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@DrMariano 181 wrote:
Optimizing thyroid hormone and hypothalamic-pituitary-adrenal axis function would help restore serotonin signaling.
How do you optimize the HPA… do the adrenal glands really get “tired” of making their hormones, or is it really just a signaling problem? For example in cushing’s disease, the adrenals never seems to get tired of making cortisol.
@leanguy 186 wrote:
How do you optimize the HPA… do the adrenal glands really get “tired” of making their hormones, or is it really just a signaling problem? For example in cushing’s disease, the adrenals never seems to get tired of making cortisol.
You make a good point.
The term “adrenal fatigue” is not really that great a term in that it is vague as to the cause. Yet it can give the impression that the adrenals are failing.
The inability to produce enough adrenal cortex hormones (signals) in response to stress is one way to define it.
In psychiatry it is termed “hypothalamic-pituitary-adrenal axis dysregulation” or HPA axis dysregulation for short. Perhaps this is a more useful term.
The cause is not clear. It may be a signaling problem from the nervous system, the other endocrine organs (e.g. testosterone can reduce adrenal function), the immune system system. It may be a metabolic problem – such as from iron deficiency and other nutritional deficiencies.
Of course, one could argue that if it is a signaling problem – particularly from then nervous system – that adrenal fatigue is a mental illness. As some researchers postulated, impaired adrenal cortex function may be due to problems in corticotropin releasing hormone signaling.
I suspect that the immune system has a large role in causing the problem. For example, excessive pro-inflammatory cytokines will trigger a defensive program in the brain which causes animals to want to sleep too much, to be tired, to isolate themselves, etc. Of course, excessive stress signaling (norepinephrine) will also cause an increase in pro-inflammatory cytokines. And other conditions would increase pro-inflammatory signals. Interestingly, treatment with cortisol helps in many cases. Of course, cortisol reduces pro-inflammatory cytokines and reduces norepinephrine production, etc. Thus, it is the entire system which is involved in impairing adrenal cortex function.
In any case, this condition of adrenal fatigue indicates a failure – or exhaustion, so to speak – of the body’s capacity to respond to stress.
On another vein, this would be the same as those Canadian researchers who found that diabetes type 1 can be caused by nervous system dysfunction. They postulated that diabetes type 1 could be called a form of a mental illness.
As a psychiatrist, that would make me happy. In fact, this would make my job easier since it would make psychiatry the top dog in the medical profession – which I already believe should be if psychiatrists knew how to treat mental illnesses as I do from an integrative viewpoint.
Since all of the intercellular signaling systems, to me, are part of the mind, this is not a surprise to me.
@chaos 193 wrote:
This is a very interesting way to examine the issue.
Using the term HPA dysregulation instead of the term “adrenal fatigue” is probably a more accurate.
It also frees the doctor into looking at the rest of the system, rather than overly focusing on hormone replacement, to look at the actual causes of low cortisol production.
@DrMariano 200 wrote:
Using the term HPA dysregulation instead of the term “adrenal fatigue” is probably a more accurate.
It also frees the doctor into looking at the rest of the system, rather than overly focusing on hormone replacement, to look at the actual causes of low cortisol production.
I see. As opposed to directly treating the adrenals with cortisol (though that may be the way one must go), why not look for the root cause?
What happens if you treat the adrenals with low dose of testosterone monotherapy or try some low dose tamoxifen/clomiphene citrate instead of directly treating with cortisol and other adrenal steroids??
Since you have many times stated that testosterone is a strong norepinephrine signal reducer couldnt low doses of T over a long long period of time restore the HPA axis and adrenal responsiveness??
Do you feel that not only adrenal output is impaired but also the sensitivity of tissues to cortisol effects plays some role too??
When i was at my lowest levels i felt i had way decreased spatial orientation and understanding of 3d environment plus low levels of taste and smell, but never really understood if it was due to cortisol on its own or other hormones played a role in that as well. I supplemented with HC at that time but didnt see any serious improvement, apart from sleep issues which got slightly better.
@Shaolin 312 wrote:
What happens if you treat the adrenals with low dose of testosterone monotherapy or try some low dose tamoxifen/clomiphene citrate instead of directly treating with cortisol and other adrenal steroids??
Since you have many times stated that testosterone is a strong norepinephrine signal reducer couldnt low doses of T over a long long period of time restore the HPA axis and adrenal responsiveness??
Do you feel that not only adrenal output is impaired but also the sensitivity of tissues to cortisol effects plays some role too??
