase during a race and with the magnitude of mental stress, lead to increased allergic reactions derived from a lower type-1 to type-2 cytokine ratio, along with mobilization and functional augmentation of neutrophils and monocytes.

Increasing physical stress and intensity of exercise over the recreational level has a much higher influence on immunity. Surprisingly, although marathon running is physically challenging, no effect on hypertension is reported in these subjects, or in subjects involved in any recreational sports, unless there is overtraining.

While the hormonal and immunological changes in recreational marathon runners return to normal after 72 h, athletes involved in high levels of endurance running, with short periods to recover, experience a decline in achieved immunity [13]. If the periods of recovery are too short, physical or emotional stress will occur, which will increase the risk for infections. Professional athletes, who have to perform chronically in seasonal sports, often suffer from lung infections due to decreased recovery time.

If an increase in extreme temperature, or other additional stress, is imposed on marathon runners, certain steroidal hormones, such as aldosterone, increase 40% in order to manage water content in the body through the renin-angiotensin cascade [13]. Gender differences in the regulation of aldosterone secretion seems to be apparent, as females are more affected by the deregulation than are males [13].

Healthy well-trained elite soldiers under extreme stress

Elite Norwegian ranger soldiers who were stationed in a winter training camp and for 1 week subjected to sleep deprivation and food restriction (1500 kcal/day) were studied for 2 weeks. During this period they experienced extreme physical and mental stress which resulted in 1) an elimination of circadian hormone rhythms; 2) an increase in hormones at the top of the hormone cascade, such as cholesterol, DHEA, pregnenolone, and aldosterone (Figures 1 and 6); 3) a decrease in the hormones at the bottom of the steroidal hormone cascade (Figure 6) (estradiol did not change during the first 48 h but then decreased to about 50% [14]); and, 4) a reduction in immunity, particularly in the unspecific cellular system [14, 15, 22, 40–42].

It has been established that increased stress reduces immunity, increases risk of cancer development, accelerates aging, and activates many stress-related diseases [43]. During the Norwegian military training program alterations were found in immune-related blood components. There was an increase in the number of neutrophil granulocytes and monocytes, and a reduction of eosinophils and lymphocytes, and small alterations in the basophil granulocytes [15]. All the lymphocyte subgroups (CD4-T cells, CD8-T cells, B-cells and NK cells) decreased during the study period, as did interleukin-6 and the immunoglobulins (IgM by 20%–35%, IgA by 10%–20% and IgG by 10%–15%), but no significant alterations were found for interleukin 1, 2, and 4 [15]. No significant changes were found for TNF-α, although a slight increase was found when it was measured by a bio-assay [15]. Despite these changes, however, there was no clinical evidence indicating that increased infections occurred during or after the test period [14, 15, 22, 40–42]. This suggests a certain activation of the cellular, non-specific, immune function [15].

Further, it was shown by Opstad that extreme physical stress plus sleep deprivation reduces testosterone (Figure 3), and increases DHEA, aldosterone (Figure 1), and gluco-corticosteroids (Figure 7) [14, 15, 22, 40–42]. Although hormonal changes may be seen as a consequence of stress, some of these changes may be interpreted as immediate protective adaptations. For instance, the increase of the glucocorticoids may be responsible for the improvement in breathing that the cadets who suffered from light asthma experienced, and may represent an increase in adaptive immunity. However, this adaptation may be partially counterbalanced by a five-fold increase of aldosterone. This increase in aldosterone in the soldiers without asthma caused an increased risk of experiencing edema and breathing problems [14].

Figure 7:

Schematic depiction if steroidal hormone cascade and the influence of severe extreme winter training in healthy elite soldiers, solid line.

Red solid line increase and black solid line denotes for decrease. For explanation and reference see text.

