marianco
Doctor of Medicine
anonymous said:
I do not agree with this theory for adrenal fatigue. It is overly simplistic and does not jive with clinical experience.
For one thing, it doesn't define "stress". From my point of view, Dr. Mariano's Definition of Stress = excessive norepinephrine signaling = excessive sympathetic nervous system activity. Using this definition and by understanding signaling circuits in the mind/body, then the physiologic adaptations and changes are clearer.
Dopamine is a control signal on the norepinephrine-releasing nerves (i.e. sympathetic nervous system). Dopamine is AUTOMATICALLY and immediately reduced in signaling strength in order to increase norepinephrine signaling when the brain recognizes a stress. This is why when anxious or angry (conditions where norepinephrine is in excess), a basketball player is more likely to miss the basket. The situation is actually more complicated: if adrenal function can match norepinephrine signaling, and can then reduce norepinephrine signaling through its myriad hormones released in response to stress, then norepinephrine does not become excessive and dopamine can be maintained. This is why some players, such as Kobe, can make clutch shots.
Increased glucocorticoid receptor density may result from a deficit of Cortisol - which occurs in adrenal fatigue. In the absence of a signal, receptor density may increase. In the presence of a signal, receptor density is reduced. This is one mechanism for tolerance.
Cortisol, by interrupting the norepinephrine-CRH positive feedback loop, reduces norepinephrine production - helping reduce excessive norepinephrine production. This then allows dopamine production to be restored. But Cortisol is not the only adrenal cortex signal released when norpepinephrine is high - Progesterone, DHEA, Testosterone, Pregnenolone, Estradiol, Aldosterone, etc. are also increased. Adrenal fatigue often means also the loss of these signals, not just Cortisol. These have complex actions on the nervous system.
Hydrocortisone DOES NOT always improve adrenal function. The situation is involves multiple signaling systems and is thus more complex. When hydrocortisone is used alone, it slows down adrenal output leading to a deficit in progesterone, DHEA, estradiol, testosterone, etc. etc. This can lead then to an increase in sympathetic nervous system activity since these other signals can summate to a stronger anti-stress signal than hydrocortisone alone. This is why some people become more anxious rather than less anxious on hydrocortisone or why some people become more brain-fogged on hydrocortisone. They get worse rather than better. When using hydrocortisone, the one or more of the other adrenal signals may also have to be replaced to avoid creating a deficit and worsening of one's condition.
Adrenal fatigue does not always occur from "chronic stress". It can occur immediately from acute stress - as in posttraumatic stress disorder. However, many with PTSD are already predisposed to adrenal fatigue since they may be hypothyroid or have an already high-stress nervous system.
People often think Amphetamine primarily increases dopamine. However, it also strongly increases norepinephrine signaling - more so than dopamine. This is why amphetamine is more likely to cause irritability and aggressive behavior than Ritalin-based stimulants. And, excess amphetamine use can lead to adrenal fatigue, not the opposite. This is why escalating doses of Adderall can cause a child with ADHD to develop a mood disorder, i.e. anger problems. If norepinephrine is controlled by other signaling systems, then the dopamine signal from amphetamine can be emphasized.
SSRIs can help adrenal fatigue and Chronic Fatigue Syndrome. You just have to know how to use them - like any other intervention. Serotonin is another control signal on the sympathetic nervous system. Additionally, it blocks the brain's perception of stress. Thus a stimulus is less likely to be interpreted as stressful. Excessive serotonin signaling reduces dopamine signaling. This can inadvertently lead to an increase in norepinephrine signaling. The sum of the dopamine deficit and excess norepinephrine is agitation, restlessness, increased anxiety, etc. Thus, serotonin has a distinct upper limit depending on the sum of the other control signals.
The adrenal cortex clearly undergoes changes in response to stress (i.e. norepinephrine signaling - which leads to an increase in CRH, then ACTH, then Cortisol). It enlarges in response to stress - just as a muscle hypertrophies in response to the stress of weight lifting. This ability, however, to make cortisol, pregnenolone, DHEA, testosterone, estradiol, progesterone, aldosterone, etc. (not just cortisol) becomes limited as it's production capacity fatigues. It is a metabolic problem. Possible mechanisms include oxidative damage to mitochondrial structure or other intracellular structures as oxidative radicals become excessive as demand for production of steroid hormones increases. It may be necessary to recycle and create new structures in order to recover. When muscles are overtaxed by excessive weight lifting, there is also damage to muscle cell structure, which has to be repaired or muscle atrophy occurs instead of muscle growth. Such mechanisms may analogously be taking place in the adrenal cortex. Steroid hormones are more taxing to create than neurotransmitters.
It takes a long time to recover from adrenal fatigue. This is one reason I don't agree with a neurotransmitter and glucocorticoid receptor density explanation. For example, we can simply and rapidly increase dopamine signaling by flooding the system with carbidopa/levodopa or by using a pure dopamine agonist such as Bromocriptine or Mirapex. Why doesn't this immediately solve adrenal fatigue? It doesn't. neurostransmitters and receptor density can change rapidly, but restoration of cortisol production does not.
Note that the "hypercortisolism" of depression, in my experience, doesn't exist in real life. This is where the literature is FULL of bad science - exceptionally poorly designed studies. In computer science, there is the statement that bad data in = bad results out. The authors of these studies completely misunderstood Hans Seyle's General Adaptation Syndrome. When cortisol is high, the patient is actually adapting well to the stress. Only when cortisol becomes deficient does a patient seek help. I have not seen a patient with hypercortisolism - other than in patients with Cushings syndrome - either the disease or excessive glucocorticoid treatment (e.g. chronic use of high dose prednisone).
Cheers.
