- This topic is empty.
-
Posts
-
Memory and creativity are related to mania.Bipolar individuals, whose disorder was not severe, tended to show greater degrees of creativity and well being
People who have depression, CFS, and adrenal insufficiency (low catecholamine type) have LOW BRAIN CATECHOLAMINE. People who have Low brain catecholamines suffer from a loss of well being, loss of creativity, loss of motivation.
I have myself low cortisol production with low catecholamine level especially brain noradrenaline. Jay Goldstein explain very well the neurosomatic people in this good book “betrayal the brain”
Here just an explanation of Goldstein
There are four influences on how and why an individual will get CFS/FMS.
1) Genetic susceptibility. This tendency can be strong or weak or anything in between. If it is strong, a person will develop a neurosomatic illness no matter what, often beginning in childhood. Otherwise, expression of the trait is influenced by other factors i.e., childhood abuse, viral infections, anesthetics, pronounced physical or emotional stress, childbirth, trauma. There is an increased family history of panic disorder. There is often a history of psoriasis, allergies or asthma, sleep disturbances, irritable bowel syndrome, premenstrual syndrome, bruxism, or tinnitis.
2) Developmental issues. While toddlers’ brains are still developing and forming neural network connections, it is important that the child be in a safe nurturing environment. If a child feels unsafe for a period of time from birth to puberty, his brain learns to be hypervigilant and to interpret the saliency of sensory input differently than a child who feels secure i.e., their brains learn to attach increased relevance to incoming stimuli instead of ignoring irrelevant stimuli. The prefrontal cortex, which gates sensory input according to its saliency every millisecond, must learn what is salient over time and integrate those experiences and attitudes with a genetic developmental predisposition.
This also leads to elevated levels of substance P, enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol levels with consequent downregulation of the HPA axis. Central norepinephrine levels are low, contributing to dysautonomia.
3)Viral infections. Viruses can produce persistent or hit & run infections which could alter neuronal transport as well as production of neurotransmitters in a genetically predisposed individual. More than one virus may be involved. Two viruses may interact with each other and enhance virulence. Viral gene products and host gene products may interact as well. Flu-like illnesses are known to deplete brain norepinephrine. Cognitive dysfunction in CFS/FMS may be caused by a similar mechanism as the gp120 glycoprotein in AIDS causes dementia.
4)Environmental triggers. The influence of genetic, developmental and/or viral factors results in impaired flexibility of the brain to alter the function of its neural networks to deal with changing internal or external circumstances i.e., a reduction in neural plasticity, a decreased ability to re-regulate the brain’s response to stimuli. The synaptic density of neurons fluctuates depending on circulating levels of various neurotransmitters and hormones. In CFS there is decreased neural plasticity, therefore various stimuli (smells, increased concentration, exertion, shopping malls) make the individual sick.
@Jean 882 wrote:
People who have depression, CFS, and adrenal insufficiency (low catecholamine type) have LOW BRAIN CATECHOLAMINE. People who have Low brain catecholamines suffer from a loss of well being, loss of creativity, loss of motivation.
I have myself low cortisol production with low catecholamine level especially brain noradrenaline. Jay Goldstein explain very well the neurosomatic people in this good book “betrayal the brain”
Here just an explanation of Goldstein
There are four influences on how and why an individual will get CFS/FMS.
…
This also leads to elevated levels of substance P, enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol levels with consequent downregulation of the HPA axis. Central norepinephrine levels are low, contributing to dysautonomia.
…
4)Environmental triggers. The influence of genetic, developmental and/or viral factors results in impaired flexibility of the brain to alter the function of its neural networks to deal with changing internal or external circumstances i.e., a reduction in neural plasticity, a decreased ability to re-regulate the brain’s response to stimuli. The synaptic density of neurons fluctuates depending on circulating levels of various neurotransmitters and hormones. In CFS there is decreased neural plasticity, therefore various stimuli (smells, increased concentration, exertion, shopping malls) make the individual sick.
Thank you for bringing up Jay Goldstein, M.D. Unfortunately, he retired before I ever got a chance to talk with him or learn directly from him. But his books are some of my favorites. And notably, Jay Goldstein, M.D. was also a psychiatrist before he left psychiatry to go into primary care, specializing in the assessment and treatment of chronic fatigue syndrome. When I read his books, I thought he was far ahead of his time – too far, actually, for most people to understand him. He is exceedingly bright. However, I believe he also burned out, retiring too early. Which is a loss to all of us. I would have loved to hob-knob and talk shop with him.There are problems, however, in Jay Goldstein’s ideas. First of all, he overly focused on the central nervous system to the exclusion of the endocrine system and immune system, metabolism and nutritional factors, in his search for causes of chronic fatigue syndrome. Perhaps because he was a psychiatrist he did this. But as a result, he missed the huge set of interactions that are possible when one considers the nervous system, endocrine system, and immune system as one system, as I do. He still separated mind from body – which I believe is an arbitrary delineation.