Aspartate amino transaminase (ASAT) and alanine aminotransaminase (ALAT) are normally considered to reflect tissue damage or necrosis and are important diagnostic tools for many diseases, including myocardial infarction [44]. During the ranger training course isoenzyme analysis showed that almost all of the increase in plasma enzymes during the study period originated from striated muscles [14, 15, 22, 40–42]. It is now well established that these enzymes also increase during sports competition, as well as during ordinary physical training [45]. Serum cholesterol, triglycerides and the lipoproteins, Apo-B, Apo-A-I and Apo-A-II, decreased during the course and were unaffected by adequate food or extra sleep [14, 15, 22, 40–42].

There was no sign of hepatic malfunction as evidenced by normal levels of hepatic enzymes. Further, there was no significant increase in the levels of atrial natriuretic peptide (ANP), and the ANP response to a bicycle exercise test was decreased, rather than increased. No significant alterations were found in plasma electrolytes except for serum chloride, which decreased during the study period [14, 15, 22, 40–42].

A 3–4 times increase in both gastric acid concentration and a production of 5–10-fold increase in bile acids was noted in these soldiers during the testing period [14, 15, 22, 40–42]. A suggestion that severe physical stress is related to increase gastric acid production is supported by the fact that many of the same gastrointestinal alterations seen in these soldiers have been observed in healthy young men without previous history of gastrointestinal disease [46].

There was a recovery phase of 1 week until steroidal hormones returned to pre-exercise levels. It took about 10 days for full recovery for all hormonal circadian rhythms to return to normal [14]. Mental performances that decreased dramatically in these soldiers during the stress period returned to normal in 10 days [14].

Steroidal hormone cascade and PTSD

In a recent study in veteran soldiers suffering from combat-related PTSDs, we detected systematic deviations in the steroidal hormone cascade, exceeding those seen in healthy soldiers under extreme stress, or in marathon runners (Figures 1–3) [7]. The most striking differences between the two groups were that the PTSD patients had increased markers of metabolic diseases, such as cholesterol and triglycerides; increased surrogate markers for diabetes, liver inflammation, and hypertension (Table 1); and increased pregnenolone, aldosterone, DHEA, 17-hydroxyprogesterone and progesterone (Figure 2). These changes have been corroborated by other investigators, and are also observed in traumatized refugee children suffering from speaking loss [8]. Conversely, there was a constant decline in estradiol and testosterone in these PTSD subjects (Table 2). In contrast to marathon runners and soldiers under extreme physical and mental stress, cortisol levels in PTSD subjects were decreased [7].

As was also seen in the stressed Norwegian cadet soldiers, veterans with PTSD also experienced reduced breathing and increased edema, although rate and extend were higher. Unlike the stressed Norwegian elite soldiers, however, PTSD subjects were at risk for increased infection and hypertension, while the stressed Norwegian soldiers were not (Table 3).

Schizophrenia (SI), bipolar disorder (BD), compared to PTSD

Subjects with PTSD, SI or BD all share hormone and disease similarities, (Tables 1–3). All have (a) reduced estradiol levels; (b) COMT alterations; (c) a propensity for CVD; (d) an increased risk of lung diseases (Tables 1–3); and, (e) increased levels of DHEA and pregnenolone during a psychotic bipolar attack, in the non-psychotic state, or under a none-affective schizophrenic disorder (Table 2). However, there are differences in the steroidal hormone cascade in the affective and non-affective states of these conditions. In the non-psychotic state in BD and SI, testosterone is decreased (Table 2), but is increased in both genders during a psychotic attack (Table 2) [57, 58]. Further, aromatase inhibitors, which are a class of drugs used in the treatment of breast and ovarian cancer in postmenopausal women, are known to increase testosterone, decrease estradiol, and thus have been known to trigger SI [59].

Effect of steroidal hormone changes in gynecology and men

Studd pointed out that BD is sometimes difficult to distinguish to premenstrual dysphoric disorders [31], where estradiol is low in the plasma of fertile women. The luteal phase is the latter phase of the menstrual cycle. It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis [60]. Due to reduced estradiol and increased progesterone, during the luteal phases, women with SMDs are more at risk of having SI or BD attacks [12, 35] than at other times of the female hormonal cycle. Estradiol easily accesses the central nervous system and modulates a number of positive intracerebral processes [61]. Reduced estradiol is involved in the etiology and course of psychotic illnesses (Table 2), and the increased incidence of BD in women reaching menopause supports the hypothesis that reduced estradiol may have a causative relationship with this disease [61]. In BD, the relationship between childbirth and the first onset or recurrence of the condition is one of the most reproducible findings in psychiatric research [61]. The role of estradiol in the etiology of psychotic attacks is not fully understood and it is not clear why in men and women it is considered to be beneficial.