When i was at my lowest levels i felt i had way decreased spatial orientation and understanding of 3d environment plus low levels of taste and smell, but never really understood if it was due to cortisol on its own or other hormones played a role in that as well. I supplemented with HC at that time but didnt see any serious improvement, apart from sleep issues which got slightly better.
To summarize some issues a lot (since the actual mechanisms can be mind-bogglingly complex):
Chronic or traumatic stress may lead to hypothalamic-pituitary-adrenal axis dysregulation (the term which I believe is more accurate to use than the term “adrenal fatigue”), HPA dysregulation for short.
HPA dysregulation leads to lower production of adrenal cortex signals/hormones. This includes lower cortisol and/or DHEA, progesterone, pregnenolone, testosterone, estradiol, or aldosterone.
The primary signal for stress is norepinephrine. Norepinephrine is in a positive feedback loop with corticotropin releasing hormone. This positive feedback loop is interrupted by cortisol signaling. To increase norepinephrine, the brain has to also reduce production of some or all of the control signals that suppress norepinephrine signaling. These include reductions in serotonin, dopamine, GABA, etc.
Stress (particularly if it is a perceived threat), may lead to an increase in pro-inflammatory cytokine signaling from the brain and from the immune system (which is directly innervated by neurons of the sympathetic nervous system – the primary norepinephrine-releasing neurons of the nervous system). Stress may also lead to an increase in histamine signaling from brain mast cells. These changes lead to an activation of the immune system. These changes in large excesses may lead to an increase in inflammatory processes. The loss of anti-inflammatory signaling – which includes cortisol, DHEA, progesterone and testosterone – exacerbates these pro-inflammatory changes.
Excessive pro-inflammatory cytokine signaling may trigger automatic defensive programs in the brain. Defensive programs may induce behavioral changes including depressed mood, loss of interest or motivation in activities, loss of enjoyment from activities, social isolation, changes in sleep including the desire to sleep excessively.
There may be a loss of energy from excessive pro-inflammatory cytokine signaling. The actual mechanisms of the loss of energy are not clear. I currently speculate that perhaps there may be impaired brain astrocyte conversion of thyroxine (T4) to triiodothyronine (T3) – which leads to a hypothyroid central nervous system with a euthyroid body (as in Alzheimer’s disease). Perhaps the increase in pro-inflammatory cytokines is one of the signaling problems leading to HPA dysregulation, aside from excessive norepinephrine signaling. However, other regulatory systems may also be involved – such as the opiate signaling systems (which also involve dopamine signaling).
HPA dysregulation, from whatever cause, leads to a loss of energy. The loss of energy production, however, under some circumstances. These circumstances include bipolar disorder and attention deficit/hyperactivity disorder with hyperactivity. In these cases, norepinephrine production is an effective signal for energy.
Nutrition plays a large role in the development of HPA dysregulation. Omega 3 vs. Omega 6 balance helps determine the balance between inflammation and anti-inflammation. Various nutrients (such as the B-vitamins, fat soluble vitamins, magnesium, etc) are cofactors for many of the processes involving signal production. Vitamin A and D are generally anti-inflammatory signals. Vitamin D reduces insulin resistance (which helps the body tolerate low blood sugar from impaired cortisol signaling), increases serotonin and dopamine production. Vitamin A helps regulate the sensitivity to various hormones/signals such as thyroid hormone.
The other endocrine signaling systems such as the reproductive system are in play. Testosterone helps reduce norepinephrine, increases dopamine production. It also suppresses adrenocorticotropin releasing hormone and directly inhibits adrenal cortex activity – this may be significant depending on the sum of signaling interactions and problems a person has. Estrogen acts similarly to a monoamine oxidase inhibitor – thus increasing serotonin, norepinephrine and dopamine (but serotonin primarily). Estrogen in relative excess may be pro-inflammatory, reduces free thyroid hormone. Thyroid hormone signaling loss is compensated by an increase in norepinephrine production with simultaneous activation of adrenal cortex signals. Over time, however, this compensation may fail as HPA dysregulation occurs. Insulin, glucagon, the incretins, etc. also have a role. Insulin, itself, is pro-inflammatory. Growth hormone has a calming effect and is anti-inflammatory. Etc. etc. etc. etc.
The entry point of all these processes is stress. This is represented primarily by norepinephrine signaling. However histamine (from brain mast cells) and pro-inflammatory cytokines (from brain microglia) are also involved in the process. Stress induces responses that are ostensibly designed to improve survival. The problem is that in the modern world, these responses may be dysfunctional instead.