Second, he did not do lab tests. Rather, he gave patients various medications to elicit their reaction to them. Then by knowing the mechanisms of action of the medications and their reactions to the medications, he extrapolated the presumed pathophysiology underlying chronic fatigue syndrome. This style of logic is called the pharmacological bridge. This is the same logic that allowed psychiatrists to come up with the biogenic amine hypothesis for depression. There are flaws in using this type of logic. First of all, how does one know, for example, that the reactions reflect secondary, tertiary, etc. responses to the initial medication? Using the pharmacological bridge can lead one astray if it is one’s only tool. If he did lab testing also, he would have had a better chance to determine what is going on.
Thus, I believe he missed a lot and did not see the whole body causes of chronic fatigue syndrome. But he did get in right in that overactivity in certain areas of the brain can lead to chronic fatigue and to fibromyalgia.
In any case, I greatly enjoy his books, the enormous research he did (which gives me large numbers of references, thank you, Jay) and the thought processed he employed.
The two primary catecholamines in the brain are Dopamine and Norepinephrine. A few neurons employ Epinephrine, but so far, they don’t have a large role in brain function.
Generally, I do not see low brain norepinephrine (noradrenaline) levels in chronic fatigue syndrome. It may be low in patients who want to sleep all the time. But generally, the patients I see have insomnia instead. Insomnia is condition caused by excessive norepinephrine production.When cortisol is low, norepinephrine generally goes too high since cortisol can no longer control norepinephrine signaling well.
Loss of well being may reflect low dopamine with high norepinephrine levels. Dopamine is the reward signal, the signal that one feels well, whatever the norepinephrine level is – high or low. But the levels of dopamine and norepinephrine may also be a secondary reflection of immune system pro-inflammatory vs. antiinflammatory balance, current endocrine status, current nutritional status, etc.
Loss of motivation my reflect low dopamine and/or low norepinephrine, but also may reflect high pro-inflammatory cytokine signaling, low cortisol signaling, low estrogen signaling, suboptimal nutritional status supporting these signals, etc. etc.
Loss of creativity may reflect the sum of multiple signaling and metabolic problems not just low dopamine or low norepinephrine.
What can one do to identify the imbalance in cytokines? Are there any specific blood tests which would go beyond the normal scope of LP-PLA2, CRP, CBC, ect?
If one has low dopamine and high norephipherine in an adrenal related illness what modalities could be applied to help rectify this case. Will quest diagnostics catecholamine test provide enough information to see what part of the adrenals are over or under active?
If one has low dopamine, adrenaline, norepinepherine, low serotonin, would one look towards potential intestinal issues or factors that could be altered amino acid metabolism. What factors would alter amino acid metabolism?Thak you for your answer – I met Jay Golstein 12 year’s ago at Orange in California.
At this times, I was an holidayDr Golstein have atypical approach who consist to try many drug. I don’t have an appointment but he receveid me at this desk because I have just come from Europe.
He explain to me the importance of catecholamines and CFS.
He known a lot about the autonomic nervous system in health and disease but many CFS are not only a disease of nervous system.
I’ve learning from the book of Goldstein but I learn more from Dr marianco – Why ? I known many anti-aging doctors in europe but it’s very rare to see a doctor who incorporate the brain (CNS), immun system, hormone and life style….Everything work in concert.The first time I met Dr Golstein he give me a alpha stimulant nasal spray for beginning, this nasal spray decreased fatigue and give me more mental clarity; but with time the spray doesn’t work. Dr Golstein give me a list of many drug to try
Nothing work really very well for me and after 10 drug to try (no dexedrine), I’ve stopped to try another drug, because I’m spetick about this approach.At this time, I feel better with my HC, levo+ armour and some T gel but I have some residuel psychiatry symptoms (difficulty of organisation, ADD (difficulty to finish some work, sometime brain fog, difficulty to focus…), need to lay down often….
Best regards
@hardasnails1973 887 wrote:
What can one do to identify the imbalance in cytokines? Are there any specific blood tests which would go beyond the normal scope of LP-PLA2, CRP, CBC, ect?
It would be nice to be able to measure the interleukins, tumor necrosis factors, interferons, etc. But medical technology has not advanced to the point we can measure and monitor specific cytokines on a regular basis yet. It hasn’t even advanced to the point of regularly monitoring nutritional status past amino acids yet. From my point of view, if it isn’t available from major laboratories, it isn’t available as a standard test yet.
If one has low dopamine and high norephipherine in an adrenal related illness what modalities could be applied to help rectify this case.
