initially, it prevents fatigue, and seems to stimulate pituitary hormone responsible for electrolyte imbalances.
This suggests that if massive increases or sudden crashes in cortisol production occur, the entire HPA axis and CNS will go into a negative feed back loop and deplete the glucose substrate or food source in the body, causing a rapid decline in cortisol and BG. As long as the BG drops occur, glucocorticoids will struggle to keep up, and risk spiking. The spiking does not occur in healthy people, which is why they do not get the symptoms of a spike. The increased attempt to regulate this by releasing NA and cortisol will further deplete BG below baseline and create the crashes associated with Addisonian crises.
High levels of stress hormones and prolactin seem to come along with the decreasing blood sugar and hormone sensitivity, dopamine uptake and sensitivity decreases, ADD and brain fog increase. Either stupor or mania will come at this point depending on how underutilized the various dopamine/serotonin systems are, how low BG is, and how over or under sensitized the cholinergic system is. Potentially a very overstimulated cholinergic system and low DA with selectively overly stimulated serotonin 5-HT receptors could explain the ADD, paranoia, and intense anxiety.
Keep in mind that under stimulated aspects of the 5-HT system present the baseline GAD and depression symptoms initially, and often were for many years- cortisol, stress, anxiety, GI tract, OCD, racing thoughts, over excitation oriented. So it is VERY unclear as to whether 5-HT is over or under stimulated, but a severe nuero-chemical imbalance is clear. And that imbalance along with low BG and glucocorticoid spikes create anxiety, brain fog, ADD, IBS, OCD, depression, dehydration, and fatigue.
Hormone sensitivity seems to decrease strongly during the day, serotonin and blood sugar start to decline after 5 am, creativity, inspiration, drive, affection, and sociability, all wain, the decrease of catecholamine begins. When cortisol crashes, there is no cortisol catabolism to sustain BG.
On the other hand, controlled mania with the help of rhodiola and caffeine, with high blood sugar, was often perceived well; associated with over-stimulation of receptors leading to exhibited behavior of dopaminergic interest and serotonergic pathos/creativity., but clearly creates problems. There seems to be risk of unwanted symptoms and dependence on healthy glucose metabolism and moderate levels of exercise, which are absent. Imbalance of glucocorticoid dependent catecholamine causes fatigue and is consistently associated withpoor cognition, poor empathy, poor mathematical analysis, terrible memory recall, terrible creativity, and incredibly bad concentration. Because the circadian rhythm is so indicated in the symptomatology of the overall disorder, there is a strong probability that the dorsomedial lateral nuclei of the hypothalamus is signaling release factor hormones at inappropriate times of the day, indicating a broad spectrum homeostatic maladaptive approach by the suprachiasmal nuclei. One hypothesis is that adrenaline deficiencies could be causing the psychological and endocrinological symptoms. These adrenaline deficiencies strongly suggest issues with anaerobic lactate induced myalgic muscle fatigue, commonly associated with CFS, and also general adrenal insufficiency. Side effects of the adrenaline hormone deficiency would result in blood pressure and peripheral circulatory related issues, which would further intensify adenine nucleotide loss and poor ATP synthesis. Because of both sympathetic and parasympathetic autonomic nervous system dysfunction, the paradoxical side effects of various treatments would at least be partly explained. Stimulating treatments leading to fatigue would partly be explained by the extremely poorly understood connection between multi-organ axis and their effects on one another. Thus, between adverse effects on other physiological axis and the metabolic toxins associated with impaired mitochondrial function, both mediated by adrenaline, adrenergic side effects such as axiety and blood pressure fluctuation would be common. Ultimately, most peripheral experienced side effects would fluctuate wildly correspondingly with the level of adrenaline as determined by diurnal rhythm environmental cues. The net effect of adrenaline deficiency and muscle hypoxia and ATP decrease would be decreased glycolytic function. Because of a delayed hypothalamic-pituitary-adrenal diurnal response however, a second hypothesis suggests that melatonin and nocturnal homeostatic triggers form binding reactions which lead to an ultimate inappropriate burst of various hormones during nocturnal hours. These hormones are often not secreted adequately during the day, and therefore have a propensity towards high bursts when finally released. This could explain the phenomena of night owl behavior and insomnia. The underlying patho-etiology behind adrenal fatigue and metabolic disorders seem to commonly contain the never ceasing changes in system-wide receptor sensitivity, transport mechanisms, and imbalances caused by other multi-organ axis. Treatment of symptoms will surely result in failure because of those constant changes, so a better approach would be to manipulate the suprachiasmal nuclei in order to govern the entire body and to also take optimal doses of nutrients required by important systems like the HPA-axis.