As men have more stable hormone levels, only age and diseases are contributing factors to developing SMDs. Men are at risk of increased psychosis [62] earlier in life, and the propensity for psychological trauma (“traumatization”) when testosterone decreases is increased in older age [62].

Steroidal hormones and CVD

Estradiol and some of its metabolites reduce cardiovascular risk as a vasodilator and providing NO (Figure 5), and provide psychological stability in women and in men. The estradiol metabolites, particularly 2ME2, are key steroids that have influence on SMDs (Figure 5). As inflammatory conditions exist in SMD, the so-called 16-hydroxypathway, which has no beneficial effect on blood pressure, angiogenesis, and cell repair, is favored [63]. Although estrogen metabolites have not been regularly studied in these subjects, it is known that COMT is inhibited in PTSD, in SI, BD (Figure 8) (Tables 1–3). COMT is involved in producing 2ME2 (Figure 8) and a reduction of estradiol will lead to a reduction of 2ME2, which may explain the typical left ventricular lung blood pressure abnormality (Figure 5) seen frequently in patients with SMDs. Patients with SMDs and patients with anxiety and depression, exhibit high rates of lung arterial blood pressure. This debilitating disease occurs more frequently in women [63] and that the vascular protective effects of estradiol are mediated largely by its downstream metabolites by CYP1A1/CYP1B1 to 2-hydroxy-estradiol, and 2-hydroxy-estradiol, in turn, is converted to 2ME2 by catechol-O-methyl transferase (Figures 2 and 5). 2ME2 has no estrogenic activity and its effects are mediated by estrogen receptor-independent mechanisms [63]. Estradiol and 2ME2, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells (Figure 5). Estradiol is preferably pro-mitogenic, pro-angiogenic and anti-apoptotic, whereas 2ME2 is anti-mitogenic, anti-angiogenic and pro-apoptotic [63] (Figure 5). “Unbalanced estradiol metabolism,” resulting in 16-hydroxy-estradiol, takes place if inflammation is occurring and may lead to the development of PAH [63].

Figure 8:

Simultaneous metabolism of estradiol metabolites and proteins through COMT V108/158 Val Val. COMT denotes for catechol-O-methyltransferase (COMT) is one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine, but also 2-hydroxyestradiol to 2-methoxyestradiol.It may this be interpreted as a classical enzyme inhibition, which may be described by Michaelis-Menten Kinetics.

An inverse cholesterol/stress relationship was found when severe physical and mental stress was induced shortly acutely to healthy soldiers (Figure 7) and healthy marathon runners (Figure 6). As such, decreases in cholesterol may have some beneficial effects as the reduction of cholesterol and triglycerides in recreational marathon runners may lead to improvement in blood rheology, allowing for a higher oxygen supply. In addition, improvement in breathing caused by increased glucocorticoids helps performance and increases O₂ consumption. This is also seen in pregnant women as an aid in providing higher amounts of oxygen to the fetus by increasing VEGF [64].

Aldosterone, which is synthesized in the renal system, is increased under stress (Figures 1 and 2), causing edema, with negative effect on breathing and induces CVD [65]. Lithium is a strong antagonist of aldosterone and is used as a means to treat psychotic attacks. Disturbance of water and sodium in the lung in a manic-depressive illness and SI is common (Table 3). Increased aldosterone is also responsible for increased anxiety, and anxiety is a common denominator in SMDs.