1. MEDICATIONS: I address excessive norepinephrine signaling using one or more of the many psychiatric and non-psychiatric medications. If anything, the vast majority of psychiatric medications have as an endpoint, reduction of norepinephrine signaling. Sometimes, dopamine agonists or reuptake inhibitors are useful.
2. SIGNALS: Improving anti-stress signaling is important to help balance excessive norepinephrine/stress signaling.
3. METABOLISM-NUTRITION: Improving nutritional status would help improve non-stress related energy production and would help anti-stress signaling.
4. BEHAVIOR-PSYCHOLOGY: Reduction in environmental stress, psychological stresses, improving skills to adapt to stresses.
Will quest diagnostics catecholamine test provide enough information to see what part of the adrenals are over or under active?
No.
The adrenal gland has two parts: the medulla and the cortex.
The fractionated catecholamine test gives one an idea of adrenal medullary function – e.g. production of norepinephrine and epinephrine.
Other tests are necessary to help monitor adrenal cortex function.
If one has low dopamine, adrenaline, norepinepherine, low serotonin, would one look towards potential intestinal issues or factors that could be altered amino acid metabolism.
Low central nervous system dopamine, norepinephrine and serotonin would be an unusual case. For example, dopamine production and serotonin production are generally inverse to each other. Both dopamine and serotonin are control signals to the locus ceruleus, which produces norepinephrine. Thus having all three low is unusual. Epinephrine in the central nervous system is produced in miniscule amounts compared to the other catecholeamines. Thus stating it is low begs the question: by what criteria?
When it comes to measurements from the body, as opposed to the central nervous system: low dopamine has no clear meaning since dopamine in the body comes mostly from dopamine leakage from norepinephrine neurons. Dopamine production would reflect primarily norepinephrine production.
When body epinephrine and norepinephrine measurements are low, then I would think about factors that can disconnect the sympathetic nervous system from the adrenal medulla, such as diabetes.
When it comes to intestinal issues, the primary concerns wold be:
1. Is there adequate protein and fat intake – since fat is necessary for adequate absorption of many amino acids.
2. Are there factors which impair nutrient absorption, such as mineral deficiencies, inflammatory bowel disease, gastric bypass surgery, concurrent nutrients (e.g. tryptophan being more easily absorbed if there are carbohydrates available), etc. etc.?What factors would alter amino acid metabolism?
Amino Acid metabolism is a huge subject which cannot be discussed fully. One would have to be more specific since the subject encompasses everything from enzyme synthesis, protein synthesis, DNA, RNA synthesis, creation of structures such as receptors, various peptide signals, myelin chain formation, formation of cellular organelles, etc. etc. etc. etc. etc. etc.
If you mean amino acid absorption, then factors that affect absorption and thus availability to cells of specific amino acids for purposes of cellular metabolism would be considered as discussed above.
I agree with you that Low central nervous system dopamine, norepinephrine and serotonin would be an unusual case
But if you look the Golstein theory, CFS have a low central NA, and the strategy of Golstein is to improve central NA with (gabapentin, Nimodipine, lidocaine….)
If one has a problem communicating with Noradrenaline (NA), they will feel fatigued. If you are fatigued, this could be you. An NA communication problem could be caused by clogged NA receptors or an NA deficiency. Deficiencies can be caused by problems in the synthesis of the NA. If you have a cake with 10 ingredients and one of them is missing, you are going to have trouble making that cake. Why would one be missing? Perhaps the transportation for that item to your kitchen counter had trouble, or something that is used to make that one ingredient was missing.
Noradrenaline Synthesis
There are several steps to NA synthesis, as summarized below:1) Phenylalanine mixes with some enzymes (converts chemical to another chemical) and cofactors (more ingredients) to make Tyrosine. One can buy Tyrosine at the health food store to supplement.
2) Tyrosine mixes with some enzymes and cofactors to make Dopamine, a neurotransmitter itself.
3) Dopamine mixes with some enzymes and cofactors to make the Noradrenaline (NA) neurotransmitter.
4) Noradrenaline (NA) eventually dissolves by mixing with some enzymes and cofactors to make VMA, which can be measured in urine. If it is not seen here, one has a problem with one of the above steps.
We summarize below:
* Phenylalanine + enzyme + cofactors -> Tyrosine
* Tyrosine + enzyme + cofactors -> Dopamine
* Dopamine + enzyme (DBH) + cofactors -> Noradrenaline (NA)
* NA + enzyme + cofactors -> VMAFor the names of the enzymes and cofactors and details involving NA synthesis, click here.
