http://www.definitivemind.com/forums/showthread.php?t=49

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.

===

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.