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Given the complexity of the interactions involved, a single intervention may or may not work. Which direction an intervention goes depends on the sum of the changes that occur as a result of that intervention. In psychiatry, the usual answer to a question is “It depends.”
Stress is the entry point. Environmental and behavioral interventions would clearly help with few downsides.
Low dose testosterone may help, particularly in women, by helping to reduce norepinephrine and increasing dopamine signaling, and helping to reduce pro-inflammatory signaling. Low dose testosterone would not help in men since it may do nothing or it would suppress endogenous production of testosterone, leading to lower overall testosterone levels. Men would need replacement doses of testosterone. Testosterone, however, may also worsen adrenal cortex function depending on a person’s susceptibility to this. In men, exogenous testosterone treatment also suppresses testicular thyroid releasing hormone production, leading to a loss of thyroid hormone production, which then leads to an increase in norepinephrine production. This is why in certain men, even if hypogonadal, testosterone treatment is intolerable. The rest of the system has to be optimized before testosterone treatment can be done.
Tamoxifen (I would prefer this to Clomiphene due to the visual changes that can occur with Clomiphene) is a weak estrogen. This blocks the stronger estrogens from being sensed by the brain. This then causes the brain to release more Luteinizing Hormone to stimulate testosterone production, leading to estrogen production. The increase in testosterone would have the effects listed previously. The problem is that Tamoxifen also blocks estrogen. This leads to lower estrogen signaling activity. Estrogen helps control norepinephrine by increasing serotonin and dopamine production. Estrogen is also needed to improve sensitivity to testosterone by increasing testosterone receptor production. Estrogen is also important in generating energy, motivation, drive, competitiveness, sex drive (libido). Estrogen (particularly in women) is important for neuron growth and memory. The loss of estrogen signaling, depending on the balance with testosterone, may lead to negative effects. If testosterone production is driven high enough, then perhaps this would improve things overall. This is particularly true in men. However, in women, this may not occur and destabilization of the system and dysfunction may occur instead. This is why many women do not like treatment with Tamoxifen or Arimidex for breast cancer.
Cortisol treatment alone may or may not work. Cortisol treatment in sub-replacement doses helps because it helps break the norepinephrine-CRH positive feedback loop. Cortisol also acts in the brain to improve concentration/focus by allowing the brain to ignore emotionally distracting memories or information. Cortisol also is the most important anti-inflammatory signal that reduces immune system activity. Cortisol triggers gluconeogenesis – helping improve blood sugar production. etc. etc. Thus it can be a useful component of treatment. However, Cortisol treatment alone also suppresses adrenal cortex activity. Thus, there is also a loss of pregnenolone, progesterone, DHEA, testosterone, estradiol, aldosterone, etc. If this loss is large enough, then the person may be worse off than without treatment. Since the majority of these other signals are calming, help control norepinephrine, are anti-inflammatory signals, a significant loss may cause the opposite intended effect of cortisol treatment. This is where some people become more tired, get “brain fog”, become more anxious, etc. on cortisol monotherapy.
A systematic treatment has to be considered to address the multiple issues that invariably occur, contributing to HPA dysregulation. Single modality treatments may help – particularly in those people who don’t have large problems in the rest of their system. But often, in more severe cases, they don’t. A systemic approach would then be needed. I would count the person who responds to monotherapy as very fortunate.
Very good detailed explanation. I would like to mention I’ve had success reducing stress signals with Relora (patented magnolia/phellodendron extract). There have been several clinical studies on its ability to restore adrenal balance. It also seems to work better over time, instead of inducing tolerance like many other drugs and supplements. I know it is marketed as a cortisol reducer, however it seems to be adaptogenic; only reducing high levels of cortisol.
I understand its a very complicated process to treat someone with such a dysfunction, its a pity that in most textbooks approaches like this are not found, and the best written is about low dose hydrocortisone or antidepressants being able to help.
Relora?? What if you have adrenal fatigue and you try this?? Would it help you think??
Where did you order it from??
@Shaolin 319 wrote:
Relora?? What if you have adrenal fatigue and you try this?? Would it help you think?? Where did you order it from??
Some say its counterproductive in adrenal fatigue, but I disagree. It seems helpful in reducing the stress signals that cause adrenal dysfunction in the first place. I have had less anxiety and better sleep since taking it. It can be found in most health food stores, or online.
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