Noradrenaline Problems
The following are things that can go wrong with the Noradrenaline system:a) DBH is inactivated by lead, mercury, excess manganese, H2S (hydrogen sulfide synthesized during fermentation in small intestine by harmful bacteria and yeast), and sulfa-drugs (asthmatic inhalants, many antibiotics). Low DBH disrupts the synthesis of Dopamine, which disrupts the synthesis of NA.
b) One of the chemicals used to make NA is deficient.
c) Some the chemicals used to make NA are having trouble getting into the brain.
d) The NA receptor at the receiving nerve cell is blocked (e.g. due to a heavy metal molecule or excess sulfur toxins from impaired sulfoxidation). If this is the case, the VMA and NA levels may be normal, yet one still has a problem; and one would probably respond to an NA-Agonist drug that stimulates that specific blocked receptor.
e) Sulfides can impair the conversion of Dopamine to Noradrenaline if one has low levels of the protective Sulfite Oxidase enzyme.
@Jean 938 wrote:
I agree with you that Low central nervous system dopamine, norepinephrine and serotonin would be an unusual case
But if you look the Golstein theory, CFS have a low central NA, and the strategy of Golstein is to improve central NA with (gabapentin, Nimodipine, lidocaine….)
Here is a description he wrote about his ideas about Chronic Fatigue:
http://www.alasbimnjournal.cl/revistas/7/goldstein.html
Here is a preview of his book, Betrayal by the Brain in Google Books: http://books.google.com/books?id=_QiuiW1PH4MC&printsec=frontcover&dq=jay+goldstein+theory+for+chronic+fatigue&source=gbs_similarbooks_r&cad=2
Twenty of his treatments include:Acetazolamide
Ascorbic Acid
Baclofen
Cannabinoids
Ergoloid Mesylates (Hydergine)
Felbamate
Gabapentin
Lamotrigine
Glycine
Antihistamines (H2 blockers which also block H1)
Hydrochlorothiazide
Oxytocin
Pentazocine (Talwin)
Pindolol
Risperidone (Risperdal)
Spironolactone (Aldactone)
Sumatriptan
Tacrine (Cognex)
Venlafaxine (Effexor)
Ketamine
From the above article he wrote, an excerpt is here:THE PATHOPHYSIOLOGY AND TREATMENT OF CHRONIC FATIGUE SYNDROME AND OTHER NEUROSOMATIC DISORDERS: COGNITIVE THERAPY IN A PILL
Article Nº AJ07-5
Jay A. Goldstein, M.D.
701 N. Glassell St. Orange CA 92867 USA
E-Mail: jmrm44@aol.comCita/Reference:
Goldstein, J. The Pathophysiology and Treatment of Chronic Fatigue Syndrome and Other Neurosomati Disorders: Cognitive Therapy in a Pill. Alasbimn Journal2(7): April 2000. Article Nº AJ07-5. http://www.alasbimnjournal.cl/revistas/7/goldstein.htmlChronic Fatigue Syndrome and its many related disorders are in part, a disorder of the management of sensory input and selection of cognitions by the brain. Information from inside and outside the body is misperceived, resulting in appropriate sensations. Touch can be painful, odors can cause illness, climbing a flight of stairs can be like climbing a mountain. If input is dysregulated, output will be also, because the brain will make regulatory decisions on improper “data processing.” Actually, processing occurs properly, but “gating,” the control of data input and output from processing centers, is dysfunctional. Thus, patients frequently complain, “my body doesn´t work right.” Information from inside the brain (cognitions) may be similarly dysregulated, resulting in inappropriate self-evaluation, self-monitoring, and self-prediction. These cognitions may occur automatically and cause a patient to make erroneous interpretations of situations, e.g., for depression, “people don´t like me, therefore, they will reject me.”
There are many possible beliefs that a person can have at any one moment. The perception of the saliency of these beliefs by prefrontal cortical neural networks determines which of them will be attended to, and thus given more “synaptic weight.” Information with sufficient synaptic weight will enter the “gate” into various neural networks. Inappropriate perception of saliency will allow improper gating of beliefs producing dysfunctional cognitions. These dysfunctional cognitions can produce dysphoric and inappropriate mood and/or behavioral states, i.e., psychiatric disorders such as depression, anxiety, paranoia, panic attacks, mania, etc.
The cognitions may be changed by psychotherapy. The best studied therapy is cognitive, or cognitive behavioral therapy (CBT). Similar therapies are interpersonal therapy (IPT) and eye movement desensitization and reprogramming (EMDR). Pharmacotherapy, when successful, can also change the way a person thinks, and thereby change his attitudes and emotional responses.