Impaired immunity in SMD

Immunity may be directly involved in the (a) etiology, (b) severity and, (c) reduction of life span seen in patients suffering from SMDs. The immune system and its relation to psychiatric disorders have attracted many investigators, but there is still controversy about the extent of immunological changes associated with different psychiatric disorders [66, 67]. It is now established that the innate immunity system is compromised in many mental diseases [66]; affecting lymphocytes, active T-lymphocytes and natural killer (NK) cells (Table 3). It has also now been confirmed that the immune response is particularly altered in manic episodes, which results in a reduction in immunity defence against inflammation and infectious diseases [68].

Particularly the adrenal steroidal hormone androstenediol is synthesized in nerve cells and is a key in neurogenesis (Figure 9). Loria showed that androstenediol modulates immunity, cell repair, and is involved in the prevention of infections (Figure 10) [47]. All these conditions are severely impaired in SI, BD, and PTSD [69, 70]. Further, it is particularly important to note that a relationship seems to exist between traumatic brain injury (caused by car accidents) [71], and the development of PTSD [72].

Figure 9:

Schematic depiction of steroidal metabolism in nerve cells.

ER denotes for estrogen receptor, IL denotes for interleukin, Adiol for androstenediol and androstenediol. HSD denotes for hydroxysteroidhydrogenase, transcriptional integrators CBP are up-regulated by androgen ablation and may influence antagonist/agonist balance of non-steroidal anti-androgens. B cell-activating factor (BAFF) is an important factor in autoimmune disease.

Figure 10:

Schematic comparison of aldiol(s) (androstenediol, androstanediol) and cortisol accordingly to Loria [47].

Stress, the developing brain, and autism

It is interesting to note that recent findings that the increased stress hormone levels present in the developing fetal brain causing autism are similar to those hormones that are increased in patients suffering from psychotic state of schizophrenia, or who suffer from bipolar disease and are discussed in this review [73, 74].

COMT and dopamine

Steroidal hormones started in the Cambrian period, lasting from 541.0 to 485.4 million years ago [77], where estradiol was the first steroidal hormone followed by many other steroidal hormones [75]. Many similarities to manage stress response on the genetic level can be found in humans and in yeasts and have to be seen as remnants of the old stress response system: for example, COMT enzyme and dopamine, which interfere in humans with estradiol metabolism, are considered classical hormones related to well-being in humans, are however, typical stress hormone in plants and in yeasts, managing cellular stress defense [79]. It has not been fully understood how estrogens acts in the striatum to rapidly modulate dopamine neural transmission and dopamine-mediated behaviors (Figure 8) [80, 81]. Catechol estrogens 4-, and 2-hydroxy-estradiol (but not 2-methoxy-estradiol) significantly enhance amphetamine-induced striatal dopamine release [80, 81]. Specific COMT enzymes regulates dopamine and 2-hydroxymetabolism of estradiol simultaneously [16, 17, 82–86] (Figure 8). In the evolutionary process, dopamine, which is considered in humans as a molecule related to well-being, exists in plants and in yeasts before the steroidal hormones were created, as part in the stress response of plants and yeasts to conduct cellular DNA and tissue repair [79]. Based on available literature, COMT relates hypertension and well-being through estradiol and dopamine metabolism [16, 17, 82–86]. Therefore, any reduction of estradiol may also increase COMT’s reducing effect on dopamine, and estradiol may be seen as a competitive inhibitor of COMT (Figure 8) [16, 17, 82–86]. 2-Hydroxy-estradiol significantly inhibits tyrosine kinase in a non-competitive manner, revealing a strong preference for synthesis of dopamine, rather than noradrenaline or adrenaline [87].

Aldosterone

The renin-angiotensin-aldosterone system (RAAS) is crucial in the regulation of renal reabsorption of water and sodium [77, 88, 89]. Lithium, an antipsychotic medication, reduces excess aldosterone in SMD [23, 24]. It is interesting to note that aldosterone, at the upper end of the human steroidal hormone cascade, was added very late in the evolutionary process: Aldosterone occupies an evolutionary transition between water- and air-breathing, when fish conquered land and oxygen could only be extracted from water and not from the surrounding air, and was therefore necessary to potentiate the corticoid response to hypoxia and supported the conquest of land [90].