Genetic Influences, Hypothalamus-mediated Metabolic Responses, the Pineal Gland, and, Circadian Rhythm, and Glycolysis;
Adipocyte Hormone Influence on Insulin Sensitivity, Mitochondrial Oxidative Capacity, and Anti-oxidants; Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. This review will address the biology, actions, and regulation of three adipocyte hormones—leptin, acylation stimulating protein (ASP), and adiponectin—with an emphasis on the most recent literature. The main biological role of leptin appears to be adaptation to reduced energy availability rather than prevention of obesity. Hence, leptin prevents insulin resistance and reduced energy expenditure. In addition to the well-known consequences of absolute leptin deficiency, subjects with heterozygous leptin gene mutations have low circulating leptin levels and increased body adiposity. Leptin treatment dramatically improves metabolic abnormalities (insulin resistance and hyperlipidemia) in patients with relative leptin deficiency due to lipoatrophy. Leptin production is primarily regulated by insulin-induced changes of adipocyte metabolism. Dietary fat and fructose, which do not increase insulin secretion, lead to reduced leptin production, suggesting a mechanism for high-fat/high-sugar diets to increase energy intake and weight gain. ASP increases the efficiency of triacylglycerol synthesis in adipocytes leading to enhanced postprandial lipid clearance. In mice, ASP deficiency results in reduced body fat, obesity resistance, and improved insulin sensitivity.Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-and may contribute to increased insulin sensitivity. Adiponectin and leptin co-treatment normalizes insulin action in lipoatrophic insulin-resistant animals. These effects may be mediated by AMP kinase–induced fat oxidation, leading to reduced intramyocellular and liver triglyceride content. The production of all three hormones is influenced by nutritional status.These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance.Leptin can increase insulin sensitivity, and this action appears to be mediated by direct and indirect (CNS) effects to activate AMP kinase (AMP-K) and increase muscle fatty acid oxidation (FAOx), leading to decreased intramyocellular lipid (IMCL) content. Adiponectin increases insulin sensitivity, decreases hepatic glucose production (HGP), and lowers glucose plasma levels. The insulin-sensitizing effects of adiponectin appear to be mediated by activation of AMP-K, resulting in increased FAOx, and a lowering of hepatic triglyceride and IMCL content. Adiponectin expression and secretion are inhibited by catecholamines, glucocorticoids, TNF-, interleukin-6 (IL-6), increased adipocyte size, and possibly decreased adipocyte insulin sensitivity. FFA, free fatty acid. These relationships indicate that AMP-K and FAOx would directly be stimulated by intense exercise capable of raising AMP-K and metabolizing lipids. It also suggests that prolonged stress responses, through LC-NE and CRH systemic responses, lead to insulin resistance and reduced adiponectin and leptin. Adiponectin seems to take precedence in importance over leptin. Decreased adiponectin and leptin along with increased adipocyte size seem to work with increased ASP to create raised insulin levels. ASP production is stimulated by insulin and by the presence of chylomicrons/VLDL after meals. All the above suggests that hyperinsulinemia, increased hepatic triglyceride and glucose production, and stress creates a negative feedback loop leading to further ASP production, decreased leptin and adiponectin, and insulin resistance. A balancing effect on the metabolism to limit large spikes in blood lipid and glucose levels, which result in insulin spikes and reactive hypoglycemic incidents, is essential.With ATP catabolism, adenosine diphosphate (ADP) levels accumulate, forcing the cell to try to balance ATP/ADP ratios in order to maintain energy stasis. However, these reactions ultimately lead to an increased intracellular concentration of adenosine monophosphate (AMP). In an effort to try to control energy balance, the cell catabolizes AMP, ultimately forming inosine, hypoxanthine, and adenine. These catabolic end products are washed out of the cell, resulting in a net loss of purines and an ultimate reduction in the total pool of adenine nucleotides. Recovery and recycling of these is essential. The availability of 5-phosphoribosyl-l-pyrophosphate (PRPP) is rate limiting in adenine nucleotide de novo synthesis and salvage pathways, which is essential to recovery. PRPP is formed through pyrophosphorylation of ribose-5-phosphate that is, itself, synthesized from glucose via the pentose phosphate pathway (PPP; or hexose monophosphate shunt).The rate-limiting enzymes in the PPP, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, are poorly expressed in muscle cells. As such, in skeletal muscle the PPP is suppressed, limiting ribose availability as a substrate to drive the purine nucleotide pathway and retarding nucleotide synthesis during or following metabolism decrease.Impairment in mitochondrial oxidative phosphorylation and potentially diminished glucose metabolism impact ATP turnover, suggesting that the muscles of fibromyalgia patients are energy starved. Hence, with the cascading loss of ATP and resulting adenine nucleotide catabolism, a lack of regenerative PRPP, the ability to salvage ribose-5-phosphate for pyrophosphorylation to PRPP is decreased. Gluconeogenesis and glycolysis are hence directly tied to the synthesis of glucose-6-phosphate which is needed to produce PRPP in aerobic metabolism. Further, evidence indicates that decreased capillaries within fibromyalgia muscle fibers, which reduce the oxidative capacity, leading to the limited energy turnover, purine pool depletion, and increased pain.