The basic problem is the misperception of the saliency of information by the prefrontal cortex, which regulates gating as well neurotransmitter secretion by neurons which secrete the excitatory amino acid glutamate. There appears to be dysregulation of prefrontal cortex glutamate secretion as well as “tuning” of the N-methyl-d-aspartate (NMDA) receptor for glutamate by various other neurotransmitters, especially gamma-aminobutyric acid. If the NMDA receptor is activated by weak stimuli, too much input will be recognized as being novel, and thus possibly threatening. This malfunction causes decreased levels of several neurotransmitters, especially norepinephrine and dopamine.
The cause of prefrontal cortex dysfunction is an interaction of genetic predisposition, intrauterine development, and environmental factors. Rapid pharmacologic remediaton of CFS symptoms can be achieved by multiple approaches to enhance norepinephrine secretion from the locus ceruleus and the superior cervical ganglion, as well as dopamine secretion to the ventral tegmental area and into the mesolimbic and mesocortical pathways. Levels of longer-acting neuropeptide co-transmittters would increase also, as well as those of ATP and adenosine.
Norepinephrine (PE) and Dopamine (DA) enhance the “signal-to-noise (STN) ratio” in the processing of input by the brain. If there is a high STN ratio, important information will be extracted (from) a welter of input. If STN is low, much more input will reach the cerebral cortex, some of it irrelevant. STN ratio is low in neurosomatic patients (too many stimuli are perceived as salient, novel, and attended to, usually out of awareness). This error accounts for misperception of information, as well as distractibility in stimulus situations where cues are increased, environments as disparate as malls and short-term memory testing. It may also apply to cognitive gating in psychiatric disorders (Pallanti S et al. 1999).
—
I disagree with Goldstein when it comes to low norepinephrine signaling in the brains of patients with chronic fatigue syndrome. I also disagree with him in regard to norepinephrine enhancing the “signal-to-noise ratio” of processing input by the brain.
From my observations and experience, patients with chronic fatigue have excessive norepinephrine signaling in the brain. Norepinephrine is the primary signal for distress/emergencies/stress/danger etc. When norepinephrine is high, the thalamus lowers signal-to-noise ratio, allowing nearly every signal to reach the cortex rather than only allowing selected signals in. Why? This is because this is a survival mechanism. When in trouble, an organisms sensory input is enhanced in order to provide enough information rather than too little information with which to act. This makes the organism more aware of environmental stimuli. But, of course, this can make the organism excessively sensitive to stimuli – including pain. It would also make the organism more jumpy, hypervigilant, have insomnia, etc. – symptoms of excessive norepinephrine.
When you look at what Goldstein wrote, you see that he talks about how these dysfunctional cognitions can lead to “dysphoric” moods, “anxiety, paranoia, panic attacks, mania” But these are ALL strongly contributed to by EXCESSIVE NOREPINEPHRINE SIGNALING. For example, paranoia is fear coupled with a delusional belief. Mania is a high norepinephrine state. Etc.
When you look at Goldstein’s treatments, 16 of the 20 lead to reduction in norepinephrine signaling. Tacrine, interestingly, increases acetylcholine signaling. But increasing acetylcholine signaling also reduces dopamine signaling. Using a diuretic increases renin secretion, which leads to an increase in angiotensin II production, which leads to an increase in norepinephrine signaling. He uses two diuretics. One, Acetazolamide, also makes the body more acidic. Increasing acidity has problems. For most people, decreasing excessive acidity is better in the treatment of chronic fatigue and fibromyalgia. Talwin, the last medication, is an opiate receptor agonist. Opiates increase dopamine signaling. They also may increase histamine signaling, which in turn may increase norepinephrine signaling – leading to irritability, mood swings, and in some people, hallucinations or paranoia – if the norepinephrine signal increase is excessive. Adding stress/norepinephrine signaling to opiate treatment can lead to microglial production of pro-inflammatory cytokine signals. This then may lead to a central pain condition and more fatigue – i.e. chronic fatigue and fibromyalgia and other inflammatory conditions.
My take, on review of Goldstein’s work, is that he is brilliant. I love his books and the references he has collected. But in trying to piece together the neural circuitry, I believe he got some of the circuits backwards. And he got some of the treatment backwards as well. Thus these two cancelled each other out, and the treatment worked to a certain extent.
@Jean 889 wrote:
I known many anti-aging doctors in europe but it’s very rare to see a doctor who incorporate the brain (CNS), immun system, hormone and life style….Everything work in concert.
That is because they were not trained in psychiatry. Thus they are missing my perspective – which is the perspective they try to reach but remains just out of reach.
I told Thierry Hertoghe, M.D. (Europe’s best anti-aging doctor) over lunch at one of his lectures, that he should have stayed a psychiatrist, rather than quit his psychiatry residency, and should have added his family’s knowledge of endocrinology to psychiatry. That would have been a rich combination. (From my perspective, almost all of endocrinology is a subset of psychiatry. And endocrinologists don’t study behavioral endocrinology – the textbooks are in the psychology section or the zoology section of the bookstore, not in the medical endocrinology section. They’re missing out.)