Nevertheless the once necessary evolutionary stress adaptation by aldosterone is seen critically by evolutionary scientists, since it is increased 40% in marathon runners, three-fold in exhausting winter training and, unfortunately, even irreversibly five-fold in SMD (Figure 1, Table 2), causing hypertension, edema and anxiety in SMD [65, 90]. It was argued that this necessary evolutionary adaptation is unnecessary in today’s world, as the increase in aldosterone in depression and SMD causes irreversibly lung edema and CVD [65, 90]. The increased water in lung and legs in patients suffering from SMD may be therefore a remnant from a time when species conquered land [77, 89]. Numerous studies support therefore the notion that cumulative exposure to chronic stress is a risk factor for CVD [65]. Several investigators have argued that particularly aldosterone’s involvement of chronic stress in CVD requires new directions for research [65].

Gene repair via androgens

Many genes of the stress response system are similar in plants and humans (NFkB, Bax, Map kinase, etc.) [77]. Even precursor gene exist for management of stress in yeast and plants of the p53 gene, which is a hallmark gene in mammals and humans for cell repair and is also involved in human stress response [77]: The DNA repair gene, p53, is regulated in humans by the androgens (DHEA and testosterone) metabolite androstenediol and androstanediol [91, 92]. For a long time it was assumed that plants have no p53 and p21 gene repair gene. However, only recently it was found that plants have a very similar gene precursor, the so-called suppressor of gamma response 1 (SOG1), a hallmark gene managing stress response and gene repair in plants and is although not structurally similar it is functionally similar to p53 [93]. A reduction of androgens and their metabolites over a longer time (Figure 3 and 6) impairs therefore cell repair and neurogenesis (Figure 9) and are also involved in the modulating of immunity of the mother during pregnancy (Figure 11) [94].

Figure 11:

Modulation of adiol (androstenediol) plasma during pregnancy as a means and marker to modulate immunity of the pregnant women [94].

In contrast to plasma androgens, which are reduced with age [95], the classical stress hormones (glucocorticoids, catecholamine, and the other counter regulatory hormones) increase with age, indicating that stress increases with age and that the immune protection and cell repair by androgens is reduced with age [96]. Consistent with this observation is the report that the incidence of PTSD is increased with age [48].

The increase of hypertension in SMDs may be largely caused through late effects of diabetes, bad eating habits causing arteriosclerosis. Nevertheless the increase of hypertension in man and women suffering from SMD and the increase of hypertension in female veteran soldiers during pregnancy [97, 98] may be explained by similar modification of steroidal hormones, since reduced estradiol and its metabolite 2-methoxyestradiol (2ME2) causes arterial lung hypertension [63] what is similar to pregnancy hypertension and preeclampsia [88, 99] (Figure 5).

Comparison of cellular and plasma steroidal hormones

The adrenal androgens, DHEA and their sulfate and fatty esters and pregnenolone, pass through the blood brain barrier, but in contrast to the glucocorticoids, mineralocorticoids and testosterone, the cerebral concentrations of these androgens are considerably higher in the brain than in plasma [22]. In contrast to testosterone, glucocorticoids and mineralocorticoids disappear in the brain after the removal of their respective glands, and normally have lower concentrations in the brain than in plasma [22]. Brain steroids show a rather strong circadian rhythm with the highest levels during the dark period [22]. The acrophase of corticosterone in plasma preceded the acrophase of brain DHEA and pregnenolone, indicating that plasma and brain steroids are independent from each other [22]. Thus, adrenal androgens like androstenediol causes neuronal excitation and regulate neuronal and glial growth in vitro, and also affect memory and aggressive behavior in mice (Figure 9) [47]. It may thus be concluded that steroidal hormones measured in the blood do not necessarily correlate fully to cellular and brain levels, which may have caused incorrect conclusions in the past, and which must be further investigated. But there is a correlation between steroidal hormones measured in the blood and those measured on the cellular level.

Cortisol

Cortisol is considered a classical marker for depression and for SMD (Table 2). It is our observation, though, what is a personal note, patients with SMD show increase cortisol plasma levels with time, as newly diagnosed veteran soldiers with PTSD have low cortisol levels.