Free radical proliferation occurs more within mitochondria than any other part of the cell. Furthermore, the brain uses as much as 20% of the body's glucose and ATP supply in, meaning the greatest potential for stress induced cell death occurs within the brain. Some key anti-oxidants are catalase, superoxidase dimutase, and secondary metabolite phytochemicals such as rutin, quercetin, flavanoids, and caratenoids. One of the most powerful natural anti-oxidants in the body is glutathione, but like reduced ATP and adenine nucleotide loss, net loss of overall glutathione free radical neutralization can occur. The key thing to remember is that two enzymes play important roles in these processes: Glutathione peroxidase triggers the reaction of GSH to GSSG, which is when glutathione “takes the hit” to spare the cell from the generated free radicals. Glutathione reductase triggers the conversion of GSSG back to useable GSH. These enzymes come into consideration when looking at how to support the glutathione system nutritionally.
Circulation-Metabolic NO Mediated Disorders and Relations to HPA Axis and Hypothalamus; There is evidence for a deficit in neuroendocrine regulatory mechanisms, via the vasoregulatory CNS functions, which may limit organ and tissue function directly, or indirectly through decreased blood pressure and impaired tissue level perfusion. This is closely associated with fibromyalgia and chronic fatigue syndrome. Thus, hypothalamic, pineal gland, and pituitary-adrenal dysfunction could be implicated closely with microvascular and metabolic disorder. Obesity causes the Metabolic Syndrome which is driven by microvascular inflammation, endothelial cell dysfunction, oxidative stress, activation of the angiotensin-II (ANG-II), reduced bioavailable nitric oxide (NO) and sympathetic activation. This raises inquiry into whether early obesity is associated with microvascular abnormalities in endothelial nitric oxide (eNO), neuronalNO (nNO) and Angiotensin-II that precede increased central sympathetic outflow, and metabolic syndrome in teenagers and young adults. Further, these precipitous reductions in energy and glucose pointed out above, regarding mitochondria, could effect the brain as they do the skeletal muscles, and such cognitive and affective related symptoms are well known among sufferers.Hypo-thalamic related disorders are known to lead to excess levels of glucocorticoids, loss of hippocampal learning and memory, and deleterious changes in the structure of hippocampal nerve cells and sometimes neuronal death. As is seen in IBS, cascading inflammation of brain cells is also possible via cytokine synthesizing cycles.
First, neuropeptides must be explained. Neuropeptides often act back on their cells of origin, for example to facilitate the development of patterned electrical activity. They can also act on their neighbors to bind the collective activity of a neural population into a coherent signaling entity. Finally, the coordinated population output can transmit waves of peptide secretion that act as a patterned hormonal analogue signal within the brain. At their distant targets, peptides can re-program neural networks, by effects on gene expression, synaptogenesis, and through functionally rewiring connections by priming activity-dependent release. Thus neuropeptides fit the rapid synchronized action consistent with systemic inflammation such as IBS and brain cell stress. These neuropeptides also signal and influence the cholinergic and adrenergic function of the body leading to microvascular changes capable of antagonizing optimal mitochondrial oxidative phosphorylation, glucose supply, anti-inflammatory effects, immunomodulating effect, and free radical neutralization. Key microvascular mediating hormones are vasopressin and oxytocin. Vasopressin and oxytocin have been linked to human neurological disorders such as social anxiety disorder, depression, schizophrenia and autism spectrum disorder.Precipitous falls in blood pressure are partially countered by vasopressin-induced vasoconstriction. Oxytocin secretion also occurs during inflammation and it is thought to promote insulin and glucagon secretion and thus regulate peripheral metabolism during an infection. Thus, oxytocin, vasopressin, and glucocorticoids act together to repress inflammation during a stress induced state in conjunction with stress induced release of cytokines and prostaglandins which stimulate the locus ceruleus-norepinephrine and CRH mechanisms of the endocrine system.This is more so in line with down regulated responses of the endogenous analgesic endorphin system. Inflammation causes suppression of the hypothalamic pituitary gonadal axis. However, in cases of where there is severe or prolonged chronic inflammation, there may be changes in brain and hormonal function that are deleterious. For example, many chronic inflammatory illnesses appear to be associated with fatigue, depression, sleep disorders and pain that can be attributed, in part, to cytokine- induced changes in glucocorticoid actions within the brain. Important note, chronic low grade inflammation could influence vasopressin and oxytocin.Activated immune cells synthesize pro-inflammatory peptide molecules called cytokines, among which are interleukin (IL)- 1β, IL-6 and tumour necrosis factor α (TNFα); these cytokinesbind to receptors on endothelial and perivascular cells of brain blood vessels and induce synthesis within the brain of a variety of other inflammatory molecules, including prostaglandins and additional cytokines. These substances can directly stimulate the afferent neuron terminals but also can