I have learned much from him, however, thankfully. I’ve practically memorized his lectures. Certainly his book, The Hormone Handbook, is a godsend for anyone doing hormone replacement therapy. The references in them are exquisite.
Thank you for your answer. May be you are right with high brain noradrenaline, to much cause problems.
But I try to understand. Let me explain.
When I was 35 year’s old, I was remember my first injection of 250 mg CHPT (cyclo hexane proprionate of testosterone) of testosterone shot : the first two day I feel so great. Plenty of energy,quiet mind with power, high arousal, my vigilance is so high without nervous tension, my eyes have expression of life…. after each shot of T every two week I was the same the first two day or three days. But with time I lose this effect. Now I take testo gel without this effect
I don’t think it’s come from testosterone itself but from the big aromatisation of estrogen the first three day…. oestrogen decrease MAO and increase NA and serotonin.
I’m not sure that brain NA in the prefrontal cortex have a stress effect, probably limbic NA is bad.
May be I’m wrong…It’s my feeling and instinct.
@Jean 947 wrote:
Thank you for your answer. May be you are right with high brain noradrenaline, to much cause problems.
But I try to understand. Let me explain.
When I was 35 year’s old, I was remember my first injection of 250 mg CHPT (cyclo hexane proprionate of testosterone) of testosterone shot : the first two day I feel so great. Plenty of energy,quiet mind with power, high arousal, my vigilance is so high without nervous tension, my eyes have expression of life…. after each shot of T every two week I was the same the first two day or three days. But with time I lose this effect. Now I take testo gel without this effect
I don’t think it’s come from testosterone itself but from the big aromatisation of estrogen the first three day…. oestrogen decrease MAO and increase NA and serotonin.
I’m not sure that brain NA in the prefrontal cortex have a stress effect, probably limbic NA is bad.
May be I’m wrong…It’s my feeling and instinct.
If a male is hypogonadal for an extended period of time, then the first exposure to testosterone replacement can be exhilarating. Then it eventually goes away.
Here is a simplification of what may be happening:
Testosterone increases dopamine signaling in the brain. Dopamine signaling promotes sex drive, attention, interest in activities, elevates mood, and is calming in effect since it also reduces norepinephrine signaling. Without testosterone, there may be an increase in dopamine receptor concentration due to the loss of dopamine signaling.
Testosterone, itself, has a calming effect on the brain. It helps reduce norepinephrine signaling. Losing testosterone loses another of the control signals on norepinephrine production.
The loss of testosterone production is also accompanied by a loss of testicular thyroid releasing hormone production. This results in a reduction in thyroid hormone production. This results in a reduction in metabolism and energy. The brain compensates by increasing norepinephrine production to increase energy. This increase in norepinephrine signaling can promote insomnia, irritability, anxiety. It also does not usually improve energy well.
Over time, with aging, thyroid hormone production is reduced. This compounds the problem of thyroid loss accompanying testosterone production loss, including a further increase in norepinephrine signaling to compensate for the loss.
Testosterone, overall, is an anti-inflammatory signal and helps govern adrenal function, preventing excessive production of cortisol. Without testosterone, under increased norepinephrine signaling levels, high cortisol production may occur – which may or may not cause problems.
The elevated norepinephrine signaling may then be accompanied by pro-inflammatory cytokine signaling as the brain becomes chronically elevated by stress signaling/norepinephrine. Over time, this may then cause hypothalamic-pituitary-adrenal dysregulation with low cortisol production.
Estradiol, functioning as an MAO, increases serotonin greater than norepinephrine. It promotes competitiveness, drive, sex drive, aggressiveness. Without testosterone, however, and the dopamine increase it promotes, Estradiol would tend to flatten sex drive and promote irritability and aggression, anger, instead. Unless testosterone production is very low, Estradiol can be maintained since so little in relationship to testosterone, is needed in men. The relative change in signaling strengths of each poses problems of excessive estrogen. This includes increased thyroid binding globulin and reduction of free thyroid hormone signals. Excess estrogen, by increasing serotonin excessively, may reduce sex drive.
Norepinephrine is important for sexual function. It promotes the high and excitement that accompanies sex drive / libido. But in excess, it does not. It causes tension, stress, distress, anxiety, irritability, which lowers sex drive. To increase norepinephrine, the brain may reduce serotonin, GABA, then dopamine production – causing problems with deficiencies in serotonin, GABA and dopamine.
Excessive norepinephrine production also causes insulin resistance. The increase in insulin production that results is pro-inflammatory. It also further reduces testosterone production. Insulin also promotes fat storage. The resulting increase in fat results in an increase in Leptin and other pro-inflammatory signals from fat cells.
And so on and so on. These are some of the changes that permeate the system from the loss of testicular testosterone production. Some are added to by changes in the metabolism of the other cells which produce other signals such as thyroid hormone, through the process of aging or with nutritional problems or with genetic predisposition to other signaling or metabolic problems or through structural changes such as the loss of cells in the hippocampus and other brain structures.
So what happens when testosterone is replaced?There is a reversal of some of the initial signaling problems.
Because there is a larger number of dopamine receptors from the dopamine signaling deficit caused by the loss of testosterone, there is dopamine supersensitivity to the surge of dopamine signaling that accompanies the increase in testosterone with replacement. This can cause a high – with heightened sex drive, alertness. and an elevated mood.
Testosterone would also free up thyroid hormone by reducing thyroid binding globulin, reversing estrogen’s effects, improving function from this angle. This would improve energy
Testosterone would then reduce excessive norepinephrine signaling, which as it comes more in normal physiologic strength, helps dopamine in providing a higher level of libido, sex drive, and an emotional high.
The testosterone to estrogen ratio would improve, reducing effects of excess estrogen. Insulin signaling is reduced. The body becomes less in an inflammatory state.
The person feels better, if not feels a high from the initial treatment with testosterone.
—-
Over time, however, with increased dopamine signaling, dopamine receptor production is reduced back to a normal amount. Dopamine, as the reward signal, the feel good signal, can’t be elevated for a prolonged period of time excessively, without problems occurring. It no longer becomes a reward signal if it is elevated for a prolonged period of time. Tolerance, through receptor reduction, occurs.
After the initial high, other problems also occur.
Exogenous testosterone suppresses testicular thyroid releasing hormone production. This reduces thyroid hormone production, undoing the initial increase in free thyroid hormone that testosterone caused. If there is hypothyroidism in the first place, this exacerbates that problem.
If there are other neurotransmitter, hormone, cytokine signaling problems or metabolic-nutritional problems outside of hypogonadism, these may complicate or undo what testosterone initially did.
If the man aromatizes testosterone to estrogen excessively, problems with excessive estrogen occur. If aromatization is not enough, then problems with too little estrogen occur. In either case, sex drive is impaired.
Thus, the hypogonadal man returns to Earth. And the initial high is lost.
Thank you doc,for this great explication.
I understand that the importance of regulation of the dopamine signaling. What the best dopamine signaling ?
less dopamine production with more DA receptors & high sensitivity DA postsynaptic receptors ? I think NO because is the same of depression theory of up regualtion of receptors
Or
High dopamine production with low DA receptors & less sensitivity DA post synaptic receptors ?
What the behavior of each ?
With aging who MAO b increase, I think that you are less DA production, may be you have a huge increase in DA post synaptic receptors and high affininty.
Are they a strategy to improve DA signaling (more DA production with high post synaptic DA receptors ?
I’ve reading a book, I don’t remember the name, this author explain with aging a small dose of ritalin help.
Dr Mariano:
HOW does one combat this reversal you mention below and thereby maintain a successful replacement program?
@DrMariano 954 wrote:
If a male is hypogonadal for an extended period of time, then the first exposure to testosterone replacement can be exhilarating. Then it eventually goes away.
Here is a simplification of what may be happening:
Testosterone increases dopamine signaling in the brain. Dopamine signaling promotes sex drive, attention, interest in activities, elevates mood, and is calming in effect since it also reduces norepinephrine signaling. Without testosterone, there may be an increase in dopamine receptor concentration due to the loss of dopamine signaling.
Testosterone, itself, has a calming effect on the brain. It helps reduce norepinephrine signaling. Losing testosterone loses another of the control signals on norepinephrine production.
The loss of testosterone production is also accompanied by a loss of testicular thyroid releasing hormone production. This results in a reduction in thyroid hormone production. This results in a reduction in metabolism and energy. The brain compensates by increasing norepinephrine production to increase energy. This increase in norepinephrine signaling can promote insomnia, irritability, anxiety. It also does not usually improve energy well.
Over time, with aging, thyroid hormone production is reduced. This compounds the problem of thyroid loss accompanying testosterone production loss, including a further increase in norepinephrine signaling to compensate for the loss.
Testosterone, overall, is an anti-inflammatory signal and helps govern adrenal function, preventing excessive production of cortisol. Without testosterone, under increased norepinephrine signaling levels, high cortisol production may occur – which may or may not cause problems.
The elevated norepinephrine signaling may then be accompanied by pro-inflammatory cytokine signaling as the brain becomes chronically elevated by stress signaling/norepinephrine. Over time, this may then cause hypothalamic-pituitary-adrenal dysregulation with low cortisol production.
Estradiol, functioning as an MAO, increases serotonin greater than norepinephrine. It promotes competitiveness, drive, sex drive, aggressiveness. Without testosterone, however, and the dopamine increase it promotes, Estradiol would tend to flatten sex drive and promote irritability and aggression, anger, instead. Unless testosterone production is very low, Estradiol can be maintained since so little in relationship to testosterone, is needed in men. The relative change in signaling strengths of each poses problems of excessive estrogen. This includes increased thyroid binding globulin and reduction of free thyroid hormone signals. Excess estrogen, by increasing serotonin excessively, may reduce sex drive.
Norepinephrine is important for sexual function. It promotes the high and excitement that accompanies sex drive / libido. But in excess, it does not. It causes tension, stress, distress, anxiety, irritability, which lowers sex drive. To increase norepinephrine, the brain may reduce serotonin, GABA, then dopamine production – causing problems with deficiencies in serotonin, GABA and dopamine.
Excessive norepinephrine production also causes insulin resistance. The increase in insulin production that results is pro-inflammatory. It also further reduces testosterone production. Insulin also promotes fat storage. The resulting increase in fat results in an increase in Leptin and other pro-inflammatory signals from fat cells.
And so on and so on. These are some of the changes that permeate the system from the loss of testicular testosterone production. Some are added to by changes in the metabolism of the other cells which produce other signals such as thyroid hormone, through the process of aging or with nutritional problems or with genetic predisposition to other signaling or metabolic problems or through structural changes such as the loss of cells in the hippocampus and other brain structures.
So what happens when testosterone is replaced?There is a reversal of some of the initial signaling problems.
Because there is a larger number of dopamine receptors from the dopamine signaling deficit caused by the loss of testosterone, there is dopamine supersensitivity to the surge of dopamine signaling that accompanies the increase in testosterone with replacement. This can cause a high – with heightened sex drive, alertness. and an elevated mood.
Testosterone would also free up thyroid hormone by reducing thyroid binding globulin, reversing estrogen’s effects, improving function from this angle. This would improve energy
Testosterone would then reduce excessive norepinephrine signaling, which as it comes more in normal physiologic strength, helps dopamine in providing a higher level of libido, sex drive, and an emotional high.
The testosterone to estrogen ratio would improve, reducing effects of excess estrogen. Insulin signaling is reduced. The body becomes less in an inflammatory state.
The person feels better, if not feels a high from the initial treatment with testosterone.
—-
Over time, however, with increased dopamine signaling, dopamine receptor production is reduced back to a normal amount. Dopamine, as the reward signal, the feel good signal, can’t be elevated for a prolonged period of time excessively, without problems occurring. It no longer becomes a reward signal if it is elevated for a prolonged period of time. Tolerance, through receptor reduction, occurs.
After the initial high, other problems also occur.
Exogenous testosterone suppresses testicular thyroid releasing hormone production. This reduces thyroid hormone production, undoing the initial increase in free thyroid hormone that testosterone caused. If there is hypothyroidism in the first place, this exacerbates that problem.
If there are other neurotransmitter, hormone, cytokine signaling problems or metabolic-nutritional problems outside of hypogonadism, these may complicate or undo what testosterone initially did.
If the man aromatizes testosterone to estrogen excessively, problems with excessive estrogen occur. If aromatization is not enough, then problems with too little estrogen occur. In either case, sex drive is impaired.
Thus, the hypogonadal man returns to Earth. And the initial high is lost.
Wow Dr. M I think you hurt your self on that last post Great Info I never read anything like this about low testosterone answers a lot of my problems.
Thank you for being you.
Phil@dano 1001 wrote:
Dr Mariano:
HOW does one combat this reversal you mention below and thereby maintain a successful replacement program?
The situation isn’t totally negative.
As long as one attempts to optimize the entire system, then testosterone will generally have a good effect on libido to one’s satisfaction.
If a good amount of testosterone in men – 650 ng/dl – is present and problems remain, then there is more work to be done on the rest of the system to improve function.
Generally, it is very difficult to maintain the testosterone high and very high level of libido as seen in the teenage years. Enough dopamine neurons, for example, may have died off as a result of agin, to prevent full return to a high state.
It is highly important to optimize nutrition to improve function. This may entail more meats and saturated fats in the diet, for example.
Keeping testosterone at fairly flat levels may help, since peaks of testosterone may result in reduction in dopamine receptors and an increase in dopamine reuptake transporters. Keeping testosterone at flat levels may require more frequent dosing. The extreme flat dosing is achieved via testosterone pellet placement.
Once as many factors are addressed, one can then look to see if growth hormone replacement is needed. This may further increase libido in some people.
- You must be logged in to reply to this topic.